Sample records for naloxone diclophenac dipyridamole

  1. Metabolic intervention in surgical patients. An assessment of the effect of somatostatin, ranitidine, naloxone, diclophenac, dipyridamole, or salbutamol infusion on energy and protein kinetics in surgical patients using stable and radioisotopes

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Shaw, J.H.; Wolfe, R.R.

    1988-03-01

    We have assessed the effect of a variety of forms of metabolic intervention on both energy and protein metabolism in 44 severely ill surgical patients. The patients were studied either in the basal state or while receiving total parenteral nutrition (TPN), and the metabolic effects were assessed using the primed-constant infusion of a combination of stable isotopes and radioisotopes. Somatostatin infusion, either in the basal state or in the TPN, did not change glucose kinetics, but there was a significant decrease in the rate of net protein catabolism (NPC). In the basal studies the rate of NPC decreased from 3.4more » +/- 0.7 g/kg/d to 2.9 +/- 0.7 g/kg/d (p less than 0.002), while in the TPN patients the corresponding values were 1.48 +/- 0.61 g/kg/d and 1.10 +/- 0.50 g/kg/d, respectively (p less than 0.005). Histamine type 2 blockade with ranitidine did not significantly alter glucose kinetics, but in both the TPN patients and in the basal state ranitidine was associated with a significant decrease in the rate of NPC. In the basal state rate of NPC was 2.44 +/- 0.53 g/kg/d and during ranitidine infusion the value was 2.08 +/- 0.42 g/kg/d (p less than 0.04). Naloxone infusion did not alter glucose kinetics, but there was a significant decrease in the rate of NPC from a basal value of 2.6 +/- 0.6 g/kg/d to 2.3 +/- 0.5 g/kg/d (p less than 0.04). The infusion of the prostaglandin antagonists diclofenac or dipyridamole resulted in increases in the plasma insulin level, and as a result glucose turnover decreased in both groups. In the diclofenac group the rate of glucose turnover decreased from 14.4 +/- 1.7 mumol/kg/min to 12.6 +/- 1.3 mumol/kg/min (p less than 0.02). Neither prostaglandin antagonist resulted in any significant change in the rate of NPC.« less

  2. Dipyridamole and paracetamol overdose resulting in multi-organ failure.

    PubMed

    Cullis, P S; Watson, D; Cameron, A; McKee, R F

    2013-08-01

    Dipyridamole intoxication is rare and few reports exist amongst the current literature. A case of dipyridamole and paracetamol overdose is described in a previously healthy 58-year-old woman, which resulted in multi-organ failure requiring dialysis, inotropic support, ventilation and extensive surgical intervention for small bowel ischaemia. This case highlights the dangers of an unusually large overdose of a commonly prescribed drug, and reviews current knowledge of dipyridamole intoxication.

  3. False-negative dipyridamole-thallium-201 myocardial imaging after caffeine infusion

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Smits, P.; Corstens, F.H.; Aengevaeren, W.R.

    1991-08-01

    The vasodilator effect of intravenously administered dipyridamole may be caused by an increase in endogenous plasma adenosine levels. The authors evaluated the effect of caffeine, an adenosine receptor antagonist, on the diagnostic results of dipyridamole-201Tl myocardial imaging in eight patients with coronary artery disease. Caffeine infusion significantly attenuated the dipyridamole-induced fall in blood pressure and the accompanied increase in heart rate. The infusion of dipyridamole alone resulted in chest pain and ST-segment depressions on the electrocardiogram in four patients, whereas none of these problems occurred when the tests were repeated after caffeine. In six of eight patients, caffeine was responsiblemore » for false-negative dipyridamole-201Tl tests. Semiquantitive scores of the dipyridamole-induced 201Tl perfusion defects were decreased by caffeine from 9.0 {plus minus} 0.9 to 2.0 {plus minus} 1.1 points (p less than 0.05). Computerized analysis revealed a caffeine-mediated reduction in the percent reversibility of the images from 46% {plus minus} 16% to 6% {plus minus} 10% (p less than 0.05). They conclude that the use of caffeinated products prior to dipyridamole-201Tl testing may be responsible for false-negative findings.« less

  4. Caffeine reduces dipyridamole-induced myocardial ischemia

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Smits, P.; Aengevaeren, W.R.; Corstens, F.H.

    1989-10-01

    The mechanism of action of coronary vasodilation after dipyridamole may be based on inhibition of cellular uptake of circulating endogenous adenosine. Since caffeine has been reported to be a competitive antagonist of adenosine we studied the effect of caffeine on the outcome of dipiridamole-{sup 201}Tl cardiac imaging in one patient. During caffeine abstinence dipyridamole induced myocardial ischemia with down-slope ST depressions on the ECG, and reversible perfusion defects on the scintigrams. When the test was repeated 1 wk later on similar conditions, but now shortly after infusion of caffeine (4 mg/kg), the ECG showed nodepressions, and the scintigrams only slightmore » signs of ischemia. We conclude that when caffeine abstinence is not sufficient, the widespread use of coffee and related products may be responsible for false-negative findings in dipyridamole-201Tl cardiac imaging.« less

  5. Perpetuating stigma or reducing risk? Perspectives from naloxone consumers and pharmacists on pharmacy-based naloxone in 2 states.

    PubMed

    Green, Traci C; Case, Patricia; Fiske, Haley; Baird, Janette; Cabral, Shachan; Burstein, Dina; Schwartz, Victoriana; Potter, Nathan; Walley, Alexander Y; Bratberg, Jeffrey

    Little is known about attitudes of pharmacists and consumers to pharmacy naloxone. We examined perceptions and experiences of pharmacy naloxone from people with opioid use disorder, patients taking chronic opioids for pain, caregivers of opioid users, and pharmacists from 2 early pharmacy naloxone adopter states: Massachusetts and Rhode Island. Eight focus groups (4 per state) were held in October to December 2015. Participants were recruited from pharmacies, health clinics, and community organizations; pharmacists were recruited from professional organizations and pharmacy colleges. Focus groups were led by trained qualitative researchers using a topic guide, and recorded and transcribed for analysis. Five analysts developed and applied a coding scheme to transcripts. Thematic analysis involved synthesis of coded data and connections between key themes, with comparisons across the groups. Sixty-one participants included patients with chronic pain (n = 15), people with opioid use disorders (n = 19), caregivers (n = 16), and pharmacists (n = 11). A majority of pharmacists had dispensed naloxone to patients; a minority of all consumer participants had obtained pharmacy naloxone. Four themes emerged: consumer fear of future consequences if requesting naloxone; pharmacists' concerns about practice logistics related to naloxone; differing perceptions of how opioid safety is addressed in the pharmacy; and solutions to addressing these barriers. Whereas consumer groups differed in awareness of naloxone and availability at pharmacies, all groups expressed support for the pharmacist's role and preferences for a universal offer of naloxone based on clear criteria. Pharmacies complement community naloxone provision to patients and caregivers. To overcome stigma of naloxone receipt, increased public awareness of naloxone and pharmacist training about naloxone and addiction are required. Pharmacists should offer naloxone via universal opt-out strategies-where all patients

  6. Pitfalls of Intranasal Naloxone

    PubMed Central

    Zuckerman, Matthew; Weisberg, Stacy N.; Boyer, Edward W.

    2016-01-01

    We present a case of failed prehospital treatment of fentanyl induced apnea with intranasal (IN) naloxone. While IN administration of naloxone is becoming more common in both lay and pre-hospital settings, older EMS protocols utilized intravenous (IV) administration. Longer-acting, higher potency opioids, such as fentanyl, may not be as easily reversed as heroin, and studies evaluating IN administration in this population are lacking. In order to contribute to our understanding of the strengths and limitations of IN administration of naloxone, we present a case where it failed to restore ventilation. We also describe peer reviewed literature that supports the use of IV naloxone following heroin overdose and explore possible limitations of generalizing this literature to opioids other than heroin and to IN routes of administration. PMID:24830404

  7. Naloxone reversal of buprenorphine-induced respiratory depression.

    PubMed

    van Dorp, Eveline; Yassen, Ashraf; Sarton, Elise; Romberg, Raymonda; Olofsen, Erik; Teppema, Luc; Danhof, Meindert; Dahan, Albert

    2006-07-01

    The objective of this investigation was to examine the ability of the opioid antagonist naloxone to reverse respiratory depression produced by the mu-opioid analgesic, buprenorphine, in healthy volunteers. The studies were designed in light of the claims that buprenorphine is relatively resistant to the effects of naloxone. In a first attempt, the effect of an intravenous bolus dose of 0.8 mg naloxone was assessed on 0.2 mg buprenorphine-induced respiratory depression. Next, the effect of increasing naloxone doses (0.5-7 mg, given over 30 min) on 0.2 mg buprenorphine-induced respiratory depression was tested. Subsequently, continuous naloxone infusions were applied to reverse respiratory depression from 0.2 and 0.4 mg buprenorphine. All doses are per 70 kg. Respiration was measured against a background of constant increased end-tidal carbon dioxide concentration. An intravenous naloxone dose of 0.8 mg had no effect on respiratory depression from buprenorphine. Increasing doses of naloxone given over 30 min produced full reversal of buprenorphine effect in the dose range of 2-4 mg naloxone. Further increasing the naloxone dose (doses of 5 mg or greater) caused a decline in reversal activity. Naloxone bolus doses of 2-3 mg, followed by a continuous infusion of 4 mg/h, caused full reversal within 40-60 min of both 0.2 and 0.4 mg buprenorphine-induced respiratory depression. Reversal of buprenorphine effect is possible but depends on the buprenorphine dose and the correct naloxone dose window. Because respiratory depression from buprenorphine may outlast the effects of naloxone boluses or short infusions, a continuous infusion of naloxone may be required to maintain reversal of respiratory depression.

  8. Effect of dipyridamole plus aspirin on hemodialysis graft patency.

    PubMed

    Dixon, Bradley S; Beck, Gerald J; Vazquez, Miguel A; Greenberg, Arthur; Delmez, James A; Allon, Michael; Dember, Laura M; Himmelfarb, Jonathan; Gassman, Jennifer J; Greene, Tom; Radeva, Milena K; Davidson, Ingemar J; Ikizler, T Alp; Braden, Gregory L; Fenves, Andrew Z; Kaufman, James S; Cotton, James R; Martin, Kevin J; McNeil, James W; Rahman, Asif; Lawson, Jeffery H; Whiting, James F; Hu, Bo; Meyers, Catherine M; Kusek, John W; Feldman, Harold I

    2009-05-21

    Arteriovenous graft stenosis leading to thrombosis is a major cause of complications in patients undergoing hemodialysis. Procedural interventions may restore patency but are costly. Although there is no proven pharmacologic therapy, dipyridamole may be promising because of its known vascular antiproliferative activity. We conducted a randomized, double-blind, placebo-controlled trial of extended-release dipyridamole, at a dose of 200 mg, and aspirin, at a dose of 25 mg, given twice daily after the placement of a new arteriovenous graft until the primary outcome, loss of primary unassisted patency (i.e., patency without thrombosis or requirement for intervention), was reached. Secondary outcomes were cumulative graft failure and death. Primary and secondary outcomes were analyzed with the use of a Cox proportional-hazards regression with adjustment for prespecified covariates. At 13 centers in the United States, 649 patients were randomly assigned to receive dipyridamole plus aspirin (321 patients) or placebo (328 patients) over a period of 4.5 years, with 6 additional months of follow-up. The incidence of primary unassisted patency at 1 year was 23% (95% confidence interval [CI], 18 to 28) in the placebo group and 28% (95% CI, 23 to 34) in the dipyridamole-aspirin group, an absolute difference of 5 percentage points. Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P=0.03) and inhibited stenosis. The incidences of cumulative graft failure, death, the composite of graft failure or death, and serious adverse events (including bleeding) did not differ significantly between study groups. Treatment with dipyridamole plus aspirin had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts. (ClinicalTrials.gov number, NCT00067119.) 2009 Massachusetts Medical Society

  9. Predictors of participant engagement and naloxone utilization in a community-based naloxone distribution program.

    PubMed

    Rowe, Christopher; Santos, Glenn-Milo; Vittinghoff, Eric; Wheeler, Eliza; Davidson, Peter; Coffin, Philip O

    2015-08-01

    To describe characteristics of participants and overdose reversals associated with a community-based naloxone distribution program and identify predictors of obtaining naloxone refills and using naloxone for overdose reversal. Bivariate statistical tests were used to compare characteristics of participants who obtained refills and reported overdose reversals versus those who did not. We fitted multiple logistic regression models to identify predictors of refills and reversals; zero-inflated multiple Poisson regression models were used to identify predictors of number of refills and reversals. San Francisco, California, USA. Naloxone program participants registered and reversals reported from 2010 to 2013. Baseline characteristics of participants and reported characteristics of reversals. A total of 2500 participants were registered and 702 reversals were reported from 2010 to 2013. Participants who had witnessed an overdose [adjusted odds ratio (AOR)=2.02, 95% confidence interval (CI)= 1.53-2.66; AOR = 2.73, 95% CI = 1.73-4.30] or used heroin (AOR = 1.85, 95% CI =  1.44-2.37; AOR = 2.19, 95% CI = 1.54-3.13) or methamphetamine (AOR=1.71, 95% CI=1.37-2.15; AOR=1.61, 95% CI=1.18-2.19) had higher odds of obtaining a refill and reporting a reversal, respectively. African American (AOR = 0.63, 95% CI = 0.45-0.88) and Latino (AOR = 0.65, 95% CI =  0.43-1.00) participants had lower odds of obtaining a naloxone refill, whereas Latino participants who obtained at least one refill reported a higher number of refills [incidence rate ratio (IRR) = 1.33 (1.05-1.69)]. Community naloxone distribution programs are capable of reaching sizeable populations of high-risk individuals and facilitating large numbers of overdose reversals. Community members most likely to engage with a naloxone program and use naloxone to reverse an overdose are active drug users. © 2015 Society for the Study of Addiction.

  10. Aspirin and Extended-Release Dipyridamole

    MedlinePlus

    The combination of aspirin and extended-release dipyridamole is in a class of drugs called antiplatelet agents. It works by preventing excessive blood clotting. It is used to reduce the risk of stroke in patients who have had or ...

  11. Ocular Applications of Dipyridamole: A Review of Indications and Routes of Administration

    PubMed Central

    Isakov, Itzhak; Wlassoff, Wjatschesslaw; Ingram, April; Barishak, Y. Robert

    2016-01-01

    Abstract Dipyridamole was introduced decades ago as a treatment for angina, subsequently found to inhibit platelet aggregation. It is most commonly used, and approved for use in thromboembolism prevention, following surgery. Some of its recognized effects such as adenosine uptake inhibition, elevation of cAMP and cGMP levels, vasodilation, and tissue perfusion are important in various ocular disorders. For this reason, dipyridamole represents an interesting candidate as a therapeutic target for the treatment of eye disorders affecting different ocular structures. The aim of this article is to review the evidence and current understanding of the mechanisms by which dipyridamole exerts its effects on different ocular tissues, discuss the role of dipyridamole in clinical practice, and highlight areas of use and routes of administration. PMID:26696547

  12. Effect of Dipyridamole plus Aspirin on Hemodialysis Graft Patency

    PubMed Central

    Dixon, Bradley S.; Beck, Gerald J.; Vazquez, Miguel A.; Greenberg, Arthur; Delmez, James A.; Allon, Michael; Dember, Laura M.; Himmelfarb, Jonathan; Gassman, Jennifer J.; Greene, Tom; Radeva, Milena K.; Davidson, Ingemar J.; Ikizler, T. Alp; Braden, Gregory L.; Fenves, Andrew Z.; Kaufman, James S.; Cotton, James R.; Martin, Kevin J.; McNeil, James W.; Rahman, Asif; Lawson, Jeffery H.; Whiting, James F.; Hu, Bo; Meyers, Catherine M.; Kusek, John W.; Feldman, Harold I.

    2014-01-01

    BACKGROUND Arteriovenous graft stenosis leading to thrombosis is a major cause of complications in patients undergoing hemodialysis. Procedural interventions may restore patency but are costly. Although there is no proven pharmacologic therapy, dipyridamole may be promising because of its known vascular antiproliferative activity. METHODS We conducted a randomized, double-blind, placebo-controlled trial of extended-release dipyridamole, at a dose of 200 mg, and aspirin, at a dose of 25 mg, given twice daily after the placement of a new arteriovenous graft until the primary outcome, loss of primary unassisted patency (i.e., patency without thrombosis or requirement for intervention), was reached. Secondary outcomes were cumulative graft failure and death. Primary and secondary outcomes were analyzed with the use of a Cox proportional-hazards regression with adjustment for prespecified covariates. RESULTS At 13 centers in the United States, 649 patients were randomly assigned to receive dipyridamole plus aspirin (321 patients) or placebo (328 patients) over a period of 4.5 years, with 6 additional months of follow-up. The incidence of primary unassisted patency at 1 year was 23% (95% confidence interval [CI], 18 to 28) in the placebo group and 28% (95% CI, 23 to 34) in the dipyridamole–aspirin group, an absolute difference of 5 percentage points. Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = 0.03) and inhibited stenosis. The incidences of cumulative graft failure, death, the composite of graft failure or death, and serious adverse events (including bleeding) did not differ significantly between study groups. CONCLUSIONS Treatment with dipyridamole plus aspirin had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts. (ClinicalTrials.gov number, NCT00067119.) PMID

  13. Naloxone-induced electrographic seizures in the primate.

    PubMed

    Snyder, E W; Shearer, D E; Beck, E C; Dustmann, R E

    1980-01-01

    Electrographic seizure activity was recorded shortly following naxolone injections in artificially ventilated, methadone-treated stump-tailed macaques. Plasma-methadone concentrations prior to seizure activity were many times higher than those that have produced respiratory depression and death in nonventilated monkeys. The duration of seizure activity was clearly related to the dose of naloxone. Naloxone was without epileptogenic properties in animals that had not been pretreated with methadone. The results suggest that methadone and naloxone have additive epileptogenic properties when high blood levels of methadone are achieved in the artificially ventilated primate. Naloxone was devoid of antagonistic properties with respect to opiate-induced electroencephalographic spiking activity.

  14. Co-prescribing naloxone does not increase liability risk.

    PubMed

    Davis, Corey S; Burris, Scott; Beletsky, Leo; Binswanger, Ingrid

    2016-01-01

    The opioid overdose epidemic claims the lives of tens of thousands of Americans every year. Opioid overdose is reversible by the administration of naloxone, a pure antagonist now available in formulations specifically designed and labeled for layperson use. Despite broad support for layperson access to naloxone from professional organizations, health officials, and clinical experts, qualitative studies suggest that some providers have concerns about legal risks associated with naloxone prescribing, particularly co-prescribing naloxone to pain patients. Such concerns are unfounded. The legal risk associated with prescribing naloxone is no higher than that associated with any other medication and is lower than many. Additionally, laws in a majority of states provide explicit legal protections for providers who prescribe or dispense naloxone, in many cases extending this protection to prescriptions issued to friends, family members, and others. In this large and increasing number of states, the liability risk of prescribing or dispensing naloxone in good faith to a patient at risk of overdose (or, in states where such prescribing is permitted, to an associate of such a patient) is either extremely low or absent entirely. Where a prescriber determines, in his or her clinical judgment, that a patient is at risk of overdose, co-prescribing naloxone is a reasonable and prudent clinical and legal decision. No clinician should fail or refuse to issue such a prescription based on liability concerns.

  15. Naloxone Injection

    MedlinePlus

    ... emergency medical treatment to reverse the life-threatening effects of a known or suspected opiate (narcotic) overdose. ... is also used after surgery to reverse the effects of opiates given during surgery. Naloxone injection is ...

  16. Reversibility by dipyridamole of thallium-201 myocardial scan defects in patients with sarcoidosis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tellier, P.; Paycha, F.; Antony, I.

    1988-08-01

    In order to clarify the significance of anginal pain and myocardial thallium-201 scan defects in cardiac sarcoidosis, the pharmacologic effect of dipyridamole on myocardial perfusion was assessed by planar thallium-201 myocardial scintigraphy in patients with sarcoidosis. Thallium-201 myocardial scintigraphy was performed at rest and after 0.56 mg/kg intravenous dipyridamole during four minutes in 16 patients with sarcoidosis. The myocardial scan (45-degree and 70-degree left anterior oblique, and anterior views) was divided into 15 segments. Results were evaluated by the number of segmental defects and with a global perfusion score (from 0 to 60) by a semi-quantitative index depending on themore » size and severity of myocardial thallium-201 defects. Thirteen of the 16 patients showed partial or total reversion of their thallium-201 defects on redistribution scanning either at rest or after dipyridamole. The mean (+/- SD) number of myocardial perfusion defects that were present in all the patients decreased from 5.31 +/- 1.78 at rest to 3.25 +/- 2.52 after redistribution (p less than 0.001) and to 2.19 +/- 2.10 after dipyridamole (p less than 0.001). The mean global perfusion score increased from 53.2 +/- 3.0 at rest to 56.2 +/- 2.9 after redistribution (p less than 0.001) and to 57.2 +/- 2.7 after dipyridamole (p less than 0.001). A significant correlation (r = 0.82, p less than 0.001) was found between the increase of global perfusion score on redistribution and after dipyridamole. The reversibility of myocardial scan defects is a common finding in sarcoidosis. It makes unlikely the role of scar fibrosis or extensive confluent granulomas as a mechanism for such defects. The effect of dipyridamole suggests the presence of reversible disorders lying at the coronary microvascular level.« less

  17. Police officer attitudes towards intranasal naloxone training.

    PubMed

    Ray, Bradley; O'Donnell, Daniel; Kahre, Kailyn

    2015-01-01

    One approach to reduce fatal opioid overdose is by distributing naloxone to law enforcement officers. While several cities have implemented these naloxone programs, little research has investigated officer attitudes about their training. The present research attempts to fill this gap by analyzing survey data from police officers following intranasal naloxone training. All of the police officers within the same district in Indianapolis, Indiana, underwent training to recognize opioid overdose and to administer intranasal naloxone (N=117). Following training, officers completed a survey that measured prior experience with opioid overdose, perceived importance of training, and items from the Opioid Overdose Attitudes Scale (OOAS) to measure attitudes following training. The officers had overwhelmingly positive feelings about the training, that it was not difficult, and that other officers should be trained to use naloxone. The OOAS items suggest that officers know the appropriate actions to take in the event of an overdose and feel that administering intranasal naloxone will not be difficult. Finally, we found that officers who had more experience with opioid overdose had more positive attitudes about the training. Distributing naloxone to police officers is likely a trend that will continue so it is important to understand how police officers respond to training to assure that future trainings are as effective as possible. Further research is needed to investigate the impact that these programs have on the community. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. Caged Naloxone: Synthesis, Characterization, and Stability of 3- O-(4,5-Dimethoxy-2-nitrophenyl)carboxymethyl Naloxone (CNV-NLX).

    PubMed

    Lewin, Anita H; Fix, Scott E; Zhong, Desong; Mayer, Louise D; Burgess, Jason P; Mascarella, S Wayne; Reddy, P Anantha; Seltzman, Herbert H; Carroll, F Ivy

    2018-03-21

    The photolabile analogue of the broad-spectrum opioid antagonist naloxone, 3- O-(4,5-dimethoxy-2-nitrophenyl)carboxymethyl naloxone (also referred to as "caged naloxone", 3- O-(α-carboxy-6-nitroveratryl)naloxone, CNV-NLX), has been found to be a valuable biochemical probe. While the synthesis of CNV-NLX is simple, its characterization is complicated by the fact that it is produced as a mixture of α R,5 R,9 R,13 S,14 S and α S,5 R,9 R,13 S,14 S diastereomers. Using long-range and heteronuclear NMR correlations, the 1 H NMR and 13 C NMR resonances of both diastereomers have been fully assigned, confirming the structures. Monitoring of solutions of CNV-NLX in saline buffer, in methanol, and in DMSO has shown CNV-NLX to be stable for over a week under fluorescent laboratory lights at room temperature. Exposure of such solutions to λ 365 nm from a hand-held UV lamp led to the formation of naloxone and CNV-related breakdown products.

  19. Does Naloxone Prevent Seizure in Tramadol Intoxicated Patients?

    PubMed Central

    Eizadi-Mood, Nastaran; Ozcan, Dilek; Sabzghabaee, Ali Mohammad; Mirmoghtadaee, Parisa; Hedaiaty, Mahrang

    2014-01-01

    Background: Tramadol poisoning has increased in recent years. Seizure is one of the side-effects of tramadol toxicity. There is a controversy about possible preventive effect of naloxone in tramadol poisoning induced seizure. Therefore, this study was performed to compare seizure incidence in tramadol poisoning patients who received and did not receive naloxone, as an opioid antagonist. Methods: This study involved prospective data collection followed by retrospective analysis on 104 tramadol poisoning patients who were admitted in a referral poisoning center. The incidences of seizure were compared between patients received naloxone and those did not. Outcome was considered as survived without or with complications and death. Logistic Regression analysis was used to determine the effects of different variables on seizure incidence. Results: 70 (67.3%) of the patients were men. The mean age of the patients was 26.3 ± 9 years old. 18.3% of the patients received naloxone in their treatment period. Seizure incidence was significantly higher among tramadol poisoning patients who did not receive naloxone compare with those received naloxone (14.1% vs. 5.1%). Among different variable studied, age had a significant effect on predicting of seizure (odds ratio = 2.09; 95% of confidence interval: 1.82-2.26; P value, 0.004). Conclusions: Although the seizure incidence was lower in patients with tramadol poisoning who received naloxone, the logistic regression did not support the preventive effect of naloxone on seizure in tramadol poisoning cases. PMID:24829714

  20. High doses of L-naloxone but neither D-naloxone nor beta-funaltrexamine prevent hyperthermia-induced seizures in rat pups.

    PubMed

    Laorden, M L; Miralles, F S; Puig, M M

    1988-03-01

    The effects of the non-specific opiate antagonist L-naloxone and the inactive isomer D-naloxone, as well as the specific mu receptor antagonist beta-funaltrexamine, have been examined on hyperthermia-induced seizures in unrestrained 15 days old rats. Saline-injected animals exposed to an ambient temperature of 40 degrees C showed a gradual increase in body temperature reaching a maximum of 42 +/- 0.1 degrees C at 50 min exposure. At this time all the pups had seizures and died. Similar results were obtained when the animals were pretreated with different doses of D-naloxone and beta-funaltrexamine. Rats pretreated with L-naloxone also showed an increase in rectal temperature; but the temperature was lower than in saline-injected animals. Only high doses of L-naloxone prevented seizures and deaths. These data indicate that endogenous opioid peptides may play a role in seizures induced by hyperthermia and that receptors other than mu receptors could be involved in hyperthermia-induced seizures.

  1. Assessment of provider attitudes toward #naloxone on Twitter.

    PubMed

    Haug, Nancy A; Bielenberg, Jennifer; Linder, Steven H; Lembke, Anna

    2016-01-01

    As opioid overdose rates continue to pose a major public health crisis, the need for naloxone treatment by emergency first responders is critical. Little is known about the views of those who administer naloxone. The current study examines attitudes of health professionals on the social media platform Twitter to better understand their perceptions of opioid users, the role of naloxone, and potential training needs. Public comments on Twitter regarding naloxone were collected for a period of 3 consecutive months. The occupations of individuals who posted tweets were identified through Twitter profiles or hashtags. Categories of emergency service first responders and medical personnel were created. Qualitative analysis using a grounded theory approach was used to produce thematic content. The relationships between occupation and each theme were analyzed using Pearson chi-square statistics and post hoc analyses. A total of 368 individuals posted 467 naloxone-related tweets. Occupations consisted of professional first responders such as emergency medical technicians (EMTs), firefighters, and paramedics (n = 122); law enforcement officers (n = 70); nurses (n = 62); physicians (n = 48); other health professionals including pharmacists, pharmacy technicians, counselors, and social workers (n = 31); naloxone-trained individuals (n = 12); and students (n = 23). Primary themes included burnout, education and training, information seeking, news updates, optimism, policy and economics, stigma, and treatment. The highest levels of burnout, fatigue, and stigma regarding naloxone and opioid overdose were among nurses, EMTs, other health care providers, and physicians. In contrast, individuals who self-identified as "naloxone-trained" had the highest optimism and the lowest amount of burnout and stigma. Provider training and refinement of naloxone administration procedures are needed to improve treatment outcomes and reduce provider stigma. Social networking sites such as Twitter

  2. Naloxone fails to prolong seizure length in ECT.

    PubMed

    Rasmussen, K G; Pandurangi, A K

    1999-12-01

    Electroconvulsive shock (ECS) in animals has been shown to enhance endogenous opiate systems. The anticonvulsant effects of ECS are also partially blocked by the opiate receptor antagonist naloxone, leading some investigators to postulate that the anticonvulsant effects of ECS are mediated by activation of endogenous opiates. If such a phenomenon occurs in humans, then naloxone might prolong seizure length in electroconvulsive therapy (ECT). In the present study, nine patients were given 2.0 mg intravenous (i.v.) naloxone 2 minutes prior to one-half of their ECT treatments. Motor seizure length was measured via the cuff technique. EEG tracings were read by an investigator blind to naloxone status. There was no difference between the two groups in either EEG or nonblindly evaluated motor seizure length. It is concluded that a dose of 2 mg naloxone does not effectively increase seizure length in ECT.

  3. Police Officers Can Safely and Effectively Administer Intranasal Naloxone.

    PubMed

    Fisher, Rian; O'Donnell, Daniel; Ray, Bradley; Rusyniak, Daniel

    2016-01-01

    Opioid overdose rates continue to rise at an alarming rate. One method used to combat this epidemic is the administration of naloxone by law enforcement. Many cities have implemented police naloxone administration programs, but there is a minimal amount of research examining this policy. The following study examines data over 18 months, after implementation of a police naloxone program in an urban setting. We describe the most common indications and outcomes of naloxone administration as well as examine the incidence of arrest, immediate detention, or voluntary transport to the hospital. In doing so, this study seeks to describe the clinical factors surrounding police use of naloxone, and the effects of police administration. All police officer administrations were queried from April 2014 through September 2015 (n = 126). For each incident we collected the indication, response, and disposition of the patient that was recorded on a "sick-injured civilian" report that officers were required to complete after administration of naloxone. All of the relevant information was abstracted from this report into an electronic data collection form that was then input into SPSS for analysis. The most common indication for administration was unconscious/unresponsive (n = 117; 92.9%) followed by slowed breathing (n = 72; 57.1%), appeared blue (n = 63; 50.0%) and not breathing (n = 41; 32.5%). After administration of naloxone the majority of patients regained consciousness (n = 82; 65.1%) followed by began to breath (n = 71; 56.3%). However, in 17.5% (n = 22) of the cases "Nothing" happened when naloxone was administered. The majority of patients were transported voluntarily to the hospital (n = 122; 96.8%). Lastly, there was only one report where the patient became combative. Our study shows that police officers trained in naloxone administration can correctly recognize symptoms of opioid overdose, and can appropriately administer naloxone without significant adverse effects or

  4. Community pharmacist knowledge, attitudes and confidence regarding naloxone for overdose reversal.

    PubMed

    Nielsen, Suzanne; Menon, Nadia; Larney, Sarah; Farrell, Michael; Degenhardt, Louisa

    2016-12-01

    Given the potential to expand naloxone supply through community pharmacy, the aim of this study was to estimate Australian pharmacists': (1) level of support for overdose prevention, (2) barriers and facilitators for naloxone supply and (3) knowledge about naloxone administration. Online survey from nationally representative sample of community pharmacies. Australia, September-November 2015. A total of 1317 community pharmacists were invited to participate with 595 responses (45.1%). We assessed attitudes towards harm reduction, support for overdose prevention, attitudes and knowledge about naloxone. We tested the association between attitudes towards harm reduction and different aspects of naloxone supply. Pharmacists were willing to receive training about naloxone (n = 479, 80.5%) and provide naloxone with a prescription (n = 537, 90.3%). Fewer (n = 234, 40.8%) were willing to supply naloxone over-the-counter. Positive attitudes towards harm reduction were associated with greater willingness to supply naloxone with a prescription [odds ratio (OR) = 1.15, 95% confidence interval (CI) = 1.11-1.19] and over-the-counter (OR = 1.13, 95% CI = 1.09-1.17). Few pharmacists were confident they could identify appropriate patients (n = 203, 34.1%) and educate them on overdose and naloxone use (n = 190, 31.9%). Mean naloxone knowledge scores were 1.8 (standard deviation 1.7) out of 5. More than half the sample identified lack of time, training, knowledge and reimbursement as potential barriers for naloxone provision. Community pharmacists in Australia appear to be willing to supply naloxone. Low levels of knowledge about naloxone pharmacology and administration highlight the importance of training pharmacists about overdose prevention. © 2016 Society for the Study of Addiction.

  5. Increase in Naloxone Prescriptions Dispensed in US Retail Pharmacies Since 2013.

    PubMed

    Jones, Christopher M; Lurie, Peter G; Compton, Wilson M

    2016-04-01

    Distribution of naloxone, traditionally through community-based naloxone programs, is a component of a comprehensive strategy to address the epidemic of prescription opioid and heroin overdose deaths in the United States. Recently, there has been increased focus on naloxone prescription in the outpatient setting, particularly through retail pharmacies, yet data on this practice are sparse. We found an 1170% increase in naloxone dispensing from US retail pharmacies between the fourth quarter of 2013 and the second quarter of 2015. These findings suggest that prescribing naloxone in the outpatient setting complements traditional community-based naloxone programs.

  6. Pharmacokinetics of a new, nasal formulation of naloxone.

    PubMed

    Tylleskar, Ida; Skulberg, Arne Kristian; Nilsen, Turid; Skarra, Sissel; Jansook, Phatsawee; Dale, Ola

    2017-05-01

    Nasal naloxone is wanted for bystander administration in opioid overdose and as a needle-free alternative for emergency medical personnel. Epidemiologic studies have indicated a therapeutic effect of bystander administration of low-concentration/high-volume formulations. The objective for this study was to describe the nasal pharmacokinetics of a new high-concentration/low-volume nasal formulation of naloxone. This was an open, randomized triple crossover trial in healthy, human volunteers (n = 12) where two doses of nasal naloxone (0.8 and 1.6 mg) and one intravenous dose (1.0 mg) were compared. Fifteen serum samples were collected before and until 6 h after naloxone administration. Quantification of naloxone was performed by a validated liquid chromatography-tandem mass spectrometry method. Bioavailability was 0.54 (0.45-0.63) for the 0.8 mg and 0.52 (0.37-0.67) for the 1.6 mg nasal naloxone formulation. Maximum concentration levels (C max ) were 1.45 ng/ml (1.07-1.84) for 0.8 mg and 2.57 ng/ml (1.49-3.66) for the 1.6 mg. Time to maximum concentrations (T max ) were reached at 17.9 min (11.4-24.5) and 18.6 min (14.4-22.9) for the 0.8 mg and the 1.6 mg doses, respectively. This nasal naloxone formulation had a rapid, systemic uptake and higher bioavailability than naloxone formulations not designed for IN use. This indicates that an optimized high-concentration/low-volume nasal spray formulation may deliver a therapeutic dose. The 1.6 mg nasal dose provided serum concentrations that surpassed those of 1.0 mg IV after 15-20 min and stayed above for the rest of the study period.

  7. Law enforcement attitudes towards naloxone following opioid overdose training.

    PubMed

    Purviance, Donna; Ray, Bradley; Tracy, Abigail; Southard, Erik

    2017-01-01

    Opioid intoxication and overdoses are life-threatening emergencies requiring rapid treatment. One response to this has been to train law enforcement to detect the signs of an opioid overdose and train them to administer naloxone to reverse the effects. Although not a new concept, few studies have attempted to examine this policy. At 4 different locations in Indiana, law enforcement personnel were trained to detect the signs of an opioid-related overdose and how to administer naloxone to reverse the effects of the overdose. Pre and post surveys were administered at each location (N = 97). To examine changes in attitudes following training, the authors included items from the Opioid Overdose Attitudes Scale (OOAS), which measures respondents' competency, concerns, and readiness to administer naloxone. Among the full sample, naloxone training resulted in significant increases in competency, concerns, and readiness. Examining changes in attitudes by each location revealed that the training had the greatest effect on competency to administer naloxone and in easing concerns that law enforcement personal might have in administering naloxone. This study adds to others in showing that law enforcement personnel are receptive to naloxone training and that the OOAS is able to capture these attitudes. This study advances this literature by examining pre-post changes across multiple locations. As the distribution of naloxone continues to proliferate, this study and the OOAS may be valuable towards the development of an evidence-based training model for law enforcement.

  8. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone

    PubMed Central

    Hutchinson, Mark R.; Zhang, Yingning; Brown, Kimberley; Coats, Benjamen D.; Shridhar, Mitesh; Sholar, Paige W.; Patel, Sonica J.; Crysdale, Nicole Y.; Harrison, Jacqueline A.; Maier, Steven F.; Rice, Kenner C.; Watkins, Linda R.

    2008-01-01

    Although activated spinal cord glia contribute importantly to neuropathic pain, how nerve injury activates glia remains controversial. It has recently been proposed, on the basis of genetic approaches, that toll-like receptor 4 (TLR4) may be a key receptor for initiating microglial activation following L5 spinal nerve injury. The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury (CCI). Established neuropathic pain was reversed by intrathecally delivered TLR4 receptor antagonists derived from lipopolysaccharide. Additionally, (+)-naltrexone, (+)-naloxone, and (-))-naloxone, which we show here to be TLR4 antagonists in vitro on both stably transfected HEK293-TLR4 and microglial cell lines, suppressed neuropathic pain with complete reversal upon chronic infusion. Immunohistochemical analyses of spinal cords following chronic infusion revealed suppression of CCI-induced microglial activation by (+)-naloxone and (-))-naloxone, paralleling reversal of neuropathic pain. Together, these CCI data support the conclusion that neuron-to-glia signaling through TLR4 is important not only for initiating neuropathic pain, as suggested previously, but also for maintaining established neuropathic pain. Furthermore, these studies suggest that the novel TLR4 antagonists (+)-naloxone and (-))-naloxone can each fully reverse established neuropathic pain upon multi-day administration. This finding with (+)-naloxone is of potential clinical relevance. This is because (+)-naloxone is an antagonist that is inactive at the (-))-opioid selective receptors on neurons that produce analgesia. Thus, these data suggest that (+)-opioid antagonists such as (+)-naloxone may be useful clinically to suppress glial activation, yet (-))-opioid agonists suppress pain. PMID:18662331

  9. Naloxone for Opioid Overdose and the Role of the Pharmacist.

    PubMed

    Toderika, Yuliana; Williams, Shalonda

    2018-02-01

    With the rise of the opioid epidemic in the United States and increased mortality as a result of opioid overdoses, there have been many national and statewide initiatives to combat this health crisis. Many states have expanded accessibility to naloxone, an opioid-reversal agent. Naloxone is safe, cost-effective, and nonaddictive. In addition, simple administration allows naloxone to be used by patients, family members, caregivers, and bystanders in the event of an opioid overdose. While a great emphasis has been placed on the prescribing practices of health care providers as it pertains to opioid therapy for chronic pain, a new focus has been placed on coprescribing naloxone with opioids for high-risk patients. Naloxone standing orders have allowed health care providers, including pharmacists, to prescribe, dispense, and/ or administer the medication in an attempt to save lives. In addition, pharmacists play a role in counseling and educating patients, family members, caregivers, and bystanders on the safe administration of naloxone in the event of an emergency.

  10. Nebulized naloxone gently and effectively reverses methadone intoxication.

    PubMed

    Mycyk, Mark B; Szyszko, Amy L; Aks, Steven E

    2003-02-01

    A 46-year-old woman presented to the Emergency Department with lethargy and respiratory depression after ingesting methadone. Initial oxygen saturation of 61% on room air did not improve with supplemental oxygenation. As venous access was initially unobtainable, naloxone was administered by nebulizer. Within 5 min oxygen saturation was 100% and mental status was normal. The patient did not develop severe withdrawal symptoms. Naloxone hydrochloride has been administered by various routes to treat opioid toxicity. Our report describes the successful use of nebulized naloxone for methadone toxicity.

  11. Naloxone inhibits nod-like receptor protein 3 inflammasome.

    PubMed

    Lin, Han-Yu; Chang, Ya-Ying; Kao, Ming-Chang; Huang, Chun-Jen

    2017-11-01

    Naloxone, an opioid receptor antagonist, possesses potent anti-inflammation effects. We previously confirmed the effects of naloxone on inhibiting upregulation of inflammatory cytokine interleukin-1β (IL-1β). Production of mature form IL-1β is mediated by the nod-like receptor protein 3 (NLRP3) inflammasome, a multiprotein complex composed of NLRP3, and the adaptor protein apoptosis-associated speck-like protein contains a caspase recruitment domain (ASC). We elucidated whether naloxone could inhibit the activation of NLRP3 inflammasome. To induce IL-1β production and NLRP3 inflammasome activation, the human monocytic leukemia cell line THP-1 cells were first primed with lipopolysaccharide (LPS, 1 μg/mL) and then activated with adenosine triphosphate (ATP, 1 mM). For NLRP3 transcription, THP-1 cells were only treated with LPS priming. Enzyme-link immunosorbent assay data revealed that the concentration of IL-1β in THP-1 cells treated with LPS plus ATP was significantly higher than that in THP-1 cells treated with LPS plus ATP plus naloxone (0.1 μM) (P < 0.001). Real-time quantitative reverse transcription and polymerase chain reaction data also revealed that NLRP3 mRNA concentration in THP-1 cells treated with LPS was significantly higher than that in THP-1 cells treated with LPS plus naloxone (P = 0.001). ASC speck formation, that is, ASC assembles into a large protein complex, is an indicator for NLRP3 inflammasome activation. Our data revealed that the percentage of cells containing ASC specks in THP-1 cells treated with LPS plus ATP was also significantly higher than that in THP-1 cells treated with LPS plus ATP plus naloxone (P < 0.001). Naloxone inhibits NLRP3 inflammasome activation. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Naloxone Antagonizes Soman-induced Central Respiratory Depression in Rats.

    PubMed

    Škrbić, Ranko; Stojiljković, Miloš P; Ćetković, Slavko S; Dobrić, Silva; Jeremić, Dejan; Vulović, Maja

    2017-06-01

    The influence of naloxone on respiration impaired by the highly toxic organophosphate nerve agent soman in anaesthetized rats was investigated. Soman, administered in a dose that was ineffective in blocking the electrically induced contractions of the phrenic nerve-diaphragm preparation in situ, induced a complete block of the spontaneous respiratory movements of the diaphragm, indicating the domination of central over the peripheral effects. Naloxone dose-dependently antagonized the soman-induced respiratory blockade. Atropine, at a dose that was per se ineffective in counteracting soman-induced respiratory depression, potentiated the protective effects of naloxone and completely restored respiration. Naloxone remained completely ineffective in antagonizing respiratory depression induced by the muscarinic receptor agonist the oxotremorine. It is assumed that naloxone antagonizes soman-induced respiratory inhibition by blocking endogenous opioidergic respiratory control pathways that are independent of the stimulation of muscarinic receptors. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  13. Dipyridamole for preventing recurrent ischemic stroke and other vascular events: a meta-analysis of individual patient data from randomized controlled trials.

    PubMed

    Leonardi-Bee, Jo; Bath, Philip M W; Bousser, Marie-Germaine; Davalos, Antoni; Diener, Hans-Christoph; Guiraud-Chaumeil, Bernard; Sivenius, Juhani; Yatsu, Frank; Dewey, Michael E

    2005-01-01

    Results from randomized controlled trials of dipyridamole, given with or without aspirin, for secondary prevention after ischemic stroke or transient ischemic attack (TIA) have given conflicting results. We performed a meta-analysis using individual patient data from relevant randomized controlled trials. Randomized controlled trials involving dipyridamole in patients with previous ischemic stroke or TIA were sought from searches of the Cochrane Library, other electronic databases, references lists, earlier reviews, and contact with the manufacturer of dipyridamole. Individual patient data were merged from 5 of 7 relevant trials involving 11 459 patients. Results were adjusted for age, gender, qualifying event, and history of previous hypertension. Recurrent stroke was reduced by dipyridamole as compared with control (OR, 0.82; 95% CI, 0.68 to 1.00), and by combined aspirin and dipyridamole versus aspirin alone (OR, 0.78; 95% CI, 0.65 to 0.93), dipyridamole alone (OR, 0.74; 95% CI, 0.60 to 0.90), or control (OR, 0.61; 95% CI, 0.51 to 0.71). The point estimates obtained for the comparisons of aspirin and dipyridamole versus control (OR, 0.63; significant) or versus aspirin (OR, 0.88; nonsignificant) were similar if the data from the largest trial, ESPS II (which provided 57% of data), were excluded. Similar findings were observed for nonfatal stroke. The combination of aspirin and dipyridamole also significantly reduced the composite outcome of nonfatal stroke, nonfatal myocardial infarction, and vascular death as compared with aspirin alone (OR, 0.84; 95% CI, 0.72 to 0.97), dipyridamole alone (OR, 0.76; 95% CI, 0.64 to 0.90), or control (OR, 0.66; 95% CI, 0.57 to 0.75). Vascular death was not altered in any group. Dipyridamole, given alone or with aspirin, reduces stroke recurrence in patients with previous ischemic cerebrovascular disease. The combination of aspirin and dipyridamole also reduces the composite of nonfatal stroke, nonfatal myocardial infarction, and

  14. Implementing an overdose education and naloxone distribution program in a health system.

    PubMed

    Devries, Jennifer; Rafie, Sally; Polston, Gregory

    To design and implement a health system-wide program increasing provision of take-home naloxone in patients at risk for opioid overdose, with the downstream aim of reducing fatalities. The program includes health care professional education and guidelines, development, and dissemination of patient education materials, electronic health record changes to promote naloxone prescriptions, and availability of naloxone in pharmacies. Academic health system, San Diego, California. University of California, San Diego Health (UCSDH), offers both inpatient and outpatient primary care and specialty services with 563 beds spanning 2 hospitals and 6 pharmacies. UCSDH is part of the University of California health system, and it serves as the county's safety net hospital. In January 2016, a multisite academic health system initiated a system-wide overdose education and naloxone distribution program to prevent opioid overdose and opioid overdose-related deaths. An interdisciplinary, interdepartmental team came together to develop and implement the program. To strengthen institutional support, naloxone prescribing guidelines were developed and approved for the health system. Education on naloxone for physicians, pharmacists, and nurses was provided through departmental trainings, bulletins, and e-mail notifications. Alerts in the electronic health record and preset naloxone orders facilitated co-prescribing of naloxone with opioid prescriptions. Electronic health record reports captured naloxone prescriptions ordered. Summary reports on the electronic health record measured naloxone reminder alerts and response rates. Since the start of the program, the health system has trained 252 physicians, pharmacists, and nurses in overdose education and take-home naloxone. There has been an increase in the number of prescriptions for naloxone from a baseline of 4.5 per month to an average of 46 per month during the 3 months following full implementation of the program including

  15. Use of Intranasal Naloxone by Basic Life Support Providers.

    PubMed

    Weiner, Scott G; Mitchell, Patricia M; Temin, Elizabeth S; Langlois, Breanne K; Dyer, K Sophia

    2017-01-01

    Intranasal delivery of naloxone to reverse the effects of opioid overdose by Advanced Life Support (ALS) providers has been studied in several prehospital settings. In 2006, in response to the increase in opioid-related overdoses, a special waiver from the state allowed administration of intranasal naloxone by Basic Life Support (BLS) providers in our city. This study aimed to determine: 1) if patients who received a 2-mg dose of nasal naloxone administered by BLS required repeat dosing while in the emergency department (ED), and 2) the disposition of these patients. This was a retrospective review of patients transported by an inner-city municipal ambulance service to one of three academic medical centers. We included patients aged 18 and older that were transported by ambulance between 1/1/2006 and 12/12/2012 and who received intranasal naloxone by BLS providers as per a state approved protocol. Site investigators matched EMS run data to patients from each hospital's EMR and performed a chart review to confirm that the patient was correctly identified and to record the outcomes of interest. Descriptive statistics were then generated. A total of 793 patients received nasal naloxone by BLS and were transported to three hospitals. ALS intervened and transported 116 (14.6%) patients, and 11 (1.4%) were intubated in the field. There were 724 (91.3%) patients successfully matched to an ED chart. Hospital A received 336 (46.4%) patients, Hospital B received 210 (29.0%) patients, and Hospital C received 178 (24.6%) patients. Mean age was 36.2 (SD 10.5) years and 522 (72.1%) were male; 702 (97.1%) were reported to have abused heroin while 21 (2.9%) used other opioids. Nasal naloxone had an effect per the prehospital record in 689 (95.2%) patients. An additional naloxone dose was given in the ED to 64 (8.8%) patients. ED dispositions were: 507 (70.0%) discharged, 105 (14.5%) admitted, and 112 (15.5%) other (e.g., left against medical advice, left without being seen, or

  16. Overdose Education and Naloxone Rescue Kits for Family Members of Opioid Users: Characteristics, Motivations and Naloxone Use

    PubMed Central

    Bagley, Sarah M; Peterson, Joanne; Cheng, Debbie M.; Jose, Charles; Quinn, Emily; O’Connor, Patrick G.; Walley, Alexander Y.

    2016-01-01

    Background In response to the overdose epidemic, a network of support groups for family members in Massachusetts has been providing overdose education and naloxone rescue kits (OEN). The aims of this study were to describe the characteristics, motivations and benefits of family members who receive OEN and to describe the frequency of naloxone used during an overdose rescue. Methods This cross-sectional, multisite study surveyed attendees of community support groups for family members of opioid users where OEN training was offered using a 42 item self-administered survey that included demographics, relationship to opioid user, experience with overdose, motivations to receive OEN, and naloxone rescue kit use. Results Of 126 attendees who completed surveys at 8 sites, most attendees were white (95%), female (78%), married or partnered (74%), parents of an opioid user (85%), and provide financial support for opioid user (52%). The OEN trainees (79%) were more likely than attendees not trained (21%) to be parents of an opioid user (91% v 65%, p <0.05), provide financial support to an opioid user (58% v 30%, p <0.05), and to have witnessed an overdose (35% v 12%, p=0.07). The major motivations to receive training were: wanting a kit in their home (72%), education provided at the meeting (60%) and hearing about benefits from others (57%). Sixteen parents reported witnessing their child overdose and five attendees had used naloxone successfully during an overdose rescue. Conclusions Support groups for families of people who use opioids are promising venues to conduct overdose prevention trainings, because attendees are motivated to receive training and will use naloxone to rescue people when witnessing an overdose. Further study is warranted to understand how to optimize this approach to overdose prevention in the community setting. PMID:25564892

  17. Pharmacy-based statewide naloxone distribution: A novel "top-down, bottom-up" approach.

    PubMed

    Morton, Kate J; Harrand, Brianna; Floyd, Carly Cloud; Schaefer, Craig; Acosta, Julie; Logan, Bridget Claire; Clark, Karen

    To highlight New Mexico's multifaceted approach to widespread pharmacy naloxone distribution and to share the interventions as a tool for improving pharmacy-based naloxone practices in other states. New Mexico had the second highest drug overdose death rate in 2014 of which 53% were related to prescription opioids. Opioid overdose death is preventable through the use of naloxone, a safe and effective medication that reverses the effects of prescription opioids and heroin. Pharmacists can play an important role in providing naloxone to individuals who use prescription opioids. Not applicable. Not applicable. A multifaceted approach was utilized in New Mexico from the top down with legislative passage of provisions for a statewide standing order and New Mexico Department of Health support for pharmacy-based naloxone delivery. A bottom up approach was also initiated with the development and implementation of a training program for pharmacists and pharmacy technicians. Naloxone Medicaid claims were used to illustrate statewide distribution and utilization of the pharmacist statewide standing order for naloxone. Percent of pharmacies dispensing naloxone in each county were calculated. Trained pharmacy staff completed a program evaluation form. Questions about quality of instruction and ability of trainer to meet stated objectives were rated on a Likert scale. There were 808 naloxone Medicaid claims from 100 outpatient pharmacies during the first half of 2016, a 9-fold increase over 2014. The "A Dose of R x eality" training program evaluation indicated that participants felt the training was free from bias and met all stated objectives (4 out of 4 on Likert scale). A multi-pronged approach coupling state and community collaboration was successful in overcoming barriers and challenges associated with pharmacy naloxone distribution and ensured its success as an effective avenue for naloxone acquisition in urban and rural communities. Copyright © 2017 American Pharmacists

  18. What is known about community pharmacy supply of naloxone? A scoping review.

    PubMed

    Nielsen, Suzanne; Van Hout, Marie Claire

    2016-06-01

    There is growing evidence that expanded supply of take-home naloxone to prevent opioid overdose deaths is needed. Potential routes for expansion of naloxone provision include through community pharmacies. The aim of this scoping review is to establish what is known about community pharmacy supply of naloxone, in light of unique challenges and opportunities present in pharmacy settings. A scoping review methodology was employed using the six stage iterative process advocated by Arksey and O'Malley (2005) and Levac et al. (2010). Searches used key words and terms such as 'naloxone'; 'overdose prevention/drug overdose/opiate overdose'; 'community/retail pharmacy'; 'pharmacist/pharmacy/community pharmacy/pharmaceutical services'; 'professional practice/role'; 'community care'; attitude of health personnel'; 'training/supply/cost'. Appropriate search terms were selected for each database. After initial exploratory searches, comprehensive searches were conducted with Cochrane Database of Systematic Reviews, Medline, Medline in Process, Embase, PsycINFO and CINAHL. Eligibility criteria centered on whether studies broadly described supply of naloxone in community pharmacy or had content relating to community pharmacy supply. The search identified 95 articles, of which 16 were related to pharmacy supply of naloxone. Five themes were presented after initial review of the data and consultation with the project Expert Group, and are; 'Pharmacists Perceptions of Naloxone: Facilitators and Barriers', 'Patient Populations: Identification and Recruitment', 'Supply Systems and Cost', 'Legal Issues', and 'Training of Pharmacists and Community Pharmacy Naloxone Recipients'. Findings from this scoping review suggest that community pharmacy based supply of take-home naloxone warrants the community pharmacy based route for distribution of take home naloxone provision warrants further consideration and development. Existing strengths include a range of established supply models, and

  19. Low-energy Bluetooth for detecting real-world penetrance of bystander naloxone kits: a pilot study.

    PubMed

    Lai, Jeffrey T; Chapman, Brittany P; Boyle, Katherine L; Boyer, Edward W; Chai, Peter R

    2018-01-03

    Opioid overdose is a growing public health emergency in the United States. The antidote naloxone must be administered rapidly after opioid overdose to prevent death. Bystander or "take-home" naloxone programs distribute naloxone to opioid users and other community members to increase naloxone availability at the time of overdose. However, data describing the natural history of take-home naloxone in the hands of at-risk individuals is lacking. To understand patterns of naloxone uptake in at-risk users, we developed a smart naloxone kit that uses low-energy Bluetooth (BLE) to unobtrusively detect the transit of naloxone through a hospital campus. In this paper, we describe development of the smart naloxone kit and results from the first 10 participants in our pilot study.

  20. Do heroin overdose patients require observation after receiving naloxone?

    PubMed

    Willman, Michael W; Liss, David B; Schwarz, Evan S; Mullins, Michael E

    2017-02-01

    Heroin use in the US has exploded in recent years, and heroin overdoses requiring naloxone are very common. After awakening, some heroin users refuse further treatment or transport to the hospital. These patients may be at risk for recurrent respiratory depression or pulmonary edema. In those transported to the emergency department, the duration of the observation period is controversial. Additionally, non-medical first responders and lay bystanders can administer naloxone for heroin and opioid overdoses. There are concerns about the outcomes and safety of this practice as well. To search the medical literature related to the following questions: (1) What are the medical risks to a heroin user who refuses ambulance transport after naloxone? (2) If the heroin user is treated in the emergency department with naloxone, how long must they be observed prior to discharge? (3) How effective in heroin users is naloxone administered by first responders and bystanders? Are there risks associated with naloxone distribution programs? We searched PubMed and GoogleScholar with search terms related to each of the questions listed above. The search was limited to English language and excluded patents and citations. The search was last updated on September 31, 2016. The articles found were reviewed for relevance to our objective questions. Eight out of 1020 citations were relevant to the first 2 questions, 5 of 707 were relevant to the third question and 15 of 287 were relevant to the fourth question. In the prehospital environment, does a heroin user revived with naloxone always require ambulance transport and what are the medical risks if ambulance transport is refused after naloxone? The eight articles were all observational studies done either prospectively or retrospectively. Two studies focused on heroin overdoses and included 1069 patients not transported to the hospital. No deaths occurred in this group. In counting the patients from all eight studies, some of which

  1. Predictors of Delayed Postoperative Respiratory Depression Assessed From Naloxone Administration

    PubMed Central

    Weingarten, Toby N.; Herasevich, Vitaly; McGlinch, Maria C.; Beatty, Nicole C.; Christensen, Erin D.; Hannifan, Susan K.; Koenig, Amy E.; Klanke, Justin; Zhu, Xun; Gali, Bhargavi; Schroeder, Darrell R.; Sprung, Juraj

    2015-01-01

    Background To identify patient and procedural characteristics associated with postoperative respiratory depression or sedation that required naloxone intervention. Methods We identified patients who received naloxone to reverse opioid-induced respiratory depression or sedation within 48 hours after discharge from anesthetic care (transfer from the post anesthesia care unit, or transfer from the operating room to postoperative areas) between July 1, 2008 and June 30, 2010. Patients were matched to two controls based on age, sex, and exact type of procedure performed during the same year. A chart review was performed to identify patient, anesthetic and surgical factors that may be associated with risk for intervention requiring naloxone. In addition, we identified all patients who developed adverse respiratory events [hypoventilation, apnea, oxyhemoglobin desaturation, pain/sedation mismatch] during Phase I anesthesia recovery. We performed conditional logistic regression taking into account the 1:2 matched set case-control study design to assess patient and procedural characteristics associated with naloxone use. Results We identified 134 naloxone administrations, 58% within 12 hours of discharge from anesthesia care, with incidence of 1.6 per 1,000 (95% CI 1.3 – 1.9) anesthetics. Presence of obstructive sleep apnea (odds ratio = 2.45, 95%CI 1.27-4.66, P = 0.008), and diagnosis of adverse respiratory event in postanesthesia recovery room (odds ratio = 5.11, 95%CI 2.32-11.27, P < 0.001) were associated with increased risk for requiring naloxone to treat respiratory depression or sedation following discharge from anesthesia care. Following discharge from anesthesia care, patients administered naloxone used a greater median dose of opioids (10 [interquartile range 0, 47.1] vs. 5 [0, 24.8] intravenous morphine equivalents, P = 0.020) and more medications with sedating side effects (N = 41 [31%] vs. 24 [9%], P<0.001). Conclusion Obstructive sleep apnea and adverse

  2. Opioid Overdose Prevention Programs Providing Naloxone to Laypersons - United States, 2014.

    PubMed

    Wheeler, Eliza; Jones, T Stephen; Gilbert, Michael K; Davidson, Peter J

    2015-06-19

    Drug overdose deaths in the United States have more than doubled since 1999. During 2013, 43,982 drug overdose deaths (unintentional, intentional [suicide or homicide], or undetermined intent) were reported. Among these, 16,235 (37%) were associated with prescription opioid analgesics (e.g., oxycodone and hydrocodone) and 8,257 (19%) with heroin. For many years, community-based programs have offered opioid overdose prevention services to laypersons who might witness an overdose, including persons who use drugs, their families and friends, and service providers. Since 1996, an increasing number of programs provide laypersons with training and kits containing the opioid antagonist naloxone hydrochloride (naloxone) to reverse the potentially fatal respiratory depression caused by heroin and other opioids. In July 2014, the Harm Reduction Coalition (HRC), a national advocacy and capacity-building organization, surveyed 140 managers of organizations in the United States known to provide naloxone kits to laypersons. Managers at 136 organizations completed the survey, reporting on the amount of naloxone distributed, overdose reversals by bystanders, and other program data for 644 sites that were providing naloxone kits to laypersons as of June 2014. From 1996 through June 2014, surveyed organizations provided naloxone kits to 152,283 laypersons and received reports of 26,463 overdose reversals. Providing opioid overdose training and naloxone kits to laypersons who might witness an opioid overdose can help reduce opioid overdose mortality.

  3. Engaging Law Enforcement in Overdose Reversal Initiatives: Authorization and Liability for Naloxone Administration

    PubMed Central

    Carr, Derek; Southwell, Jessica K.; Beletsky, Leo

    2015-01-01

    Opioid overdose is reversible through the timely administration of naloxone, which has been used by emergency medical services for decades. Law enforcement officers (LEOs) are often the first emergency responders to arrive at an overdose, but they are not typically equipped with naloxone. This is rapidly changing; more than 220 law enforcement agencies in 24 states now carry naloxone. However, rollout in some departments has been hampered by concerns regarding officer and agency liability. We systematically examined the legal risk associated with LEO naloxone administration. LEOs can be authorized to administer naloxone through a variety of mechanisms, and liability risks related to naloxone administration are similar to or lower than those of other activities in which LEOs commonly engage. PMID:26066921

  4. One-on-one care management and procurement of Naloxone for ambulatory use.

    PubMed

    Whittington, Richard; Whittington, Kathleen; Whittington, John; Porter, Joel; Zimmermann, Karla; Case, Holly; Berg, Stacey

    2018-02-16

    Morbidity and mortality from prescription opioids has reached unprecedented levels. Opioids remain part of chronic pain treatment in primary care. This study was designed to determine whether one-on-one care management increases procurement of Naloxone, an opioid antagonist shown to reduce morbidity and mortality in opioid overdoses. Participants included all patients ≥18 years enrolled in a primary care-based chronic pain management program and who were prescribed a daily dose of opioids for treatment of chronic pain. In total, 153 patients chose to participate. Each had a 1 h one-on-one education meeting with a registered nurse. Among the enrolled, eight patients (5.2%) had procured Naloxone prior to intervention. Overall, 31 additional patients (20.2%) procured Naloxone after intervention, a 288% relative improvement in the attainment of Naloxone (P < 0.0001) (χ2 = 29.032 with 1 degree freedom). Of the 114 participants who never procured Naloxone, 69.3% believed it was unnecessary, 20% forgot about Naloxone, 8% said it was cost prohibitive, 3.5% had access concerns and 0.9% had concerns about side effects. Direct one-on-one nurse care management sessions were associated with an increased procurement of Naloxone in a primary care-based pain management program. A significant number of patients believed Naloxone was unnecessary after the intervention.

  5. Use of Naloxone by Emergency Medical Services During Opioid Drug Overdose Resuscitation Efforts

    PubMed Central

    Sumner, Steven Allan; Mercado-Crespo, Melissa C.; Spelke, M. Bridget; Paulozzi, Leonard; Sugerman, David E.; Hillis, Susan D.; Stanley, Christina

    2015-01-01

    Naloxone administration is an important component of resuscitation attempts by emergency medical services (EMS) for opioid drug overdoses. However, EMS providers must first recognize the possibility of opioid overdose in clinical encounters. As part of a public health response to an outbreak of opioid overdoses in Rhode Island, we examined missed opportunities for naloxone administration and factors potentially influencing EMS providers’ decision to administer naloxone. We reviewed medical examiner files on all individuals who died of an opioid-related drug overdose in Rhode Island from January 1, 2012 through March 31, 2014, underwent attempted resuscitation by EMS providers, and had records available to assess for naloxone administration. We evaluated whether these individuals received naloxone as part of their resuscitation efforts and compared patient and scene characteristics of those who received naloxone to those who did not receive naloxone via chi-square, t-test, and logistic regression analyses. One hundred and twenty-four individuals who underwent attempted EMS resuscitation died due to opioid overdose. Naloxone was administered during EMS resuscitation attempts in 82 (66.1%) of cases. Females were nearly three-fold as likely not to receive naloxone as males (OR 2.9; 95% CI 1.2–7.0; p-value 0.02). Additionally, patients without signs of potential drug abuse also had a greater than three-fold odds of not receiving nalox-one (OR 3.3; 95% CI 1.2–9.2; p-value 0.02). Older individuals, particularly those over age 50, were more likely not to receive naloxone than victims younger than age 30 (OR 4.8; 95% CI 1.3–17.4; p-value 0.02). Women, older individuals, and those patients without clear signs of illicit drug abuse, were less likely to receive naloxone in EMS resuscitation attempts. Heightened clinical suspicion for opioid overdose is important given the recent increase in overdoses among patients due to prescription opioids. PMID:26383533

  6. Ultra-low dose (+)-naloxone restores the thermal threshold of morphine tolerant rats.

    PubMed

    Chou, Kuang-Yi; Tsai, Ru-Yin; Tsai, Wei-Yuan; Wu, Ching-Tang; Yeh, Chun-Chang; Cherng, Chen-Hwan; Wong, Chih-Shung

    2013-12-01

    As known, long-term morphine infusion leads to tolerance. We previously demonstrated that both co-infusion and post-administration of ultra-low dose (±)-naloxone restores the antinociceptive effect of morphine in morphine-tolerant rats. However, whether the mechanism of the action of ultra-low dose (±)-naloxone is through opioid receptors or not. Therefore, in the present study, we further investigated the effect of ultra-low dose (+)-naloxone, it does not bind to opioid receptors, on the antinociceptive effect of morphine. Male Wistar rats were implanted with one or two intrathecal (i.t.) catheters; one catheter was connected to a mini-osmotic pump, used for morphine (15 μg/h), ultra-low dose (+)-naloxone (15 pg/h), morphine plus ultra-low dose (+)-naloxone (15 pg/h) or saline (1 μl/h) infusion for 5 days. On day 5, either ultra-low dose (+)-naloxone (15 pg) or saline (5 μl) was injected via the other catheter immediately after discontinued morphine or saline infusion. Three hours later, morphine (15 μg in 5 μl saline) or saline were given intrathecally. All rats received nociceptive tail-flick test every 30 minutes for 120 minutes after morphine challenge at different temperature (45-52°C, respective). Our results showed that, both co-infusion and post-treatment of ultra-low dose (+)-naloxone with morphine preserves the antinociceptive effect of morphine. Moreover, in the post administration rats, ultra-low dose (+)-naloxone further enhances the antinociceptive effect of morphine. This study provides an evidence for ultra-low dose (+)-naloxone as a therapeutic adjuvant for patients who need long-term opioid administration for pain management. Copyright © 2013. Published by Elsevier B.V.

  7. Naloxone attenuates the conditioned place preference induced by wheel running in rats.

    PubMed

    Lett, B T; Grant, V L; Koh, M T

    2001-02-01

    Pairings, during which an episode of wheel running is followed by confinement in a distinctive place, produce conditioned place preference (CPP) in rats. This finding indicates that wheel running has a rewarding effect that outlasts the activity itself. In two similar experiments, we tested the hypothesis that this rewarding effect of wheel running is mediated by endogenous opioids. During a paired trial, the rats in the naloxone group were first allowed to wheel run for 2 h, then injected with naloxone (0.5 or 0.1 mg/kg in Experiments 1 and 2, respectively), and 10 min later placed in a distinctive chamber. During an unpaired trial, these rats were confined in an adjoining chamber without wheel running. Naloxone was injected before placement in both chambers, so that if naloxone-induced conditioned place aversion occurred, it would have counteracting effects on performance during the preference test. The rats in the saline group were similarly treated, except that saline was injected instead of naloxone. CPP occurred in the saline group, but not in the naloxone group. Thus, naloxone attenuated the CPP induced by wheel running. This finding supports the hypothesis that the rewarding effect of wheel running is mediated by endogenous opioids.

  8. Comparison of exercise, dobutamine-atropine and dipyridamole-atropine stress echocardiography in detecting coronary artery disease

    PubMed Central

    Nedeljkovic, Ivana; Ostojic, Miodrag; Beleslin, Branko; Djordjevic-Dikic, Ana; Stepanovic, Jelena; Nedeljkovic, Milan; Stojkovic, Sinisa; Stankovic, Goran; Saponjski, Jovica; Petrasinovic, Zorica; Giga, Vojislav; Mitrovic, Predrag

    2006-01-01

    Background Dipyridamole and dobutamine stress echocardiography testing are most widely utilized, but their sensitivity remained suboptimal in comparison to routine exercise stress echocardiography. The aim of our study is to compare, head-to-head, exercise, dobutamine and dipyridamole stress echocardiography tests, performed with state-of-the-art protocols in a large scale prospective group of patients. Methods Dipyridamole-atropine (Dipatro: 0.84 mg/kg over 10 min i.v. dipyridamole with addition of up to 1 mg of atropine), dobutamine-atropine (Dobatro: up to 40 mcg/kg/min i.v. dobutamine with addition of up to 1 mg of atropine) and exercise (Ex, Bruce) were performed in 166 pts. Of them, 117 pts without resting wall motion abnormalities were enrolled in study (91 male; mean age 54 ± 10 years; previous non-transmural myocardial infarction in 32 pts, angina pectoris in 69 pts and atypical chest pain in 16 pts). Tests were performed in random sequence, in 3 different days, within 5 day period under identical therapy. All patients underwent coronary angiography. Results Significant coronary artery disease (CAD; ≥50% diameter stenosis) was present in 69 pts (57 pts 1-vessel CAD, 12 multivessel CAD) and absent in 48 pts. Sensitivity (Sn) was 96%, 93% and 90%, whereas specificity (Sp) was 92%, 92% and 87% for Dobatro, Dipatro and Ex, respectively (p = ns). Concomitant beta blocker therapy did not influence peak rate-pressure product and Sn of Dobatro and Dipatro (p = ns). Conclusion When state-of-the-art protocols are used, dipyridamole and dobutamine stress echocardiography have comparable and high diagnostic accuracy, similar to maximal post-exercise treadmill stress echocardiography. PMID:16672046

  9. Comparison of exercise, dobutamine-atropine and dipyridamole-atropine stress echocardiography in detecting coronary artery disease.

    PubMed

    Nedeljkovic, Ivana; Ostojic, Miodrag; Beleslin, Branko; Djordjevic-Dikic, Ana; Stepanovic, Jelena; Nedeljkovic, Milan; Stojkovic, Sinisa; Stankovic, Goran; Saponjski, Jovica; Petrasinovic, Zorica; Giga, Vojislav; Mitrovic, Predrag

    2006-05-03

    Dipyridamole and dobutamine stress echocardiography testing are most widely utilized, but their sensitivity remained suboptimal in comparison to routine exercise stress echocardiography. The aim of our study is to compare, head-to-head, exercise, dobutamine and dipyridamole stress echocardiography tests, performed with state-of-the-art protocols in a large scale prospective group of patients. Dipyridamole-atropine (Dipatro: 0.84 mg/kg over 10 min i.v. dipyridamole with addition of up to 1 mg of atropine), dobutamine-atropine (Dobatro: up to 40 mcg/kg/min i.v. dobutamine with addition of up to 1 mg of atropine) and exercise (Ex, Bruce) were performed in 166 pts. Of them, 117 pts without resting wall motion abnormalities were enrolled in study (91 male; mean age 54 +/- 10 years; previous non-transmural myocardial infarction in 32 pts, angina pectoris in 69 pts and atypical chest pain in 16 pts). Tests were performed in random sequence, in 3 different days, within 5 day period under identical therapy. All patients underwent coronary angiography. Significant coronary artery disease (CAD; > or =50% diameter stenosis) was present in 69 pts (57 pts 1-vessel CAD, 12 multivessel CAD) and absent in 48 pts. Sensitivity (Sn) was 96%, 93% and 90%, whereas specificity (Sp) was 92%, 92% and 87% for Dobatro, Dipatro and Ex, respectively (p = ns). Concomitant beta blocker therapy did not influence peak rate-pressure product and Sn of Dobatro and Dipatro (p = ns). When state-of-the-art protocols are used, dipyridamole and dobutamine stress echocardiography have comparable and high diagnostic accuracy, similar to maximal post-exercise treadmill stress echocardiography.

  10. Expanding access to naloxone for family members: The Massachusetts experience.

    PubMed

    Bagley, Sarah M; Forman, Leah S; Ruiz, Sarah; Cranston, Kevin; Walley, Alexander Y

    2018-05-01

    The Massachusetts Department of Public Health Overdose Education and Naloxone Distribution Program provides overdose education and naloxone rescue kits to people at risk for overdose and bystanders, including family members. Using Massachusetts Department of Public Health data, the aims are to: (i) describe characteristics of family members who receive naloxone; (ii) identify where family members obtain naloxone; and (iii) describe characteristics of rescues by family members. We conducted a retrospective review using program enrollee information collected on a standardised form between 2008 and 2015. We calculated descriptive statistics, including demographics, current substance use, enrolment location, history of witnessed overdoses and rescue attempt characteristics. We conducted a stratified analysis comparing family members who used drugs with those who did not. Family members were 27% of total program enrollees (n = 10 883/40 801). Family members who reported substance use (n = 4679) were 35.6 years (mean), 50.6% female, 76.3% non-Hispanic white, 75.6% had witnessed an overdose, and they obtained naloxone most frequently at HIV prevention programs. Family members who did not report substance use (n = 6148) were 49.2 years (mean), 73.8% female, 87.9% non-Hispanic white, 35.3% had witnessed an overdose, and they obtained naloxone most frequently at community meetings. Family members were responsible for 20% (n = 860/4373) of the total rescue attempts. The Massachusetts experience demonstrates that family members can be active participants in responding to the overdose epidemic by rescuing family members and others. Targeted intervention strategies for families should be included in efforts to expand overdose education and naloxone in Massachusetts. © 2017 Australasian Professional Society on Alcohol and other Drugs.

  11. Experience of low-dose aminophylline use to relieve minor adverse effects of dipyridamole in patients undergoing stress myocardial perfusion imaging.

    PubMed

    Lin, Li-Fan; Cheng, Cheng-Yi; Hou, Cheng-Han; Ku, Chih-Hung; Tseng, Neng-Chuan; Shen, Daniel H Y

    2014-06-01

    Intravenous administration of aminophylline is widely adopted to reverse dipyridamole-related adverse effects (AEs) during stress myocardial perfusion imaging (MPI). The study aimed to investigate the efficacy of lower-dose aminophylline to relieve minor AEs. 2,250 consecutive patients undergoing dipyridamole-stressed MPI were enrolled. Information concerning AE occurrence and dosages of aminophylline was collected to evaluate the efficacy of lower-dose aminophylline. A logistic regression was used to determine independent predictors of dipyridamole-related AE occurrence. No severe AE was noted. Overall mild AE incidence was 37.0% (833/2,250 patients). Initial low-dose (25 mg) aminophylline relieved symptoms in 98.8% of patients with mild AEs (823/833 patients). An extra 25 mg aminophylline sufficed to reverse all such AEs. Mean body mass index (BMI) differed significantly between patients with and without any AE [25.6 vs 25.1 (P = .009)]. There was no significant difference between two subgroups in mean age, male gender prevalence, body height and weight, dipyridamole dose/BMI, or prevalence of significant perfusion defect(s) on MPI. Multivariable logistic regression demonstrated BMI remained the independent predictor of dipyridamole-related AE occurrence (odds ratio 1.028, 95% confidence interval 1.007-1.049, P = .01). Low-dose (≦50 mg, and usually 25 mg) aminophylline seems sufficient to relieve mild dipyridamole-related AEs during stress MPI.

  12. Pharmacists' role in opioid overdose: Kentucky pharmacists' willingness to participate in naloxone dispensing.

    PubMed

    Freeman, Patricia R; Goodin, Amie; Troske, SuZanne; Strahl, Audra; Fallin, Amanda; Green, Traci C

    To assess pharmacists' willingness to initiate the dispensing of naloxone. As of 2015, Kentucky law permits certified pharmacists to dispense naloxone under a physician-approved protocol. Electronic survey (e-mail) gauging perception of pharmacists' role in opioid overdose and attitudes toward, and barriers to, naloxone dispensing. All Kentucky pharmacists with active licenses in 2015. Ordinal logistic regression was used to estimate the impact of pharmacist characteristics and attitudes on willingness to initiate naloxone dispensing, where the dependent variable was operationalized as a Likert-type question on a scale of 1 (not at all willing) to 6 (very willing). Of 4699 practicing Kentucky pharmacists, 1282 responded, of which 834 were community practitioners (response rate 27.3%). Pharmacists reported varying willingness to initiate naloxone dispensing, with 37.3% very willing (score 5 or 6) and 27.9% not willing (score 1 or 2). However, a majority of pharmacists reported willingness to dispense naloxone with a valid prescription (54.0%, score 5 or 6). Women pharmacists were 1.3 times more likely than men to be willing to initiate naloxone dispensing (95% confidence interval [CI] 1.0-1.6). Those who reported confidence in identifying individuals at risk for overdose were 1.2 times more likely to initiate dispensing, and those who reported confidence in ability to educate patients about overdose were 1.6 times more likely to express willingness to initiate naloxone dispensing (95% CIs, respectively, 1.0-1.3 and 1.4-1.8). Community pharmacists reported barriers to naloxone access at higher rates than pharmacists from other practice settings. Kentucky pharmacists are divided in their willingness to initiate naloxone dispensing; however, those who are confident in their ability to identify overdose risks are more willing. Increasing pharmacist confidence through appropriately designed education programs could facilitate pharmacist participation in naloxone

  13. Community-based opioid overdose prevention programs providing naloxone - United States, 2010.

    PubMed

    2012-02-17

    Drug overdose death rates have increased steadily in the United States since 1979. In 2008, a total of 36,450 drug overdose deaths (i.e., unintentional, intentional [suicide or homicide], or undetermined intent) were reported, with prescription opioid analgesics (e.g., oxycodone, hydrocodone, and methadone), cocaine, and heroin the drugs most commonly involved . Since the mid-1990s, community-based programs have offered opioid overdose prevention services to persons who use drugs, their families and friends, and service providers. Since 1996, an increasing number of these programs have provided the opioid antagonist naloxone hydrochloride, the treatment of choice to reverse the potentially fatal respiratory depression caused by overdose of heroin and other opioids. Naloxone has no effect on non-opioid overdoses (e.g., cocaine, benzodiazepines, or alcohol) . In October 2010, the Harm Reduction Coalition, a national advocacy and capacity-building organization, surveyed 50 programs known to distribute naloxone in the United States, to collect data on local program locations, naloxone distribution, and overdose reversals. This report summarizes the findings for the 48 programs that completed the survey and the 188 local programs represented by the responses. Since the first opioid overdose prevention program began distributing naloxone in 1996, the respondent programs reported training and distributing naloxone to 53,032 persons and receiving reports of 10,171 overdose reversals. Providing opioid overdose education and naloxone to persons who use drugs and to persons who might be present at an opioid overdose can help reduce opioid overdose mortality, a rapidly growing public health concern.

  14. Lack of effect of naloxone on prolactin and seizures in electroconvulsive therapy.

    PubMed

    Sperling, M R; Melmed, S; McAllister, T; Price, T R

    1989-01-01

    Both opiate agonist and antagonist injection have been reported to modulate prolactin secretion, alter brain excitability and produce seizures, and modify the postictal state. We studied the effects of administration of high-dose naloxone, an opiate antagonist, on postictal prolactin levels, seizure duration, and postictal behavior, using patients undergoing electroconvulsive therapy (ECT) as a seizure model. Seven patients had 8 mg naloxone injected prior to one ECT treatment and saline injected prior to another treatment, with the order of injection randomized. Before ECT and 15 min after ECT, prolactin levels were drawn, and no blunting of the expected postictal prolactin elevation by naloxone injection was observed. We found no evidence that endogenous opiates trigger prolactin secretion during seizures. Seizure duration was also similar in saline and naloxone groups, and naloxone did not reverse postictal depression, as has been reported in an animal model.

  15. A content review of online naloxone Continuing Education courses for pharmacists in states with standing orders.

    PubMed

    Carpenter, Delesha M; Roberts, Courtney A; Westrick, Salisa C; Ferreri, Stefanie P; Kennelty, Korey A; Look, Kevin A; Abraham, Olufunmilola; Wilson, Courtenay

    2017-11-21

    Many community pharmacists are uncomfortable educating patients about naloxone, an opioid reversal agent. To examine whether training materials prepare pharmacists to counsel patients and caregivers about naloxone, online naloxone education materials for pharmacists in the 13 states with standing orders were analyzed. Two coders reviewed 12 naloxone training programs and extracted data for 15 topics that were clustered in four categories: background/importance, naloxone products, business/operations, and communication. Programs that included communication content were coded for whether they: 1) suggested specific verbiage for naloxone counseling; 2) recommended evidence-based communication practices; and 3) included example naloxone conversations. Most programs covered the majority of topics, with the exception of extended treatment for individuals who overdose and naloxone storage/expiration information. Eleven programs addressed pharmacist-patient communication, although information on communication was often limited. Only one program included an example pharmacist-patient naloxone conversation, but the conversation was 10 min long and occurred in a private room, limiting its applicability to most community pharmacies. Online naloxone training materials for pharmacists include limited content on how to communicate with patients and caregivers. Training materials that include more in-depth content on communication may increase pharmacists' confidence to discuss the topics of overdose and naloxone. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Opiate users' knowledge about overdose prevention and naloxone in New York City: a focus group study

    PubMed Central

    Worthington, Nancy; Markham Piper, Tinka; Galea, Sandro; Rosenthal, David

    2006-01-01

    Background Drug-induced and drug-related deaths have been increasing for the past decade throughout the US. In NYC, drug overdose accounts for nearly 900 deaths per year, a figure that exceeds the number of deaths each year from homicide. Naloxone, a highly effective opiate antagonist, has for decades been used by doctors and paramedics during emergency resuscitation after an opiate overdose. Following the lead of programs in Europe and the US who have successfully distributed take-home naloxone, the Overdose Prevention and Reversal Program at the Lower East Side Harm Reduction Center (LESHRC) has started providing a similar resource for opiate users in NYC. Participants in the program receive a prescription for two doses of naloxone, with refills as needed, and comprehensive training to reduce overdose risk, administer naloxone, perform rescue breathing, and call 911. As of September 2005, 204 participants have received naloxone and been trained, and 40 have revived an overdosing friend or family member. While naloxone accessibility stands as a proven life-saving measure, some opiates users at LESHRC have expressed only minimal interest in naloxone use, due to past experiences and common misconceptions. Methods In order to improve the naloxone distribution program two focus groups were conducted in December 2004 with 13 opiate users at LESHRC to examine knowledge about overdose and overdose prevention. The focus groups assessed participants' (i) experiences with overdose response, specifically naloxone (ii) understanding and perceptions of naloxone, (iii) comfort level with naloxone administration and (iv) feedback about increasing the visibility and desirability of the naloxone distribution program. Results Analyses suggest that there is both support for and resistance to take-home naloxone, marked by enthusiasm for its potential role in reviving an overdosing individual, numerous misconceptions and negative views of its impact and use. Conclusion Focus group

  17. Interactions among aging, gender, and gonadectomy effects upon naloxone hypophagia in rats.

    PubMed

    Islam, A K; Beczkowska, I W; Bodnar, R J

    1993-11-01

    The present study examined the dose-dependent (0.25-5 mg/kg) effects of systemic naloxone upon deprivation-induced intake and high-fat intake as functions of age (4, 8, 14, and 20 months), gender, and gonadectomy in rats. Significant increases in body weight were observed as functions of age and gonadectomy. Whereas aging significantly reduced basal deprivation-induced intake, it generally failed to alter basal high-fat intake. Whereas age, gender, and gonadectomy failed to alter the decreases in deprivation-induced intake following low (0.25-2.5 mg/kg) naloxone doses, sham males displayed significantly greater age-related and gender-related inhibition following the 5 mg/kg dose of naloxone. Young gonadectomized rats displayed significant increases in naloxone's inhibition of deprivation-induced intake as well. More dramatic changes occurred in naloxone's inhibition of high-fat intake. Naloxone's potency increased in sham female rats as a function of age, and decreased in sham males and ovariectomized females as a function of age. Whereas sham males and ovariectomized females were most sensitive to naloxone's inhibition of high-fat intake at young ages, sham females were most sensitive at older ages. These data indicate that effects of age, gender, and gonadectomy upon naloxone-induced hypophagia dissociate as a function of the type of intake. Because selective opioid antagonist studies demonstrate that deprivation-induced intake is mediated by the mu1 receptor and high-fat intake is mediated by kappa and mu2 receptors, it is postulated that the differential effects of aging, gender, and gonadectomy variables upon opioid mediation of the two forms of intake may reflect their interaction with different opioid receptor subtypes.

  18. Naloxone-induced seizures in rats infected with Borna disease virus.

    PubMed

    Solbrig, M V; Koob, G F; Lipkin, W I

    1996-04-01

    The opioid antagonist naloxone is widely used in the emergency treatment of nontraumatic coma. Although it is uncommon for serious side effects to result from administration of opiate antagonists, we report that naloxone can have epileptogenic effects in the context of encephalitis. In an experimental model of viral encephalitis, rats infected with Borna disease virus developed myoclonic, generalized clonic, or atonic seizures; behavior arrest; and staring spells when treated with naloxone. These findings suggest a novel neuropharmacologic link, through opioid peptide systems, between epilepsy and encephalitis and disclose a potential contraindication to use of opioid antagonists in nontraumatic coma.

  19. Effect of surfactants, gastric emptying, and dosage form on supersaturation of dipyridamole in an in vitro model simulating the stomach and duodenum.

    PubMed

    Mitra, A; Fadda, H M

    2014-08-04

    The purpose of this study was to investigate the influence of gastric emptying patterns, surfactants, and dosage form on the supersaturation of a poorly soluble weakly basic drug, dipyridamole, using an in vitro model mimicking the dynamic environment of the upper gastrointestinal tract, and, furthermore, to evaluate the usefulness of this model in establishing correlations to in vivo bioavailability for drugs with solubility/dissolution limited absorption. A simulated stomach duodenum model comprising four compartments was used to assess supersaturation and precipitation kinetics as a function of time. It integrates physiologically relevant fluid volumes, fluid transfer rates, and pH changes of the upper GI tract. Monoexponential gastric emptying patterns simulating the fasted state were compared to linear gastric emptying patterns simulating the fed state. The effect of different surfactants commonly used in oral preparations, specifically, sodium lauryl sulfate (SLS), poloxamer-188, and polysorbate-80, on dipyridamole supersaturation was investigated while maintaining surface tension of the simulated gastric fluids at physiological levels and without obtaining artificial micellar solubilization of the drug. The supersaturation behavior of different dose strengths of dipyridamole was explored. Significant levels of dipyridamole supersaturation were observed in the duodenal compartment under all the different in vivo relevant conditions explored. Dipyridamole supersaturation ratios of up to 11-fold have been observed, and supersaturation has been maintained for up to 120 min. Lower duodenal concentrations of dipyridamole were observed under linear gastric emptying patterns compared to mononexponential gastric emptying. The mean duodenal area under concentration-time curves (AUC60min) for the dipyridamole concentration profile in the duodenal compartment is significantly different for all the surfactants explored (P < 0.05). Our investigations with the different

  20. An Innovative Model for Naloxone Use Within an OTP Setting: A Prospective Cohort Study

    PubMed Central

    Katzman, Joanna G.; Takeda, Mikiko Y.; Bhatt, Snehal R.; Moya Balasch, Monica; Greenberg, Nina; Yonas, Howard

    2018-01-01

    Objectives: Unintentional opioid overdose deaths are a public health crisis, and naloxone is the most effective harm reduction tool to curb many of these deaths. There is growing evidence that take-home naloxone can prevent opioid overdose in targeted populations. The goal of this study is to measure the opioid overdose reversal rate with take-home naloxone among participants with a diagnosis of opioid use disorder (OUD) in an opioid treatment program (OTP) setting. Methods: Patients enrolled in an outpatient OTP program were eligible for this prospective cohort study between April 4, 2016 and July 4, 2016. Two hundred forty-four study participants received overdose education, instruction on how to use naloxone, and were provided with 2 doses of a take-home naloxone auto-injector kit. They were subsequently followed for 3 months. Results: Thirty-one study participants reported overdose reversals using naloxone auto-injector kits on 38 community members. All overdose reversals were heroin-related. Eighty-seven per cent of the community members reversed with naloxone were friends or relatives of the study participants. Conclusions: This study validates that naloxone is not commonly used on the index study participant, but is often used on a secondary target among people who inject drugs. The large number of overdose reversals reported in this prospective study suggests that this novel model for naloxone use may be replicated at other OTP settings to reduce opioid overdose deaths. PMID:29227321

  1. Pharmacokinetics and -dynamics of intramuscular and intranasal naloxone: an explorative study in healthy volunteers.

    PubMed

    Skulberg, Arne Kristian; Tylleskar, Ida; Nilsen, Turid; Skarra, Sissel; Salvesen, Øyvind; Sand, Trond; Loftsson, Thorsteinn; Dale, Ola

    2018-03-22

    This study aimed to develop a model for pharmacodynamic and pharmacokinetic studies of naloxone antagonism under steady-state opioid agonism and to compare a high-concentration/low-volume intranasal naloxone formulation 8 mg/ml to intramuscular 0.8 mg. Two-way crossover in 12 healthy volunteers receiving naloxone while receiving remifentanil by a target-controlled infusion for 102 min. The group were subdivided into three different doses of remifentanil. Blood samples for serum naloxone concentrations, pupillometry and heat pain threshold were measured. The relative bioavailability of intranasal to intramuscular naloxone was 0.75. Pupillometry showed difference in antagonism; the effect was significant in the data set as a whole (p < 0.001) and in all three subgroups (p < 0.02-p < 0.001). Heat pain threshold showed no statistical difference. A target-controlled infusion of remifentanil provides good conditions for studying the pharmacodynamics of naloxone, and pupillometry was a better modality than heat pain threshold. Intranasal naloxone 0.8 mg is inferior for a similar dose intramuscular. Our design may help to bridge the gap between studies in healthy volunteers and the patient population in need of naloxone for opioid overdose. clinicaltrials.gov : NCT02307721.

  2. Prevention of hyperthermia-induced seizures in immature rats by a hydantoin derivative of naloxone.

    PubMed

    Chatterjie, N; Laorden, M L; Puig, M M; Alexander, G J

    1989-01-01

    The non-specific opiate antagonist naloxone protects immature rats from hyperthermic seizures which occur when the animals are exposed to an environment of 40 degrees C and 55% humidity. Most of the currently used antiepileptic therapeutic agents can be said to contain either a hydantoin or a moiety stereochemically closely related to one. We have added a hydantoin group to naloxone and created a new combined chemical, naloxyl-6-alpha spirohydantoin. The new compound was ten times as effective as naloxone against hyperthermic seizures in 15-day old rat pups. Unlike naloxone, the new naloxone-hydantoin derivative retained a protective effect 24 hrs after injection.

  3. Opioid overdose and naloxone education in a substance use disorder treatment program.

    PubMed

    Lott, David C; Rhodes, Jonathan

    2016-04-01

    Opioid users in treatment are at high risk of relapse and overdose, making them an important target for efforts to reduce opioid overdose mortality. Overdose Education (OE) is one such intervention, and this study tests the effectiveness of OE in a community substance use disorder treatment program. Opioid users were recruited from a community treatment center for the study. The Opioid Overdose Knowledge Scale (OOKS) was administered before and after an educational intervention (small group lecture, slideshow, and handout based on previously published content) to assess knowledge of the risks, signs, and actions associated with opioid overdose, including use of naloxone. Additional survey questions assessed naloxone access, naloxone education, and overdose experiences at treatment and 3-month follow-up. Subjects (n = 43) were 28% female and had a mean age of 31 years. OOKS scores were compared at pre-intervention, post-intervention, and follow-up, and results were also compared with a historical non-intervention control group (n = 14). Total score on the OOKS increased significantly from pre- to post-education, and improvement was maintained at follow-up (p < .0001). OOKS subdomains of actions and naloxone use also had significant increases (p < .0001). Four subjects reported possessing naloxone in the past, and only one subject who did not already have naloxone at the time of treatment had obtained it at follow-up. Education about opioid overdose and naloxone use in a community treatment program increases overdose knowledge, providing support for the idea of making OE a routine part of substance use disorder treatment. However, the rate of follow through on accessing naloxone was low with this education-only intervention. © 2016 The Authors. The American Journal on Addictions Published by American Academy of Addiction Psychiatry.

  4. Expanded access to naloxone among firefighters, police officers, and emergency medical technicians in Massachusetts.

    PubMed

    Davis, Corey S; Ruiz, Sarah; Glynn, Patrick; Picariello, Gerald; Walley, Alexander Y

    2014-08-01

    Naloxone is a medication that reverses respiratory depression from opioid overdose if given in time. Paramedics routinely administer naloxone to opioid overdose victims in the prehospital setting, and many states are moving to increase access to the medication. Several jurisdictions have expanded naloxone administration authority to nonparamedic first responders, and others are considering that step. We report here on policy change in Massachusetts, where several communities have equipped emergency medical technicians, law enforcement officers, and firefighters with naloxone.

  5. Changes of electrocardiogram and hemodynamics in response to dipyridamole: In vivo comparative analyses using anesthetized beagle dogs and microminipigs.

    PubMed

    Ando, Kentaro; Takahara, Akira; Nakamura, Yuji; Wada, Takeshi; Chiba, Koki; Goto, Ai; Lubna, Nur Jaharat; Hagiwara-Nagasawa, Mihoko; Izumi-Nakaseko, Hiroko; Hoshiai, Kiyotaka; Akie, Yasuki; Naito, Atsuhiko T; Sugiyama, Atsushi

    2018-02-01

    Microminipigs are expected as a novel animal model for cardiovascular pharmacological experiments. Since inherent vulnerability of coronary circulation of microminipigs has not been characterized, we performed dipyridamole-stress test to both microminipigs and beagle dogs, and compared the results. Dipyridamole in doses of 0.056 and 0.56 mg/kg were intravenously infused over 10 min (n = 4 for each animal). Dipyridamole decreased the systolic/diastolic blood pressures and double product in dogs as well as in microminipigs; but it did not significantly alter the heart rate or the global balance between the myocardial oxygen demand and supply in either animal. While organic coronary arterial stenosis was not detected in either animal, dogs have well-developed epicardial intracoronary networks unlike microminipigs. Like in humans, dipyridamole did not affect the ST segment of microminipigs, whereas it substantially depressed that in dogs. The results indicate the onset of subendocardial ischemia by dipyridamole in dogs may be partly associated with their well-developed native coronary collateral channels. Microminipigs would be more useful to evaluate the drugs which may affect the coronary circulation in the pre-clinical study than dogs. Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  6. Prehospital Naloxone Administration as a Public Health Surveillance Tool: A Retrospective Validation Study.

    PubMed

    Lindstrom, Heather A; Clemency, Brian M; Snyder, Ryan; Consiglio, Joseph D; May, Paul R; Moscati, Ronald M

    2015-08-01

    Abuse or unintended overdose (OD) of opiates and heroin may result in prehospital and emergency department (ED) care. Prehospital naloxone use has been suggested as a surrogate marker of community opiate ODs. The study objective was to verify externally whether prehospital naloxone use is a surrogate marker of community opiate ODs by comparing Emergency Medical Services (EMS) naloxone administration records to an independent database of ED visits for opiate and heroin ODs in the same community. A retrospective chart review of prehospital and ED data from July 2009 through June 2013 was conducted. Prehospital naloxone administration data obtained from the electronic medical records (EMRs) of a large private EMS provider serving a metropolitan area were considered a surrogate marker for suspected opiate OD. Comparison data were obtained from the regional trauma/psychiatric ED that receives the majority of the OD patients. The ED maintains a de-identified database of narcotic-related visits for surveillance of narcotic use in the metropolitan area. The ED database was queried for ODs associated with opiates or heroin. Cross-correlation analysis was used to test if prehospital naloxone administration was independent of ED visits for opiate/heroin ODs. Naloxone was administered during 1,812 prehospital patient encounters, and 1,294 ED visits for opiate/heroin ODs were identified. The distribution of patients in the prehospital and ED datasets did not differ by gender, but it did differ by race and age. The frequency of naloxone administration by prehospital providers varied directly with the frequency of ED visits for opiate/heroin ODs. A monthly increase of two ED visits for opiate-related ODs was associated with an increase in one prehospital naloxone administration (cross-correlation coefficient [CCF]=0.44; P=.0021). A monthly increase of 100 ED visits for heroin-related ODs was associated with an increase in 94 prehospital naloxone administrations (CCF=0.46; P=.0012

  7. Adjunctive Counseling During Brief and Extended Buprenorphine-Naloxone Treatment for Prescription Opioid Dependence

    PubMed Central

    Weiss, Roger D.; Potter, Jennifer Sharpe; Fiellin, David A.; Byrne, Marilyn; Connery, Hilary S.; Dickinson, William; Gardin, John; Griffin, Margaret L.; Gourevitch, Marc N.; Haller, Deborah L.; Hasson, Albert L.; Huang, Zhen; Jacobs, Petra; Kosinski, Andrzej S.; Lindblad, Robert; McCance-Katz, Elinore F.; Provost, Scott E.; Selzer, Jeffrey; Somoza, Eugene C.; Sonne, Susan C.; Ling, Walter

    2012-01-01

    Context No randomized trials have examined treatments for prescription opioid dependence, despite its increasing prevalence. Objective To evaluate the efficacy of brief and extended buprenorphine-naloxone treatment, with different counseling intensities, for patients dependent upon prescription opioids. Setting, Participants 653 treatment-seeking outpatients dependent on prescription opioids, at 10 U.S. sites from June 2006-July 2009. Design Multi-site, randomized clinical trial, using a two-phase adaptive treatment research design. Brief treatment (Phase 1) included 2-week buprenorphine-naloxone stabilization, 2-week taper, and 8-week post-medication follow-up. Patients with successful opioid use outcomes exited the study; unsuccessful patients entered Phase 2: extended (12-week) buprenorphine-naloxone treatment, 4-week taper, and 8-week post-medication follow-up. Main outcome measures Pre-defined “successful outcome” in each phase: composite measures indicating minimal or no opioid use, based on urine-confirmed self-reports. Interventions In both phases, patients were randomized to Standard Medical Management (SMM) or SMM+Opioid Drug Counseling (ODC); all received buprenorphine-naloxone. Results During Phase 1, only 6.6% (43/653) of patients had successful outcomes, with no difference between the SMM and SMM+ODC. In contrast, 49.2% (177/360) attained successful outcomes in Phase 2 during extended buprenorphine-naloxone treatment (week 12), with no difference between counseling conditions. Success rates 8 weeks after completing the buprenorphine-naloxone taper (Phase 2, week 24) dropped sharply to 8.6% (31/360), again with no counseling difference. In secondary analyses, successful Phase 2 outcomes were far more common while taking buprenorphine-naloxone than 8 weeks post-taper (49.2% (177/360) vs. 8.6% (31/360), p<0.001). Chronic pain did not affect opioid use outcomes; a history of ever using heroin was associated with lower Phase 2 success rates while

  8. Naloxone and epinephrine are equally effective for cardiopulmonary resuscitation in a rat asphyxia model.

    PubMed

    Chen, M-H; Xie, L; Liu, T-W; Song, F-Q; He, T

    2006-10-01

    It is not known whether naloxone is as efficacious as epinephrine during cardiopulmonary resuscitation (CPR). The aim of the study was to compare the effects of naloxone and epinephrine on the outcomes of CPR following asphyxial cardiac arrest in rats. Cardiac arrest was induced with asphyxia by clamping the tracheal tubes. Twenty-four Sprague-Dawley rats were randomized prospectively into a saline group (treated with normal saline, 1 ml intravenously, n = 8), an epinephrine group (treated with epinephrine, 0.04 mg/kg intravenously, n = 8) or a naloxone group (treated with naloxone, 1 mg/kg intravenously, n = 8) in a blind fashion during resuscitation after asphyxial cardiac arrest. After 5 min of untreated cardiac arrest, conventional manual CPR was started and each drug was administered at the same time. The rates of restoration of spontaneous circulation (ROSC) were one of eight (12.5%), seven of eight (87.5%) and seven of eight (87.5%) in the saline, epinephrine and naloxone groups, respectively. The rates of ROSC in the epinephrine and naloxone groups were equal and significantly greater than that in the saline group (P = 0.01 and P = 0.01, respectively). The administration of naloxone or epinephrine alone may increase the resuscitation rate, and both drugs are equally effective for CPR in a rat asphyxia model. However, the mechanism by which naloxone produces its efficacy during CPR remains unclear and further experimentation will be necessary.

  9. Effects of a sustained-release naloxone pellet on luteinizing hormone secretion in female rats.

    PubMed

    Gabriel, S M; Simpkins, J W

    1983-11-01

    Studies were undertaken to develop a naloxone implant capable of chronically blocking opioid receptors for several weeks in an effort to evaluate the effect of this prolonged narcotic antagonism on luteinizing hormone (LH) secretion in female rats. Antagonism of opiate receptors was achieved with a tablet formulation which contained 75 mg naloxone free base and a high content of the insoluble binding material, Mg stearate. Subcutaneous placement of this implant prevented morphine-induced analgesia for 2 weeks and antagonized the LH suppressory effects of morphine (15 or 30 mg/kg) administration. Thus, this naloxone delivery system is capable of chronically occupying the opioid receptors which mediate morphine's effects on analgesia and LH secretion. Despite this, the naloxone pellet only moderately enhanced the initial rate of increase in LH secretion following ovariectomy (day 1) and was ineffective in further augmenting LH secretion at 3 and 7 days after implantation. In rats which were ovariectomized and implanted immediately with estradiol-containing Silastic capsules, the naloxone pellet was ineffective in altering LH secretion 1, 3 or 7 days later. Thus, while chronic exposure to naloxone persistently antagonizes the pharmacologic actions of morphine, the naloxone pellet only transiently blocked the tonic inhibitory effect of endogenous opioid peptides. The mechanism by which the LH secretory effects of naloxone are lost following chronic exposure to the antagonist are at present unknown, but may involve the activation of compensatory mechanisms which are inhibitory to LH secretion.

  10. Patients with stable chronic obstructive pulmonary disease can safely undergo intravenous dipyridamole thallium-201 imaging.

    PubMed

    Shaffer, J; Simbartl, L; Render, M L; Snow, E; Chaney, C; Nishiyama, H; Rauf, G C; Wexler, L F

    1998-08-01

    Patients with chronic obstructive pulmonary disease are usually excluded from intravenous dipyridamole thallium-201 testing. We developed a nurse-administered protocol to screen and pretreat patients so they could be safely tested. We prospectively screened patients referred for intravenous dipyridamole thallium testing and retrospectively reviewed a comparison group of patients who had undergone intravenous dipyridamole testing before our bronchospasm protocol. We studied 492 consecutive patients referred for intravenous dipyridamole thallium testing, separating those with complete data (n = 451) into two groups: group A (n = 72), patients assessed to be at risk for intravenous dipyridamole-induced bronchospasm who received our bronchospasm treatment protocol; and group B (n = 379), patients assessed to be free of risk, who did not receive our bronchospasm protocol. Group C (n = 89) was a retrospective comparison group of patients who had undergone intravenous dipyridamole testing before initiation of the protocol. Patients were considered at risk for an adverse event if any of the following were present: peak flow < or =400 ml at the time of the test (spirometry by nurse) that increased to >400 ml after bronchodilator treatment, wheezing audible with stethoscope, history of chronic obstructive pulmonary disease or asthma or dyspnea on exertion at less than four blocks, or resting respiratory rate >18 breaths/min. The test was considered contraindicated if resting oxygen saturation was <85%, respiratory rate < or =36 breaths/min, or peak flow measured by peak flowmeter <400 ml after bronchodilator inhalant (albuterol or metaproterenol sulfate by spacer) at a dose of up to six puffs. One minute after injections of thallium-201, patients at risk were given 50 mg aminophylline by slow intravenous injection. We looked for major and minor adverse effects and divided them into three categories: (1) minor events (transient headache, abdominal discomfort, or nausea

  11. In Vitro Dissolution of Fluconazole and Dipyridamole in Gastrointestinal Simulator (GIS), Predicting in Vivo Dissolution and Drug-Drug Interaction Caused by Acid-Reducing Agents.

    PubMed

    Matsui, Kazuki; Tsume, Yasuhiro; Amidon, Gregory E; Amidon, Gordon L

    2015-07-06

    Weakly basic drugs typically exhibit pH-dependent solubility in the physiological pH range, displaying supersaturation or precipitation along the gastrointestinal tract. Additionally, their oral bioavailabilities may be affected by coadministration of acid-reducing agents that elevate gastric pH. The purpose of this study was to assess the feasibility of a multicompartmental in vitro dissolution apparatus, Gastrointestinal Simulator (GIS), in predicting in vivo dissolution of certain oral medications. In vitro dissolution studies of fluconazole, a BCS class I, and dipyridamole, a BCS class II weak bases (class IIb), were performed in the GIS as well as United States Pharmacopeia (USP) apparatus II and compared with the results of clinical drug-drug interaction (DDI) studies. In both USP apparatus II and GIS, fluconazole completely dissolved within 60 min regardless of pH, reflecting no DDI between fluconazole and acid-reducing agents in a clinical study. On the other hand, seven-fold and 15-fold higher concentrations of dipyridamole than saturation solubility were observed in the intestinal compartments in GIS with gastric pH 2.0. Precipitation of dipyridamole was also observed in the GIS, and the percentage of dipyridamole in solution was 45.2 ± 7.0%. In GIS with gastric pH 6.0, mimicking the coadministration of acid-reducing agents, the concentration of dipyridamole was equal to its saturation solubility, and the percentage of drug in solution was 9.3 ± 2.7%. These results are consistent with the clinical DDI study of dipyridamole with famotidine, which significantly reduced the Cmax and area under the curve. An In situ mouse infusion study combined with GIS revealed that high concentration of dipyridamole in the GIS enhanced oral drug absorption, which confirmed the supersaturation of dipyridamole. In conclusion, GIS was shown to be a useful apparatus to predict in vivo dissolution for BCS class IIb drugs.

  12. [Neuroprotective effect of naloxone in brain damage caused by repeated febrile seizure].

    PubMed

    Shan, Ying; Qin, Jiong; Chang, Xing-zhi; Yang, Zhi-xian

    2004-04-01

    The brain damage caused by repeated febrile seizure (FS) during developing age is harmful to the intellectual development of children. So how to decrease the related damage is a very important issue. The main purpose of the present study was to find out whether the non-specific opiate antagonist naloxone at low dose has the neuroprotective effect on seizure-induced brain damage. Warm water induced rat FS model was developed in this study. Forty-seven rats were randomly divided into two groups: normal control group (n = 10) and hyperthermic seizure groups (n = 37). The latter was further divided into FS control group (n = 13) and naloxone-treated group (n = 24). The dose of naloxone is different in two naloxone-treated groups (12/each group), in one group the dose was 1 mg/kg, in the other one 2 mg/kg. Seven febrile seizures were induced in each rat of hyperthermic seizure groups with the interval of 2 days. The rats were weighed and injected intraperitoneally with naloxone once the FS occurred in naloxone-treated group, while the rats of the other groups were injected with 0.9% sodium chloride. Latency, duration and grade of FS in different groups were observed and compared. HE-staining and the electron microscopy (EM) were used to detect the morphologic and ultrastructural changes of hippocampal neurons. In naloxone-treated group, the rats' FS duration and FS grade (5.02 +/- 0.63, 2.63 +/- 0.72) were significantly lower (t = 5.508, P < 0.01; t = 8.439, P < 0.01) than those in FS control group (7.70 +/- 2.25 min, 4.52 +/- 0.49), although no significant gap was observed on FS latency between them. In FS control group, HE-staining pattern of hippocampal CA(1) and CA(2) showed lots of disordered neurons with confused polarity and vacuoles formed. Nuclei were with various size, some rounded and some oblong. While in naloxone-treated groups, the arrangement of neurons was regular, only a small quantity of neurons had changed polarity and vacuoles formed. Most nuclei

  13. Beneficial effects of naloxone in a patient with intestinal pseudoobstruction

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Schang, J.C.; Devroede, G.

    1985-06-01

    A 15-day course of Naloxone treatment was given to a patient with intestinal pseudoobstruction who had previously undergone subtotal colectomy with terminal ileostomy for invalidating constipation. The effects of the drug were assessed according to symptoms, by recording the myoelectric activity of the stomach, and by measuring gastric emptying of a radiolabeled solid-liquid meal and the intestinal transit time of radiopaque markers. All tests were performed 1) at baseline; 2) after 2 wk with Naloxone 1.6 mg subcutaneous per day; and 3) after 8 days of placebo. Results showed that before treatment gastric emptying of solids was delayed, emptying ofmore » liquids was normal, myoelectric activity of the stomach was normal, small intestinal transit time of radiopaque markers was considerably increased while ileal output was markedly decreased. After Naloxone, gastric emptying of solids was markedly accelerated, emptying of liquids remained normal, gastric electrical spiking activity increased, small intestinal transit time strikingly decreased, and ileal output increased. After placebo, a tendency to return to pretreatment values was observed. This observation suggests that Naloxone may be helpful in the treatment of some patients with intestinal pseudoobstruction.« less

  14. Self-management of buprenorphine/naloxone among online discussion board users.

    PubMed

    Brown, Shan-Estelle; Altice, Frederick L

    2014-06-01

    Buprenorphine/naloxone is an effective medication used to treat opioid dependence. Patients in treatment and those using it illegally without prescriptions have discussed using buprenorphine/naloxone anonymously on Internet discussion boards. Their beliefs about self-treatment and efforts to self-treat are not well known. To identify facilitators of self-treatment by online buprenorphine/naloxone users. A qualitative, retrospective study of discussion board postings from September 2010 to November 2012 analyzed 121 threads from 13 discussion boards using grounded theory. Facilitators of self-management themes that emerged included: (1) a ready supply of buprenorphine/naloxone from a variety of sources; (2) distrust of buprenorphine prescribers and pharmaceutical companies; (3) the declaration that buprenorphine/naloxone is a "bad-tasting" medicine; (4) the desire to adopt a different delivery method other than sublingually; and (5) a desire to become completely "substance-free." The sublingual film formulation appears to be an important facilitator in self-treatment because it can more easily be apportioned to extend the medication because of limited supply, cost, or to taper. CONCLUSIONS/IMPORTANCE: The findings indicate a range of self-management activities ranging from altering the amount taken to modifying the physical medication composition or changing the administration route; some of these behaviors constitute problematic extra-medical use. Contributors to discussion boards seem to trust each other more than they trust pharmacists and prescribing physicians. The shared knowledge and behaviors of this understudied online community are important to healthcare providers because of the previously unknown precautions and risks taken to self-treat.

  15. Self-Management of Buprenorphine/Naloxone Among Online Discussion Board Users

    PubMed Central

    Brown, Shan-Estelle; Altice, Frederick L.

    2017-01-01

    Background Buprenorphine/naloxone is an effective medication used to treat opioid dependence. Patients in treatment and those using it illegally without prescriptions have discussed using buprenorphine/naloxone anonymously on Internet discussion boards. Their beliefs about self-treatment and efforts to self-treat are not well known. Objectives To identify facilitators of self-treatment by online buprenorphine/naloxone users. Methods A qualitative, retrospective study of discussion board postings from September 2010 to November 2012 analyzed 121 threads from 13 discussion boards using grounded theory. Results Facilitators of self-management themes that emerged included: (1) a ready supply of buprenorphine/naloxone from a variety of sources; (2) distrust of buprenorphine prescribers and pharmaceutical companies; (3) the declaration that buprenorphine/naloxone is a “bad-tasting” medicine; (4) the desire to adopt a different delivery method other than sublingually; and (5) a desire to become completely “substance-free.” The sublingual film formulation appears to be an important facilitator in self-treatment because it can more easily be apportioned to extend the medication because of limited supply, cost, or to taper. Conclusions/Importance The findings indicate a range of self-management activities ranging from altering the amount taken to modifying the physical medication composition or changing the administration route; some of these behaviors constitute problematic extra-medical use. Contributors to discussion boards seem to trust each other more than they trust pharmacists and prescribing physicians. The shared knowledge and behaviors of this understudied online community are important to healthcare providers because of the previously unknown precautions and risks taken to self-treat. PMID:24779501

  16. Prolonged-Release Oxycodone/Naloxone Improves Anal Sphincter Relaxation Compared to Oxycodone Plus Macrogol 3350.

    PubMed

    Poulsen, Jakob Lykke; Brock, Christina; Grønlund, Debbie; Liao, Donghua; Gregersen, Hans; Krogh, Klaus; Drewes, Asbjørn Mohr

    2017-11-01

    Opioid analgesics inhibit anal sphincter function and contribute to opioid-induced bowel dysfunction (OIBD). However, it is unknown whether the inhibition can be reduced by opioid antagonism with prolonged-release (PR) naloxone and how this compares to laxative treatment. To compare the effects of combined PR oxycodone/naloxone or PR oxycodone plus macrogol 3350 on anal sphincter function and gastrointestinal symptoms. A randomized, double-blind, crossover trial was conducted in 20 healthy men. Participants were treated for 5 days with combined PR oxycodone/naloxone or PR oxycodone plus macrogol 3350. Resting anal pressure, anal canal distensibility, and relaxation of the internal sphincter to rectal distension were evaluated before treatment (baseline) and on day 5. The Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire, stool frequency, and stool consistency were assessed daily. Both PR oxycodone/naloxone and PR oxycodone plus macrogol treatment decreased sphincter relaxation compared to baseline (- 27.5%; P < 0.001 and - 14.7%; P = 0.01). However, sphincter relaxation was increased after PR naloxone/oxycodone treatment compared to macrogol (difference = + 17.6%; P < 0.001). Resting anal pressure and anal canal distensibility did not differ between treatments. PAC-SYM abdominal symptoms score was lower during PR naloxone compared to macrogol (0.2 vs. 3.2; P = 0.002). The number of bowel movements was lower during PR naloxone versus macrogol (4.2 vs. 5.4; P = 0.035). Relaxation of the internal anal sphincter was significantly better after PR oxycodone/naloxone treatment compared to PR oxycodone plus macrogol 3350. These findings highlight that OIBD may require specific therapy against the complex, pan-intestinal effects of opioids.

  17. Clinical experience with fortnightly buprenorphine/naloxone versus buprenorphine in Italy: preliminary observational data in an office-based setting.

    PubMed

    Amato, Patrizia

    2010-01-01

    Buprenorphine/naloxone is a new option for the management of opioid dependence. It has a reduced potential for abuse or misuse compared with methadone and buprenorphine alone, and has a long half-life allowing less frequent dosing. Buprenorphine/naloxone appears to be well suited for the management of opioid dependence in an office-based setting. The aim of this study was to evaluate the efficacy and safety of a buprenorphine/naloxone combination treatment in an office-based setting. Therefore, we evaluated the effect on misuse/diversion, quality of care, quality of life and service delivery. Seventy-eight patients were switched to buprenorphine/naloxone from either methadone or buprenorphine alone; the median duration of previous buprenorphine or methadone treatment was 10 years. Patients received buprenorphine/naloxone and were evaluated throughout a 1-year follow-up period. Treatment was self-administered by the patients every 2 weeks and the mean buprenorphine dosage at 1 year was 8 mg/day. Comparisons were made before and after the switch for patients who switched from buprenorphine alone to buprenorphine/naloxone. Switching to buprenorphine/naloxone was not associated with clinically relevant problems in 50% of patients studied. Buprenorphine/naloxone provided satisfactory coverage of withdrawal symptoms in 78.1% of patients, and 50% of patients were satisfied with buprenorphine/naloxone therapy. Seventy-eight per cent of patients reported improved psychosocial functioning. The majority of patients (approximately 85%) were negative for opioids during toxicological testing. A significantly higher proportion of treatment recipients were highly satisfied during buprenorphine/naloxone administration (p < 0.001 compared with buprenorphine given before the switch). Other outcomes were similar during buprenorphine and buprenorphine/naloxone administration. Fortnightly self-administration of buprenorphine/naloxone appeared to be cost saving for the clinic

  18. Extended vs Short-term Buprenorphine-Naloxone for Treatment of Opioid-Addicted Youth

    PubMed Central

    Woody, George E.; Poole, Sabrina A.; Subramaniam, Geetha; Dugosh, Karen; Bogenschutz, Michael; Abbott, Patrick; Patkar, Ashwin; Publicker, Mark; McCain, Karen; Potter, Jennifer Sharpe; Forman, Robert; Vetter, Victoria; McNicholas, Laura; Blaine, Jack; Lynch, Kevin G.; Fudala, Paul

    2008-01-01

    Context The usual treatment for opioid-addicted youth is detoxification and counseling. Extended medication-assisted therapy may be more helpful. Objective To evaluate the efficacy of continuing buprenorphine-naloxone for 12 weeks vs detoxification for opioid-addicted youth. Design, Setting, and Patients Clinical trial at 6 community programs from July 2003 to December 2006 including 152 patients aged 15 to 21 years who were randomized to 12 weeks of buprenorphine-naloxone or a 14-day taper (detox). Interventions Patients in the 12-week buprenorphine-naloxone group were prescribed up to 24 mg per day for 9 weeks and then tapered to week 12; patients in the detox group were prescribed up to 14 mg per day and then tapered to day 14. All were offered weekly individual and group counseling. Main Outcome Measure Opioid-positive urine test result at weeks 4, 8, and 12. Results The number of patients younger than 18 years was too small to analyze separately, but overall, patients in the detox group had higher proportions of opioid-positive urine test results at weeks 4 and 8 but not at week 12 ( χ22 = 4.93, P = .09). At week 4, 59 detox patients had positive results (61%; 95% confidence interval [CI] = 47%-75%) vs 58 12-week buprenorphine-naloxone patients (26%; 95% CI = 14%-38%). At week 8, 53 detox patients had positive results (54%; 95% CI = 38%-70%) vs 52 12-week buprenorphine-naloxone patients (23%; 95% CI = 11%-35%). At week 12, 53 detox patients had positive results (51%; 95% CI = 35%-67%) vs 49 12-week buprenorphine-naloxone patients (43%; 95% CI = 29%-57%). By week 12, 16 of 78 detox patients (20.5%) remained in treatment vs 52 of 74 12-week buprenorphine-naloxone patients (70%; χ12 = 32.90, P < .001). During weeks 1 through 12, patients in the 12-week buprenorphine-naloxone group reported less opioid use ( χ12 = 18.45, P < .001), less injecting ( χ12 = 6.00, P = .01), and less nonstudy addiction treatment ( χ12 = 25.82, P < .001). High levels of opioid use

  19. Prescribe to Prevent: Overdose Prevention and Naloxone Rescue Kits for Prescribers and Pharmacists

    PubMed Central

    Lim, Jamie K.; Bratberg, Jeffrey P.; Davis, Corey S.; Green, Traci C.; Walley, Alexander Y.

    2016-01-01

    In March of 2015, the United States Department of Health and Human Services identified 3 priority areas to reduce opioid use disorders and overdose, which are as follows: opioid-prescribing practices; expanded use and distribution of naloxone; and expansion of medication-assisted treatment. In this narrative review of overdose prevention and the role of prescribers and pharmacists in distributing naloxone, we address these priority areas and present a clinical scenario within the review involving a pharmacist, a patient with chronic pain and anxiety, and a primary care physician. We also discuss current laws related to naloxone prescribing and dispensing. This review was adapted from the Prescribe to Prevent online continuing medical education module created for prescribers and pharmacists (http://www.opioidprescribing.com/naloxone_module_1-landing). PMID:27261669

  20. Effects of naloxone distribution to likely bystanders: Results of an agent-based model.

    PubMed

    Keane, Christopher; Egan, James E; Hawk, Mary

    2018-05-01

    Opioid overdose deaths in the US rose dramatically in the past 16 years, creating an urgent national health crisis with no signs of immediate relief. In 2017, the President of the US officially declared the opioid epidemic to be a national emergency and called for additional resources to respond to the crisis. Distributing naloxone to community laypersons and people at high risk for opioid overdose can prevent overdose death, but optimal distribution methods have not yet been pinpointed. We conducted a sequential exploratory mixed methods design using qualitative data to inform an agent-based model to improve understanding of effective community-based naloxone distribution to laypersons to reverse opioid overdose. The individuals in the model were endowed with cognitive and behavioral variables and accessed naloxone via community sites such as pharmacies, hospitals, and urgent-care centers. We compared overdose deaths over a simulated 6-month period while varying the number of distribution sites (0, 1, and 10) and number of kits given to individuals per visit (1 versus 10). Specifically, we ran thirty simulations for each of thirteen distribution models and report average overdose deaths for each. The baseline comparator was no naloxone distribution. Our simulations explored the effects of distribution through syringe exchange sites with and without secondary distribution, which refers to distribution of naloxone kits by laypersons within their social networks and enables ten additional laypersons to administer naloxone to reverse opioid overdose. Our baseline model with no naloxone distribution predicted there would be 167.9 deaths in a six month period. A single distribution site, even with 10 kits picked up per visit, decreased overdose deaths by only 8.3% relative to baseline. However, adding secondary distribution through social networks to a single site resulted in 42.5% fewer overdose deaths relative to baseline. That is slightly higher than the 39

  1. Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: Phase I healthy volunteer study.

    PubMed

    McDonald, Rebecca; Lorch, Ulrike; Woodward, Jo; Bosse, Björn; Dooner, Helen; Mundin, Gill; Smith, Kevin; Strang, John

    2018-03-01

    Take-home naloxone can prevent death from heroin/opioid overdose, but pre-provision is difficult because naloxone is usually given by injection. Non-injectable alternatives, including naloxone nasal sprays, are currently being developed. To be effective, the intranasal (i.n.) spray dose must be adequate but not excessive, and early absorption must be comparable to intramuscular (i.m.) injection. We report on the pharmacokinetics (PK) of a specially produced concentrated novel nasal spray. The specific aims were to: (1) estimate PK profiles of i.n. naloxone, (2) compare early systemic exposure with i.n. versus i.m. naloxone and (3) estimate i.n. bioavailability. Open-label, randomized, five-way cross-over PK study. Clinical trials facility (Croydon, UK). Thirty-eight healthy volunteers (age 20-54 years; 11 female). Three doses of i.n. (1 mg/0.1 ml, 2 mg/0.1 ml, 4 mg/0.2 ml) versus 0.4 mg i.m. (reference) and 0.4 mg intravenous (i.v.) naloxone. Regular blood samples were taken, with high-frequency sampling during the first 15 minutes to capture early systemic exposure. PK parameters were determined from plasma naloxone concentrations. Exploratory analyses involved simulation of repeat administration. Mean peak concentration (C max ) values for 1 mg (1.51 ng/ml), 2 mg (2.87 ng/ml) and 4 mg (6.02 ng/ml) i.n. exceeded 0.4 mg i.m. (1.27 ng/ml) naloxone. All three i.n. doses rapidly achieved plasma levels > 50% of peak concentrations (T50%) by 10 minutes, peaking at 15-30 minutes (T max ). For comparison, the i.m. reference reached T max at 10 minutes. Mean bioavailability was 47-51% for i.n. relative to i.m. naloxone. Simulation of repeat dosing (2 × 2 mg i.n. versus 5 × 0.4 mg i.m. doses) at 3-minute intervals showed that comparable plasma naloxone concentrations would be anticipated. Concentrated 2 mg intranasal naloxone is well-absorbed and provides early exposure comparable to 0.4 mg intramuscular naloxone, following the 0.4

  2. Surveying the opinions of Pennsylvania Chiefs of Police toward officers carrying and administering naloxone.

    PubMed

    Smyser, Paul A; Lubin, Jeffrey S

    2018-01-01

    Recent legislation in Pennsylvania allows police officers to administer naloxone to individuals in an opioid overdose. Pressure has subsequently been placed on police departments to adopt naloxone programs. To survey Pennsylvania Chiefs of Police regarding potential obstacles to officer-administered naloxone, and their overall opinion toward such programs. A confidential survey was administered at the Annual Conference for the Pennsylvania Chiefs of Police Association and online over the organization's listserv. Respondents rated their level of concern toward four potential obstacles on a Likert scale from 1 to 5. A fifth question asked the degree to which they agree that the benefits of naloxone programs outweigh the risks. Of 180 attendees, 36 Chiefs of Police responded at the conference and 48 to the online survey. The potential agitation of revived victims was their largest reported concern, with 60% responding either a 4 or 5; this was followed by officers correctly identifying situations to use naloxone (42%), the cost of the medication (38%), and the additional administrative duties of the department (32%). Overall 60% responded they "Strongly Agree" or "Agree" the benefits of naloxone programs outweigh the risks, while 23% responded "Strongly Disagree" or "Disagree." No significant differences were seen when separating participants from rural and urban counties or from counties with high, medium, and low rates of overdose fatalities. The results suggest that although a significant subset shows concern for the above obstacles, the majority of Chiefs of Police believe that the benefits of equipping officers with naloxone outweigh the risks.

  3. Intranasal naloxone administration by police first responders is associated with decreased opioid overdose deaths.

    PubMed

    Rando, Jessica; Broering, Derek; Olson, James E; Marco, Catherine; Evans, Stephen B

    2015-09-01

    This study sought to answer the question, "Can police officers administer intranasal naloxone to drug overdose victims to decrease the opioid overdose death rate?" This prospective interventional study was conducted in Lorain County, OH, from January 2011 to October 2014. Starting October 2013, trained police officers administered naloxone to suspected opioid overdose victims through a police officer naloxone prescription program (NPP). Those found by the county coroner to be positive for opioids at the time of death and those who received naloxone from police officers were included in this study. The rate of change in the total number of opioid-related deaths in Lorain County per quarter year, before and after initiation of the NPP, and the trend in the survival rate of overdose victims who were given naloxone were analyzed by linear regression. Significance was established a priori at P < .05. Data from 247 individuals were eligible for study inclusion. Opioid overdose deaths increased significantly before initiation of the police officer NPP with average deaths per quarter of 5.5 for 2011, 15.3 for 2012, and 16.3 for the first 9 months of 2013. After initiation of the police officer NPP, the number of opioid overdose deaths decreased each quarter with an overall average of 13.4. Of the 67 participants who received naloxone by police officers, 52 (77.6%) survived, and 8 (11.9%) were lost to follow-up. Intranasal naloxone administration by police first responders is associated with decreased deaths in opioid overdose victims. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Knowledge of naloxone and take-home naloxone programs among a sample of people who inject drugs in Australia: Variations across capital cities.

    PubMed

    Dietze, Paul M; Stare, Mark; Cogger, Shelley; Nambiar, Dhanya; Olsen, Anna; Burns, Lucinda; Lenton, Simon

    2018-05-01

    Take-home naloxone (THN) programs targeting people who inject drugs (PWID) have been running in some Australian states and territories since 2012. In this study, we aimed to determine the extent to which PWID in the capital cities of all Australian states and territories are aware of naloxone and THN programs, whether awareness of these programs has changed over time. Data were obtained from cross-sectional surveys of a total of 2088 PWID conducted annually as part of the Illicit Drug Reporting System from 2013 to 2015. Specific questions about THN added to the survey in 2013 allowed assessment of the extent to which sampled PWID were aware of naloxone and its function and THN programs in Australia and whether they had participated in a THN program. These main outcomes were examined over time and across states and territories using a mix of descriptive statistics and logistic regression. Over 80% of the sample reported having heard of naloxone across survey years. Less than half of the participants reported having heard of THN programs in 2013 (35%), but this increased to just over (52%) half in 2015 (P < 0.01). Changes over time differed across cities with increases in reports of having heard of THN occurring over time most clearly in those cities with operational THN programs. Around half of the PWID sampled for this study are aware of THN programs. Further work is needed to ensure widespread awareness of THN programs which should include implementing THN in all Australian states and territories. © 2017 Australasian Professional Society on Alcohol and other Drugs.

  5. Effective Use of Naloxone by Law Enforcement in Response to Multiple Opioid Overdoses.

    PubMed

    Kitch, Bryan B; Portela, Roberto C

    2016-01-01

    Growing rates of opioid abuse and overdose throughout the nation have lead some community organizations to develop naloxone administration programs. In Pitt County North Carolina, two of our law enforcement agencies were trained in the identification of opioid overdose and use of naloxone therapy. Attributed partially to introduction of fentanyl into the illicit drug market, our community experienced a 48-hour period in which officers successfully deployed five doses of antagonist medication to four individuals. This article presents case descriptions demonstrating the feasibility and safety of law enforcement naloxone programs.

  6. Naloxone reversal of an overdose of a novel, long-acting transdermal fentanyl solution in laboratory Beagles.

    PubMed

    Freise, K J; Newbound, G C; Tudan, C; Clark, T P

    2012-08-01

    Opioid overdose in dogs is manifested by clinical signs such as excessive sedation, bradycardia, and hypothermia. The ability of two different intramuscular (i.m.) naloxone reversal regimens to reverse the opioid-induced effects of a fivefold overdose of long-acting transdermal fentanyl solution was evaluated in dogs. Twenty-four healthy Beagles were administered a single 13 mg/kg dose (fivefold overdose) of transdermal fentanyl solution and randomized to two naloxone reversal regimen treatment groups, hourly administration for 8 h of 40 (n = 8) or 160 μg/kg i.m. (n = 16). All dogs were sedated and had reduced body temperatures and heart rates (HRs) prior to naloxone administration. Both dosage regimens significantly reduced sedation (P < 0.001), and the 160 μg/kg naloxone regimen resulted in a nearly threefold lower odds of sedation than that of the 40 μg/kg i.m. naloxone regimen (P < 0.05). Additionally, naloxone significantly increased the mean body temperatures and HR (P < 0.001), although the 160 μg/kg regimen increased body temperature and HR more (P < 0.05). However, the narcotic side effects of fentanyl returned within 1-3 h following termination of the naloxone dosage regimens. The opioid-induced effects of an overdose of transdermal fentanyl solution can be safely and effectively reversed by either 40 or 160 μg/kg i.m. naloxone administered at hourly intervals. © 2012 Blackwell Publishing Ltd.

  7. Opioid overdose prevention and naloxone rescue kits: what we know and what we don't know.

    PubMed

    Kerensky, Todd; Walley, Alexander Y

    2017-01-07

    The opioid use and overdose crisis is persistent and dynamic. Opioid overdoses were initially driven in the 1990s and 2000s by the increasing availability and misuse of prescription opioids. More recently, opioid overdoses are increasing at alarming rates due to wider use of heroin, which in some places is mixed with fentanyl or fentanyl derivatives. Naloxone access for opioid overdose rescue is one of the US Department of Health and Human Services' three priority areas for responding to the opioid crisis. This article summarizes the known benefits of naloxone access and details unanswered questions about overdose education and naloxone rescue kits. Hopefully future research will address these knowledge gaps, improve the effectiveness of opioid overdose education and naloxone distribution programs, and unlock the full promise of naloxone rescue kits.

  8. Reduction of indium-111 platelet deposition on Dacron vascular grafts in humans by aspirin plus dipyridamole

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Stratton, J.R.; Ritchie, J.L.

    Aspirin plus dipyridamole reduces platelet accumulation on short-term Dacron vascular grafts in man. To determine whether drug inhibition of platelet deposition is sustained on older grafts, we studied 18 men aged 41 to 87 years who had Dacron aortic bifurcation grafts in place a mean of 43.4 months (range 9.8 to 121.0) before and during short-term therapy with aspirin (325 mg tid) plus dipyridamole (75 mg tid). During both the baseline and drug studies, indium-111 (/sup 111/In) platelet deposition was quantitated by two techniques, standard planar imaging performed at 24, 48, and 72 hr after injection of platelets and singlemore » photon emission computed tomographic imaging performed at 24 and 72 hr after injection. All analyses were performed in a blinded fashion. On both the planar and tomographic images, platelet accumulation on the graft was quantitated by a graft/blood ratio that compared activity in the graft to simultaneously collected whole blood /sup 111/In platelet activity. Aspirin plus dipyridamole reduced the tomographic graft/blood ratio at 24 hr (20.6 +/- 3.5 vs 17.3 +/- 2.5) (+/-SEM) and at 72 hr (29.0 +/- 4.8 vs 25.0 +/- 4.1) after injection of platelets (p = .02). Dacron vascular grafts. Similarly, the planar graft/blood ratio was reduced at 24 hr (2.7 +/- 0.5 vs 2.4 +/- 0.5), 48 hr (3.7 +/- 0.9 vs 3.1 +/- 0.7), and 72 hr (4.0 +/- 0.9 vs 3.6 +/- 0.8) (p = .04). We conclude that aspirin (325 mg tid) plus dipyridamole (75 mg tid) reduces platelet accumulation on long-term Dacron vascular grafts.« less

  9. Are take-home naloxone programmes effective? Systematic review utilizing application of the Bradford Hill criteria.

    PubMed

    McDonald, Rebecca; Strang, John

    2016-07-01

    Fatal outcome of opioid overdose, once detected, is preventable through timely administration of the antidote naloxone. Take-home naloxone provision directly to opioid users for emergency use has been implemented recently in more than 15 countries worldwide, albeit mainly as pilot schemes and without formal evaluation. This systematic review assesses the effectiveness of take-home naloxone, with two specific aims: (1) to study the impact of take-home naloxone distribution on overdose-related mortality; and (2) to assess the safety of take-home naloxone in terms of adverse events. PubMed, MEDLINE and PsychINFO were searched for English-language peer-reviewed publications (randomized or observational trials) using the Boolean search query: (opioid OR opiate) AND overdose AND prevention. Evidence was evaluated using the nine Bradford Hill criteria for causation, devised to assess a potential causal relationship between public health interventions and clinical outcomes when only observational data are available. A total of 1397 records (1164 after removal of duplicates) were retrieved, with 22 observational studies meeting eligibility criteria. Due to variability in size and quality of the included studies, meta-analysis was dismissed in favour of narrative synthesis. From eligible studies, we found take-home naloxone met all nine Bradford Hill criteria. The additional five World Health Organization criteria were all either met partially (two) or fully (three). Even with take-home naloxone administration, fatal outcome was reported in one in 123 overdose cases (0.8%; 95% confidence interval = 0.4, 1.2). Take-home naloxone programmes are found to reduce overdose mortality among programme participants and in the community and have a low rate of adverse events. © 2016 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.

  10. Opioid Overdose Reversal with Naloxone (Narcan, Evzio)

    MedlinePlus

    ... Teens Search Connect with NIDA : Facebook LinkedIn Twitter YouTube Flickr RSS Menu Home Drugs of Abuse Commonly ... and no insurance. Where can I get naloxone? YouTube embedded video: https://www.youtube-nocookie.com/embed/ ...

  11. Naloxone injections into CA3 disrupt pattern completion associated with relapse from cocaine seeking

    PubMed Central

    Kirk, Ryan A.; Clark, Jascha K.; Moore, Angela; Keefe, Kristen

    2016-01-01

    The goal of the present research was to assess the degree to which a pattern completion process operates in cue-induced relapse to cocaine-seeking behavior. Using a novel cue-preference version of the place preference task, rats were administered cocaine or saline, which resulted in a preference for the cocaine-paired cues. After 21 days of abstinence and prior to the preference test, for one group, PBS or naloxone was injected into the CA3 subregion of the hippocampus and for a second group, saline or naloxone was injected systemically. The results indicated that infusions of naloxone into CA3 or systemic injections produced a marked disruption for one and two cues, but had minimal disruptive effect for three or four cues, suggesting that naloxone injections disrupt CA3 function and trigger a deficit in a pattern completion process. Thus, it appears that cue-based activation of the dorsal CA3 might be a critical trigger via a pattern completion process. Based on additional analyses it appears that there is a disruption primarily for object touches for one cue naloxone injections into the CA3 or systemic injections, but no effect on time (spatial context). PMID:26815290

  12. Prescription naloxone: a novel approach to heroin overdose prevention.

    PubMed

    Sporer, Karl A; Kral, Alex H

    2007-02-01

    The mortality and morbidity from heroin overdose have increased in the United States and internationally in the last decade. The lipid solubility allows the rapid deposition of heroin and its metabolites into the central nervous system and accounts for the "rush" experienced by users and for the toxicity. Risk factors for fatal and nonfatal heroin overdoses such as recent abstinence, decreased opiate tolerance, and polydrug use have been identified. Opiate substitution treatment such as methadone or buprenorphine is the only proven method of heroin overdose prevention. Death from a heroin overdose most commonly occurs 1 to 3 hours after injection at home in the company of other people. Numerous communities have taken advantage of this opportunity for treatment by implementing overdose prevention education to active heroin users, as well as prescribing naloxone for home use. Naloxone is a specific opiate antagonist without agonist properties or potential for abuse. It is inexpensive and nonscheduled and readily reverses the respiratory depression and sedation caused by heroin, as well as causing transient withdrawal symptoms. Program implementation considerations, legal ramifications, and research needs for prescription naloxone are discussed.

  13. Nonprescription naloxone and syringe sales in the midst of opioid overdose and hepatitis C virus epidemics: Massachusetts, 2015.

    PubMed

    Stopka, Thomas J; Donahue, Ashley; Hutcheson, Marguerite; Green, Traci C

    To determine the prevalence of nonprescription naloxone and sterile syringe sales, factors associated with nonprescription sales, geospatial access to nonprescription naloxone and syringe-selling pharmacies, and targets for potential interventions. Cross-sectional study. Massachusetts has experienced steep increases in reported opioid overdoses and hepatitis C virus cases in the past decade. Pharmacists have the potential to play a substantial role in increasing access to nonprescription naloxone and sterile syringes, which can reverse opioid overdoses and decrease hepatitis C virus transmission, respectively. We completed brief telephone surveys with 809 of 1042 retail pharmacies across Massachusetts (response rate = 77.6%) during 2015 to assess experience with nonprescription sales of naloxone and sterile syringes. Our primary outcomes were the stocking and selling of naloxone in the pharmacy (yes or no) for nonprescription sales and nonprescription syringe sales (yes or no). We conducted multivariable regression analyses and created maps using a geographic information system to identify factors associated with nonprescription sales of naloxone and sterile syringes, and to improve our understanding of geospatial access to pharmacy-based naloxone and syringe sales. More than 97% of pharmacies reported selling sterile syringes without requiring a prescription, and 45% of pharmacies reported stocking and selling naloxone. Factors associated with nonprescription sales included hours of operation, experience with and interest in harm reduction activities, and presence in an opioid overdose hotspot. Geographic access to nonprescription sale of sterile syringes is widespread, whereas geospatial access to naloxone is limited. Training to understand the benefits, applications, and distribution needs of naloxone is of interest to surveyed pharmacists. Access to sterile syringes through nonprescription sales is strong across Massachusetts, and although more than 350

  14. Overdose Education and Naloxone for Patients Prescribed Opioids in Primary Care: A Qualitative Study of Primary Care Staff.

    PubMed

    Binswanger, Ingrid A; Koester, Stephen; Mueller, Shane R; Gardner, Edward M; Goddard, Kristin; Glanz, Jason M

    2015-12-01

    The rate of fatal unintentional pharmaceutical opioid poisonings has increased substantially since the late 1990s. Naloxone is an effective opioid antidote that can be prescribed to patients for bystander use in the event of an overdose. Primary care clinics represent settings in which large populations of patients prescribed opioids could be reached for overdose education and naloxone prescription. Our aim was to investigate the knowledge, attitudes and beliefs about overdose education and naloxone prescription among clinical staff in primary care. This was a qualitative study using focus groups to elucidate both clinic-level and provider-level barriers and facilitators. Ten primary care internal medicine, family medicine and infectious disease/HIV practices in three large Colorado health systems. A focus group guide was developed based on behavioral theory. Focus group transcripts were coded for manifest and latent meaning, and analyzed for themes using a recursive approach that included inductive and deductive analysis. Themes emerged in four content areas related to overdose education and naloxone prescription: knowledge, barriers, benefits and facilitators. Clinical staff (N = 56) demonstrated substantial knowledge gaps about naloxone and its use in outpatient settings. They expressed uncertainty about who to prescribe naloxone to, and identified a range of logistical barriers to its use in practice. Staff also described fears about offending patients and concerns about increased risk behaviors in patients prescribed naloxone. When considering naloxone, some providers reflected critically and with discomfort on their own opioid prescribing. These barriers were balanced by beliefs that prescribing naloxone could prevent death and result in safer opioid use behaviors. Findings from these qualitative focus groups may not be generalizable to other settings. In addition to evidence gaps, logistical and attitudinal barriers will need to be addressed to enhance

  15. Effects of morphine and naloxone on feline colonic transit

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Krevsky, B.; Libster, B.; Maurer, A.H.

    1989-01-01

    The effects of endogenous and exogenous opioid substances on feline colonic transit were evaluated using colonic transit scintigraphy. Naloxone accelerated emptying of the cecum and ascending colon, and filling of the transverse colon. Endogenous opioid peptides thus appear to play a significant role in the regulation of colonic transit. At a moderate dose of morphine cecum and ascending colon transit was accelerated, while at a larger dose morphine had no effect. Since naloxone, a relatively nonspecific opioid antagonist, and morphine, a principally mu opioid receptor agonist, both accelerate proximal colonic transit, a decelerating role for at least one of themore » other opioid receptors is inferred.« less

  16. Preventing deaths from rising opioid overdose in the US – the promise of naloxone antidote in community-based naloxone take-home programs

    PubMed Central

    Straus, Michele M; Ghitza, Udi E; Tai, Betty

    2013-01-01

    The opioid overdose epidemic is an alarming and serious public health problem in the United States (US) that has been escalating for 11 years. The 2011 National Survey on Drug Use and Health (NSDUH) demonstrated that 1 in 20 persons in the US aged 12 or older reported nonmedical use of prescription painkillers in the past year. Prescription drug overdose is now the leading cause of accidental death in the United States – surpassing motor vehicle accidents. Great efforts have been initiated to curb the overdose crisis. Notable examples of these efforts are (1) the Drug Enforcement Administration’s (DEA) National Take-Back Initiative instituted in 2010; (2) the Prescription Drug Monitoring Programs (PDMPs) implemented in most US states to provide practitioners with point-of-care information regarding a patient’s controlled substance use; (3) the naloxone rescue programs initiated in the community to avert mortality resulting from overdose. The use of naloxone rescue strategies has gained traction as an effective measure to prevent fatal opioid overdose. Many US federal-government agencies are working to make these strategies more accessible to first responders and community participants. This new approach faces many challenges, such as accessibility to naloxone and the equipment and training needed to administer it, but none is more challenging than the fear of legal repercussions. US federal-government agencies, local governments, health care institutions, and community-based organizations have begun to tackle these barriers, and naloxone take-home programs have gained recognition as a feasible and sensible preventive strategy to avoid a fatal result from opioid overdose. Although many challenges still need to be overcome, it is important for federal government research agencies to initiate and support independent and rigorous evaluation of these programs to inform policymakers how effective these programs can be to save lives and curb the opioid overdose

  17. Non-randomized intervention study of naloxone co-prescription for primary care patients on long-term opioid therapy for pain

    PubMed Central

    Coffin, Phillip O.; Behar, Emily; Rowe, Christopher; Santos, Glenn-Milo; Coffa, Diana; Bald, Matthew; Vittinghoff, Eric

    2018-01-01

    Background Unintentional overdose involving opioid analgesics is a leading cause of injury-related death in the United States. Objectives To evaluate the feasibility and impact of implementing naloxone prescription to patients prescribed opioids for chronic pain. Design 2-year non-randomized intervention study. Setting 6 safety net primary care clinics in San Francisco. Participants 1985 adults receiving long-term opioids for pain. Intervention Providers and clinic staff were trained and supported in naloxone prescribing. Measurements Outcomes were proportion of patients prescribed naloxone, opioid-related emergency department (ED) visits, and prescribed opioid dose based on chart review. Results 38.2% of 1,985 patients on long-term opioids were prescribed naloxone. Patients on higher doses of opioids and with a past 12-month opioid-related emergency department (ED) visit were independently more likely to be prescribed naloxone. Patients who received a naloxone prescription had 47% fewer opioid-related ED visits per month six months after the receipt of the prescription (IRR=0.53, 95%CI=0.34–0.83, P=0.005) and 63% fewer visits after one year (IRR=0.37, 95%CI=0.22–0.64, P<0.001), compared to patients who did not receive naloxone. There was no net change over time in opioid dose among those who received naloxone compared to those who did not (IRR 1.03, 95% CI 0.91–1.27, P = 0.61). Limitations Results are observational and may not be generalizable beyond safety net settings. Conclusion Naloxone can be co-prescribed to primary care patients prescribed opioids for pain. When advised to offer naloxone to all patients on opioids, providers may prioritize those with established risk factors. Providing naloxone in primary care settings may have ancillary benefits such as reducing opioid-related adverse events. Funding Source National Institutes of Health grant R21DA036776 PMID:27366987

  18. Picrotoxin-induced behavioral tolerance and altered susceptibility to seizures: effects of naloxone.

    PubMed

    Thomas, J; Nores, W L; Pariser, R

    1993-07-01

    The role of opiate mechanisms in the development of tolerance and altered susceptibility to seizures after repeated injections of picrotoxin was investigated. Independent groups of rats were pretreated with naloxone (0.3, 1.0, 3.0, and 10.0 mg/kg) or the saline vehicle and then tested for seizures induced by picrotoxin. The procedure was performed on 3 days at 1-week intervals, for a total of 3 testing days. Latencies to different types of seizures, the duration of postseizure immobility, and the number of focal seizure episodes were scored. In the vehicle-treated group, repeated picrotoxin injections led to an increased susceptibility to myoclonic and focal seizures and to decreased duration of postseizure immobility. Naloxone pretreatment significantly decreased the duration of the postseizure akinetic periods in the 1.0- and 10.0-mg/kg groups across all days, suggesting that endogenous opiates are involved in postseizure immobility and that there are interactions between opiate and picrotoxin mechanisms in some seizure-related behaviors. Naloxone did not alter the development of tolerance or sensitivity, indicating that naloxone-insensitive opiate mechanisms or nonopiate mechanisms may be involved in these processes.

  19. Therapeutic switch to buprenorphine/naloxone from buprenorphine alone: clinical experience in an Italian addiction centre.

    PubMed

    Montesano, Franco; Zaccone, Domenico; Battaglia, Egidio; Genco, Felice; Mellace, Vincenzo

    2010-01-01

    Pharmacological therapy has an important place in the management of opioid dependence. Methadone has been the mainstay of therapy but has a number of limitations. Buprenorphine monotherapy is another option, but misuse and diversion can have negative consequences. The opioid receptor antagonist, naloxone, has been added to buprenorphine to create a combination product with a reduced potential for misuse and diversion. This study evaluated the use of buprenorphine/naloxone for 24 weeks as a pharmacological management of opioid-dependent patients after therapeutic switch from buprenorphine alone. Patients (n = 43) received sublingual tablets of buprenorphine/naloxone. The buprenorphine dose was 2-24 mg (mean 16). Patients saw a physician, including an interview using a structured data sheet, and had counselling each week. Assessments were performed at week 2 (period 1), week 6 (period 2), week 16 (period 3) and week 24 (period 4). Laboratory immunoenzymatic testing was performed weekly to detect drugs in the urine. The management of withdrawal symptoms was rated as 'satisfactory' by 67% of patients during period 1 and 91% during period 4. The majority of patients was highly satisfied with therapy and considered that buprenorphine/naloxone provided good control of cravings. Two patients dropped out of therapy, but all others continued to receive buprenorphine throughout the study. Approximately 50% of patients stated that they disliked the sensory properties (taste, colour, odour and feel) of buprenorphine/naloxone. Adverse effects were as would be expected on the basis of the mechanism of action of buprenorphine (i.e. opioid-induced constipation) and for patients undergoing drug withdrawal. Only 2% of patients attempted the intravenous misuse of buprenorphine/naloxone, none of whom experienced any gratifying effects. Opioid-dependent patients maintained on buprenorphine monotherapy can be safely switched to a sublingual buprenorphine/naloxone tablet without any loss

  20. Neighborhood-Level and Spatial Characteristics Associated with Lay Naloxone Reversal Events and Opioid Overdose Deaths.

    PubMed

    Rowe, Christopher; Santos, Glenn-Milo; Vittinghoff, Eric; Wheeler, Eliza; Davidson, Peter; Coffin, Philip O

    2016-02-01

    There were over 23,000 opioid overdose deaths in the USA in 2013, and opioid-related mortality is increasing. Increased access to naloxone, particularly through community-based lay naloxone distribution, is a widely supported strategy to reduce opioid overdose mortality; however, little is known about the ecological and spatial patterns of the distribution and utilization of lay naloxone. This study aims to investigate the neighborhood-level correlates and spatial relationships of lay naloxone distribution and utilization and opioid overdose deaths. We determined the locations of lay naloxone distribution sites and the number of unintentional opioid overdose deaths and reported reversal events in San Francisco census tracts (n = 195) from 2010 to 2012. We used Wilcoxon rank-sum tests to compare census tract characteristics across tracts adjacent and not adjacent to distribution sites and multivariable negative binomial regression models to assess the association between census tract characteristics, including distance to the nearest site, and counts of opioid overdose deaths and naloxone reversal events. Three hundred forty-two opioid overdose deaths and 316 overdose reversals with valid location data were included in our analysis. Census tracts including or adjacent to a distribution site had higher income inequality, lower percentage black or African American residents, more drug arrests, higher population density, more overdose deaths, and more reversal events (all p < 0.05). In multivariable analysis, greater distance to the nearest distribution site (up to a distance of 4000 m) was associated with a lower count of Naloxone reversals [incidence rate ratio (IRR) = 0.51 per 500 m increase, 95% CI 0.39-0.67, p < 0.001] but was not significantly associated with opioid overdose deaths. These findings affirm that locating lay naloxone distribution sites in areas with high levels of substance use and overdose risk facilitates reversals of opioid overdoses in those

  1. Lay responder naloxone access and Good Samaritan law compliance: postcard survey results from 20 Indiana counties.

    PubMed

    Watson, Dennis P; Ray, Bradley; Robison, Lisa; Huynh, Philip; Sightes, Emily; Walker, La Shea; Brucker, Krista; Duwve, Joan

    2018-04-06

    To reduce fatal drug overdoses, two approaches many states have followed is to pass laws expanding naloxone access and Good Samaritan protections for lay persons with high likelihood to respond to an opioid overdose. Most prior research has examined attitudes and knowledge among lay responders in large metropolitan areas who actively use illicit substances. The present study addresses current gaps in knowledge related to this issue through an analysis of data collected from a broader group of lay responders who received naloxone kits from 20 local health departments across Indiana. Postcard surveys were included inside naloxone kits distributed in 20 Indiana counties, for which 217 returned cards indicated the person completing it was a lay responder. The survey captured demographic information and experiences with overdose, including the use of 911 and knowledge about Good Samaritan protections. Few respondents had administered naloxone before, but approximately one third had witnessed a prior overdose and the majority knew someone who had died from one. Those who knew someone who had overdosed were more likely to have obtained naloxone for someone other than themselves. Also, persons with knowledge of Good Samaritan protections or who had previously used naloxone were significantly more likely to have indicated calling 911 at the scene of a previously witnessed overdose. Primary reasons for not calling 911 included fear of the police and the person who overdosed waking up on their own. Knowing someone who has had a fatal or non-fatal overdose appears to be a strong motivating factor for obtaining naloxone. Clarifying and strengthening Good Samaritan protections, educating lay persons about these protections, and working to improve police interactions with the public when they are called to an overdose scene are likely to improve implementation and outcomes of naloxone distribution and opioid-related Good Samaritan laws.

  2. Naloxone Distribution and Training for Patients with High-Risk Opioid Use in a Veterans Affairs Community-Based Primary Care Clinic.

    PubMed

    Raffel, Katie E; Beach, Leila Y; Lin, John; Berchuck, Jacob E; Abram, Shelly; Markle, Elizabeth; Patel, Shalini

    2018-03-30

    Naloxone distribution has historically been implemented in a community-based, expanded public health model; however, there is now a need to further explore primary care clinic-based naloxone delivery to effectively address the nationwide opioid epidemic. To create a general medicine infrastructure to identify patients with high-risk opioid use and provide 25% of this population with naloxone autoinjector prescription and training within a 6-month period. The quality improvement study was conducted at an outpatient clinic serving 1238 marginally housed veterans with high rates of comorbid substance use and mental health disorders. Patients at high risk of opioid-related adverse events were identified using the Stratification Tool for Opioid Risk Management and were contacted to participate in a one-on-one, 15-minute, hands-on naloxone training led by nursing staff. The number of patients identified at high risk and rates of naloxone training/distribution. There were 67 patients identified as having high-risk opioid use. None of these patients had been prescribed naloxone at baseline. At the end of the intervention, 61 patients (91%) had been trained in the use of naloxone. Naloxone was primarily distributed by licensed vocational nurses (42/61, 69%). This study demonstrates the feasibility of high-risk patient identification and of a primary care-based and nursing-championed naloxone distribution model. This delivery model has the potential to provide access to naloxone to a population of patients with opioid use who may not be engaged in mental health or specialty care.

  3. The possible protective effects of dipyridamole on ischemic reperfusion injury of priapism

    PubMed Central

    Karaguzel, Ersagun; Bayraktar, Cemil; Kutlu, Omer; Yulug, Esin; Mentese, Ahmet; Okatan, Ali Ertan; Colak, Fatih; Ozer, Serap; O.Kazaz, Ilke

    2016-01-01

    ABSTRACT Purpose To investigate the protective effects against ischemia reperfusion injury of dipyridamole in a model of induced priapism in rats. Materials and Methods Twenty-four male Sprague-Dawley rats were divided into four groups, control, P/R, P/R+DMSO and P/R+D. 3ml blood specimens were collected from vena cava inferior in order to determine serum MDA, IMA, TAS, TOS and OSI values, and penile tissue was taken for histopathological examination in control group. Priapism was induced in P/R group. After 1h, priapism was concluded and 30 min reperfusion was performed. In P/R+DMSO group 1ml/kg DMSO was administered intraperitoneally 30 min before reperfusion, while in P/R+D group 10mg/kg dipyridamole was administered intraperitoneally 30 min before reperfusion. Blood and penis specimens were collected after the end of 30 min reperfusion period. Sinusoidal area (µm2), tears in tunica albuginea and injury parameters in sinusoidal endothelium of penis were investigated. Results Histopathological examination revealed no significant changes in term of sinusoidal area. A decrease in tears was observed in P/R+D group compared to P/R group (p<0.05). Endothelial injury decreased in P/R+D group compared to P/R group (p>0.05). There were no significant differences in MDA and IMA values between groups. A significant increase in TOS and OSI values was observed in P/R+D group compared to P/R group. A significant decrease in TAS levels was observed in P/R+D group compared to the P/R group. Conclusions The administration of dipyridamole before reperfusion in ischemic priapism model has a potential protective effect against histopathological injury of the penis. PMID:27136481

  4. Naloxone injections into CA3 disrupt pattern completion associated with relapse from cocaine seeking.

    PubMed

    Kesner, Raymond P; Kirk, Ryan A; Clark, Jascha K; Moore, Angela; Keefe, Kristen

    2016-07-01

    The goal of the present research was to assess the degree to which a pattern completion process operates in cue-induced relapse to cocaine-seeking behavior. Using a novel cue-preference version of the place preference task, rats were administered cocaine or saline, which resulted in a preference for the cocaine-paired cues. After 21 days of abstinence and prior to the preference test, for one group, PBS or naloxone was injected into the CA3 subregion of the hippocampus and for a second group, saline or naloxone was injected systemically. The results indicated that infusions of naloxone into CA3 or systemic injections produced a marked disruption for one and two cues, but had minimal disruptive effect for three or four cues, suggesting that naloxone injections disrupt CA3 function and trigger a deficit in a pattern completion process. Thus, it appears that cue-based activation of the dorsal CA3 might be a critical trigger via a pattern completion process. Based on additional analyses it appears that there is a disruption primarily for object touches for one cue naloxone injections into the CA3 or systemic injections, but no effect on time (spatial context). © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  5. Utilization of Gastrointestinal Simulator, an in Vivo Predictive Dissolution Methodology, Coupled with Computational Approach To Forecast Oral Absorption of Dipyridamole.

    PubMed

    Matsui, Kazuki; Tsume, Yasuhiro; Takeuchi, Susumu; Searls, Amanda; Amidon, Gordon L

    2017-04-03

    Weakly basic drugs exhibit a pH-dependent dissolution profile in the gastrointestinal (GI) tract, which makes it difficult to predict their oral absorption profile. The aim of this study was to investigate the utility of the gastrointestinal simulator (GIS), a novel in vivo predictive dissolution (iPD) methodology, in predicting the in vivo behavior of the weakly basic drug dipyridamole when coupled with in silico analysis. The GIS is a multicompartmental dissolution apparatus, which represents physiological gastric emptying in the fasted state. Kinetic parameters for drug dissolution and precipitation were optimized by fitting a curve to the dissolved drug amount-time profiles in the United States Pharmacopeia apparatus II and GIS. Optimized parameters were incorporated into mathematical equations to describe the mass transport kinetics of dipyridamole in the GI tract. By using this in silico model, intraluminal drug concentration-time profile was simulated. The predicted profile of dipyridamole in the duodenal compartment adequately captured observed data. In addition, the plasma concentration-time profile was also predicted using pharmacokinetic parameters following intravenous administration. On the basis of the comparison with observed data, the in silico approach coupled with the GIS successfully predicted in vivo pharmacokinetic profiles. Although further investigations are still required to generalize, these results indicated that incorporating GIS data into mathematical equations improves the predictability of in vivo behavior of weakly basic drugs like dipyridamole.

  6. Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth: a randomized trial.

    PubMed

    Woody, George E; Poole, Sabrina A; Subramaniam, Geetha; Dugosh, Karen; Bogenschutz, Michael; Abbott, Patrick; Patkar, Ashwin; Publicker, Mark; McCain, Karen; Potter, Jennifer Sharpe; Forman, Robert; Vetter, Victoria; McNicholas, Laura; Blaine, Jack; Lynch, Kevin G; Fudala, Paul

    2008-11-05

    The usual treatment for opioid-addicted youth is detoxification and counseling. Extended medication-assisted therapy may be more helpful. To evaluate the efficacy of continuing buprenorphine-naloxone for 12 weeks vs detoxification for opioid-addicted youth. Clinical trial at 6 community programs from July 2003 to December 2006 including 152 patients aged 15 to 21 years who were randomized to 12 weeks of buprenorphine-naloxone or a 14-day taper (detox). Patients in the 12-week buprenorphine-naloxone group were prescribed up to 24 mg per day for 9 weeks and then tapered to week 12; patients in the detox group were prescribed up to 14 mg per day and then tapered to day 14. All were offered weekly individual and group counseling. Opioid-positive urine test result at weeks 4, 8, and 12. The number of patients younger than 18 years was too small to analyze separately, but overall, patients in the detox group had higher proportions of opioid-positive urine test results at weeks 4 and 8 but not at week 12 (chi(2)(2) = 4.93, P = .09). At week 4, 59 detox patients had positive results (61%; 95% confidence interval [CI] = 47%-75%) vs 58 12-week buprenorphine-naloxone patients (26%; 95% CI = 14%-38%). At week 8, 53 detox patients had positive results (54%; 95% CI = 38%-70%) vs 52 12-week buprenorphine-naloxone patients (23%; 95% CI = 11%-35%). At week 12, 53 detox patients had positive results (51%; 95% CI = 35%-67%) vs 49 12-week buprenorphine-naloxone patients (43%; 95% CI = 29%-57%). By week 12, 16 of 78 detox patients (20.5%) remained in treatment vs 52 of 74 12-week buprenorphine-naloxone patients (70%; chi(2)(1) = 32.90, P < .001). During weeks 1 through 12, patients in the 12-week buprenorphine-naloxone group reported less opioid use (chi(2)(1) = 18.45, P < .001), less injecting (chi(2)(1) = 6.00, P = .01), and less nonstudy addiction treatment (chi(2)(1) = 25.82, P < .001). High levels of opioid use occurred in both groups at follow-up. Four of 83 patients who tested

  7. Reducing drug related deaths: a pre-implementation assessment of knowledge,barriers and enablers for naloxone distribution through general practice

    PubMed Central

    2014-01-01

    Background The Scottish Naloxone Programme aims to reduce Scotland’s high number of drug-related deaths (DRDs) caused by opiate overdose. It is currently implemented through specialist drug services but General Practitioners (GPs) are likely to have contact with drug using patients and their families and are therefore in an ideal position to direct them to naloxone schemes, or provide it themselves. This research gathered baseline data on GP’s knowledge of and willingness to be involved in DRD prevention, including naloxone administration, prior to the implementation of primary care based delivery. Methods Mixed methods were used comprising a quantitative, postal survey and qualitative telephone interviews. A questionnaire was sent to 500 GPs across Scotland. An initial mailing was followed by a reminder. A shortened questionnaire containing seven key questions was posted as a final reminder. Telephone interviews were conducted with 17 GPs covering a range of demographic characteristics and drug user experience. Results A response rate of 55% (240/439) was achieved. There was some awareness of the naloxone programme but little involvement (3.3%), 9% currently provided routine overdose prevention, there was little involvement in displaying overdose prevention information (<20%). Knowledge of DRD risk was mixed. There was tentative willingness to be involved in naloxone prescribing with half of respondents willing to provide this to drug users or friends/family. However half were uncertain GP based naloxone provision was essential to reduce DRDs. Factors enabling naloxone distribution were: evidence of effectiveness, appropriate training, and adding to the local formulary. Interviewees had limited awareness of what naloxone distribution in primary care may involve and considered naloxone supply as a specialist service rather than a core GP role. Wider attitudinal barriers to involvement with this group were expressed. Conclusions There was poor awareness of the

  8. Non-Prescription Naloxone and Syringe Sales in the Midst of Opioid Overdose and Hepatitis C Virus Epidemics: Massachusetts, 2015

    PubMed Central

    Stopka, Thomas J.; Donahue, Ashley; Hutcheson, Marguerite; Green, Traci C.

    2017-01-01

    Objectives To determine the prevalence of non-prescription naloxone and sterile syringe sales, factors associated with non-prescription sales, geospatial access to non-prescription naloxone and syringe selling pharmacies, and targets for potential interventions. Design Cross-sectional study. Setting and Participants Massachusetts has experienced steep increases in reported opioid overdoses and hepatitis C virus (HCV) cases in the past decade. Pharmacists have the potential to play a substantial role in increasing access to non-prescription naloxone and sterile syringes, which can reverse opioid overdoses and decrease HCV transmission, respectively. We completed brief telephone surveys with 809 of 1,042 retail pharmacies across Massachusetts (response rate=77.6%) during 2015 to assess experience with non-prescription sales of naloxone and sterile syringes. Outcome Measures Our primary outcomes were the stocking and selling of naloxone in the pharmacy (yes/no) for non-prescription sales, and non-prescription syringe sales (yes/no). We conducted multivariable regression analyses and created maps using a geographic information system (GIS) to identify factors associated with non-prescription sales of naloxone and sterile syringes, and to improve our understanding geospatial access to pharmacy-based naloxone and syringe sales. Results Over 97% of pharmacies reported selling sterile syringes without requiring a prescription and 45% of pharmacies reported stocking and selling naloxone. Factors associated with non-prescription sales included: hours of operation, experience with and interest in harm reduction activities, and presence in an opioid overdose hotspot. Geographic access to non-prescription sale of sterile syringes is wide-spread, while geospatial access to naloxone is more limited. Training to better understand the benefits, applications, and distribution needs of naloxone is of interest to surveyed pharmacists. Conclusion Access to sterile syringes through non

  9. Messaging to Increase Public Support for Naloxone Distribution Policies in the United States: Results from a Randomized Survey Experiment.

    PubMed

    Bachhuber, Marcus A; McGinty, Emma E; Kennedy-Hendricks, Alene; Niederdeppe, Jeff; Barry, Colleen L

    2015-01-01

    Barriers to public support for naloxone distribution include lack of knowledge, concerns about potential unintended consequences, and lack of sympathy for people at risk of overdose. A randomized survey experiment was conducted with a nationally-representative web-based survey research panel (GfK KnowledgePanel). Participants were randomly assigned to read different messages alone or in combination: 1) factual information about naloxone; 2) pre-emptive refutation of potential concerns about naloxone distribution; and 3) a sympathetic narrative about a mother whose daughter died of an opioid overdose. Participants were then asked if they support or oppose policies related to naloxone distribution. For each policy item, logistic regression models were used to test the effect of each message exposure compared with the no-exposure control group. The final sample consisted of 1,598 participants (completion rate: 72.6%). Factual information and the sympathetic narrative alone each led to higher support for training first responders to use naloxone, providing naloxone to friends and family members of people using opioids, and passing laws to protect people who administer naloxone. Participants receiving the combination of the sympathetic narrative and factual information, compared to factual information alone, were more likely to support all policies: providing naloxone to friends and family members (OR: 2.0 [95% CI: 1.4 to 2.9]), training first responders to use naloxone (OR: 2.0 [95% CI: 1.2 to 3.4]), passing laws to protect people if they administer naloxone (OR: 1.5 [95% CI: 1.04 to 2.2]), and passing laws to protect people if they call for medical help for an overdose (OR: 1.7 [95% CI: 1.2 to 2.5]). All messages increased public support, but combining factual information and the sympathetic narrative was most effective. Public support for naloxone distribution can be improved through education and sympathetic portrayals of the population who stands to benefit from

  10. Naloxone Distribution and Training for Patients with High-Risk Opioid Use in a Veterans Affairs Community-Based Primary Care Clinic

    PubMed Central

    Raffel, Katie E; Beach, Leila Y; Lin, John; Berchuck, Jacob E; Abram, Shelly; Markle, Elizabeth; Patel, Shalini

    2018-01-01

    Context Naloxone distribution has historically been implemented in a community-based, expanded public health model; however, there is now a need to further explore primary care clinic-based naloxone delivery to effectively address the nationwide opioid epidemic. Objective To create a general medicine infrastructure to identify patients with high-risk opioid use and provide 25% of this population with naloxone autoinjector prescription and training within a 6-month period. Design The quality improvement study was conducted at an outpatient clinic serving 1238 marginally housed veterans with high rates of comorbid substance use and mental health disorders. Patients at high risk of opioid-related adverse events were identified using the Stratification Tool for Opioid Risk Management and were contacted to participate in a one-on-one, 15-minute, hands-on naloxone training led by nursing staff. Main Outcome Measures The number of patients identified at high risk and rates of naloxone training/distribution. Results There were 67 patients identified as having high-risk opioid use. None of these patients had been prescribed naloxone at baseline. At the end of the intervention, 61 patients (91%) had been trained in the use of naloxone. Naloxone was primarily distributed by licensed vocational nurses (42/61, 69%). Conclusion This study demonstrates the feasibility of high-risk patient identification and of a primary care-based and nursing-championed naloxone distribution model. This delivery model has the potential to provide access to naloxone to a population of patients with opioid use who may not be engaged in mental health or specialty care. PMID:29616917

  11. Sex differences in opioid use and medical issues during buprenorphine/naloxone treatment.

    PubMed

    Barbosa-Leiker, Celestina; McPherson, Sterling; Layton, Matthew E; Burduli, Ekaterina; Roll, John M; Ling, Walter

    2018-01-01

    There are sex differences in buprenorphine/naloxone clinical trials for opioid use. While women have fewer opioid-positive urine samples, relative to men, a significant decrease in opioid-positive samples was found during treatment for men, but not women. In order to inform sex-based approaches to improve treatment outcomes, research is needed to determine if opioid use, and predictors of opioid use, differs between men and women during treatment. To test for sex differences in opioid use during a buprenorphine/naloxone clinical trial and determine if sex differences exist in the associations between addiction-related problem areas and opioid use over the course of the trial. This secondary data analysis of the National Drug Abuse Treatment Clinical Trials Network (CTN) 0003 examined sex differences (men = 347, women = 169) in opioid-positive samples in a randomized clinical trial comparing 7-day vs. 28-day buprenorphine/naloxone tapering strategies. Addiction-related problem areas were defined by Addiction Severity-Lite (ASI-L) domain composite scores. Women were more likely than men to use opioids during the course of the buprenorphine/naloxone clinical trial (B = .33, p = .01) and medical issues were positively related to submitting an opioid-positive sample during treatment for women (B = 1.67, p = .01). No ASI-L domain composite score was associated with opioid-positive samples during treatment for men. Women were more likely than men to use opioids during the course of the buprenorphine/naloxone clinical trial, and medical issues predicted opioid use during treatment for women but not men. Complementary treatment for medical problems during opioid replacement therapy may benefit women.

  12. Effect of naloxone on the antral motor response to solid food in man.

    PubMed

    Sharpe, G R; Rees, W D; Adrian, T E; Christofides, N D; Bloom, S R

    1987-04-01

    Antroduodenal motor activity was recorded in eight healthy subjects using perfused tubes connected to external strain gauge transducers. Each subject was studied over a 2.5-h period following ingestion of a solid meal, on 2 separate days. Intravenous saline was administered on one day and saline plus naloxone (40 micrograms kg-1 h-1) on the other, in randomized order. Naloxone markedly inhibited the antral motor response to food and this effect was due to decreased amplitude and contractile frequency. The duodenal motor response to solid food and the postprandial rise in serum gastrin and plasma pancreatic polypeptide were not altered by naloxone. These observations suggest that peripheral or central opiate receptors play a role in regulating the antral motor response to food.

  13. 21 CFR 522.1462 - Naloxone hydrochloride injection.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Naloxone hydrochloride injection. 522.1462 Section 522.1462 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... antagonist in dogs. (2) It is administered by intravenous, intramuscular, or subcutaneous injection at an...

  14. 21 CFR 522.1462 - Naloxone hydrochloride injection.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Naloxone hydrochloride injection. 522.1462 Section 522.1462 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... antagonist in dogs. (2) It is administered by intravenous, intramuscular, or subcutaneous injection at an...

  15. Relationship between regional myocardial blood flow and thallium-201 distribution in the presence of coronary artery stenosis and dipyridamole-induced vasodilation.

    PubMed Central

    Mays, A E; Cobb, F R

    1984-01-01

    This study assesses the relationship between the distribution of thallium-201 and myocardial blood flow during coronary vasodilation induced by intravenous dipyridamole in canine models of partial and complete coronary artery stenosis. 10 dogs were chronically instrumented with catheters in the left atrium and aorta and with a balloon occluder and electromagnetic flow probe on the proximal left circumflex coronary artery. Regional myocardial blood flow was measured during control conditions with radioisotope-labeled microspheres, and the phasic reactive hyperemic response to a 20-s transient occlusion was then recorded. Dipyridamole was then infused intravenously until phasic coronary blood flow increased to match peak hyperemic values. The left circumflex coronary artery was either partially occluded to reduce phasic blood flow to control values (group 1) or it was completely occluded (group 2), and thallium-201 and a second microsphere label were injected. 5 min later, the animals were sacrificed, the left ventricle was sectioned into 1-2-g samples, and thallium-201 activity and regional myocardial blood flow were measured. Curvilinear regression analyses between thallium-201 localization and myocardial blood flow during dipyridamole infusion demonstrated a slightly better fit to a second- as compared with a first-order model, indicating a slight roll-off of thallium activity as myocardial blood flow increases. During the dipyridamole infusion, the increases in phasic blood flow, the distributions of regional myocardial blood flow, and the relationships between thallium-201 localization and regional blood flow were comparable to values previously observed in exercising dogs with similar occlusions. These data provide basic validation that supports the use of intravenous dipyridamole and thallium-201 as an alternative to exercise stress and thallium-201 for evaluating the effects of coronary occlusive lesions on the distribution of regional myocardial blood flow

  16. Synthesis of a new photoreactive derivative of dipyridamole and its use in the manufacture of artificial surfaces with low thrombogenicity.

    PubMed

    Aldenhoff, Y B; Pijpers, A P; Koole, L H

    1997-01-01

    Photoimmobilization of dipyridamole (Persantin) was accomplished through the use of a new synthetic conjugate molecule, 1. Persantin is a powerful inhibitor of platelet activation and aggregation and is widely used as a vasodilator. Conjugate 1 consists of triply protected dipyridamole [three of the four hydroxyl groups carry a tert-butyldimethylsilyl (TBDMS) protective group) and the photoreactive 4-azidobenzoyl group. A short hydrophilic spacer chain, derived from triethylene glycol, separates the protected dipyridamole system and the photoreactive group. Compound 1 was immobilized on polyurethane sheets (Pellethane D-55) through irradiation with ultraviolet (UV) light, and the protective groups were removed afterward. The resulting modified polyurethane surfaces were characterized by different physicochemical techniques: UV extinction, contact angle measurements (captive bubble technique), and X-ray photoelectron spectroscopy (XPS). The UV extinction measurements showed the presence of 13 +/- 1 nmol of immobilized dipyridamole/cm2. The contact angle measurements revealed that the modified surface was markedly more hydrophilic than the control (i.e. unmodified polyurethane). XPS measurements clearly established the presence of immobilized dipyridamole in the outermost layers of the modified surface. This was especially clear from the XPS spectra recorded at a low take-off angle (approximately 6 degrees). Furthermore, the XPS spectra showed that the TBDMS protective groups had been quantitatively removed during the deprotection/washing treatment. The in vitro blood compatibility of the modified surface was studied with the thrombin generation assay as developed in our group, as well as with scanning electron microscopy. The thrombin generation test produced a lag time of 1275 s for the modified surface, as opposed to 569 s for the control. Scanning electron microscopy showed that far fewer platelets adhere to the modified surface (approximately 7 x 10(3)/mm2) as

  17. Placebo-mediated, Naloxone-sensitive suggestibility of short-term memory performance.

    PubMed

    Stern, Jair; Candia, Victor; Porchet, Roseline I; Krummenacher, Peter; Folkers, Gerd; Schedlowski, Manfred; Ettlin, Dominik A; Schönbächler, Georg

    2011-03-01

    Physiological studies of placebo-mediated suggestion have been recently performed beyond their traditional clinical context of pain and analgesia. Various neurotransmitter systems and immunological modulators have been used in successful placebo suggestions, including Dopamine, Cholecystokinin and, most extensively, opioids. We adhered to an established conceptual framework of placebo research and used the μ-opioid-antagonist Naloxone to test the applicability of this framework within a cognitive domain (e.g. memory) in healthy volunteers. Healthy men (n=62, age 29, SD=9) were required to perform a task-battery, including standardized and custom-designed memory tasks, to test short-term recall and delayed recognition. Tasks were performed twice, before and after intravenous injection of either NaCl (0.9%) or Naloxone (both 0.15 mg/kg), in a double-blind setting. While one group was given neutral information (S-), the other was told that it might receive a drug with suspected memory-boosting properties (S+). Objective and subjective indexes of memory performance and salivary cortisol (as a stress marker) were recorded during both runs and differences between groups were assessed. Short-term memory recall, but not delayed recognition, was objectively increased after placebo-mediated suggestion in the NaCl-group. Naloxone specifically blocked the suggestion effect without interfering with memory performance. These results were not affected when changes in salivary cortisol levels were considered. No reaction time changes, recorded to uncover unspecific attentional impairment, were seen. Placebo-mediated suggestion produced a training-independent, objective and Naloxone-sensitive increase in memory performance. These results indicate an opioid-mediated placebo effect within a circumscribed cognitive domain in healthy volunteers. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. Pain therapy with oxycodone/naloxone prolonged-release combination: case report

    PubMed Central

    Droń, Aleksandra

    2013-01-01

    Pain afflicts patients suffering from many chronic diseases and is present in 80% of cases of patients with advanced cancer who suffer from persistent pain. The aim of the pain treatment is to achieve the maximum analgesic effect while minimizing side effects. The main analgesic agent – morphine is unfortunately a therapy associated with gastrointestinal side effects. It appears that the combination of oxycodone and naloxone available as Targin® (Mundipharma) is an alternative. The paper presents a case of a 45-year-old patient who was treated effectively with oxycodone/naloxone prolonged-release tablets. This treatment has proven to be effective in providing pain and constipation control. PMID:24592131

  19. Pain therapy with oxycodone/naloxone prolonged-release combination: case report.

    PubMed

    Błaszczyk, Feliks; Droń, Aleksandra

    2013-01-01

    Pain afflicts patients suffering from many chronic diseases and is present in 80% of cases of patients with advanced cancer who suffer from persistent pain. The aim of the pain treatment is to achieve the maximum analgesic effect while minimizing side effects. The main analgesic agent - morphine is unfortunately a therapy associated with gastrointestinal side effects. It appears that the combination of oxycodone and naloxone available as Targin(®) (Mundipharma) is an alternative. The paper presents a case of a 45-year-old patient who was treated effectively with oxycodone/naloxone prolonged-release tablets. This treatment has proven to be effective in providing pain and constipation control.

  20. Responsible Management and Use of a Personal Take-Home Naloxone Supply: A Pilot Project

    ERIC Educational Resources Information Center

    McAuley, Andrew; Lindsay, George; Woods, Maureen; Louttit, Derek

    2010-01-01

    Aims: To assess if Scottish drug users, their family and friends could be trained in critical incident management and the safe and effective administration of naloxone. The project also sought to monitor whether drug users can manage their own personal take-home naloxone (THN) supply and use it appropriately in an emergency opiate overdose…

  1. Incidence and Demographics of Post-Operative Naloxone Administration: A 13-Year Experience at a Major Tertiary Teaching Institution.

    PubMed

    Khelemsky, Yury; Kothari, Rishi; Campbell, Neville; Farnad, Shahbaz

    2015-01-01

    Perioperative use of opioids is associated with the risk of opioid-induced respiratory depression. Naloxone is a competitive opioid antagonist typically administered to reverse opioid-induced respiratory depression. Postoperative administration of naloxone may be considered a proxy for significant postoperative opioid-induced respiratory depression and data regarding its use may be utilized as a quality measure. Few large studies have been done to characterize the population and define an incidence of naloxone recipients in the postoperative inpatient setting. We aimed to characterize the demographics of patients receiving postoperative naloxone, as well as the incidence of administration in the first 72 post-operative hours at a large urban academic medical center in the United States. This is a retrospective cohort study. Major urban tertiary teaching institution. The robust electronic record database of The Department of Anesthesiology at The Icahn School of Medicine at Mount Sinai, as well as the institution's data warehouse were instrumental in allowing almost 450,000 surgical cases performed between 2001 and 2014 to be screened for naloxone administration within the first 72 postoperative hours. Organ harvests, outside of OR intubations, cancelled cases, and patients age less than or equal to 18 were excluded from the total case count. Naloxone was administered 433 times in a total of 442,699 postoperative cases. This yielded an incidence of 0.1%. Additionally, the demographics of the group receiving naloxone were described. The mean age was 60, mean body mass index (BMI) was 27, 60% were women, and the mean American Society of Anesthesiologists (ASA) status was 3. Average time to naloxone administration was 21 hours (standard deviation 7) after surgery. Thirteen percent of the cases were emergent. Breakdown of anesthetic technique revealed that 81% of the cases were performed under general anesthesia, 7% with monitored anesthesia care (MAC), and 12% under

  2. Naloxone effects on behavior of inbred mice with different response to emotional stress in open field test.

    PubMed

    Nadorova, A V; Kozlovskaja, M M; Seredenin, S B

    2009-10-01

    Effects of nonspecific opiate receptor antagonist naloxone in doses of 0.1, 0.5, 1.0, 5.0, 10.0 mg/kg on open field behavior and spontaneous motor activity were studied in male BALB/c and C57Bl/6 mice. Differently directed effects of naloxone on behavioral parameters of emotional-stress reaction in BALB/c and C57Bl/6 mice were observed. Naloxone increased motor activity in the open field test in BALB/c mice, but decreased it in C57Bl/6 mice. In the absence of stress, naloxone in the studied dose range did not affect spontaneous motor activity in C57Bl/6 mice, and significantly reduced activity in BALB/c mice in doses 0.5 and 1.0 mg/kg.

  3. Basic and Advanced EMS Providers Are Equally Effective in Naloxone Administration for Opioid Overdose in Northern New England.

    PubMed

    Gulec, Nazey; Lahey, Joseph; Suozzi, James C; Sholl, Matthew; MacLean, Charles D; Wolfson, Daniel L

    2018-01-01

    Overdose mortality from illicit and prescription opioids has reached epidemic proportions in the United States, especially in rural areas. Naloxone is a safe and effective agent that has been shown to successfully reverse the effects of opioid overdose in the prehospital setting. The National EMS Scope of Practice Model currently only recommends advanced life support (ALS) providers to administer naloxone; however, some individual states have expanded this scope of practice to include intranasal (IN) administration of naloxone by basic life support (BLS) providers, including the Northern New England states. This study compares the effectiveness and appropriateness of naloxone administration between BLS and ALS providers. All Vermont, New Hampshire, and Maine EMS patient encounters between April 1, 2014 and December 31, 2016 where naloxone was administered were examined and 3,219 patients were identified. The proportion of successful reversals of opioid overdose, based on improvement in the Glasgow Coma Scale (GCS), respiratory rate (RR), and provider global assessment (GA) of response to medication was compared between BLS and ALS providers using a Chi-Squared statistic, Fisher's exact or Wilcoxon rank-sum test. There was no significant difference in the percent improvement in GCS between BLS and ALS (64% and 64% P = 0.94). There was no significant difference in the percentage of improvement in RR between BLS and ALS (45% and 48% P = 0.43). There was a significant difference in the percentage of improvement of GA between BLS and ALS (80% and 67% P < 0.001). There was no significant difference in determining appropriate cases to administer naloxone where RR < 12 and GCS < 15 between BLS and ALS (42% and 43% P = 0.94). BLS providers were as effective as ALS providers in improving patient outcome measures after naloxone administration and in identifying patients for whom administration of naloxone is appropriate. These findings support expanding the National EMS Scope

  4. Naloxone and rimonabant reduce the reinforcing properties of exercise in rats.

    PubMed

    Rasmussen, Erin B; Hillman, Conrad

    2011-12-01

    Naloxone and rimonabant block neurotransmitter action of some drugs of abuse (such as ethanol, opiates, and nicotine), and thereby reduce drug seeking and self-administration by suppressing the drugs' reinforcing properties. The present study represents an attempt to elucidate whether these drugs may also reduce rewarding properties of other events, in this case, activity-based reinforcement. In Experiment 1, 10 obese and 10 lean Zucker rats pressed a locked door under a progressive ratio schedule of reinforcement that, when unlocked, provided access to a running wheel for 2-min intervals. After baseline breakpoints were established, doses of naloxone (0.3-10 mg/kg) were administered prior to experimental sessions. Obese rats exhibited lower baseline breakpoints for wheel activity, lower response rates, and fewer revolutions compared to lean rats. Naloxone decreased revolutions and response rates for lean and obese rats, but did not reduce breakpoints. In Experiment 2, five Long-Evans rats pressed a door to unlock a wheel for 20 s of wheel activity. Doses of rimonabant (1-10 mg/kg) were administered before some experimental sessions. The highest dose of rimonabant suppressed breakpoints and response rates, but did not affect revolutions. These data suggest that both drugs reduce the reinforcing properties of wheel running, but do so in different manners: naloxone may suppress wheel-based activity (consummatory behavior), but not seeking (appetitive behavior), and rimonabant does the converse. The data also support the role of endocannabinoids in the reinforcing properties of exercise, an implication that is important in terms of CB1 antagonists as a type of pharmacotherapy.

  5. Buprenorphine and Buprenorphine/Naloxone Diversion, Misuse, and Illicit Use: An International Review

    PubMed Central

    Yokell, Michael A.; Zaller, Nickolas D.; Green, Traci C.; Rich, Josiah D.

    2011-01-01

    The diversion, misuse, and non-medically supervised use of buprenorphine and buprenorphine/naloxone by opioid users are reviewed. Buprenorphine and buprenorphine/naloxone are used globally as opioid analgesics and in the treatment of opioid dependency. Diversion of buprenorphine and buprenorphine/naloxone represents a complex medical and social issue, and has been widely documented in various geographical regions throughout the world. We first discuss the clinical properties of buprenorphine and its abuse potential. Second, we discuss its diversion and illicit use on an international level, as well as motivations for those activities. Third, we examine the medical risks and benefits of buprenorphine’s non-medically supervised use and misuse. These risks and benefits include the effect of buprenorphine’s use on HIV risk and the risk of its concomitant use with other medications and drugs of abuse. Finally, we discuss the implications of diversion, misuse, and non-medically supervised use (including potential measures to address issues of diversion); and potential areas for further research. PMID:21466501

  6. In vivo quantitation of platelet deposition on human peripheral arterial bypass grafts using indium-111-labeled platelets. Effect of dipyridamole and aspirin

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Pumphrey, C.W.; Chesebro, J.H.; Dewanjee, M.K.

    Indium-111-labeled autologous platelets, injected 48 hours after operation, were used to evaluate the thrombogenicity of prosthetic material and the effect of platelet inhibitor therapy in vivo. Dacron double-velour (Microvel) aortofemoral artery bifurcation grafts were placed in 16 patients and unilateral polytetrafluoroethylene femoropopliteal grafts were placed in 10 patients. Half the patients in each group received platelet inhibitors before operation (dipyridamole, 100 mg 4 times a day) and after operation (dipyridamole, 75 mg, and acetylsalicylic acid, 325 mg 3 times a day); the rest of the patients served as control subjects. Five-minute scintigrams of the graft region were taken with amore » gamma camera interfaced with a computer 48, 72, and 96 hours after injection of the labeled platelets. Platelet deposition was estimated from the radioactivities of the grafts and expressed as counts per 100 pixels per microcurie injected. Dipyridamole and aspirin therapy significantly reduced the number of platelets deposited on Dacron grafts and prevented platelet accumulation over 3 days. With the small amount of platelet deposition on polytetrafluoroethylene femoropopliteal artery grafts even in control patients, platelet inhibitor therapy had no demonstrable effect on platelet deposition on these grafts. It is concluded that (1) platelet deposition on vascular grafts in vivo can be quantitated by noninvasive methods, and (2) dipyridamole and aspirin therapy reduced platelet deposition on Dacron aortofemoral artery grafts.« less

  7. Naloxone inhibits and morphine potentiates. The adrenal steroidogenic response to ACTH

    NASA Technical Reports Server (NTRS)

    Heybach, J. P.; Vernikos, J.

    1980-01-01

    The adrenal actions were stereospecific since neither the positve stereoisomer of morphine, nor that of naloxone, had any effect on the adrenal response to exogenous adrenocorticotrophic hormone (ACTH). The administration of human beta endorphin to phyophysectomized rats had no effect on the adrenal corticosterone concentration nor did it alter the response of the adrenal gland to ACTH. These results indicate that morphine can potentiate the action of ACTH on the adrenal by a direct, stereospecific, dose dependent mechanism that is prevented by naloxone pretreatment and which may involve competition for ACTH receptors on the corticosterone secreting cells of the adrenal cortex.

  8. The effect of naloxone and cyproheptadine on pulmonary platelet trapping, hypotension, and platelet aggregability in traumatized dogs

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Almqvist, P.; Kuenzig, M.; Schwartz, S.I.

    1983-05-01

    Adult respiratory distress syndrome (ARDS) is a serious complication of trauma and sepsis. We have earlier shown naloxone, an opiate antagonist, and cyproheptadine, an antiserotonin drug, to be effective in reducing pulmonary platelet trapping (PPT), which is thought to play an important role in the evolution of ARDS in endotoxin-shocked dogs. Endorphins are implicated as pathophysiologic factors in shock, and serotonin is a possible mediator of their action. The present study shows naloxone and cyproheptadine to be equally effective in protecting against PPT in dogs subjected to trauma, and when naloxone is given before the trauma it also obviates themore » hypotension associated with trauma. In addition, the naloxone- and cyproheptadine-treated animals did not show the increased platelet aggregability usually seen in traumatized dogs.« less

  9. Comparison of (+)- and (−)-Naloxone on the Acute Psychomotor-Stimulating Effects of Heroin, 6-Acetylmorphine, and Morphine in Mice

    PubMed Central

    Andersen, Jannike Mørch; Boix, Fernando; Bergh, Marianne Skov-Skov; Vindenes, Vigdis; Rice, Kenner C.; Huestis, Marilyn A.; Mørland, Jørg

    2016-01-01

    Toll-like receptor 4 (TLR4) signaling is implied in opioid reinforcement, reward, and withdrawal. Here, we explored whether TLR4 signaling is involved in the acute psychomotor-stimulating effects of heroin, 6-acetylmorphine (6-AM), and morphine as well as whether there are differences between the three opioids regarding TLR4 signaling. To address this, we examined how pretreatment with (+)-naloxone, a TLR4 active but opioid receptor (OR) inactive antagonist, affected the acute increase in locomotor activity induced by heroin, 6-AM, or morphine in mice. We also assessed the effect of pretreatment with (−)-naloxone, a TLR4 and OR active antagonist, as well as the pharmacokinetic profiles of (+) and (−)-naloxone in the blood and brain. We found that (−)-naloxone reduced acute opioid-induced locomotor activity in a dose-dependent manner. By contrast, (+)-naloxone, administered in doses assumed to antagonize TLR4 but not ORs, did not affect acute locomotor activity induced by heroin, 6-AM, or morphine. Both naloxone isomers exhibited similar concentration versus time profiles in the blood and brain, but the brain concentrations of (−)-naloxone reached higher levels than those of (+)-naloxone. However, the discrepancies in their pharmacokinetic properties did not explain the marked difference between the two isomers’ ability to affect opioid-induced locomotor activity. Our results underpin the importance of OR activation and do not indicate an apparent role of TLR4 signaling in acute opioid-induced psychomotor stimulation in mice. Furthermore, there were no marked differences between heroin, 6-AM, and morphine regarding involvement of OR or TLR4 signaling. PMID:27278234

  10. Training law enforcement to respond to opioid overdose with naloxone: Impact on knowledge, attitudes, and interactions with community members.

    PubMed

    Wagner, Karla D; Bovet, L James; Haynes, Bruce; Joshua, Alfred; Davidson, Peter J

    2016-08-01

    Training law enforcement officers (LEOs) to administer naloxone to opioid overdose victims is increasingly part of comprehensive efforts to reduce opioid overdose deaths. Such efforts could yield positive interactions between LEOs and community members and might ultimately help lower overdose death rates. We evaluated a pilot LEO naloxone program by (1) assessing opioid overdose knowledge and attitudes (competency in responding, concerns about naloxone administration, and attitudes towards overdose victims) before and after a 30min training on overdose and naloxone administration, and (2) conducting qualitative interviews with LEOs who used naloxone to respond to overdose emergencies after the training. Eighty-one LEOs provided pre- and post-training data. Nearly all (89%) had responded to an overdose while serving as an LEO. Statistically significant increases were observed in nearly all items measuring opioid overdose knowledge (p's=0.04 to <0.0001). Opioid overdose competencies (p<0.001) and concerns about naloxone administration (p<0.001) significantly improved after the training, while there was no change in attitudes towards overdose victims (p=0.90). LEOs administered naloxone 11 times; nine victims survived and three of the nine surviving victims made at least one visit to substance abuse treatment as a result of a LEO-provided referral. Qualitative data suggest that LEOs had generally positive experiences when they employed the skills from the training. Training LEOs in naloxone administration can increase knowledge and confidence in managing opioid overdose emergencies. Perhaps most importantly, training LEOs to respond to opioid overdose emergencies may have positive effects for LEOs and overdose victims. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Ibogaine interferes with motivational and somatic effects of naloxone-precipitated withdrawal from acutely administered morphine.

    PubMed

    Parke, Linda A; Burton, Page; McDonald, Robert V; Kim, Joseph A; Siegel, Shepard

    2002-02-01

    It has been reported that ibogaine interferes with somatic withdrawal reactions in rats chronically treated with morphine. The present experiments demonstrated that ibogaine also interferes with motivational withdrawal reactions and somatic withdrawal reactions in rats treated with morphine on only two occasions. On each of two conditioning trials, naloxone was administered 24 h following an injection of morphine. Four hours prior to each naloxone administration, rats were injected with either ibogaine or saline. In two experiments, ibogaine interfered with naloxone-precipitated withdrawal. In Experiment 1, ibogaine-treated rats displayed a weaker aversion to the withdrawal-paired chamber, and in Experiment 2, ibogaine-treated rats displayed fewer somatic withdrawal reactions than did saline treated rats.

  12. Buprenorphine-naloxone buccal soluble film for the treatment of opioid dependence: current update.

    PubMed

    Soyka, Michael

    2015-02-01

    Opioid dependence is a severe medical disorder with a high psychiatric and somatic comorbidity and mortality rate. The opioid agonist methadone, mixed agonist-antagonist buprenorphine and the combination of buprenorphine with the opioid antagonist naloxone are the first-line maintenance treatments for opioid dependence. Risk of diversion and accidental intoxications, especially in children, are of great concern. To lower these risks, a novel buprenorphine-naloxone film has been developed and introduced in the USA and Australia. This review evaluates the available preclinical and clinical data on the novel buprenorphine-naloxone film for treatment of opioid dependence. Literature was identified through a comprehensive PubMed search. Data sources also included official FDA information and material made public by the manufacturer. Few preclinical and clinical data on safety and efficacy have been published. The pharmacological differences between the novel film and the conventional buprenorphine/naloxone are small. In an experimental study, the new formulation suppressed symptoms of opioid withdrawal. The spectrum of adverse events seems to be similar to that of the conventional sublingual tablet. Recent data show that patients prefer the novel film over the conventional sublingual tablet. Emerging surveillance data indicate a lower risk of accidental poisoning in children compared with the conventional formulation. Further clinical and preclinical data are needed to explore additional possible advantages of the new formulation.

  13. Study of controlled-release floating tablets of dipyridamole using the dry-coated method.

    PubMed

    Chen, Kai; Wen, Haoyang; Yang, Feifei; Yu, Yibin; Gai, Xiumei; Wang, Haiying; Li, Pingfei; Pan, Weisan; Yang, Xinggang

    2018-01-01

    Dipyridamole (DIP), having a short biological half-life, has a narrow absorption window and is primarily absorbed in the stomach. So, the purpose of this study was to prepare controlled-release floating (CRF) tablets of dipyridamole by the dry-coated method. The influence of agents with different viscosity, hydroxypropylmethylcellulose (HPMC) and polyvinylpyrollidon K30 (PVP K30) in the core tablet and low-viscosity HPMC and PVP K30 in the coating layer on drug release, were investigated. Then, a study with a three-factor, three-level orthogonal experimental design was used to optimize the formulation of the CRF tablets. After data processing, the optimized formulation was found to be: 80 mg HPMC K4M in the core tablet, 80 mg HPMC E15 in core tablet and 40 mg PVP K30 in the coating layer. Moreover, an in vitro buoyancy study showed that the optimized formulation had an excellent floating ability and could immediately float without a lag time and this lasted more than 12 h. Furthermore, an in vivo gamma scintigraphic study showed that the gastric residence time of the CRF tablet was about 8 h.

  14. Working together: Expanding the availability of naloxone for peer administration to prevent opioid overdose deaths in the Australian Capital Territory and beyond.

    PubMed

    Lenton, Simon; Dietze, Paul; Olsen, Anna; Wiggins, Nicole; McDonald, David; Fowlie, Carrie

    2015-07-01

    Since the mid-1990s, there have been calls to make naloxone, a prescription-only medicine in many countries, available to heroin and other opioid users and their peers and family members to prevent overdose deaths. In Australia there were calls for a trial of peer naloxone in 2000, yet at the end of that year, heroin availability and harm rapidly declined, and a trial did not proceed. In other countries, a number of peer naloxone programs have been successfully implemented. Although a controlled trial had not been conducted, evidence of program implementation demonstrated that trained injecting drug-using peers and others could successfully administer naloxone to reverse heroin overdose, with few, if any, adverse effects. In 2009 Australian drug researchers advocated the broader availability of naloxone for peer administration in cases of opioid overdose. Industrious local advocacy and program development work by a number of stakeholders, notably by the Canberra Alliance for Harm Minimisation and Advocacy, a drug user organisation, contributed to the rollout of Australia's first prescription naloxone program in the Australian Capital Territory (ACT). Over the subsequent 18 months, prescription naloxone programs were commenced in four other Australian states. The development of Australia's first take-home naloxone program in the ACT has been an 'ice-breaker' for development of other Australian programs. Issues to be addressed to facilitate future scale-up of naloxone programs concern scheduling and cost, legal protections for lay administration, prescribing as a barrier to scale-up; intranasal administration, administration by service providers and collaboration between stakeholders. © 2014 Australasian Professional Society on Alcohol and other Drugs.

  15. Homeless drug users' awareness and risk perception of peer "Take Home Naloxone" use – a qualitative study

    PubMed Central

    Wright, Nat; Oldham, Nicola; Francis, Katharine; Jones, Lesley

    2006-01-01

    Background Peer use of take home naloxone has the potential to reduce drug related deaths. There appears to be a paucity of research amongst homeless drug users on the topic. This study explores the acceptability and potential risk of peer use of naloxone amongst homeless drug users. From the findings the most feasible model for future treatment provision is suggested. Methods In depth face-to-face interviews conducted in one primary care centre and two voluntary organisation centres providing services to homeless drug users in a large UK cosmopolitan city. Interviews recorded, transcribed and analysed thematically by framework techniques. Results Homeless people recognise signs of a heroin overdose and many are prepared to take responsibility to give naloxone, providing prior training and support is provided. Previous reports of the theoretical potential for abuse and malicious use may have been overplayed. Conclusion There is insufficient evidence to recommend providing "over the counter" take home naloxone" to UK homeless injecting drug users. However a programme of peer use of take home naloxone amongst homeless drug users could be feasible providing prior training is provided. Peer education within a health promotion framework will optimise success as current professionally led health promotion initiatives are failing to have a positive impact amongst homeless drug users. PMID:17014725

  16. Reversal of overdose on fentanyl being illicitly sold as heroin with naloxone nasal spray: A case report.

    PubMed

    Fareed, Ayman; Buchanan-Cummings, Ann Marie; Crampton, Kelli; Grant, Angela; Drexler, Karen

    2015-08-01

    This is a case report describing a reversal of fentanyl overdose with naloxone nasal spray. The patient was not aware that he overdosed on fentanyl being sold as heroin. The Veterans Health Administration (VHA) has implemented an initiative to provide education for veterans, their families, friends and significant others about opioid overdose and use of naloxone reversal kits. The Atlanta VA Medical Center adopted this program to reduce the risk of opioid overdose in high risk patients. Over the past year, we provided educational sessions for 63 veterans and their families. We also prescribed 41 naloxone kits. We have received three reports of opioid overdose reversal with use of naloxone kits prescribed by the Atlanta VA Medical Center. The authors recommend that public health administrators and policy makers advocate for the implementation of these programs to reduce the rising number of overdose death in the United States and worldwide. © American Academy of Addiction Psychiatry.

  17. Reversal effect of intra-central amygdala microinjection of L-arginine on place aversion induced by naloxone in morphine conditioned rats.

    PubMed

    Karimi, Sara; Karami, Manizheh; Sahraei, Hedayat; Rahimpour, Mahnaz

    2011-01-01

    Role of nitric oxide (NO) on expression of morphine conditioning using a solely classic task has been proposed previously. In this work, the involvement of NO on the expression of opioid-induced conditioning in the task paired with an injection of naloxone was investigated. Conditioning was established in adult male Wistar rats (weighing 200-250 g) using an unbiased procedure. Naloxone (0.05-0.4 mg/kg, i.p.), a selective antagonist of mu-opioid receptor, was administered once prior to morphine response testing. NO agents were administered directly into the central amygdala (CeA) prior to naloxone injection pre-testing. Morphine (2.5-10 mg/kg, s.c.) produced a significant dose-dependent place preference in experimental animals. When naloxone (0.05-0.4 mg/kg, i.p.) was injected before testing of morphine (5 mg/kg, s.c.) response, the antagonist induced a significant aversion. This response was reversed due to injection of L-arginine (0.3-3 microg/rat), intra-CeA prior to naloxone administration. However, pre-injection of L-NAME (intra-CeA), an inhibitor of NO production, blocked this effect. The finding may reflect that NO in the nucleus participates in morphine plus naloxone interaction.

  18. Decreased coronary vasodilatory capacity in hypertrophic cardiomyopathy determined by split-dose thallium-dipyridamole myocardial scintigraphy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Koga, Y.; Yamaguchi, R.; Ogata, M.

    1990-05-01

    Split-dose thallium-dipyridamole myocardial scintigraphy was performed in patients with nonobstructive hypertrophic cardiomyopathy (HC) who had angiographically normal coronary arteries. The dipyridamole-induced increases in thallium-201 uptake, calculated to evaluate coronary vasodilatory capacity, were significantly lower in 30 patients with HC than in 13 control subjects (177 +/- 58 vs 281 +/- 46%) and the reductions were observed in both the septal and lateral segments. The reductions of the septal segment in HC patients were significantly greater than those in 10 hypertensive patients with comparable degrees of septal hypertrophy. Of patients with HC, 16 had increases in thallium uptake well below themore » normal range. Compared with those having normal increases, these patients had significantly lower exercise duration (11 vs 15 minutes), with 33% having ST depression develop at a workload less than or equal to 80 watts. These data indicate that approximately one-half of patients with HC have impaired coronary vasodilatory capacity that could be an important pathophysiologic abnormality of HC resulting in the development of myocardial ischemia and the impairment of cardiac performance during exercise.« less

  19. No Clinically Relevant Drug-Drug Interactions between Methadone or Buprenorphine-Naloxone and Antiviral Combination Glecaprevir and Pibrentasvir

    PubMed Central

    Kosloski, Matthew P.; Zhao, Weihan; Asatryan, Armen; Kort, Jens; Geoffroy, Pierre

    2017-01-01

    ABSTRACT The combination of glecaprevir (formerly ABT-493), a nonstructural protein 3/4A (NS3/4A) protease inhibitor, and pibrentasvir (formerly ABT-530), an NS5A protein inhibitor, is being developed as treatment for HCV genotype 1 to 6 infection. The pharmacokinetics, pharmacodynamics, safety, and tolerability of methadone or buprenorphine-naloxone when coadministered with the glecaprevir-pibrentasvir combination in HCV-negative subjects on stable opioid maintenance therapy were investigated in a phase 1, single-center, two-arm, multiple-dose, open-label sequential study. Subjects received methadone (arm 1) or buprenorphine-naloxone (arm 2) once daily (QD) per their existing individual prescriptions alone (days 1 to 9) and then in combination with glecaprevir at 300 mg QD and pibrentasvir at 120 mg QD (days 10 to 16) each morning. Dose-normalized exposures were similar with and without glecaprevir and pibrentasvir for (R)- and (S)-methadone (≤5% difference) and for buprenorphine and naloxone (≤24% difference); the norbuprenorphine area under the curve was 30% higher with glecaprevir and pibrentasvir, consistent with maximum and trough plasma concentrations that increased by 21% to 25%. No changes in pupil response, short opiate withdrawal scale score, or desire for drugs questionnaire were observed when glecaprevir and pibrentasvir were added to methadone or buprenorphine-naloxone therapy. No dose adjustment is required when glecaprevir and pibrentasvir are coadministered with methadone or buprenorphine-naloxone. PMID:28807904

  20. Application of human factors engineering (HFE) to the design of a naloxone auto-injector for the treatment of opioid emergencies.

    PubMed

    Raffa, Robert B; Taylor, Robert; Pergolizzi, Joseph V; Nalamachu, Srinivas; Edwards, Eric S; Edwards, Evan T

    2017-02-01

    The increased use of opioids for chronic treatment of pain and the resulting epidemic of opioid overdoses have created a major public health challenge. Parenteral naloxone has been used since the 1970's to treat opioid overdose. Recently, a novel naloxone auto-injector device (EVZIO, kaleo, Inc., Richmond, VA) was approved by the Food and Drug Administration. In this article, we review the Human Factors Engineering (HFE) process used in the development and testing of this novel naloxone auto-injector currently used in nonmedical settings for the emergency treatment of known or suspected opioid overdose. HFE methods were employed throughout the product development process for the naloxone auto-injector including formative and summative studies in order to optimize the auto-injector's user interface, mitigate use-related hazards and increase reliability during an opioid emergency use scenario. HFE was also used to optimize the product's design and user interface in order to reduce or prevent user confusion and misuse. The naloxone auto-injector went through a rigorous HFE process that included perceptual, cognitive, and physical action analysis; formative usability evaluations; use error analysis and summative design validation studies. Applying HFE resulted in the development of a product that is safe, fast, easy and predictably reliable to deliver a potentially life-saving dose of naloxone during an opioid overdose emergency. The naloxone auto-injector may be considered as a universal precaution option for at-risk patients prescribed opioids or those who are at increased risk for an opioid overdose emergency.

  1. HIV testing and sexual risk reduction counseling in office-based buprenorphine/naloxone treatment.

    PubMed

    Edelman, E Jennifer; Moore, Brent A; Caffrey, Sarah; Sikkema, Kathleen J; Jones, Emlyn S; Schottenfeld, Richard S; Fiellin, David A; Fiellin, Lynn E

    2013-01-01

    We assessed the feasibility and preliminary efficacy of human immunodeficiency virus (HIV) testing with sexual risk reduction counseling for opioid-dependent patients initiating office-based buprenorphine/naloxone treatment. We conducted a 14-week randomized, controlled trial with 30 patients (original target of 114) assigned to receive buprenorphine/naloxone induction/stabilization and HIV testing with Brief Sexual Risk Management (BSRM) or Enhanced Sexual Risk Management (ESRM). We evaluated process measures and compared outcomes at baseline and during the 3-month follow-up. Similar proportions of patients receiving BSRM and ESRM underwent HIV testing (93% vs 80%; P = 0.28) and completed counseling sessions (80% vs 67%; P = 0.40). Brief Sexual Risk Management sessions were shorter than ESRM sessions (15.4 vs 23.4 minutes), with comparable manual adherence (P = 0.80). Outcomes did not vary by BSRM versus ESRM. Although the recruitment of opioid-dependent patients with sexual risk behaviors is challenging, HIV testing with sexual risk reduction counseling in office-based buprenorphine/naloxone treatment practice is feasible. Interventions to decrease sexual risk behaviors among a segment of this population are necessary.

  2. Naloxone for heroin, prescription opioid, and illicitly made fentanyl overdoses: Challenges and innovations responding to a dynamic epidemic.

    PubMed

    Fairbairn, Nadia; Coffin, Phillip O; Walley, Alexander Y

    2017-08-01

    Community-based overdose prevention programs first emerged in the 1990's and are now the leading public health intervention for overdose. Key elements of these programs are overdose education and naloxone distribution to people who use opioids and their social networks. We review the evolution of naloxone programming through the heroin overdose era of the 1990's, the prescription opioid era of the 2000's, and the current overdose crisis stemming from the synthetic opioid era of illicitly manufactured fentanyl and its analogues in the 2010's. We present current challenges arising in this new era of synthetic opioids, including variable potency of illicit drugs due to erratic adulteration of the drug supply with synthetic opioids, potentially changing efficacy of standard naloxone formulations for overdose rescue, potentially shorter overdose response time, and reports of fentanyl exposure among people who use drugs but are opioid naïve. Future directions for adapting naloxone programming to the dynamic opioid epidemic are proposed, including scale-up to new venues and social networks, new standards for post-overdose care, expansion of supervised drug consumption services, and integration of novel technologies to detect overdose and deliver naloxone. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Additional diagnostic value of systolic dysfunction induced by dipyridamole stress cardiac magnetic resonance used in detecting coronary artery disease.

    PubMed

    Husser, Oliver; Bodí, Vicente; Sanchís, Juan; Mainar, Luis; Núñez, Julio; López-Lereu, María P; Monmeneu, José V; Ruiz, Vicente; Rumiz, Eva; Moratal, David; Chorro, Francisco J; Llácer, Angel

    2009-04-01

    Dipyridamole stress perfusion cardiovascular magnetic resonance (CMR) is used to detect coronary artery disease (CAD). However, few data are available on the diagnostic value of the systolic dysfunction induced by dipyridamole. This study investigated whether the induction of systolic dysfunction supplements the diagnostic information provided by perfusion imaging in the detection of CAD. Overall, 166 patients underwent dipyridamole CMR and quantitative coronary angiography, with CAD being defined as a stenosis > or =70%. Systolic dysfunction at rest, systolic dysfunction with dipyridamole, induced systolic dysfunction, and stress first-pass perfussion deficit (PD) and delayed enhancement were quantified. In the multivariate analysis, PD (hazard ratio [HR]=1.6; 95% confidence interval [CI], 1.33-1.91;P< .0001) and induced systolic dysfunction (OR=1.8; 95% CI, 1.18-2.28; P< .007) were independently associated with CAD and had a sensitivity and specificity of 92% and 62% and 43% and 96%, respectively. Patients were categorized as having no ischemia (Group 1), PD but no induced systolic dysfunction (Group 2), or induced systolic dysfunction irrespective of PD (Group 3). In Group 3, the prevalence of CAD was higher than in Group 1 or 2 (96% vs. 22% and 79%, respectively; P=.001) and the risk of CAD was two-fold higher than in Group 2 (OR=2.34; 95% CI, 1.07-5.13; P=.034). Compared with Group 2, more hypoperfused segments were observed in Group 3 (6.2+/-2.6 vs. 7.4+/-3.4; P=.044), and more diseased vessels (1.4+/-1.0 vs. 1.8+/-0.9; P=.036). Adding induced systolic dysfunction to perfusion and clinical data improved the multivariate model's C-statistic for predicting CAD (0.81 vs. 0.87; P=.02). Combining induced systolic dysfunction with perfusion imaging increases the diagnostic accuracy of detecting CAD and enables patients with severe ischemia and a high probability of CAD to be identified.

  4. The Implementation of Buprenorphine/Naloxone in College Health Practice

    ERIC Educational Resources Information Center

    DeMaria, Peter A., Jr.; Patkar, Ashwin A.

    2008-01-01

    Opiate abuse and dependence have become important concerns for college healthcare providers. The passage of the Drug Addiction Treatment Act of 2000 and the approval of the combination buprenorphine/naloxone for office-based treatment of opiate dependence have increased the options available for college students and their healthcare providers. The…

  5. Comparison of the cardiovascular effects of meptazinol and naloxone following haemorrhagic shock in rats and cats.

    PubMed Central

    Chance, E.; Paciorek, P. M.; Todd, M. H.; Waterfall, J. F.

    1985-01-01

    The cardiovascular effects of the opioid mixed agonist-antagonist, meptazinol, and the opioid antagonist, naloxone, have been evaluated in conscious rats, anaesthetized rats and anaesthetized cats following the induction of haemorrhagic shock. The mean arterial pressure of conscious rats decreased by 17-29 mmHg following a haemorrhage of 20% of blood volume. Meptazinol (17 mg kg-1, i.m.) administered after haemorrhage evoked a rapid and sustained increase in mean arterial pressure to pre-haemorrhage levels. Naloxone (10 mg kg-1, i.v.) also increased mean arterial pressure to a level significantly higher than post-haemorrhage values. Neither haemorrhage nor subsequent drug treatments evoked significant changes in the heart rates of conscious rats. In anaesthetized rats, 20% haemorrhage evoked decreases in mean arterial pressure, heart rate and cardiac output. Blood flow to the heart, skin, skeletal muscle, kidneys, spleen and liver (arterial) was decreased. Meptazinol and naloxone increased blood pressure and total peripheral resistance, but did not significantly alter heart rate or cardiac output. Hepatic arterial flow decreased further in both drug and vehicle treated groups. In addition meptazinol slightly reduced skeletal muscle flow. In anaesthetized cats 40% haemorrhage decreased mean arterial pressure by 46 +/- 3 mmHg. An intravenous infusion of either meptazinol or naloxone (cumulative 2 mg kg-1, i.v.) partially restored blood pressure. In experimental animal models of haemorrhagic shock, meptazinol has a similar cardiovascular profile to naloxone. The established analgesic activity of meptazinol may confer an advantage in some shock states. PMID:4052729

  6. Effects of phenazepam on the behavior of C57BL/6 and BALB/c mice in the open field test after naloxone pretreatment.

    PubMed

    Seredenin, S B; Nadorova, A V; Kolik, L G; Yarkova, M A

    2013-07-01

    We studied the effects of phenazepam (0.075 mg/kg) after pretreatment (5 minutes before) with naloxone (10 mg/kg) on open-field behavior of C57Bl/6 and BALB/c mice. In ex vivo experiments, we studied the effects of naloxone (1 and 10 mg/kg) on receptor binding of [(3)H]-flunitrazepam by membranes of brain fraction (P1+P2) of C57Bl/6 and BALB/c mice. It was shown that naloxone increased motor activity in the open field in BALB/c mice and decreased this parameter in C57Bl/6 mice. During combined treatment, naloxone potentiated the activating effects of phenazepam on the open-field behavior of BALB/c mice and slightly increased the sedative effect of this drug in C57Bl/6 mice. Naloxone stimulated reception of [(3)H]-flunitrazepam in BALB/c mice and slightly increased radioligand binding in C57Bl/6 mice. These data attest to enhanced reception in benzodiazepine site of GABAA-receptor under conditions of opioid receptor blockade, the presence of anxiolytic or sedative (depending on the phenotype of the response to emotional stress) effect of naloxone, and co-directed effects of naloxone and benzodiazepine tranquilizer on open-field behavior of C57Bl/6 and BALB/c mice.

  7. Facilitators and Barriers to Naloxone Kit Use Among Opioid-Dependent Patients Enrolled in Medication Assisted Therapy Clinics in North Carolina.

    PubMed

    Khatiwoda, Prasana; Proeschold-Bell, Rae Jean; Meade, Christina S; Park, Lawrence P; Proescholdbell, Scott

    2018-01-01

    BACKGROUND Naloxone-an opioid antagonist that reverses the effects of opioids-is increasingly being distributed in non-medical settings. We sought to identify the facilitators of, and barriers to, opioid users using naloxone kits in North Carolina. METHODS In 2015, we administered a 15-item survey to a convenience sample of 100 treatment seekers at 4 methadone/buprenorphine Medication Assisted Therapy (MAT) clinics in North Carolina. RESULTS Seventy-four percent of participants reported having ever gotten a naloxone kit; this percentage was higher for females (81%) than males (63%) ( P = .06). The primary reason given for not having a kit was not knowing where to get one. Only 6% had heard of kits from the media and only 5% received one from a medical provider. Among kit recipients, 56% of both females and males reported mostly or sometimes carrying the kit, with additional participants reporting always. Reasons for not carrying a kit were no longer being around drugs, forgetting it, and the kit being too large. Men discussed the difficulties of carrying the naloxone kits, which are currently too large to fit in a pocket. Ninety-four percent of naloxone users reported intending to call emergency services in case of an overdose emergency. LIMITATIONS Study limitations included a small sample, participants limited to MAT clinics, and a predominantly white sample. CONCLUSIONS MAT treatment seekers reported a willingness to carry and use naloxone kits. Education, outreach, media, and medical providers need to promote naloxone kits. A smaller kit may increase the likelihood of men carrying one. ©2018 by the North Carolina Institute of Medicine and The Duke Endowment. All rights reserved.

  8. Bone Regeneration in Critical Bone Defects Using Three-Dimensionally Printed β-Tricalcium Phosphate/Hydroxyapatite Scaffolds Is Enhanced by Coating Scaffolds with Either Dipyridamole or BMP-2

    PubMed Central

    Ishack, Stephanie; Mediero, Aranzazu; Wilder, Tuere; Ricci, John L.; Cronstein, Bruce N.

    2017-01-01

    Bone defects resulting from trauma or infection need timely and effective treatments to restore damaged bone. Using specialized three-dimensional (3-D) printing technology we have created custom 3-D scaffolds of hydroxyapatite (HA)/Beta-Tri-Calcium Phosphate (β-TCP) to promote bone repair. To further enhance bone regeneration we have coated the scaffolds with dipyridamole, an agent that increases local adenosine levels by blocking cellular uptake of adenosine. 15% HA:85% β-TCP scaffolds were designed using Robocad software, fabricated using a 3-D Robocasting system, and sintered at 1100°C for 4h. Scaffolds were coated with BMP-2 (200ng/ml), Dypiridamole 100µM or saline and implanted in C57B6 and adenosine A2A receptor knockout (A2AKO) mice with 3mm cranial critical bone defects for 2-8 weeks. Dipyridamole release from scaffold was assayed spectrophotometrically. MicroCT and histological analysis were performed. micro-computed tomography (microCT) showed significant bone formation and remodeling in HA/β-TCP- dipyridamole and HA/β-TCP -BMP-2 scaffolds when compared to scaffolds immersed in vehicle at 2, 4 and 8 weeks (n=5 per group; p≤ 0.05, p≤ 0.05 and p≤ 0.01, respectively). Histological analysis showed increased bone formation and a trend toward increased remodeling in HA/β-TCP- dipyridamole and HA/β-TCP-BMP-2 scaffolds. coating scaffolds with dipyridamole did not enhance bone regeneration in A2AKO mice. In conclusion, scaffolds printed with HA/β-TCP promote bone regeneration in critical bone defects and coating these scaffolds with agents that stimulate A2A receptors and growth factors can further enhance bone regeneration. These coated scaffolds may be very useful for treating critical bone defects due to trauma, infection or other causes. PMID:26513656

  9. Safety and tolerability of the switch from buprenorphine to buprenorphine/naloxone in an Italian addiction treatment centre.

    PubMed

    Stimolo, Clementina; Favero, Valentina Del; Zecchinato, Giancarlo; Buson, Roberto; Cusin, Davide; Pellachin, Patrizia; Simonetto, Pamela

    2010-01-01

    Abuse and misuse of pharmacological therapies represent major challenges in the healthcare system, particularly in patients receiving long-acting opioid drugs for the treatment of heroin or opioid addiction. The partial mu-opioid receptor agonist buprenorphine is used to treat opioid dependence, but diversion and misuse may occur. The sublingual combination formulation of buprenorphine and the opioid receptor antagonist naloxone (buprenorphine/naxolone) is associated with a reduced abuse potential, and has been shown to have promising efficacy for the treatment of opioid dependence. This observational study assessed the safety and efficacy of sublingual buprenorphine/naloxone combination therapy in patients with opioid dependence after therapeutic switch from buprenorphine monotherapy. A total of 94 patients being treated with buprenorphine monotherapy (average dose 8 mg/day; mean duration of therapy 840 days) were switched to buprenorphine/naloxone combination therapy. Patients were asked to rate their level of satisfaction with buprenorphine/naloxone combination treatment with respect to the management of withdrawal symptoms, and urinary toxicology tests were carried out before and 14 days after switching to combination therapy. Within 3 months, 75/94 patients (80%) previously treated with buprenorphine monotherapy had switched to sublingual buprenorphine/naloxone combination treatment (average dose buprenorphine 8 mg). Among patients receiving combination treatment for >3 months, 83% were receiving medication either weekly or fortnightly, based on the results of toxicological testing. A reduction in positive urinary toxicology tests was observed in patients within two weeks after being switched to combination treatment (before switch: 28, 9 and 2 positive tests for heroin, cocaine and heroin + cocaine, respectively vs 11, 3 and 1 after switch) and a total of 64 patients of the 75 who switched to combination therapy (85%) were satisfied with the management of

  10. Memantine improves buprenorphine/naloxone treatment for opioid dependent young adults.

    PubMed

    Gonzalez, Gerardo; DiGirolamo, Gregory; Romero-Gonzalez, Mauricio; Smelson, David; Ziedonis, Douglas; Kolodziej, Monika

    2015-11-01

    Opioid use disorders are considered a serious public health problem among young adults. Current treatment is limited to long-term opioid substitution therapy, with high relapse rates after discontinuation. This study evaluated the co-administration of memantine to brief buprenorphine pharmacotherapy as a treatment alternative. 13-week double-blind placebo-controlled trial evaluating 80 young adult opioid dependent participants treated with buprenorphine/naloxone 16-4mg/day and randomized to memantine (15mg or 30mg) or placebo. Primary outcomes were a change in the weekly mean proportion of opioid use, and cumulative abstinence rates after rapid buprenorphine discontinuation on week 9. Treatment retention was not significantly different between groups. The memantine 30mg group was significantly less likely to relapse and to use opioids after buprenorphine discontinuation. Among participants abstinent on week 8, those in the memantine 30mg group (81.9%) were significantly less likely to relapse after buprenorphine was discontinued compared to the placebo group (30%) (p<0.025). Also, the memantine 30mg group had significantly reduced opioid use (mean=0, SEM±0.00) compared to the placebo group (mean=0.33, SEM±0.35; p<0.004) during the last 2 weeks of study participation. Memantine 30mg significantly improved short-term treatment with buprenorphine/naloxone for opioid dependent young adults by reducing relapse and opioid use after buprenorphine discontinuation. Combined short-term treatment with buprenorphine/naloxone may be an effective alternative treatment to long-term methadone or buprenorphine maintenance in young adults. Published by Elsevier Ireland Ltd.

  11. Effects of opiate-like peptides, morphine, and naloxone in the photosensitive baboon, Papio papio.

    PubMed

    Meldrum, B S; Menini, C; Stutzmann, J M; Naquet, R

    1979-07-13

    The effects of intracerebroventricular (i.c.v.) or systemic injections of Met- or Leu-enkephalin, beta-endorphin, FK 33.824 (D-Ala2, MePhe4, Met(O5)-ol-enkephalin) and of morphine and naloxone have been studied in baboons, Papio papio, which spontaneously show photically induced epileptic responses. Animals were chronically implanted with epidural or deep recording electrodes and a cannula in one lateral ventricle, and tested whilst seated in a primate chair. In some animals the natural syndrome was enhanced by the prior administration of DL-allylglycine, 100--200 mg/kg, i.v. Met- or Leu-enkephalin, 1--10 mg, i.c.v., did not lead to any manifest focal or generalized seizure discharges. Nor did it lead to any consistent enhancement or reduction of photically induced myoclonic responses (as tested 5--10 min after injection). beta-Endorphin, 0.1--0.5 mg, i.c.v., did not enhance or impair photically induced myoclonic responses. FK 33.824, 0.1--0.5 mg, i.c.v., depressed respiration and slowed EEG background rhythms for 9--15 h. This was associated with a loss of myoclonic responses to photic stimulation. These effects were reversed for 20--40 min following the injection of naloxone, 1 mg/kg i.m. A depression of respiration and a slowing of EEG rhythms was seen beginning 5--20 min after FK 33.824, 2 or 4 mg/kg, i.v. The higher dose also abolished photically induced myoclonic responses. Naloxone, 1 mg/kg, definitively reversed these effects. Morphine, 5--10 mg i.c.v., tended to increase the latency to onset of generalized myoclonus during photic stimulation. Myoclonic responses were delayed or diminished after morphine, 5 mg/kg, i.m. Naloxone, 1--2 mg/kg i.m., reversed this effect. Naloxone, 0.2--5.0 mg/kg i.m., alone, did not significantly modify photically induced myoclonus, either in animals of low or high initial responsiveness, or in those pretreated with allylglycine.

  12. "Once I'd done it once it was like writing your name": Lived experience of take-home naloxone administration by people who inject drugs.

    PubMed

    McAuley, Andrew; Munro, Alison; Taylor, Avril

    2018-05-23

    The supply of naloxone, the opioid antagonist, for peer administration ('take-home naloxone' (THN)) has been promoted as a means of preventing opioid-related deaths for over 20 years. Despite this, little is known about PWID experiences of take-home naloxone administration. The aim of this study was to advance the evidence base on THN by producing one of the first examinations of the lived-experience of THN use among PWID. Qualitative, face to face, semi-structured interviews were undertaken at a harm reduction service with individuals known to have used take-home naloxone in an overdose situation in a large urban area in Scotland. Interpretative Phenomenological Analysis (IPA) was then applied to the data from these in-depth accounts. The primary analysis involved a total of 8 PWID (seven male, one female) known to have used take-home naloxone. This paper focuses on the two main themes concerning naloxone administration: psychological impacts of peer administration and role perceptions. In the former, the feelings participants encounter at different stages of their naloxone experience, including before, during and after use, are explored. In the latter, the concepts of role legitimacy, role adequacy, role responsibility and role support are considered. This study demonstrates that responding to an overdose using take-home naloxone is complex, both practically and emotionally, for those involved. Although protocols exist, a multitude of individual, social and environmental factors shape responses in the short and longer terms. Despite these challenges, participants generally conveyed a strong sense of therapeutic commitment to using take-home naloxone in their communities. Copyright © 2018 Elsevier B.V. All rights reserved.

  13. Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial.

    PubMed

    Bath, Philip M; Woodhouse, Lisa J; Appleton, Jason P; Beridze, Maia; Christensen, Hanne; Dineen, Robert A; Duley, Lelia; England, Timothy J; Flaherty, Katie; Havard, Diane; Heptinstall, Stan; James, Marilyn; Krishnan, Kailash; Markus, Hugh S; Montgomery, Alan A; Pocock, Stuart J; Randall, Marc; Ranta, Annemarei; Robinson, Thompson G; Scutt, Polly; Venables, Graham S; Sprigg, Nikola

    2018-03-03

    Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67-1·20, p=0·47). By contrast, intensive antiplatelet therapy was

  14. Seizure and electroencephalographic changes in the newborn period induced by opiates and corrected by naloxone infusion.

    PubMed

    da Silva, O; Alexandrou, D; Knoppert, D; Young, G B

    1999-03-01

    To describe the association between opioid administration in the newborn period and neurologic abnormalities. Case reports of two infants who presented with seizure activity and abnormal electroencephalograms associated with opiate administration, and reversed by naloxone. The first was a preterm infant who developed a burst-suppression pattern on the electroencephalogram while receiving a continuous infusion of morphine and muscle paralysis. Naloxone injection during the electroencephalogram recording reversed the burst-suppression pattern. The second was a term infant receiving fentanyl infusion for pain control following surgery, who presented with motor seizure that was only partially controlled with barbiturates. An abnormal electroencephalogram recording during the opiate infusion improved with naloxone administration. Our observations indicate a potential for neurologic abnormalities, including induction of seizure activity and electroencephalogram abnormalities, suggesting caution when opiates are used for sedation and/or pain control in the newborn period.

  15. From Evidence to Policy: The Scottish National Naloxone Programme

    ERIC Educational Resources Information Center

    McAuley, Andrew; Best, David; Taylor, Avril; Hunter, Carole; Robertson, Roy

    2012-01-01

    Drug-related death (DRD) is a major public health problem globally, with rates in Scotland higher than any other UK region and among the highest in Europe. One of the most important public health interventions to emerge aimed at tackling rising DRD rates is the distribution of naloxone, the opioid antagonist, for peer administration. The Scottish…

  16. The effects of meptazinol in comparison with pentazocine, morphine and naloxone in a rat model of anaphylactic shock.

    PubMed Central

    Paciorek, P. M.; Todd, M. H.; Waterfall, J. F.

    1985-01-01

    The actions of meptazinol, pentazocine, morphine and naloxone on the cardiovascular changes accompanying anaphylactic shock were evaluated in ovalbumin-sensitized anaesthetized rats. Pretreatment with meptazinol and pentazocine prevented the fall in mean arterial pressure associated with antigen challenge, whereas morphine and naloxone attenuated but did not completely prevent, this change. None of the drugs significantly altered the antigen-induced decreases in heart rate. All the drugs partially reversed the fall in mean arterial pressure when given after antigen challenge although the activity of naloxone was less marked. Pretreatment with reserpine prevented the restoration of blood pressure by all drugs. Additional experiments with meptazinol showed that pretreatment with phentolamine prevented its pressor action. In pithed non-sensitized rats the frequency-pressor response curve to splanchnic stimulation was shifted to the left by meptazinol and shifted to the right by pentazocine, but the changes were small Morphine and naloxone had no significant effects. It was concluded that opioid mixed agonist-antagonists reverse the cardiovascular changes associated with anaphylactic shock. These effects appear to be mediated by facilitation of sympathetic neurotransmission. PMID:3978318

  17. The effects of meptazinol in comparison with pentazocine, morphine and naloxone in a rat model of anaphylactic shock.

    PubMed

    Paciorek, P M; Todd, M H; Waterfall, J F

    1985-02-01

    The actions of meptazinol, pentazocine, morphine and naloxone on the cardiovascular changes accompanying anaphylactic shock were evaluated in ovalbumin-sensitized anaesthetized rats. Pretreatment with meptazinol and pentazocine prevented the fall in mean arterial pressure associated with antigen challenge, whereas morphine and naloxone attenuated but did not completely prevent, this change. None of the drugs significantly altered the antigen-induced decreases in heart rate. All the drugs partially reversed the fall in mean arterial pressure when given after antigen challenge although the activity of naloxone was less marked. Pretreatment with reserpine prevented the restoration of blood pressure by all drugs. Additional experiments with meptazinol showed that pretreatment with phentolamine prevented its pressor action. In pithed non-sensitized rats the frequency-pressor response curve to splanchnic stimulation was shifted to the left by meptazinol and shifted to the right by pentazocine, but the changes were small Morphine and naloxone had no significant effects. It was concluded that opioid mixed agonist-antagonists reverse the cardiovascular changes associated with anaphylactic shock. These effects appear to be mediated by facilitation of sympathetic neurotransmission.

  18. Findings of a Naloxone Database and its Utilization to Improve Safety and Education in a Tertiary Care Medical Center.

    PubMed

    Rosenfeld, David M; Betcher, Jeffrey A; Shah, Ruby A; Chang, Yu-Hui H; Cheng, Meng-Ru; Cubillo, Efrain I; Griffin, Julia M; Trentman, Terrence L

    2016-03-01

    Analyzing hospital naloxone use may assist in identification of areas for quality and safety improvement. Our primary objective is to quantitate the incidence of hospital naloxone use and to assess certain patient populations at risk. During the years 2008 to 2011, each clinical scenario where naloxone was administered on an in-patient care ward was reviewed. The events were assessed to separate situations where naloxone rescue was effective in reversing opioid-induced intoxication vs. others. Further analysis was conducted to stratify patient populations at greatest risk. Naloxone was administered for well-defined opioid-induced respiratory depression and oversedation 61% of the time, the remainder used for patient deterioration of other etiology. Surgical populations are at risk with an incidence of 3.8/1,000 hospitalized patients, and this is the greatest within 24 hours of surgery. General surgical patients represent the highest surgical patient risk at 5.5/1,000. Medical patients represent lower risk at 2.0/1,000. Patients with patient-controlled analgesia and epidural opioid infusion are high risk at 12.1 and 13.1/1,000 patients, respectively. Many quality and safety interventions were gradually implemented in response to this data and are summarized. These include nursing and provider education, electronic medical record modification, and more stringent patient monitoring practices. Examination of naloxone use can assist in the identification and stratification of patients at risk for opioid-induced respiratory depression and oversedation and can serve as a driver for improvements in hospital patient safety. This information can also guide other institutions interested in similar improvements. © 2015 World Institute of Pain.

  19. Identification of the ENT1 antagonists dipyridamole and dilazep as amplifiers of oncolytic herpes simplex virus-1 replication.

    PubMed

    Passer, Brent J; Cheema, Tooba; Zhou, Bingsen; Wakimoto, Hiroaki; Zaupa, Cecile; Razmjoo, Mani; Sarte, Jason; Wu, Shulin; Wu, Chin-lee; Noah, James W; Li, Qianjun; Buolamwini, John K; Yen, Yun; Rabkin, Samuel D; Martuza, Robert L

    2010-05-15

    Oncolytic herpes simplex virus-1 (oHSV) vectors selectively replicate in tumor cells, where they kill through oncolysis while sparing normal cells. One of the drawbacks of oHSV vectors is their limited replication and spread to neighboring cancer cells. Here, we report the outcome of a high-throughput chemical library screen to identify small-molecule compounds that augment the replication of oHSV G47Delta. Of the 2,640-screened bioactives, 6 compounds were identified and subsequently validated for enhanced G47Delta replication. Two of these compounds, dipyridamole and dilazep, interfered with nucleotide metabolism by potently and directly inhibiting the equilibrative nucleoside transporter-1 (ENT1). Replicative amplification promoted by dipyridamole and dilazep were dependent on HSV mutations in ICP6, the large subunit of ribonucleotide reductase. Our results indicate that ENT1 antagonists augment oHSV replication in tumor cells by increasing cellular ribonucleoside activity. (c)2010 AACR.

  20. Role of vagal afferents in the ventilatory response to naloxone during loaded breathing in the rabbit.

    PubMed

    Delpierre, S; Pugnat, C; Duté, N; Jammes, Y

    1995-02-15

    It was previously shown that inspiratory resistive loading (IRL) increases the cerebrospinal fluid (CSF) level of beta endorphin in awake goats, and also that the slower ventilation induced by injection of this substance into the CSF of anesthetized dogs is suppressed after vagotomy. In the present study, performed on anesthetized rabbits, we evaluated the part played by vagal afferents in the ventilatory response to IRL after opioid receptor blockade by naloxone. During unloaded breathing, naloxone injection did not modify baseline ventilation. Conversely, naloxone partially reversed IRL-induced hypoventilation through an increase in respiratory rate. This effect was abolished after either vagotomy or cold blockade of large vagal fibers, but it persisted after procaine blockade of thin vagal fibers. These results suggest that pulmonary stretch receptors, which are connected to some large vagal afferent fibers, would play a major role in the ventilatory response to IRL under opioid receptor inhibition.

  1. Bone regeneration in critical bone defects using three-dimensionally printed β-tricalcium phosphate/hydroxyapatite scaffolds is enhanced by coating scaffolds with either dipyridamole or BMP-2.

    PubMed

    Ishack, Stephanie; Mediero, Aranzazu; Wilder, Tuere; Ricci, John L; Cronstein, Bruce N

    2017-02-01

    Bone defects resulting from trauma or infection need timely and effective treatments to restore damaged bone. Using specialized three-dimensional (3D) printing technology we have created custom 3D scaffolds of hydroxyapatite (HA)/beta-tri-calcium phosphate (β-TCP) to promote bone repair. To further enhance bone regeneration we have coated the scaffolds with dipyridamole, an agent that increases local adenosine levels by blocking cellular uptake of adenosine. Nearly 15% HA:85% β-TCP scaffolds were designed using Robocad software, fabricated using a 3D Robocasting system, and sintered at 1100°C for 4 h. Scaffolds were coated with BMP-2 (200 ng mL -1 ), dypiridamole 100 µM or saline and implanted in C57B6 and adenosine A2A receptor knockout (A2AKO) mice with 3 mm cranial critical bone defects for 2-8 weeks. Dipyridamole release from scaffold was assayed spectrophotometrically. MicroCT and histological analysis were performed. Micro-computed tomography (microCT) showed significant bone formation and remodeling in HA/β-TCP-dipyridamole and HA/β-TCP-BMP-2 scaffolds when compared to scaffolds immersed in vehicle at 2, 4, and 8 weeks (n = 5 per group; p ≤ 0.05, p ≤ 0.05, and p ≤ 0.01, respectively). Histological analysis showed increased bone formation and a trend toward increased remodeling in HA/β-TCP- dipyridamole and HA/β-TCP-BMP-2 scaffolds. Coating scaffolds with dipyridamole did not enhance bone regeneration in A2AKO mice. In conclusion, scaffolds printed with HA/β-TCP promote bone regeneration in critical bone defects and coating these scaffolds with agents that stimulate A2A receptors and growth factors can further enhance bone regeneration. These coated scaffolds may be very useful for treating critical bone defects due to trauma, infection or other causes. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 366-375, 2017. © 2015 Wiley Periodicals, Inc.

  2. Patient perspectives on an opioid overdose education and naloxone distribution program in the U.S. Department of Veterans Affairs.

    PubMed

    Oliva, Elizabeth M; Nevedal, Andrea; Lewis, Eleanor T; McCaa, Matthew D; Cochran, Michael F; Konicki, P Eric; Davis, Corey S; Wilder, Christine

    2016-01-01

    In an effort to prevent opioid overdose mortality among Veterans, Department of Veterans Affairs (VA) facilities began implementing opioid overdose education and naloxone distribution (OEND) in 2013 and a national program began in 2014. VA is the first national health care system to implement OEND. The goal of this study is to examine patient perceptions of OEND training and naloxone kits. Four focus groups were conducted between December 2014 and February 2015 with 21 patients trained in OEND. Participants were recruited from a VA residential facility in California with a substance use disorder treatment program (mandatory OEND training) and a homeless program (optional OEND training). Data were analyzed using matrices and open and closed coding approaches to identify participants' perspectives on OEND training including benefits, concerns, differing opinions, and suggestions for improvement. Veterans thought OEND training was interesting, novel, and empowering, and that naloxone kits will save lives. Some veterans expressed concern about using syringes in the kits. A few patients who never used opioids were not interested in receiving kits. Veterans had differing opinions about legal and liability issues, whether naloxone kits might contribute to relapse, and whether and how to involve family in training. Some veterans expressed uncertainty about the effects of naloxone. Suggested improvements included active learning approaches, enhanced training materials, and increased advertisement. OEND training was generally well received among study participants, including those with no indication for a naloxone kit. Patients described a need for OEND and believed it could save lives. Patient feedback on OEND training benefits, concerns, opinions, and suggestions provides important insights to inform future OEND training programs both within VA and in other health care settings. Training is critical to maximizing the potential for OEND to save lives, and this study

  3. [Effects of naloxone on the expression of stem cell factor and C-kit receptor in combined oxygen-glucose deprivation of primary cultured human embryonic neuron in vitro].

    PubMed

    Zhu, Bo; Li, Lan-ying; Lü, Guo-yi; Xue, Yu-liang; Ye, Tie-hu

    2010-04-01

    To explore the effects of naloxone on the expression of c-kit receptor (c-kit R) and its ligand stem cell factor (SCF) in human embryo neuronal hypoxic injury. Serum-free cerebral cortical cultures prepared from embryonic human brains were deprived of both oxygen and glucose which would set up an environment more likely with that of in vivo ischemic injury. Neurons in 24-well culture plates were randomly divided into four groups: control group, hypoxia group, naloxone 0.5 microg/ml group and naloxone 10 microg/ml group. MTT assay and biological analysis were performed to study the cell death and the changes of extracellular concentrations of lactate dehydrogenase (LDH) after combined oxygen-glucose deprivation. Neurons in 25 ml culture flasks were also randomly allocated into four groups as previously described. Intracellular total RNA were extracted at different time points: pre-hypoxia, immediately after hypoxia, and 3, 6, 12, and 24 hours after reoxygenation. The changes of SCF/c-kit R mRNA expression in hypoxic neurons treated with different concentrations of naloxone pre and post oxygen-glucose deprivation were determined with RT-PCR. The cell vitality detected by MTT assay decreased significantly in hypoxia group and naloxone 0.5 microg/ml group when compared with control group (P<0.01), while no significant difference was found between naloxone 0.5 microg/ml group and hypoxia group or between naloxone 10 microg/ml group and control group. Extracellular concentration of LDH significantly increased in hypoxia group (P<0.05), while no difference was found between naloxone 0.5 microg/ml group and control group, between naloxone 0.5 microg/ml and hypoxia group, or between naloxone 10 microg/ml and control group (all P>0.05). Immediately after oxygen-glucose deprivation, the expression of SCF/c-kit R mRNA increased significantly (P<0.01). Among those the expression of SCF presented a distribution of double-peak value within 24 hours. After treated with different

  4. Propranolol blocks the stimulatory effects of naloxone on ventilation and oxygen consumption in hamsters.

    PubMed

    Schlenker, E H; Eikanger, J

    1997-06-01

    The purposes of these studies were: 1) to determine the effects of various doses of propranolol, a nonspecific beta-adrenergic antagonist, on ventilation, oxygen consumption, and body temperature in hamsters, and 2) to test the hypothesis that in hamsters the stimulatory effects of naloxone, an opioid receptor antagonist, on ventilation and oxygen consumption occur, at least in part, through the release of catecholamines that act via beta-adrenergic receptors. Propranolol, a non-specific beta adrenergic receptor antagonist, at a 20 mg/kg depressed body temperature, oxygen consumption, tidal volume, and ventilation relative to saline. The lower dose of 10 mg/kg had only transitory effects on tidal volume at 60 min and ventilation at 30 min post-injection-Naloxone (1 mg/kg) relative to saline stimulated ventilation and oxygen consumption. These effects were blocked by propranolol pretreatment. The results of these experiments demonstrate that in the hamster, 1) body temperature, oxygen consumption, and ventilation appear to be modulated by beta-adrenergic receptors, and 2) the stimulatory effects of naloxone on oxygen consumption and ventilation may occur through the interaction of endogenous opioids and beta-adrenergic receptor systems.

  5. Knowledge of Opioid Overdose and Attitudes to Supply of Take-Home Naloxone Among People with Chronic Noncancer Pain Prescribed Opioids.

    PubMed

    Nielsen, Suzanne; Peacock, Amy; Lintzeris, Nicholas; Bruno, Raimondo; Larance, Briony; Degenhardt, Louisa

    2018-03-01

    Take-home naloxone (THN) is recommended in response to pharmaceutical opioid-related mortality. Some health professionals are reluctant to discuss THN for fear of causing offense. The aims of this study were to assess knowledge of opioid overdose and attitudes toward THN for opioid overdose reversal in people with chronic noncancer pain (CNCP). Prospective cohort study. Australia, September to October 2015. A subset of participants (N = 208) from a cohort of people prescribed restricted opioids for CNCP. Questions added in the two-year telephone interviews examined knowledge of overdose symptoms and attitudes toward community supply of naloxone. Associations with overdose risk factors and naloxone supply eligibility criteria with attitudes toward naloxone were explored. Fourteen percent reported ever experiencing opioid overdose symptoms. Participants correctly identified fewer than half of the overdose signs and symptoms. After receiving information on naloxone, most participants (60%), thought it was a "good" or "very good" idea. Few participants reported that they would be "a little" (N = 21, 10%) or "very" offended (N = 7, 3%) if their opioid prescriber offered them naloxone. Positive attitudes toward THN were associated with male gender (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.09-3.50), past year cannabis use (OR = 2.52, 95% CI = 1.03-6.16), and past year nicotine use (OR = 2.11, 95% CI = 1.14-3.91). Most participants had positive attitudes toward THN but low knowledge about opioid overdose symptoms. Strategies for educating patients and their caregivers on opioid toxicity are needed. THN may be best targeted toward those with risk factors in terms of overdose prevention and acceptability.

  6. Retrospective Analysis of Opioid Medication Incidents Requiring Administration of Naloxone

    PubMed Central

    Neil, Katherine; Marcil, Allison; Kosar, Lynette; Dumont, Zack; Ruda, Lisa; McMillan, Kaitlyn

    2013-01-01

    Background: Opioid analgesics are high-alert medications known to cause adverse drug events. Objectives: The purpose of this study was to determine the cause of opioid incidents requiring administration of naloxone, an opioid reversal agent. The specific objectives were to determine the number of opioid incidents and the proportion of incidents documented through occurrence reporting and to characterize the incidents by phase in the medication-use process, by type of incident, and by drug responsible for toxic effects. Methods: A retrospective chart analysis was conducted using records from 2 acute care centres in the Regina Qu’Appelle Health Region. The study included inpatients who received naloxone for reversal of opioid toxicity resulting from licit, in-hospital opioid use. Cases were classified as preventable or nonpreventable. Preventable cases were analyzed to determine the phase of the medication-use process during which the incident occurred. These cases were also grouped thematically by the type of incident. The drug most likely responsible for opioid toxicity was determined for each case. The proportion of cases documented by occurrence reporting was also noted. Results: Thirty-six cases involving administration of naloxone were identified, of which 29 (81%) were deemed preventable. Of these 29 preventable cases, the primary medication incident occurred most frequently in the prescribing phase (23 [79%]), but multiple phases were often involved. The cases were grouped into 6 themes according to the type of incident. Morphine was the drug that most frequently resulted in toxic effects (18 cases [50%]). Only two of the cases (5.6%) were documented by occurrence reports. Conclusion: Preventable opioid incidents occurred in the acute care centres under study. A combination of medication safety initiatives involving multiple disciplines may be required to decrease the incidence of these events and to better document their occurrence. PMID:24159230

  7. Qualitative assessment of take-home naloxone program participant and law enforcement interactions in British Columbia.

    PubMed

    Deonarine, Andrew; Amlani, Ashraf; Ambrose, Graham; Buxton, Jane A

    2016-05-21

    The British Columbia take-home naloxone (BCTHN) program has been in operation since 2012 and has resulted in the successful reversal of over 581 opioid overdoses. The study aims to explore BCTHN program participant perspectives about the program, barriers to participants contacting emergency services (calling "911") during an overdose, and perspectives of law enforcement officials on naloxone administration by police officers. Two focus groups and four individual interviews were conducted with BCTHN program participants; interviews with two law enforcement officials were also conducted. Qualitative analysis of all transcripts was performed. Positive themes about the BCTHN program from participants included easy to understand training, correcting misperceptions in the community, and positive interactions with emergency services. Potential barriers to contacting emergency services during an overdose include concerns about being arrested for outstanding warrants or for other illegal activities (such as drug possession) and confiscation of kits. Law enforcement officials noted that warrants were complex situational issues, kits would normally not be confiscated, and admitted arrests for drug possession or other activities may not serve the public good in an overdose situation. Law enforcement officials were concerned about legal liability and jurisdictional/authorization issues if naloxone administration privileges were expanded to police. Program participants and law enforcement officials expressed differing perspectives about warrants, kit confiscation, and arrests. Facilitating communication between BCTHN program participants and other stakeholders may address some of the confusion and remove potential barriers to further improving program outcomes. Naloxone administration by law enforcement would require policies to address jurisdiction/authorization and liability issues.

  8. Implementing take-home naloxone in an urban community pharmacy.

    PubMed

    Akers, Joshua L; Hansen, Ryan N; Oftebro, Ryan D

    Morbidity and mortality associated with opioid use have increased across the nation, growing into what can only be described as an epidemic. In Washington State between 2002 and 2004, the statewide death rate attributed to any opioid was 6.6 per 100,000 people, but between 2011 and 2013 it increased to 8.6 per 100,000 people. Pharmacies provide a unique access point for harm reduction services to patients due to their ease of accessibility in the community. In development of a take-home naloxone (THN) program, there were multiple areas that needed to be considered. These included product selection, collaborative practice agreements, training format and materials, managing patient and provider expectations, partnerships, and community perception of the service. Initial demographics from our experience of people obtaining THN showed a significant difference in the median age from other available programs in the area (57 years vs. 34, 35, and 31). These people tended to be bystanders, instead of end users of opioids, which led to redirecting marketing of our program. We provided community and group trainings for various organizations around the greater Seattle area. We have trained approximately 1400 unique individuals on how to recognize and respond to an opioid overdose, and how to administer naloxone. One organization reports 20 successful overdose rescues from 99 kits (100% intranasal route) dispensed by our pharmacy (20.2% rescue rate). Since 2012 when our THN program began, we have seen growth of these programs across the state. Based on data through 2015, deaths from heroin in King County have decreased for the first time in the last 7 years, and the number of people seeking treatment for heroin addiction has increased. Take-home naloxone programs can be successfully implemented into community pharmacies to increase access and awareness of opioid overdose recognition and response. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc

  9. Ultralow Dose of Naloxone as an Adjuvant to Intrathecal Morphine Infusion Improves Perceived Quality of Sleep but Fails to Alter Persistent Pain

    PubMed Central

    Lundborg, Christopher; Bjersing, Jan; Dahm, Peter; Hansson, Elisabeth; Biber, Björn

    2015-01-01

    Introduction: This randomized, cross-over, double-blind, controlled study of continuous intrathecal morphine administration in patients with severe, long-term pain addresses whether the supplementation of low doses of naloxone in this setting is associated with beneficial clinical effects. Methods: All of the study subjects (n=11) provided informed consent and were recruited from a subset of patients who were already undergoing long-term treatment with continuous intrathecal morphine because of difficult-to-treat pain. The patients were (in a randomized order) also given intrathecal naloxone (40 ng/24 h or 400 ng/24 h). As control, the patients’ ordinary dose of morphine without any additions was used. The pain (Numeric Rating Scale, NRS) during activity, perceived quality of sleep, level of activity, and quality of life as well as the levels of several proinflammatory and anti-inflammatory cytokines in the blood were assessed. The prestudy pain (NRS during activity) in the study group ranged from 3 to 10. Results: A total of 64% of the subjects reported improved quality of sleep during treatment with naloxone at a dose of 40 ng per 24 hours as compared with 9% with sham treatment (P=0.024). Although not statistically significant, pain was reduced by 2 NRS steps or more during supplemental treatment with naloxone in 36% of subjects when using the 40 ng per 24 hours dose and in 18% of the subjects when using naloxone 400 ng per 24 hours dose. The corresponding percentage among patients receiving unaltered treatment was 27%. Conclusions: To conclude, the addition of an ultralow dose of intrathecal naloxone (40 ng/24 h) to intrathecal morphine infusion in patients with severe, persistent pain improved perceived quality of sleep. We were not able to show any statistically significant effects of naloxone on pain relief, level of activity, or quality of life. PMID:25629634

  10. Naloxone administration for suspected opioid overdose: An expanded scope of practice by a basic life support collegiate-based emergency medical services agency.

    PubMed

    Jeffery, Ryan M; Dickinson, Laura; Ng, Nicholas D; DeGeorge, Lindsey M; Nable, Jose V

    2017-04-01

    Opioid abuse is a growing and significant public health concern in the United States. Naloxone is an opioid antagonist that can rapidly reverse the respiratory depression associated with opioid toxicity. Georgetown University's collegiate-based emergency medical services (EMS) agency recently adopted a protocol, allowing providers to administer intranasal naloxone for patients with suspected opioid overdose. While normally not within the scope of practice of basic life support prehospital agencies, the recognition of an increasing epidemic of opioid abuse has led many states, including the District of Columbia, to expand access to naloxone for prehospital providers of all levels of training. In particular, intranasal naloxone is a method of administering this medication that potentially avoids needlestick injuries among EMS providers. Universities with collegiate-based EMS agencies are well positioned to provide life-saving treatments for patients acutely ill from opioid overdose.

  11. Aspirin plus dipyridamole has the highest surface under the cumulative ranking curves (SUCRA) values in terms of mortality, intracranial hemorrhage, and adverse event rate among 7 drug therapies in the treatment of cerebral infarction.

    PubMed

    Zhang, Jian-Jun; Liu, Xin

    2018-03-01

    The standardization for the clinical use of drug therapy for cerebral infarction (CI) has not yet determined in some aspects. In this paper, we discussed the efficacies of different drug therapies (aspirin, aspirin plus dipyridamole, aspirin plus clopidogrel, aspirin plus warfarin, cilostazol, warfarin, and ticlopidine) for CI. We searched databases of PubMed and Cochrane Library from the inception to April, 2017, randomized controlled trials (RCTs) met the inclusion and exclusion criteria were enrolled in this study. The network meta-analysis integrated evidences of direct and indirect comparisons to assess odd ratios (OR) and surface under the cumulative ranking curves (SUCRA) value. Thirteen eligible RCTs including 7 drug therapies were included into this network meta-analysis. The network meta-analysis results showed that CI patients who received aspirin plus dipyridamole presented lower mortality when compared with those received aspirin plus clopidogrel (OR = 0.46, 95% CI = 0.18-0.99), indicating aspirin plus dipyridamole therapy had better efficacy for CI. As for intracranial hemorrhage (ICH), stroke recurrence, and adverse event (AE) rate, there were no significant differences of efficacy among 7 drug therapies. Besides, SUCRA values demonstrated that in the 7 drug therapies, aspirin plus dipyridamole therapy was more effective than others (mortality: 80.67%; ICH: 76.6%; AE rate: 90.2%). Our findings revealed that aspirin plus dipyridamole therapy might be the optimum one for patients with CI, which could help to improve the survival of CI patients.

  12. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke.

    PubMed

    Sacco, Ralph L; Diener, Hans-Christoph; Yusuf, Salim; Cotton, Daniel; Ounpuu, Stephanie; Lawton, William A; Palesch, Yuko; Martin, Reneé H; Albers, Gregory W; Bath, Philip; Bornstein, Natan; Chan, Bernard P L; Chen, Sien-Tsong; Cunha, Luis; Dahlöf, Björn; De Keyser, Jacques; Donnan, Geoffrey A; Estol, Conrado; Gorelick, Philip; Gu, Vivian; Hermansson, Karin; Hilbrich, Lutz; Kaste, Markku; Lu, Chuanzhen; Machnig, Thomas; Pais, Prem; Roberts, Robin; Skvortsova, Veronika; Teal, Philip; Toni, Danilo; Vandermaelen, Cam; Voigt, Thor; Weber, Michael; Yoon, Byung-Woo

    2008-09-18

    Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens--aspirin plus extended-release dipyridamole (ASA-ERDP) versus clopidogrel. In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned. A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA-ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA-ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11). The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. (ClinicalTrials.gov number, NCT00153062.) 2008 Massachusetts Medical Society

  13. Pharmaceutical and pharmacokinetic characterization of a novel sublingual buprenorphine/naloxone tablet formulation in healthy volunteers.

    PubMed

    Fischer, Andreas; Jönsson, Martin; Hjelmström, Peter

    2015-01-01

    Bitter taste, as well as dissolve time, presents a significant challenge for the acceptability of formulations for oral transmucosal drug delivery. To characterize a novel sublingual tablet formulation of buprenorphine/naloxone with regards to pharmacokinetics, dissolve time and formulation acceptability. Dry mixing techniques were employed to produce a small and fast dissolving buprenorphine/naloxone sublingual tablet formulation, OX219 (Zubsolv®), using sucralose and menthol as sweetener and flavor to mask the bitter taste of the active ingredients. Two cross-over studies were performed in healthy volunteers to evaluate pharmacokinetics, dissolve time and acceptability of OX219 5.7/1.4 mg tablets compared to the commercially available buprenorphine/naloxone formulations Suboxone® tablets and films (8/2 mg). Buprenorphine exposure was equivalent in OX219 and Suboxone tablets. Sublingual dissolve times were significantly shorter for OX219 than for Suboxone tablets and were similar to Suboxone films. The OX219 formulation received significantly higher subjective ratings for taste and overall acceptability than both Suboxone formulations. OX219 was preferred over Suboxone tablet and film formulations by 77.4% and 88.9% of subjects, respectively. A sublingual tablet formulation with an improved acceptability has been successfully developed.

  14. Central effects of some peptide and non-peptide opioids and naloxone on thermoregulation in the rabbit

    NASA Technical Reports Server (NTRS)

    Kandasamy, S. B.; Williams, B. A.

    1983-01-01

    The effects of several peptide and non-peptide opiods and naloxone on induced hyperthermia is studied in rabbits. The effect of tyical mu, kappa, and sigma receptor antagonists (morphine, ketocyclazcine and SKF 10,0 10, 047) and some opioid peptides (Beta-endorphin /BE/, methionine-enkaphalin /ME/, and D-Ala2-methionine-enkaphalin-amide /DAME/ are determined. The role of prostaglandins (PG), cAMP, and norepinephrine (NE) in morphine, BE, and DAME induced hyperthermia is investigated. In addition, the effect of naloxone on pyrogen, arachidonic acid, PGE2, prostacyclin, dibutyryl cAMP, and NE induced hyperthermia is determined. Among other results, it is found that the three receptor antagonists induced hyperthermia in rabbits. BE, ME, and DAME were also found to cause hyperthermia, and it is suggested that they act on the same type of receptor. It is also determined that neither NE nor cAMP is involved in the hyperthermia due to morphine, BE, and DAME. It is suggested that an action of endogenous peptides on naloxone sensitive receptors plays little role in normal thermoregulation or in hyperthermia.

  15. Analytical Method Development and Validation for the Quantification of Acetone and Isopropyl Alcohol in the Tartaric Acid Base Pellets of Dipyridamole Modified Release Capsules by Using Headspace Gas Chromatographic Technique

    PubMed Central

    2018-01-01

    A simple, sensitive, accurate, robust headspace gas chromatographic method was developed for the quantitative determination of acetone and isopropyl alcohol in tartaric acid-based pellets of dipyridamole modified release capsules. The residual solvents acetone and isopropyl alcohol were used in the manufacturing process of the tartaric acid-based pellets of dipyridamole modified release capsules by considering the solubility of the dipyridamole and excipients in the different manufacturing stages. The method was developed and optimized by using fused silica DB-624 (30 m × 0.32 mm × 1.8 µm) column with the flame ionization detector. The method validation was carried out with regard to the guidelines for validation of analytical procedures Q2 demanded by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). All the validation characteristics were meeting the acceptance criteria. Hence, the developed and validated method can be applied for the intended routine analysis. PMID:29686931

  16. Analytical Method Development and Validation for the Quantification of Acetone and Isopropyl Alcohol in the Tartaric Acid Base Pellets of Dipyridamole Modified Release Capsules by Using Headspace Gas Chromatographic Technique.

    PubMed

    Valavala, Sriram; Seelam, Nareshvarma; Tondepu, Subbaiah; Jagarlapudi, V Shanmukha Kumar; Sundarmurthy, Vivekanandan

    2018-01-01

    A simple, sensitive, accurate, robust headspace gas chromatographic method was developed for the quantitative determination of acetone and isopropyl alcohol in tartaric acid-based pellets of dipyridamole modified release capsules. The residual solvents acetone and isopropyl alcohol were used in the manufacturing process of the tartaric acid-based pellets of dipyridamole modified release capsules by considering the solubility of the dipyridamole and excipients in the different manufacturing stages. The method was developed and optimized by using fused silica DB-624 (30 m × 0.32 mm × 1.8  µ m) column with the flame ionization detector. The method validation was carried out with regard to the guidelines for validation of analytical procedures Q2 demanded by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). All the validation characteristics were meeting the acceptance criteria. Hence, the developed and validated method can be applied for the intended routine analysis.

  17. Effect of Steady-State Faldaprevir on the Pharmacokinetics of Steady-State Methadone and Buprenorphine-Naloxone in Subjects Receiving Stable Addiction Management Therapy

    PubMed Central

    Joseph, David; Schobelock, Michael J.; Riesenberg, Robert R.; Vince, Bradley D.; Webster, Lynn R.; Adeniji, Abidemi; Elgadi, Mabrouk

    2014-01-01

    The effects of steady-state faldaprevir on the safety, pharmacokinetics, and pharmacodynamics of steady-state methadone and buprenorphine-naloxone were assessed in 34 healthy male and female subjects receiving stable addiction management therapy. Subjects continued receiving a stable oral dose of either methadone (up to a maximum dose of 180 mg per day) or buprenorphine-naloxone (up to a maximum dose of 24 mg-6 mg per day) and also received oral faldaprevir (240 mg) once daily (QD) for 8 days following a 480-mg loading dose. Serial blood samples were taken for pharmacokinetic analysis. The pharmacodynamics of the opioid maintenance regimens were evaluated by the objective and subjective opioid withdrawal scales. Coadministration of faldaprevir with methadone or buprenorphine-naloxone resulted in geometric mean ratios for the steady-state area under the concentration-time curve from 0 to 24 h (AUC0–24,ss), the steady-state maximum concentration of the drug in plasma (Cmax,ss), and the steady-state concentration of the drug in plasma at 24 h (C24,ss) of 0.92 to 1.18 for (R)-methadone, (S)-methadone, buprenorphine, norbuprenorphine, and naloxone, with 90% confidence intervals including, or very close to including, 1.00 (no effect), suggesting a limited overall effect of faldaprevir. Although individual data showed moderate variability in the exposures between subjects and treatments, there was no evidence of symptoms of opiate overdose or withdrawal either during the coadministration of faldaprevir with methadone or buprenorphine-naloxone or after faldaprevir dosing was stopped. Similar faldaprevir exposures were observed in the methadone- and buprenorphine-naloxone-treated subjects. In conclusion, faldaprevir at 240 mg QD can be coadministered with methadone or buprenorphine-naloxone without dose adjustment, although given the relatively narrow therapeutic windows of these agents, monitoring for opiate overdose and withdrawal may still be appropriate. (This study

  18. Effects of naloxone opiate blockade on the immunomodulation induced by exercise in rats.

    PubMed

    Bouix, O; elMezouini, M; Orsetti, A

    1995-01-01

    The purpose of this study was to examine the possible involvement of the endogenous opiate system in the changes in immune competence induced by isolated exercise. Male untrained rats were subjected to a 2.5 hours swimming exercise bout. Animals were killed 15 min after the end of the exercise. The concentration of leukocytes, lymphocytes, monocytes and granulocytes and T4 (T-helper), T8 (T-suppressor/cytotoxic), interleukin-2 receptor (IL-2R) and transferrin receptor (TrfR) positive lymphocytes were determined both in peripheral blood and spleen by flow cytometric analysis. Exercise resulted in a significant decrease in 1) blood lymphocyte and splenic granulocyte number (p < 0.05), 2) blood and splenic T4 positive lymphocytes and T4/T8 ratio (p < 0.05), and 3) blood and splenic IL-2R and TrfR positive lymphocytes (p < 0.05). The injection of the opiate blocker naloxone to exercising rats induced a decrease in the concentration and proportion of T8 positive lymphocytes, thereby restoring a normal T4/T8 ratio both in peripheral blood and spleen. Naloxone had no effect in control animals. The concentration and proportion of IL-2R and TrfR positive lymphocytes were not affected by naloxone. The mechanisms of the immunomodulation induced by isolated intense exercise are unclear. These data suggest that endogenous opiates participate in the alteration of cell-mediated immunity associated with exercise by modulating the T8 (suppressor/cytotoxic)-cell activity.

  19. Naloxone decreases the inhibitory effect of alprazolam on the release of adrenocorticotropin/cortisol induced by physical exercise in man

    PubMed Central

    Coiro, Vittorio; Volpi, Riccardo; Casti, Amos; Maffei, Maria Ludovica; Stella, Adriano; Volta, Elio; Chiodera, Paolo

    2011-01-01

    AIMS To establish the possible involvement of alprazolam (ALP) and/or opiates in the mechanism underlying the ACTH/cortisol response to physical exercise. METHODS Tests were carried out under basal conditions (exercise control test), exercise plus ALP (50 µg at time −90 min), naloxone (10 mg at time 0) or ALP plus naloxone. Plasma ACTH and serum cortisol concentrations were evaluated in blood samples taken before, during and after the bicycle ergometer tests. RESULTS ACTH and cortisol concentrations rose significantly after physical exercise. Maximum peak at time 15 min (P≤ 0.01 vs. baseline) for ACTH and at time 30 min (P≤ 0.01 vs. baseline) for cortisol. In the presence of naloxone, the ACTH and cortisol responses were significantly increased (maximum peak at time 20 min, P≤ 0.02 vs. control test for ACTH, and at time 30 min (P≤ 0.01 vs. baseline) for cortisol) whereas they were abolished by ALP. When ALP and naloxone were given together, the inhibitory effect of ALP was partial. CONCLUSIONS These data demonstrate an inhibitory effect of ALP in the regulation of the ACTH/cortisol response to physical exercise in man and suggest that GABAergic receptor activating benzodiazepines and opioids interact in the neuroendocrine secretion of ACTH/cortisol. PMID:21564163

  20. Pharmaceutical and pharmacokinetic characterization of a novel sublingual buprenorphine/naloxone tablet formulation in healthy volunteers

    PubMed Central

    Fischer, Andreas; Hjelmström, Peter

    2015-01-01

    Abstract Context Bitter taste, as well as dissolve time, presents a significant challenge for the acceptability of formulations for oral transmucosal drug delivery. Objective To characterize a novel sublingual tablet formulation of buprenorphine/naloxone with regards to pharmacokinetics, dissolve time and formulation acceptability. Methods Dry mixing techniques were employed to produce a small and fast dissolving buprenorphine/naloxone sublingual tablet formulation, OX219 (Zubsolv®), using sucralose and menthol as sweetener and flavor to mask the bitter taste of the active ingredients. Two cross-over studies were performed in healthy volunteers to evaluate pharmacokinetics, dissolve time and acceptability of OX219 5.7/1.4 mg tablets compared to the commercially available buprenorphine/naloxone formulations Suboxone® tablets and films (8/2 mg). Results Buprenorphine exposure was equivalent in OX219 and Suboxone tablets. Sublingual dissolve times were significantly shorter for OX219 than for Suboxone tablets and were similar to Suboxone films. The OX219 formulation received significantly higher subjective ratings for taste and overall acceptability than both Suboxone formulations. OX219 was preferred over Suboxone tablet and film formulations by 77.4% and 88.9% of subjects, respectively. Conclusions A sublingual tablet formulation with an improved acceptability has been successfully developed. PMID:24099551

  1. Descriptive Epidemiology for Community-wide Naloxone Administration by Police Officers and Firefighters Responding to Opioid Overdose.

    PubMed

    Heavey, Sarah Cercone; Delmerico, Alan M; Burstein, Gale; Moore, Cheryll; Wieczorek, William F; Collins, R Lorraine; Chang, Yu-Ping; Homish, Gregory G

    2018-04-01

    Recently implemented New York State policy allows police and fire to administer intranasal naloxone when responding to opioid overdoses. This work describes the geographic distribution of naloxone administration (NlxnA) by police and fire when responding to opioid overdoses in Erie County, NY, an area of approximately 920,000 people including the City of Buffalo. Data are from opioid overdose reports (N = 800) filed with the Erie County Department of Health (July 2014-June 2016) by police/fire and include the overdose ZIP code, reported drug(s) used, and NlxnA. ZIP code data were geocoded and mapped to examine spatial patterns of NlxnA. The highest NlxnA rates (range: 0.01-84.3 per 10,000 population) were concentrated within the city and first-ring suburbs. Within 3 min 27.3% responded to NlxnA and 81.6% survived the overdose. The average individual was male (70.3%) and 31.4 years old (SD = 10.3). Further work is needed to better understand NlxnA and overdose, including exploring how the neighborhood environment creates a context for drug use, and how this context influences naloxone use and overdose experiences.

  2. Distribution of naloxone for overdose prevention to chronic pain patients.

    PubMed

    Coe, Marion A; Walsh, Sharon L

    2015-11-01

    In this commentary, we reflect on the growing opioid overdose epidemic and propose that chronic pain patients prescribed opioids are contributing to growing mortality rates. We advocate for expanding naloxone access and overdose prevention training, which has historically been directed when available to injection drug users, to chronic pain patients who may be at high risk for accidental opioid overdose. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Patient Simulation for Assessment of Layperson Management of Opioid Overdose with Intranasal Naloxone in a Recently-Released Prisoner Cohort

    PubMed Central

    Kobayashi, Leo; Green, Traci C.; Bowman, Sarah E.; Ray, Madeline C.; McKenzie, Michelle S.; Rich, Josiah D.

    2016-01-01

    Introduction Investigators applied simulation to an experimental program that educated, trained and assessed at-risk, volunteering prisoners on opioid overdose (OD) prevention, recognition and layperson management with intranasal (IN) naloxone. Methods Consenting inmates were assessed for OD-related experience and knowledge then exposed on-site to standardized didactics and educational DVD (without simulation). Subjects were provided with IN naloxone kits at time of release and scheduled for post-release assessment. At follow-up, subjects were evaluated for their performance of layperson opioid OD resuscitative skills during video-recorded simulations. Two investigators independently scored each subject’s resuscitative actions with a 21-item checklist; post-hoc video reviews were separately completed to adjudicate subjects’ interactions for overall benefit or harm. Results One hundred and three prisoners completed the baseline assessment and study intervention then were prescribed IN naloxone kits. One-month follow-up and simulation data were available for 85 subjects (82.5% of trained recruits) who had been released and resided in the community. Subjects’ simulation checklist median score was 12.0 (IQR 11.0–15.0) out of 21 total indicated actions. Forty-four participants (51.8%) correctly administered naloxone; 16 additional subjects (18.8%) suboptimally administered naloxone. Non-indicated actions, primarily chest compressions, were observed in 49.4% of simulations. Simulated resuscitative actions by 80 subjects (94.1%) were determined post-hoc to be beneficial overall for patients overdosing on opioids. Conclusions As part of an opioid OD prevention research program for at-risk inmates, investigators applied simulation to 1-month follow-up assessments of knowledge retention and skills acquisition in post-release participants. Simulation supplemented traditional research tools for investigation of layperson OD management. PMID:28146450

  4. Preventing death among the recently incarcerated: an argument for naloxone prescription before release.

    PubMed

    Wakeman, Sarah E; Bowman, Sarah E; McKenzie, Michelle; Jeronimo, Alexandra; Rich, Josiah D

    2009-01-01

    Death from opiate overdose is a tremendous source of mortality, with a heightened risk in the weeks following incarceration. The goal of this study is to assess overdose experience and response among long-term opiate users involved in the criminal justice system. One hundred thirty-seven subjects from a project linking opiate-dependent individuals being released from prison with methadone maintenance programs were asked 73 questions regarding overdose. Most had experienced and witnessed multiple overdoses; 911 was often not called. The majority of personal overdoses occurred within 1 month of having been institutionalized. Nearly all participants expressed an interest in being trained in overdose prevention with Naloxone. The risk of death from overdose is greatly increased in the weeks following release from prison. A pre-release program of overdose prevention education, including Naloxone prescription, for inmates with a history of opiate addiction would likely prevent many overdose deaths.

  5. Utilizing buprenorphine–naloxone to treat illicit and prescription-opioid dependence

    PubMed Central

    Mauger, Sofie; Fraser, Ronald; Gill, Kathryn

    2014-01-01

    Objectives To review current evidence on buprenorphine–naloxone (bup/nx) for the treatment of opioid-use disorders, with a focus on strategies for clinical management and office-based patient care. Quality of evidence Medline and the Cochrane Database of Systematic Reviews were searched. Consensus reports, guidelines published, and other authoritative sources were also included in this review. Apart from expert guidelines, data included in this review constitute level 1 evidence. Findings Bup/nx is a partial μ-opioid agonist combined with the opioid antagonist naloxone in a 4:1 ratio. It has a lower abuse potential, carries less stigma, and allows for more flexibility than methadone. Bup/nx is indicated for both inpatient and ambulatory medically assisted withdrawal (acute detoxification) and long-term substitution treatment (maintenance) of patients who have a mild-to-moderate physical dependence. A stepwise long-term substitution treatment with regular monitoring and follow-up assessment is usually preferred, as it has better outcomes in reducing illicit opioid use, minimizing concomitant risks such as human immunodeficiency virus and hepatitis C transmission, retaining patients in treatment and improving global functioning. Conclusion Bup/nx is safe and effective for opioid detoxification and substitution treatment. Its unique pharmaceutical properties make it particularly suitable for office-based maintenance treatment of opioid-use disorder. PMID:24741316

  6. Effects of naloxone distribution alone or in combination with addiction treatment with or without pre-exposure prophylaxis for HIV prevention in people who inject drugs: a cost-effectiveness modelling study.

    PubMed

    Uyei, Jennifer; Fiellin, David A; Buchelli, Marianne; Rodriguez-Santana, Ramon; Braithwaite, R Scott

    2017-03-01

    In the USA, an epidemic of opioid overdose deaths is occurring, many of which are from heroin. Combining naloxone distribution with linkage to addiction treatment or pre-exposure prophylaxis (PrEP) for HIV prevention through syringe service programmes has the potential to save lives and be cost-effective. We estimated the outcomes and cost-effectiveness of five alternative strategies: no additional intervention, naloxone distribution, naloxone distribution plus linkage to addiction treatment, naloxone distribution plus PrEP, and naloxone distribution plus linkage to addiction treatment and PrEP. We developed a decision analytical Markov model to simulate opioid overdose, HIV incidence, overdose-related deaths, and HIV-related deaths in people who inject drugs in Connecticut, USA. Model input parameters were derived from published sources. We compared each strategy with no intervention, as well as simultaneously considering all strategies. Sensitivity analysis was done for all variables. Linkage to addiction treatment was referral to an opioid treatment programme for methadone. Endpoints were survival, life expectancy, quality-adjusted life-years (QALYs), number and percentage of overdose deaths averted, number of HIV-related deaths averted, total costs (in 2015 US$) associated with each strategy, and incremental cost per QALY gained. In the base-case analysis, compared with no additional intervention, the naloxone distribution strategy yielded an incremental cost-effectiveness ratio (ICER) of $323 per QALY, and naloxone distribution plus linkage to addiction treatment was cost saving compared with no additional intervention (greater effectiveness and less expensive). The most efficient strategies (ie, those conferring the greatest health benefit for a particular budget) were naloxone distribution combined with linkage to addiction treatment (cost saving), and naloxone distribution combined with PrEP and linkage to addiction treatment (ICER $95 337 per QALY) at a

  7. 78 FR 34108 - Determination That SUBOXONE (Buprenorphine Hydrochloride and Naloxone Hydrochloride) Sublingual...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-06

    ... naloxone HCl) sublingual tablets, 2 mg/0.5 mg and 8 mg/2 mg, are the subject of NDA 20-733, held by Reckitt Benckiser Pharmaceuticals, Inc. (Reckitt), and initially approved on October 8, 2002. SUBOXONE is indicated...,'' http://www.rb.com/site/rkbr/templates/mediainvestorsgeneral2.aspx?pageid=1332&cc=GB , Reckitt Benckiser...

  8. Orienting patients to greater opioid safety: models of community pharmacy-based naloxone.

    PubMed

    Green, Traci C; Dauria, Emily F; Bratberg, Jeffrey; Davis, Corey S; Walley, Alexander Y

    2015-08-06

    The leading cause of adult injury death in the U.S.A. is drug overdose, the majority of which involves prescription opioid medications. Outside of the U.S.A., deaths by drug overdose are also on the rise, and overdose is a leading cause of death for drug users. Reducing overdose risk while maintaining access to prescription opioids when medically indicated requires careful consideration of how opioids are prescribed and dispensed, how patients use them, how they interact with other medications, and how they are safely stored. Pharmacists, highly trained professionals expert at detecting and managing medication errors and drug-drug interactions, safe dispensing, and patient counseling, are an under-utilized asset in addressing overdose in the U.S. and globally. Pharmacies provide a high-yield setting where patient and caregiver customers can access naloxone-an opioid antagonist that reverses opioid overdose-and overdose prevention counseling. This case study briefly describes and provides two US state-specific examples of innovative policy models of pharmacy-based naloxone, implemented to reduce overdose events and improve opioid safety: Collaborative Pharmacy Practice Agreements and Pharmacy Standing Orders.

  9. Management of opioid painkiller dependence in primary care: ongoing recovery with buprenorphine/naloxone

    PubMed Central

    Hard, Bernadette

    2014-01-01

    Opioid painkiller dependence is a growing problem and best-practice management is not well defined. We report a case of a young woman exhibiting dependence on codeine, originally prescribed for myalgic encephalopathy, after escalating use over a 10-year period. In 2012, a consultation with a new general practitioner, who had extensive experience of patients with substance abuse, revealed the underlying dependence. After building trust for 6 months, she was able to admit to medication abuse, and was referred to the community drug and alcohol team. On presentation to the team, the patient had no pain issues and the dihydrocodeine use—600 tablets/week—solely reflected her dependence. The patient successfully underwent rapid induction with buprenorphine/naloxone as opioid substitution treatment over 2 days. She is currently stable, engaged with recovery support services and psychosocial counselling, and has just returned to work. She is maintained on a therapeutic dose of buprenorphine 10 mg/naloxone 2.5 mg. PMID:25432908

  10. Effects of aqueous, methanolic and chloroform extracts of rhizome and aerial parts of Valeriana officinalis L. on naloxone-induced jumping in morphine-dependent mice.

    PubMed

    Sharifzadeh, Mohammad; Hadjiakhoondi, Abbas; Khanavi, Mahnaz; Susanabadi, Maryam

    2006-06-01

    In the present study, the effects of rhizomes and aerial parts extracts of Valeriana officinalis L. on morphine dependence in mice have been investigated. Animals were treated subcutaneously with morphine (50, 50 and 75 mg/kg) three times daily (10 am, 1 pm and 4 pm) for 3 days, and a last dose of morphine (50 mg/kg) was administered on the fourth day. Withdrawal syndrome (jumping) was precipitated by naloxone (5 mg/kg) which was administered intraperitoneally 2 hours after the last dose of morphine. To study the effects of the aqueous, methanolic and chloroform extracts of both aerial parts and rhizome of the V. officinalis L. on naloxone-induced jumping in morphine-dependent animals, 10 injections of morphine (three administrations each day) for dependence and a dose of 5 mg/kg of naloxone for withdrawal induction were employed. Intraperitoneal injection of different doses (1, 5, 25 and 50 mg/kg) of aqueous, methanolic and chloroform extracts of the rhizome of V. officinalis L. 60 minutes before naloxone injection decreased the jumping response dose-dependently. Pre-treatment of animals with different doses (1, 5, 25, 50 and 100 mg/kg) of aqueous and methanolic extracts of aerial parts of V. officinalis L. 60 minutes before naloxone injection caused a significant decrease on naloxone-induced jumping. The chloroform extract of the aerial parts of V. officinalis L. did not show any significant changes on jumping response in morphine-dependent animals. It is concluded that the extracts of V. officinalis L. could affect morphine withdrawal syndrome via possible interactions with inhibitory neurotransmitters in nervous system.

  11. The Impact of Take-Home Naloxone Distribution and Training on Opiate Overdose Knowledge and Response: An Evaluation of the THN Project in Wales

    ERIC Educational Resources Information Center

    Bennett, Trevor; Holloway, Katy

    2012-01-01

    Aims: To determine the impact of naloxone training on knowledge of opiate overdose and confidence and willingness to take appropriate action and to examine the use of naloxone and other harm-reduction actions at the time of overdose events. Methods: The evaluation was based on a repeated-measure design, whereby clients were tested before and after…

  12. Sympathetic activity induced by naloxone-precipitated morphine withdrawal is blocked in genetically engineered mice lacking functional CRF1 receptor

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    García-Carmona, Juan-Antonio; Martínez-Laorden, Elena; Milanés, María-Victoria

    There is large body evidence indicating that stress can lead to cardiovascular disease. However, the exact brain areas and the mechanisms involved remain to be revealed. Here, we performed a series of experiments to characterize the role of CRF1 receptor (CRF1R) in the stress response induced by naloxone-precipitated morphine withdrawal. The experiments were performed in the hypothalamic paraventricular nucleus (PVN) ventrolateral medulla (VLM), brain regions involved in the regulation of cardiovascular activity, and in the right ventricle by using genetically engineered mice lacking functional CRF1R levels (KO). Mice were treated with increasing doses of morphine and withdrawal was precipitated bymore » naloxone administration. Noradrenaline (NA) turnover, c-Fos, expression, PKA and TH phosphorylated at serine 40, was evaluated by high-performance liquid chromatography (HPLC), immunohistochemistry and immunoblotting. Morphine withdrawal induced an enhancement of NA turnover in PVN in parallel with an increase in TH neurons expressing c-Fos in VLM in wild-type mice. In addition we have demonstrated an increase in NA turnover, TH phosphorylated at serine 40 and PKA levels in heart. The main finding of the present study was that NA turnover, TH positive neurons that express c-Fos, TH phosphorylated at serine 40 and PKA expression observed during morphine withdrawal were significantly inhibited in CRF1R KO mice. Our results demonstrate that CRF/CRF1R activation may contribute to the adaptive changes induced by naloxone-precipitated withdrawal in the heart and in the brain areas which modulate the cardiac sympathetic function and suggest that CRF/CRF1R pathways could be contributing to cardiovascular disease associated to opioid addiction. - Highlights: • Naloxone-precipitated morphine withdrawal increases sympathetic activity in the PVN and heart. • Co-localization of TH phosphorylated at serine 40/c-Fos in the VLM after morphine withdrawal • Naloxone

  13. The feasibility of employing a home healthcare model for education and treatment of opioid overdose using a naloxone auto-injector in a private practice pain medicine clinic.

    PubMed

    Dragovich, Anthony; Brason, Fred; Beltran, Thomas; McCoart, Amy; Plunkett, Anthony R

    2018-04-18

    The purpose of this study was to determine if employing a home healthcare model for education and treatment of opioid overdose using Evzio® (Naloxone)* auto-injector in a private practice pain clinic. A prospective survey was used to determine the feasibility of integrating a naloxone auto-injector within the patient's home with a home care training model. Twenty moderate or high-risk patients were enrolled from our chronic pain clinic. Patients who were moderate or high risk completed an evaluation survey. The naloxone auto-injector was dispensed to all patients meeting criteria. The treating provider after prescribing the naloxone auto-injector then consulted home health per standard clinical practice. All patients had home health consulted to perform overdose identification and rescue training. A Cochran's Q test was conducted to examine differences in patient knowledge pre and post training. The post training test was done 2-4 weeks later. Forty subjects enrolled after meeting inclusion/exclusion criteria. Twenty withdrew because their insurance declined coverage for the naloxone auto-injector. Those completing home health showed a statistically significant difference in their ability to correctly identify the steps needed to effectively respond to an overdose p = 0.03 Discussion: Preliminary evidence would suggest training on overdose symptom recognition and proper use of prescription naloxone for treatment in the home setting by home health staff would prove more beneficial than the clinic setting, but feasibility was hindered by unaffordable costs related to insurance coverage limitations.

  14. Evaluation of knowledge and confidence following opioid overdose prevention training: A comparison of types of training participants and naloxone administration methods.

    PubMed

    Ashrafioun, Lisham; Gamble, Stephanie; Herrmann, Michele; Baciewicz, Gloria

    2016-01-01

    The purpose of the current study was to assess the effect of opioid overdose prevention training on participants' knowledge about opioid overdose and confidence to recognize and respond to opioid overdose situations as a function of naloxone administration (i.e., injection vs. intranasal spray) and participant type (friend/family, provider, "other"). Opioid overdose prevention trainings were offered throughout a mid-sized metropolitan area in the northeast. Participants (n = 428) were trained to administer naloxone via intramuscular injection (n = 154) or intranasal spray (n = 274). All training participants were given pre-post assessments of knowledge about opioid overdose and confidence to recognize and respond to opioid overdose situations. Participants' overall knowledge and confidence increased significantly from pre- to post-training (ps < .001). There was no significant association between knowledge and route of administration or participant type. Knowledge significantly increased from pre- to post-training in all participant types (ps < .001). Confidence improved significantly from pre- to post-training across both routes of administration (ps < .001). However, confidence was higher among those who were trained using the intranasal naloxone compared to those who were trained using the intramuscular injection naloxone at pre- (p = .011) and post-training (p < .001). Confidence increased from pre- to post-training in each of the participant types (ps < .001). Post-hoc tests revealed that confidence was higher among providers and friends/family members compared to "other" participants, such as first responders, only at post-training (p < .05). Opioid overdose trainings are effective in increasing knowledge and confidence related to opioid overdose situations. Findings suggest that trainees are more confident administering naloxone via intranasal spray compared to injection. Future research should attempt to identify other factors that may increase the

  15. High dose naloxone does not improve cerebral or myocardial blood flow during cardiopulmonary resuscitation in pigs.

    PubMed

    Gervais, H W; Eberle, B; Hennes, H J; Grimm, W; Kilian, A; Konietzke, D; Massing, C; Dick, W

    1997-06-01

    In a prospective, randomized, placebo-controlled, double-blind trial we tested the hypothesis that naloxone given during cardiopulmonary resuscitation (CPR) enhances cerebral and myocardial blood flow. Twenty-one anesthetized, normoventilated pigs were instrumented for measurements of right atrial and aortic pressures, and regional organ blood flow (radiolabeled microspheres). After 5 min of untreated fibrillatory arrest, CPR was commenced using a pneumatic chest compressor/ventilator. With onset of CPR, an i.v. bolus of 40 micrograms/kg b.w. of epinephrine was given, followed by an infusion of 0.4 micrograms/kg per min. After 5 min of CPR, either naloxone, 10 mg/kg b.w. (group N, n = 11) or normal saline (group S, n = 10) was given i.v. Prior to, and after 1, 15, and 30 min of CPR, hemodynamic and blood flow measurements were obtained. After 30 min of CPR, mean arterial pressure was significantly higher in group N (26 +/- 5 vs. 13 +/- 3 mmHg, P < 0.05). Groups did not differ with respect to myocardial perfusion pressure or arterial blood gases at any time during the observation period. Regional brain and heart blood flows were not different between N and S at any point of measurement. We conclude that high-dose naloxone does not augment cerebral or myocardial blood flow during prolonged closed-chest CPR.

  16. Buprenorphine-naloxone therapy in pain management.

    PubMed

    Chen, Kelly Yan; Chen, Lucy; Mao, Jianren

    2014-05-01

    Buprenorphine-naloxone (bup/nal in 4:1 ratio; Suboxone; Reckitt Benckiser Pharmaceuticals Incorporation, Richmond, VA) is approved by the Food and Drug Administration for outpatient office-based addiction treatment. In the past few years, bup/nal has been increasingly prescribed off-label for chronic pain management. The current data suggest that bup/nal may provide pain relief in patients with chronic pain with opioid dependence or addiction. However, the unique pharmacological profile of bup/nal confers it to be a weak analgesic that is unlikely to provide adequate pain relief for patients without opioid dependence or addiction. Possible mechanisms of pain relief by bup/nal therapy in opioid-dependent patients with chronic pain may include reversal of opioid-induced hyperalgesia and improvement in opioid tolerance and addiction. Additional studies are needed to assess the implication of bup/nal therapy in clinical anesthesia and perioperative pain management.

  17. Naloxone decreases the inhibitory effect of alprazolam on the release of adrenocorticotropin/cortisol induced by physical exercise in man.

    PubMed

    Coiro, Vittorio; Volpi, Riccardo; Casti, Amos; Maffei, Maria Ludovica; Stella, Adriano; Volta, Elio; Chiodera, Paolo

    2011-06-01

    • Alprazolam (ALP), a benzodiazepine activating GABAergic receptors, is involved in ACTH secretion. • This study demonstrates a partial opioid influence in the inhibitory effect of ALP on the release of ACTH/cortisol during physical exercise. To establish the possible involvement of alprazolam (ALP) and/or opiates in the mechanism underlying the ACTH/cortisol response to physical exercise. Tests were carried out under basal conditions (exercise control test), exercise plus ALP (50 µg at time -90 min), naloxone (10 mg at time 0) or ALP plus naloxone. Plasma ACTH and serum cortisol concentrations were evaluated in blood samples taken before, during and after the bicycle ergometer tests. ACTH and cortisol concentrations rose significantly after physical exercise. Maximum peak at time 15 min (P ≤ 0.01 vs. baseline) for ACTH and at time 30 min (P ≤ 0.01 vs. baseline) for cortisol. In the presence of naloxone, the ACTH and cortisol responses were significantly increased (maximum peak at time 20 min, P ≤ 0.02 vs. control test for ACTH, and at time 30 min (P ≤ 0.01 vs. baseline) for cortisol) whereas they were abolished by ALP. When ALP and naloxone were given together, the inhibitory effect of ALP was partial. These data demonstrate an inhibitory effect of ALP in the regulation of the ACTH/cortisol response to physical exercise in man and suggest that GABAergic receptor activating benzodiazepines and opioids interact in the neuroendocrine secretion of ACTH/cortisol. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

  18. Pharmacokinetics of Sublingual Buprenorphine and Naloxone in Subjects with Mild to Severe Hepatic Impairment (Child-Pugh Classes A, B, and C), in Hepatitis C Virus-Seropositive Subjects, and in Healthy Volunteers.

    PubMed

    Nasser, Azmi F; Heidbreder, Christian; Liu, Yongzhen; Fudala, Paul J

    2015-08-01

    Suboxone(®) is a sublingual tablet of buprenorphine/naloxone, approved for the treatment of opioid dependence. The objective of this study was to quantify the impact of hepatic impairment or hepatitis C virus infection on the pharmacokinetics of buprenorphine or naloxone and their major metabolites. Forty-three subjects received a single dose of a Suboxone 2.0/0.5-mg tablet. Blood samples were collected up to 168 h and pharmacokinetic parameters were calculated using non-compartmental analysis. Statistical analysis was performed using analysis of covariance. Pharmacokinetic parameters were derived from 33 subjects. Compared with healthy subjects, for patients with severe hepatic impairment, total and peak exposures increased to 281.4 % [90 % confidence interval 187.1-423.3] and 171.8 % [117.9-250.2] for buprenorphine, 1401.9 % [707.6-2777.5] and 1129.8 % [577.2-2211.4] for naloxone. For moderate hepatic impaired subjects, naloxone total and peak exposure increased to 317.6 % [164.9-611.5] and 270.0  % [141.9-513.9]. For buprenorphine, only total exposure increased to 163.9 % [110.8-242.3]. Changes in maximum observed plasma concentration, area under the plasma concentration-time curve from time zero to time of the last quantifiable concentration, and area under the plasma concentration-time curve from time zero to infinity of buprenorphine or naloxone in subjects with mild hepatic impairment or with hepatitis C virus infection were within twofold of those of healthy subjects. Serious adverse events were not observed. Severe and moderate hepatic impairment significantly increased exposure of naloxone and to a lesser extent of buprenorphine. Therefore, buprenorphine/naloxone combination products should generally be avoided in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. However, buprenorphine/naloxone products may be used with caution for maintenance treatment in patients with moderate

  19. Scotland's national naloxone program: The prison experience.

    PubMed

    Horsburgh, Kirsten; McAuley, Andrew

    2018-05-01

    Launched in 2011, the Scottish national naloxone program marked an important development in public health policy. Central to its design were strategies to engage prisoners given their elevated risk of drug-related death in the weeks following liberation. Implementation across Scottish prisons has posed particular challenges linked to both operational issues within prison establishments and individual factors affecting staff delivering, and prisoners engaging, with the program. Barriers have been overcome through innovation and partnership working. This commentary has described how the development of the program in prisons has adapted to these challenges to a point where a largely consistent model is in place and where prisoners-on-release are reaping the benefits in terms of reduced opioid-related mortality. © 2017 Australasian Professional Society on Alcohol and other Drugs.

  20. Effectiveness of Injectable Extended-Release Naltrexone vs Daily Buprenorphine-Naloxone for Opioid Dependence: A Randomized Clinical Noninferiority Trial.

    PubMed

    Tanum, Lars; Solli, Kristin Klemmetsby; Latif, Zill-E-Huma; Benth, Jurate Šaltyte; Opheim, Arild; Sharma-Haase, Kamni; Krajci, Peter; Kunøe, Nikolaj

    2017-12-01

    To date, extended-release naltrexone hydrochloride has not previously been compared directly with opioid medication treatment (OMT), currently the most commonly prescribed treatment for opioid dependence. To determine whether treatment with extended-release naltrexone will be as effective as daily buprenorphine hydrochloride with naloxone hydrochloride in maintaining abstinence from heroin and other illicit substances in newly detoxified individuals. A 12-week, multicenter, outpatient, open-label randomized clinical trial was conducted at 5 urban addiction clinics in Norway between November 1, 2012, and December 23, 2015; the last follow-up was performed on October 23, 2015. A total of 232 adult opioid-dependent (per DSM-IV criteria) individuals were recruited from outpatient addiction clinics and detoxification units and assessed for eligibility. Intention-to-treat analyses of efficacy end points were performed with all randomized participants. Randomization to either daily oral flexible dose buprenorphine-naloxone, 4 to 24 mg/d, or extended-release naltrexone hydrochloride, 380 mg, administered intramuscularly every fourth week for 12 weeks. Primary end points (protocol) were the randomized clinical trial completion rate, the proportion of opioid-negative urine drug tests, and number of days of use of heroin and other illicit opioids. Secondary end points included number of days of use of other illicit substances. Safety was assessed by adverse event reporting. Of 159 participants, mean (SD) age was 36 (8.6) years and 44 (27.7%) were women. Eighty individuals were randomized to extended-release naltrexone and 79 to buprenorphine-naloxone; 105 (66.0%) completed the trial. Retention in the extended-release naltrexone group was noninferior to the buprenorphine-naloxone group (difference, -0.1; with 95% CI, -0.2 to 0.1; P = .04), with mean (SD) time of 69.3 (25.9) and 63.7 (29.9) days, correspondingly (P = .33, log-rank test). Treatment with extended

  1. Neural correlates underlying naloxone-induced amelioration of sexual behavior deterioration due to an alarm pheromone

    PubMed Central

    Kobayashi, Tatsuya; Kiyokawa, Yasushi; Takeuchi, Yukari; Mori, Yuji

    2015-01-01

    Sexual behavior is suppressed by various types of stressors. We previously demonstrated that an alarm pheromone released by stressed male Wistar rats is a stressor to other rats, increases the number of mounts needed for ejaculation, and decreases the hit rate (described as the number of intromissions/sum of the mounts and intromissions). This deterioration in sexual behavior was ameliorated by pretreatment with the opioid receptor antagonist naloxone. However, the neural mechanism underlying this remains to be elucidated. Here, we examined Fos expression in 31 brain regions of pheromone-exposed rats and naloxone-pretreated pheromone-exposed rats 60 min after 10 intromissions. As previously reported, the alarm pheromone increased the number of mounts and decreased the hit rate. In addition, Fos expression was increases in the anterior medial division (BNSTam), anterior lateral division (BNSTal) and posterior division (BNSTp) of the bed nucleus of the stria terminalis, parvocellular part of the paraventricular nucleus of the hypothalamus, arcuate nucleus, dorsolateral and ventrolateral periaqueductal gray, and nucleus paragigantocellularis (nPGi). Fos expression was decreased in the magnocellular part of the paraventricular nucleus of the hypothalamus. Pretreatment with naloxone blocked the pheromone-induced changes in Fos expression in the magnocellular part of the paraventricular nucleus of the hypothalamus, ventrolateral periaqueductal gray, and nPGi. Based on these results, we hypothesize that the alarm pheromone deteriorated sexual behavior by activating the ventrolateral periaqueductal gray-nucleus paragigantocellularis cluster and suppressing the magnocellular part of the paraventricular nucleus of the hypothalamus (PVN) via the opioidergic pathway. PMID:25755631

  2. Evaluating the impact of a national naloxone programme on ambulance attendance at overdose incidents: a controlled time-series analysis.

    PubMed

    McAuley, Andrew; Bouttell, Janet; Barnsdale, Lee; Mackay, Daniel; Lewsey, Jim; Hunter, Carole; Robinson, Mark

    2017-02-01

    It has been suggested that distributing naloxone to people who inject drugs (PWID) will lead to fewer attendances by emergency medical services at opioid-related overdose incidents if peer administration of naloxone was perceived to have resuscitated the overdose victim successfully. This study evaluated the impact of a national naloxone programme (NNP) on ambulance attendance at opioid-related overdose incidents throughout Scotland. Specifically, we aimed to answer the following research questions: is there evidence of an association between ambulance call-outs to opioid-related overdose incidents and the cumulative number of 'take-home naloxone' (THN) kits in issue; and is there evidence of an association between ambulance call-outs to opioid-related overdose incidents in early adopter (pilot) or later adopting (non-pilot) regions and the cumulative number of THN kits issued in those areas? Controlled time-series analysis. Scotland, UK, 2008-15. Pre-NNP implementation period for the evaluation was defined as 1 April 2008 to 31 March 2011 and the post-implementation period as 1 April 2011 to 31 March 2015. In total, 3721 ambulance attendances at opioid-related overdose were recorded for the pre-NNP implementation period across 158 weeks (mean 23.6 attendances per week) and 5258 attendances across 212 weeks in the post-implementation period (mean 24.8 attendances per week). Scotland's NNP; formally implemented on 1 April 2011. Primary outcome measure was weekly incidence (counts) of call-outs to opioid-related overdoses at national and regional Health Board level. Data were acquired from the Scottish Ambulance Service (SAS). Models were adjusted for opioid replacement therapy using data acquired from the Information Services Division on monthly sums of all dispensed methadone and buprenorphine in the study period. Models were adjusted further for a control group: weekly incidence (counts) of call-outs to heroin-related overdose in the London Borough area acquired

  3. Presence or Absence of QTc Prolongation in Buprenorphine-Naloxone Among Youth With Opioid Dependence.

    PubMed

    Poole, Sabrina A; Pecoraro, Anna; Subramaniam, Geetha; Woody, George; Vetter, Victoria L

    2016-01-01

    The aim of the study was to evaluate buprenorphine-naloxone effects on the QTc in youth with opioid dependence. Buprenorphine is a partial agonist that is an effective treatment for opioid dependence. Compared with methadone, it has a lower risk of QTc prolongation in adults, but is less studied in the youth. It may also reduce the risk of torsades de pointes (TdP)--an uncommon variant of polymorphic ventricular tachycardia--that can result in syncope, ventricular fibrillation, and sudden death. Secondary analysis of the electrocardiogram data from 95 individuals who participated in a multisite trial for youth with opioid dependence. The participants were randomized to a 2-week (DETOX) or a 12-week course of buprenorphine-naloxone (BUP). At baseline, 12-lead electrocardiograms were done at weeks 4 and 12, and QTc intervals were hand-measured and calculated using Bazett formula. Increases above 60 milliseconds were considered clinically significant, and readings above 450 milliseconds (in men) and 470 milliseconds (in women) indicated a prolonged QTc. Mean QTc intervals were higher for BUP than for DETOX participants at baseline, week 4, and week 12 (P = 0.045), and women had longer mean QTc intervals than men (P < 0.0005). Variations in the QTc intervals were observed in some; however, none were above 500 milliseconds--the level at which risk for TdP becomes more significant. In this randomized trial, the mean QTc at baseline, before randomization, was higher in BUP than in DETOX patients. Minimal changes in the QTc were seen at 4 and 12 weeks in a few patients in both groups. There was no evidence that buprenorphine-naloxone alone increased the QTc to a level that increased the risk for TdP.

  4. The Presence or Absence of QTc Prolongation in Buprenorphine-Naloxone Among Youth with Opioid Dependence

    PubMed Central

    Poole, Sabrina A.; Pecoraro, Anna; Subramaniam, Geetha; Woody, George; Vetter, Victoria L

    2015-01-01

    Objective To evaluate buprenorphine-naloxone effects on the QTc in youth with opioid dependence. Buprenorphine is a partial agonist that is an effective treatment for opioid dependence. Compared to methadone it has a lower risk of QTc prolongation in adults but is less well studied in youth. It may also reduce the risk for torsades de pointes (TdP) an uncommon variant of polymorphic ventricular tachycardia, that can result in syncope, ventricular fibrillation, and sudden death. Methods Secondary analysis of ECG data from 95 subjects who participated in a multi-site trial for youth with opioid dependence. Subjects were randomized to a 2-week (DETOX), or a 12-week course of buprenorphine-naloxone (BUP). 12-lead ECGs were done at baseline, weeks 4 and 12, and QTc intervals were hand measured and calculated using Bazett's formula. Increases > 60 milliseconds (ms) were considered clinically significant, and readings > 450 ms (males) and 470 ms (females) indicated a prolonged QTc. Results Mean QTc intervals were higher for BUP than DETOX participants at baseline, week 4, and week 12 (p = 0.045), and females had longer mean QTc intervals than males (p < 0.0005). Variations in QTc intervals were observed in some, however none were above 500 ms, the level at which risk for TdP becomes more significant. Conclusion In this randomized trial, the mean QTc at baseline, before randomization, was higher in BUP than DETOX patients. Minimal changes in the QTc were seen at 4 and 12-weeks in a few patients in both groups. There was no evidence that buprenorphine-naloxone alone increased the QTc to a level that increased the risk for TdP. PMID:26690291

  5. Studies on the lithium transport across the red cell membrane. II. Characterization of ouabain-sensitive and ouabain-insensitive Li+ transport. Effects of bicarbonate and dipyridamole.

    PubMed

    Duhm, J; Becker, B F

    1977-01-17

    In studies on Li+ net-transport across the human red cell membrane following results were obtained: 1. In K+- and Na+-free choline chloride media, Li+ is transported into the erythrocytes against an electrochemical gradient. This Li+ uphill transport as well as Li+ downhill transport into the cells is inhibited by ouabain, ATP-depletion, and by external K+ and Na+. The effects of K+ and Na+ are relieved at high Li+ concentrations. 2. Ouabain-sensitive Li+ uptake, determined at 10 mM external Na+, does not obey simple Michaelis-Menten kinetics and exhibits a maximum at about pH 7. 3. Ouabain-resistant Li+ downhill transport into erythrocytes increases with rising pH. It is comprised of a saturating component and a component linearly dependent on external Li+. The linear component is partly inhibited by dipyridamole and accelerated by bicarbonate. The bicarbonate effect can be completely blocked by dipyridamole, phlorizin and phenylbutazone. 4. Li+ release is not inhibited by ouabain, ATP-depletion and external K+. It increases with external Na+ concentration, tending to saturate at 150 mM Na+. Na+-independent Li+ release is stimulated by bicarbonate. It is concluded that ouabain-sensitive Li+ uptake is mediated at the K+-site(s) of the Na+-K+ pump. Li+, K+ and Na+ appear to compete for a common site (or sites). The stimulation of Li+ transfer by bicarbonate and the inhibition by dipyridamole suggest a participation of anionic species in ouabain-resistant Li+ transfer. The Na+-dependent Li+ release and the "saturating component" of Li+ uptake are ascribed to the Na+-dependent Li+ countertransport system.

  6. Baclofen prevents the elevated plus maze behavior and BDNF expression during naloxone precipitated morphine withdrawal in male and female mice.

    PubMed

    Pedrón, Valeria T; Varani, André P; Balerio, Graciela N

    2016-05-01

    In previous studies we have shown that baclofen, a selective GABAB receptor agonist, prevents the somatic expression and reestablishes the dopamine and μ-opioid receptors levels, modified during naloxone-precipitated morphine withdrawal syndrome in male and female mice. There are no previous reports regarding sex differences in the elevated plus maze (EPM) and the expression of BDNF in morphine-withdrawn mice. The present study analyses the behavioral and biochemical variations during morphine withdrawal in mice of both sexes, and whether these variations are prevented with baclofen. Swiss-Webster albino prepubertal mice received morphine (2 mg/kg, i.p.) twice daily, for 9 consecutive days. On the 10th day, one group of morphine-treated mice received naloxone (opioid receptor antagonist; 6 mg/kg, i.p.) 1 h after the last dose of morphine to precipitate withdrawal. A second group received baclofen (2 mg/kg, i.p.) before naloxone administration. The EPM behavior was measured during 15 min after naloxone injection. The expression of BDNF-positive cells was determined by immunohistochemistry. Withdrawn male mice showed a higher percentage of time spent and number of entries to the open arms compared to withdrawn female mice. Baclofen prevented this behavior in both sexes. BDNF expression decreased in the AcbC, BNST, CeC, and CA3 of the hippocampus while increased in the BLA of morphine withdrawn male. Baclofen pretreatment prevented the BDNF expression observed in morphine withdrawn male mice in all the brain areas studied except in the CeC. Baclofen prevention of the EPM behavior associated to morphine withdrawal could be partially related to changes in BDNF expression. © 2016 Wiley Periodicals, Inc.

  7. Assessing the Risk of Prehospital Administration of Naloxone with Subsequent Refusal of Care.

    PubMed

    Levine, Michael; Sanko, Stephen; Eckstein, Marc

    2016-01-01

    EMS providers frequently encounter opioid-toxic patients who receive naloxone and then refuse further medical care. Older studies revealed this practice to be safe. In light of the evolving patterns of opioid abuse, this study attempted to determine the safety of this practice. This is a retrospective review of all patient encounters by the Los Angeles Fire Department (LAFD) between July 1, 2011-December 31, 2013. All LAFD patient encounters are stored electronically. These electronic records were reviewed for subjects who received naloxone had a documented respiratory rate (RR) less than 12, and subsequently refused transport. Data abstracted included name, social security number (SSN), date of birth (DOB), date of EMS encounter, age, and treatment rendered. The names, SSN, and DOB, as available, were supplied to the coroner's office. The Coroner's records were reviewed to determine if a patient with the same or similar name (e.g., Jon vs. Jonathan) had died within 24 hours, 30 days, or 6 months of the initial EMS encounter. The abstractor was blinded to the study hypothesis. 205 subjects were identified; the median (IQR) age was 41 (29-53) years. 27 (13%) were female. One subject (0.49%) died within 24 hours of the initial EMS encounter. The cause of death (COD) was coronary artery disease and heroin use. Two additional subjects (1. %) died within 30 days. One of these subjects died 6 days later; the COD is unknown. The other subject died 20 days after the EMS encounter; the COD was cardiovascular disease and liver cirrhosis. No additional subjects were identified at the 6 month follow up. A third subject died of a heroin overdose 16 months after the initial EMS encounter, but was beyond the pre-defined follow up period. The practice of receiving pre-hospital naloxone by paramedics and subsequently refusing care is associated with an extremely low short- and intermediate-term mortality. Despite an evolving pattern of opioid abuse, the results of this study

  8. Development and validation of a bioanalytical method for the simultaneous determination of heroin, its main metabolites, naloxone and naltrexone by LC-MS/MS in human plasma samples: Application to a clinical trial of oral administration of a heroin/naloxone formulation.

    PubMed

    Moreno-Vicente, Raquel; Fernández-Nieva, Zuriñe; Navarro, Arantza; Gascón-Crespí, Irene; Farré-Albaladejo, Magí; Igartua, Manuela; Hernández, Rosa María; Pedraz, José Luis

    2015-10-10

    A bioanalytical method using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated for simultaneous quantification of heroin, its main metabolites and naloxone. In addition, naltrexone was detected qualitatively. This method was used to analyse human plasma samples from a clinical trial after oral administration of a heroin/naloxone formulation in healthy volunteers. O-methylcodeine was used as an internal standard. Samples were kept in an ice-bath during their processing to minimize the degradation of heroin. A short methodology based on protein precipitation with methanol was used for sample preparation. After protein precipitation, only the addition of a formic acid solution was needed to elute heroin, 6-monoacetylmorphine, morphine, naloxone and naltrexone. Morphine metabolites were evaporated to dryness and reconstituted in a formic acid solution. Chromatographic separation was achieved at 35 °C on an X-Bridge Phenyl column (150 × 4.6 mm, 5 μm) using a gradient elution with a mobile phase of ammonium formate buffer at pH 3.0 and formic acid in acetonitrile. The run time was 8 min. The analytes were monitored using a triple quadrupole mass spectrometer with positive electrospray ionization (ESI+) in multiple reaction monitoring (MRM) mode. The method was found to be linear in a concentration range of 10-2000 ng/mL for M3G and 10-1000 ng/mL for the rest of compounds. Quality controls showed accurate values between -3.6% and 4.0% and intra- and inter-day precisions were below 11.5% for all analytes. The overall recoveries were approximately 100% for all analytes including the internal standard. A rapid, specific, precise and simple method was developed for the determination of heroin, its metabolites, naloxone and naltrexone in human plasma. This method was successfully applied to a clinical trial in 12 healthy volunteers. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Naloxone treatment alters gene expression in the mesolimbic reward system in 'junk food' exposed offspring in a sex-specific manner but does not affect food preferences in adulthood.

    PubMed

    Gugusheff, J R; Ong, Z Y; Muhlhausler, B S

    2014-06-22

    We have previously reported that the opioid receptor blocker, naloxone, is less effective in reducing palatable food intake in offspring exposed to a maternal cafeteria diet during the perinatal period, implicating a desensitization of the central opioid pathway in the programming of food preferences. The present study aimed to investigate the effect of a maternal cafeteria diet and naloxone treatment on the development of the mesolimbic reward pathway and food choices in adulthood. We measured mRNA expression of key components of the reward pathway (mu-opioid receptor, proenkephalin, tyrosine hydroxylase, D1 and D2 receptors and the dopamine active transporter (DAT)) in the nucleus accumbens (NAc) and ventral tegmental area (VTA) of the offspring of control and cafeteria fed (JF) dams at weaning and after a 10-day naloxone treatment post-weaning and determined food preferences in adulthood in the remaining offspring. Naloxone treatment decreased the expression of DAT by 8.2 fold in female control offspring but increased it by 4.3 fold in female offspring of JF dams relative to the saline-injected reference groups. Proenkephalin mRNA expression was higher in the NAc of female JF offspring compared to controls, independent of naloxone treatment (P<0.05). There was no effect of naloxone treatment on food preferences in adulthood in either control or JF offspring. These data indicate that prenatal exposure to a cafeteria diet alters the impact of opioid signaling blockade in the early post-weaning period on gene expression in the central reward pathway in a sex specific manner, but that these changes in gene expression do not appear to have any persistent impact on food preferences in adulthood. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Stereoselective action of (+)-morphine over (-)-morphine in attenuating the (-)-morphine-produced antinociception via the naloxone-sensitive sigma receptor in the mouse.

    PubMed

    Wu, Hsiang-en; Hong, Jau-Shyong; Tseng, Leon F

    2007-10-01

    We have previously demonstrated that (+)-morphine and (-)-morphine given spinally stereoselectively attenuate the spinally-administered (-)-morphine-produced tail-flick inhibition in the mouse. The phenomenon has been defined as antianalgesia. Present studies were then undertaken to determine if the systemic administration of (+)-morphine and (-)-morphine also stereoselectively attenuates the systemic (-)-morphine-produced tail-flick inhibition and the effects of (+)-morphine and (-)-morphine are mediated by the naloxone-sensitive sigma receptor activation in male CD-1 mice. Pretreatment with (+)-morphine at a dose of 0.01-10 ng/kg given subcutaneously dose-dependently attenuated the tail-flick inhibition produced by subcutaneously-administered (-)-morphine (5 mg/kg). Pretreatment with (-)-morphine (0.01-1.0 mg/kg) given subcutaneously also attenuates the (-)-morphine-produced tail-flick inhibition. The ED50 values for (+)-morphine and (-)-morphine for inhibiting the (-)-morphine-produced tail-flick inhibition were estimated to be 30.6 pg/kg and 97.5 microg/kg, respectively. The attenuation of the (-)-morphine-produced tail-flick inhibition induced by (+)-morphine or (-)-morphine pretreatment was reversed by the pretreatment with (+)-naloxone or by the sigma receptor antagonist BD1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide) given subcutaneously. Pretreatment with (+)-pentazocine, a selective sigma receptor agonist, (1-10 mg/kg) given subcutaneously also attenuates (-)-morphine-produced tail-flick inhibition, which was restored by (+)-naloxone (4 mg/kg) or BD1047 (10 mg/kg) pretreated subcutaneously. It is concluded that (+)-morphine exhibits extremely high stereoselective action over (-)-morphine given systemically in attenuating the systemic (-)-morphine-produced antinociception and the antianalgesic effect of (+)-morphine and (-)-morphine is mediated by activation of the naloxone-sensitive sigma receptor.

  11. Effects of the NMDA receptor antagonist, D-CPPene, on sensitization to the operant decrement produced by naloxone in morphine-treated rats.

    PubMed

    Bespalov, A Y; Medvedev, I O; Sukhotina, I A; Zvartau, E E

    2001-04-01

    Sensitization to the rate-decreasing effects of opioid antagonists induced by acute pretreatment with opioid agonists has been suggested to reflect initial changes in opioid systems that underlie physical dependence. Glutamate receptors are implicated in the development and expression of opioid dependence, and antagonists acting at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors have been shown repeatedly to attenuate the severity of opioid withdrawal. The present study evaluated the ability of a competitive NMDA receptor antagonist, D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid), to affect morphine-induced sensitization to naloxone in rats trained to lever-press on a multiple-trial, fixed-ratio 10 schedule of food reinforcement. D-CPPene (0.3-3 mg/kg) was administered either 4 h or 30 min prior to the test session. Morphine (10 mg/kg) or its vehicle was administered 4 h before naloxone challenge (0.3-3 mg/kg). D-CPPene failed to prevent morphine-induced potentiation of the naloxone-produced decrement in operant performance. Thus, these results suggest that agonist-induced sensitization to behavioral effects of opioid antagonists may be insensitive to NMDA receptor blockade.

  12. 76 FR 71348 - Role of Naloxone in Opioid Overdose Fatality Prevention; Public Workshop; Request for Comments

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-17

    ... discussion about the potential value of making naloxone more widely available outside of conventional medical... registration on the day of the public workshop will be based on space availability. If registration reaches..., is an injectable medicine that can rapidly reverse the overdose of either prescription (e.g., Oxy...

  13. Cost-effectiveness of Extended Buprenorphine-Naloxone Treatment for Opioid-Dependent Youth: Data from a Randomized Trial

    PubMed Central

    Polsky, Daniel; Glick, Henry A.; Yang, Jianing; Subramaniam, Geetha A.; Poole, Sabrina A.; Woody, George E.

    2010-01-01

    Introduction The objective is to estimate cost, net social cost, and cost-effectiveness in a clinical trial of extended buprenorphine-naloxone treatment versus brief detoxification treatment in opioid-dependent youth. Methods Economic evaluation of a clinical trial conducted at 6 community outpatient treatment programs from July 2003 to December 2006 including 152 patients aged 15 to 21 years who were randomized to 12 weeks of buprenorphine-naloxone (BUP) or a 14-day taper (DETOX). BUP patients were prescribed up to 24 mg per day for 9 weeks and then tapered to zero at the end of week 12. DETOX patients were prescribed up to 14 mg per day and then tapered to zero on day 14. All were offered twice weekly drug counseling. Data were collected prospectively during the 12-week treatment and at follow-up interviews at months 6, 9, and 12. Results The 12-week outpatient study treatment cost was $1514 (p<0.001) higher for BUP relative to DETOX. One-year total direct medical cost was only $83 higher for BUP (p=0.97). The cost-effectiveness ratio of BUP relative to DETOX was $1,376 in terms of 1-year direct medical cost per quality-adjusted life year (QALY) and $25,049 in terms of outpatient treatment program cost per QALY. The acceptability curve suggests that the cost-effectiveness ratio of BUP relative to DETOX has an 86% chance of being accepted as cost-effective for a threshold of $100,000 per QALY. Conclusions Extended buprenorphine-naloxone treatment relative to brief detoxification is cost effective in the U.S. health care system for the outpatient treatment of opioid-dependent youth. PMID:20626379

  14. Failure to identify or effectively manage prescription opioid dependence acted as a gateway to heroin use-buprenorphine/naloxone treatment and recovery in a surgical patient.

    PubMed

    Conroy, Stephen; Hill, Duncan

    2014-12-17

    The prescribing of opioid pain medication has increased markedly in recent years, with strong opioid dispensing increasing 18-fold in Tayside, Scotland since 1995. Despite this, little data is available to quantify the problem of opioid pain medication dependence (OPD) and until recently there was little guidance on best-practice treatment. We report the case of a young mother prescribed dihydrocodeine for postoperative pain relief who became opioid dependent. When her prescription was stopped without support, she briefly used heroin to overcome her withdrawal. After re-exposure to dihydrocodeine following surgery 9 years later and treatment with methadone for dependency, she was transferred to buprenorphine/naloxone. In our clinical experience and in agreement with Department of Health and Royal College of General Practitioner guidance, buprenorphine/naloxone is the preferred opioid substitution treatment for OPD. Our patient remains within her treatment programme and has returned to work on buprenorphine 16 mg/naloxone 4 mg in conjunction with social and psychological support. 2014 BMJ Publishing Group Ltd.

  15. Evaluation of buprenorphine dosage adequacy in opioid receptor agonist substitution therapy for heroin dependence: first use of the BUprenorphine-naloxone Dosage Adequacy eVAluation (BUDAVA) questionnaire.

    PubMed

    D'Amore, Antonio; Romano, Filomena; Biancolillo, Vincenzo; Lauro, Guglielmo; Armenante, Ciro; Pizzirusso, Anna; Del Tufo, Salvatore; Ruoppolo, Ciro; Auriemma, Francesco; Cassese, Francesco; Oliva, Patrizia; Amato, Patrizia

    2012-07-01

    The dosing of opioid receptor agonist medications adequately and on an individual basis is crucial in the pharmacotherapy of opioid dependence. Clinical tools that are able to measure dose appropriateness are sorely needed. The recently developed and validated Opiate Dosage Adequacy Scale (ODAS) comprehensively evaluates the main outcomes relevant for methadone dose optimization, namely relapse, cross-tolerance, objective and subjective withdrawal symptoms, craving and overdose. Based on the ODAS, we developed a new assessment tool (BUprenorphine-naloxone Dosage Adequacy eVAluation [BUDAVA]) for evaluating dosage adequacy in patients in treatment with buprenorphine-naloxone. The main goal of this observational study was to explore whether the BUDAVA questionnaire could be used to assess buprenorphine-based, long-term substitution therapy for heroin addiction. The study included heroin-dependent patients who had been in treatment with buprenorphine-naloxone for at least 3 months. Patients (n = 196) were recruited from 11 drug abuse treatment centres in Italy. Dosage adequacy was assessed with the BUDAVA questionnaire. Patients classified as inadequately treated had their dosage modified. After 1 week, they were again administered the questionnaire to assess the adequacy of the new dosage. The buprenorphine-naloxone dosage was found to be inadequate in 61 of the 196 patients. In 13 patients, the treatment scored as inadequate only in the subjective withdrawal symptoms item of the questionnaire and therefore no dosage adjustment was made in the 2 weeks that have characterized this work. The remaining 48 inadequately treated patients had their dosage modified (42 dose increases and six dose decreases). After 1 week on the modified dosage, in 24 of these patients the new regimen was found by the assessment with the questionnaire to be adequate. These preliminary results suggest that the BUDAVA questionnaire may be useful for guiding buprenorphine-naloxone maintenance

  16. Amorphous Formulation and in Vitro Performance Testing of Instantly Disintegrating Buccal Tablets for the Emergency Delivery of Naloxone.

    PubMed

    Alqurshi, Abdulmalik; Kumar, Zahrae; McDonald, Rebecca; Strang, John; Buanz, Asma; Ahmed, Shagufta; Allen, Elizabeth; Cameron, Peter; Rickard, James A; Sandhu, Verity; Holt, Chris; Stansfield, Rebecca; Taylor, David; Forbes, Ben; Royall, Paul G

    2016-05-02

    The aim of this study was to develop a freeze-dried buccal tablet for the rapid delivery of naloxone in opioid overdose. The tablet composition was optimized to produce an amorphous matrix, which was confirmed by the absence of peaks associated with crystallinity observed by differential scanning calorimetry and powder X-ray diffraction. Tablets with high gelatin content lacked adequate porosity. Mannitol was added to the formulation to bridge and intercalate gelatin's tight polymer aggregates, however sodium bicarbonate was also required to prevent crystallization within the tablets. A linear reduction in mannitol's recrystallization enthalpy was observed with increasing sodium bicarbonate concentration (ΔrecryH = -20.3[NaHCO3] + 220.9; r(2) = 0.9, n = 18). The minimum sodium bicarbonate concentration for full inhibition of mannitol crystallization was 10.9% w/w. Freeze-dried tablets with lower amounts of sodium bicarbonate possessed a crystalline fraction that PXRD identified as mannitol hemihydrate from the unique peak at 9.7° 2θ. Mannitol's greater affinity for both ions and residual water rather than its affinity for self-association was the mechanism for the inhibition of crystallization observed here. The optimized tablet (composition mannitol 24% w/w (4.26 mg), gelatin 65% w/w (11.7 mg), sodium bicarbonate 11% w/w (1.98 mg), and naloxone 800 μg) formed predominantly amorphous tablets that disintegrated in less than 10 s. Optimized tablets were chemically and physically stable over 9 months storage at 25 °C. As speed of drug liberation is the critical performance attribute for a solid dosage form designed to deliver drug in an emergency, a novel imaging based in vitro disintegration assay for buccal tablets was developed. The assay was optimized with regard to conditions in the buccal cavity: i.e., temperature 33-37 °C, volume of medium (0.1-0.7 mL), and use of mucin-containing biorelevant medium. The disintegration assay was sensitive to temperature

  17. Effect of naloxone treatment on luteinizing hormone and testosterone concentrations in boars with high and low libido

    USDA-ARS?s Scientific Manuscript database

    The objective was to determine the effects of naloxone, an opioid peptide receptor antagonist on circulating concentrations of luteinizing hormone (LH) and testosterone in boars characterized as having high (n = 8) or low libido (n = 8) based on the willingness to mount an artificial sow and allow s...

  18. Effectiveness of Scotland's National Naloxone Programme for reducing opioid-related deaths: a before (2006-10) versus after (2011-13) comparison.

    PubMed

    Bird, Sheila M; McAuley, Andrew; Perry, Samantha; Hunter, Carole

    2016-05-01

    To assess the effectiveness for Scotland's National Naloxone Programme (NNP) by comparison between 2006-10 (before) and 2011-13 (after NNP started in January 2011) and to assess cost-effectiveness. This was a pre-post evaluation of a national policy. Cost-effectiveness was assessed by prescription costs against life-years gained per opioid-related death (ORD) averted. Scotland, in community settings and all prisons. Brief training and standardized naloxone supply became available to individuals at risk of opioid overdose. ORDs as identified by National Records of Scotland. Look-back determined the proportion of ORDs who, in the 4 weeks before ORD, had been (i) released from prison (primary outcome) and (ii) released from prison or discharged from hospital (secondary). We report 95% confidence intervals for effectiveness in reducing the primary (and secondary) outcome in 2011-13 versus 2006-10. Prescription costs were assessed against 1 or 10 life-years gained per averted ORD. In 2006-10, 9.8% of ORDs (193 of 1970) were in people released from prison within 4 weeks of death, whereas only 6.3% of ORDs in 2011-13 followed prison release (76 of 1212, P < 0.001; this represented a difference of 3.5% [95% confidence interval (CI) = 1.6-5.4%)]. This reduction in the proportion of prison release ORDs translates into 42 fewer prison release ORDs (95% CI = 19-65) during 2011-13, when 12,000 naloxone kits were issued at current prescription cost of £225,000. Scotland's secondary outcome reduced from 19.0 to 14.9%, a difference of 4.1% (95% CI = 1.4-6.7%). Scotland's National Naloxone Programme, which started in 2011, was associated with a 36% reduction in the proportion of opioid-related deaths that occurred in the 4 weeks following release from prison. © 2015 The Authors. Addiction published by JohnWiley & Sons Ltd on behalf of Society for the Study of Addiction.

  19. Medical providers' knowledge and concerns about opioid overdose education and take-home naloxone rescue kits within Veterans Affairs health care medical treatment settings.

    PubMed

    Winograd, Rachel P; Davis, Corey S; Niculete, Maria; Oliva, Elizabeth; Martielli, Richard P

    2017-01-01

    Overdose from opioids is a serious public health and clinical concern. Veterans are at increased risk for opioid overdose compared with the civilian population, suggesting the need for enhanced efforts to address overdose prevention in Department of Veterans Affairs (VA) health care settings, such as primary care clinics. Prescribing providers (N = 45) completed surveys on baseline knowledge and concerns about the VA Overdose Education and Naloxone Distribution (OEND) initiative prior to attending an OEND educational training. Survey items were grouped into 4 OEND-related categories, reflecting (1) lack of knowledge/familiarity/comfort; (2) concerns about iatrogenic effects; (3) concerns about impressions of unsafe opioid prescribing; and (4) concerns about risks of naloxone prescribing. Although certain OEND-related categories were associated with each other, concerns related to iatrogenic effects of OEND (e.g., patients will use more opioids and/or be less likely to see treatment) and lack of knowledge/familiarity/comfort with OEND were endorsed more than concerns related to giving impressions of unsafe opioid prescribing. The majority of providers endorsed the belief that those prescribing opioids to patients should be responsible for providing overdose education to those patients. System-wide naloxone prescription rates and sources increased over 320% following initiation of OEND expansion efforts, although these increases cannot be viewed as a direct result of the in-service trainings. Findings demonstrate that some providers believe they lack knowledge of opioid overdose prevention techniques and hold concerns about OEND implementation. More training of medical providers outside substance use treatment settings is needed, with particular attention to concerns about harmful consequences resulting from the receipt of naloxone.

  20. Comment on "a comparison of buprenorphine + naloxone to buprenorphine and methadone in the treatment of opioid dependence during pregnancy: maternal and neonatal outcomes".

    PubMed

    Newman, Robert G; Gevertz, Susan G

    2013-01-01

    In a recent article, Lund et al sought to compare maternal and neonatal outcomes of various treatment regimens for opioid dependence during pregnancy.1 In their background, discussion the authors state that "In the United States buprenorphine plus naloxone [Suboxone(®)] … has been the preferred form of prescribed buprenorphine due to its reduced abuse liability relative to buprenorphine alone [Subutex(®)]." This claim is certainly consistent with the view of the firm that has manufactured and sold both products, Reckitt Benckiser. In September of 2011, the company announced that it was "… discontinuing distribution and sale of Subutex(®) tablets as we believe that mono product (product containing buprenorphine alone with no naloxone) creates a greater risk of misuse, abuse and diversion …".2 Supporting evidence for the alleged "reduced abuse liability" appears to be lacking, however, and evidence cannot be located in the two references cited by Dr. Lund and his co-authors, which in fact are silent on the subject of abuse potential.3,4 In contrast, it has been reported that the transition to buprenorphine/naloxone from the mono formulation has been associated with "… no reduction in injection risk behaviors among IDUs."5.

  1. Evaluating the impact of a national naloxone programme on ambulance attendance at overdose incidents: a controlled time–series analysis

    PubMed Central

    Bouttell, Janet; Barnsdale, Lee; Mackay, Daniel; Lewsey, Jim; Hunter, Carole; Robinson, Mark

    2016-01-01

    Abstract Background and Aims It has been suggested that distributing naloxone to people who inject drugs (PWID) will lead to fewer attendances by emergency medical services at opioid‐related overdose incidents if peer administration of naloxone was perceived to have resuscitated the overdose victim successfully. This study evaluated the impact of a national naloxone programme (NNP) on ambulance attendance at opioid‐related overdose incidents throughout Scotland. Specifically, we aimed to answer the following research questions: is there evidence of an association between ambulance call‐outs to opioid‐related overdose incidents and the cumulative number of ‘take‐home naloxone’ (THN) kits in issue; and is there evidence of an association between ambulance call‐outs to opioid‐related overdose incidents in early adopter (pilot) or later adopting (non‐pilot) regions and the cumulative number of THN kits issued in those areas? Design Controlled time–series analysis. Setting Scotland, UK, 2008–15. Participants Pre‐NNP implementation period for the evaluation was defined as 1 April 2008 to 31 March 2011 and the post‐implementation period as 1 April 2011 to 31 March 2015. In total, 3721 ambulance attendances at opioid‐related overdose were recorded for the pre‐NNP implementation period across 158 weeks (mean 23.6 attendances per week) and 5258 attendances across 212 weeks in the post‐implementation period (mean 24.8 attendances per week). Intervention Scotland's NNP; formally implemented on 1 April 2011. Measurements Primary outcome measure was weekly incidence (counts) of call‐outs to opioid‐related overdoses at national and regional Health Board level. Data were acquired from the Scottish Ambulance Service (SAS). Models were adjusted for opioid replacement therapy using data acquired from the Information Services Division on monthly sums of all dispensed methadone and buprenorphine in the study period. Models were adjusted further

  2. The impact of supersaturation level for oral absorption of BCS class IIb drugs, dipyridamole and ketoconazole, using in vivo predictive dissolution system: Gastrointestinal Simulator (GIS).

    PubMed

    Tsume, Yasuhiro; Matsui, Kazuki; Searls, Amanda L; Takeuchi, Susumu; Amidon, Gregory E; Sun, Duxin; Amidon, Gordon L

    2017-05-01

    The development of formulations and the assessment of oral drug absorption for Biopharmaceutical Classification System (BCS) class IIb drugs is often a difficult issue due to the potential for supersaturation and precipitation in the gastrointestinal (GI) tract. The physiological environment in the GI tract largely influences in vivo drug dissolution rates of those drugs. Thus, those physiological factors should be incorporated into the in vitro system to better assess in vivo performance of BCS class IIb drugs. In order to predict oral bioperformance, an in vitro dissolution system with multiple compartments incorporating physiologically relevant factors would be expected to more accurately predict in vivo phenomena than a one-compartment dissolution system like USP Apparatus 2 because, for example, the pH change occurring in the human GI tract can be better replicated in a multi-compartmental platform. The Gastrointestinal Simulator (GIS) consists of three compartments, the gastric, duodenal and jejunal chambers, and is a practical in vitro dissolution apparatus to predict in vivo dissolution for oral dosage forms. This system can demonstrate supersaturation and precipitation and, therefore, has the potential to predict in vivo bioperformance of oral dosage forms where this phenomenon may occur. In this report, in vitro studies were performed with dipyridamole and ketoconazole to evaluate the precipitation rates and the relationship between the supersaturation levels and oral absorption of BCS class II weak base drugs. To evaluate the impact of observed supersaturation levels on oral absorption, a study utilizing the GIS in combination with mouse intestinal infusion was conducted. Supersaturation levels observed in the GIS enhanced dipyridamole and ketoconazole absorption in mouse, and a good correlation between their supersaturation levels and their concentration in plasma was observed. The GIS, therefore, appears to represent in vivo dissolution phenomena and

  3. Predictors of Abstinence: National Institute of Drug Abuse Multisite Buprenorphine/Naloxone Treatment Trial in Opioid-Dependent Youth

    ERIC Educational Resources Information Center

    Subramaniam, Geetha A.; Warden, Diane; Minhajuddin, Abu; Fishman, Marc J.; Stitzer, Maxine L.; Adinoff, Bryon; Trivedi, Madhukar; Weiss, Roger; Potter, Jennifer; Poole, Sabrina A.; Woody, George E.

    2011-01-01

    Objective: To examine predictors of opioid abstinence in buprenorphine/naloxone (Bup/Nal)-assisted psychosocial treatment for opioid-dependent youth. Method: Secondary analyses were performed of data from 152 youth (15-21 years old) randomly assigned to 12 weeks of extended Bup/Nal therapy or up to 2 weeks of Bup/Nal detoxification with weekly…

  4. Milk caseins as useful vehicle for delivery of dipyridamole drug.

    PubMed

    Dezhampanah, Hamid; Esmaili, Masoomeh; Hasani, Leila

    2018-05-01

    The interaction of bovine milk α- and β-caseins as an efficient drug carrier system with Dipyridamole (DIP) was investigated using spectroscopy and molecular docking studies at different temperatures (20-37 °C). FTIR, CD, and fluorescence spectroscopy methods demonstrated that α- and β-caseins interact with DIP molecule mainly via hydrophobic and hydrophilic interactions and change in secondary structure of α- and β-caseins. DIP showed a higher quenching efficiency and binding constant of α-casein than β-casein. There was only one binding site for DIP and it was located on the surface of the protein molecule. The thermodynamic parameters of calculation showed that the binding process occurs spontaneously and demonstrated that α- and β-caseins provide very good binding and entrapment to DIP via hydrogen bonds, Van der Waals forces, and hydrophobic interactions. Fluorescence resonance energy transfer, synchronous fluorescence spectroscopy, and docking study showed that DIP binds to the Trp residues of α- and β-casein molecules with short distances. Docking study showed that DIP molecule made several hydrogen bonds and van der Waals interactions with α- and β-caseins. The study of cell culture and micellar solubility of DIP demonstrated α- and β-caseins relatively the same helping in delivery of DIP. Milk α- and β-caseins are considered as a useful vehicle for the solublization and stabilization of DIP in aqueous solution at natural pH.

  5. Comparison of the myocardial blood flow response to regadenoson and dipyridamole: a quantitative analysis in patients referred for clinical 82Rb myocardial perfusion PET.

    PubMed

    Goudarzi, Behnaz; Fukushima, Kenji; Bravo, Paco; Merrill, Jennifer; Bengel, Frank M

    2011-10-01

    Regadenoson is a novel selective A2A adenosine receptor agonist, which is administered as an intravenous bolus at a fixed dose. It is currently not clear if the absolute flow increase in response to this fixed dose is a function of distribution volume in individual patients or if it is generally comparable to the previous standard agents dipyridamole or adenosine, which are dosed based on weight. We used quantitative analysis of clinical 82Rb PET/CT studies to obtain further insights. A total of 104 subjects with normal clinical rest/stress 82Rb perfusion PET/CT were included in a retrospective analysis. To rule out confounding factors, none had evidence of prior cardiac disease, ischaemia or infarction, cardiomyopathy, diabetes with insulin use, calcium score>400, renal disease or other significant systemic disease. A group of 52 patients stressed with regadenoson were compared with a group of 52 patients stressed with dipyridamole before regadenoson became available. The groups were matched for clinical characteristics, risk factors and baseline haemodynamics. Myocardial blood flow (MBF) and myocardial flow reserve (MFR) were quantified using a previously validated retention model, after resampling of dynamic studies from list-mode 82Rb datasets. At rest, heart rate, blood pressure and MBF were comparable between the groups. Regadenoson resulted in a significantly higher heart rate (34±14 vs. 23±10 beats per minute increase from baseline; p<0.01) and rate-pressure product. Patients in the regadenoson group reported less severe symptoms and required less aminophylline. Stress MBF and MFR were not different between the groups (2.2±0.6 vs. 2.1±0.6 ml/min/g, p=0.39, and 2.9±0.8 vs. 2.8±0.7, p=0.31, respectively). In the regadenoson group, there was no correlation between stress flow or MFR and body weight or BMI. Despite its administration at a fixed dose, regadenoson results in an absolute increase in MBF which is comparable to that following dipyridamole

  6. The Acute Administration of the Selective Dopamine D3 Receptor Antagonist SB-277011A Reverses Conditioned Place Aversion Produced by Naloxone Precipitated Withdrawal From Acute Morphine Administration in Rats

    PubMed Central

    RICE, ONARAE V.; GARDNER, ELIOT L.; HEIDBREDER, CHRISTIAN A.; ASHBY, CHARLES R.

    2014-01-01

    We examined the effect of SB-277011A, a selective D3 receptor antagonist, on the conditioned place aversion (CPA) response associated with naloxone-induced withdrawal from acute morphine administration in male Sprague-Dawley rats. Morphine (5.6 mg/kg i.p.) was given, followed 4 hrs later by naloxone (0.3 mg/kg i.p.) and prior to placing the animals in one specific chamber of the test apparatus. All animals were subjected to 2 of these trials. A significant CPA occurred in animals that received an i.p. injection of vehicle 30 minutes prior to the measurement of chamber preference. The pretreatment of animals (30 minutes prior to testing) with 3 mg/kg i.p. of SB-277011A did not significantly alter the CPA compared to animals treated with vehicle (1 ml/kg i.p. of deionized distilled water). In contrast, the acute pretreatment of animals with 6, 12 or 24 mg/kg i.p. of SB-277011A significantly decreased the CPA compared to vehicle-treated animals. In fact, the 12 and 24 mg/kg doses of SB-277011A significantly increased the time spent in the chamber where animals were paired with morphine and naloxone. These results suggest that the selective antagonism of D3 receptors attenuates the CPA produced by a model of naloxone-induced withdrawal from acute morphine dependence. PMID:21905128

  7. Effectiveness of Scotland's National Naloxone Programme for reducing opioid‐related deaths: a before (2006–10) versus after (2011–13) comparison

    PubMed Central

    McAuley, Andrew; Perry, Samantha; Hunter, Carole

    2016-01-01

    Abstract Aims To assess the effectiveness for Scotland's National Naloxone Programme (NNP) by comparison between 2006–10 (before) and 2011–13 (after NNP started in January 2011) and to assess cost‐effectiveness. Design This was a pre–post evaluation of a national policy. Cost‐effectiveness was assessed by prescription costs against life‐years gained per opioid‐related death (ORD) averted. Setting Scotland, in community settings and all prisons. Intervention Brief training and standardized naloxone supply became available to individuals at risk of opioid overdose. Measurements ORDs as identified by National Records of Scotland. Look‐back determined the proportion of ORDs who, in the 4 weeks before ORD, had been (i) released from prison (primary outcome) and (ii) released from prison or discharged from hospital (secondary). We report 95% confidence intervals for effectiveness in reducing the primary (and secondary) outcome in 2011–13 versus 2006–10. Prescription costs were assessed against 1 or 10 life‐years gained per averted ORD. Findings In 2006–10, 9.8% of ORDs (193 of 1970) were in people released from prison within 4 weeks of death, whereas only 6.3% of ORDs in 2011–13 followed prison release (76 of 1212, P < 0.001; this represented a difference of 3.5% [95% confidence interval (CI) = 1.6–5.4%)]. This reduction in the proportion of prison release ORDs translates into 42 fewer prison release ORDs (95% CI = 19–65) during 2011–13, when 12 000 naloxone kits were issued at current prescription cost of £225 000. Scotland's secondary outcome reduced from 19.0 to 14.9%, a difference of 4.1% (95% CI = 1.4–6.7%). Conclusions Scotland's National Naloxone Programme, which started in 2011, was associated with a 36% reduction in the proportion of opioid‐related deaths that occurred in the 4 weeks following release from prison. PMID:26642424

  8. Expectancy Effects on Conditioned Pain Modulation Are Not Influenced by Naloxone or Morphine.

    PubMed

    France, Christopher R; Burns, John W; Gupta, Rajnish K; Buvanendran, Asokumar; Chont, Melissa; Schuster, Erik; Orlowska, Daria; Bruehl, Stephen

    2016-08-01

    Recent studies suggest that participant expectations influence pain ratings during conditioned pain modulation testing. The present study extends this work by examining expectancy effects among individuals with and without chronic back pain after administration of placebo, naloxone, or morphine. This study aims to identify the influence of individual differences in expectancy on changes in heat pain ratings obtained before, during, and after a forearm ischemic pain stimulus. Participants with chronic low back pain (n = 88) and healthy controls (n = 100) rated heat pain experience (i.e., "test stimulus") before, during, and after exposure to ischemic pain (i.e., "conditioning stimulus"). Prior to testing, participants indicated whether they anticipated that their heat pain would increase, decrease, or remain unchanged during ischemic pain. Analysis of the effects of expectancy (pain increase, decrease, or no change), drug (placebo, naloxone, or morphine), and group (back pain, healthy) on changes in heat pain revealed a significant main effect of expectancy (p = 0.001), but no other significant main effects or interactions. Follow-up analyses revealed that individuals who expected lower pain during ischemia reported significantly larger decreases in heat pain as compared with those who expected either no change (p = 0.004) or increased pain (p = 0.001). The present findings confirm that expectancy is an important contributor to conditioned pain modulation effects, and therefore significant caution is needed when interpreting findings that do not account for this individual difference. Opioid mechanisms do not appear to be involved in these expectancy effects.

  9. Clinician Beliefs and Attitudes about Buprenorphine/Naloxone Diversion

    PubMed Central

    Schuman-Olivier, Zev; Connery, Hilary; Griffin, Margaret L.; Wyatt, Steve A.; Wartenberg, Alan A.; Borodovsky, Jacob; Renner, John A.; Weiss, Roger D.

    2013-01-01

    Background and Objectives Concern about diversion of buprenorphine/naloxone (B/N) in the U.S. may affect prescribing patterns and policy decisions. This study examines addiction treatment clinician beliefs and attitudes regarding B/N diversion. Methods Participants (n=369) completed a 34-item survey in 2010 during two national symposia on opioid dependence. We conducted multivariable regression, examining the relationship of perceived danger from B/N diversion with clinician characteristics and their beliefs about B/N treatment and diversion. We compared causal beliefs about diversion among clinicians with and without B/N treatment experience. Results Forty percent of clinicians believed that B/N diversion is a dangerous problem. The belief that B/N diversion increases accidental overdoses in the community was strongly associated with perceived danger from B/N diversion. Conclusions and Scientific Significance Attitudes and beliefs, not education level, were associated with clinician’s perceived danger from B/N diversion. Clinicians with greater B/N patient experience were more likely to believe treatment access barriers are the major cause of B/N diversion. PMID:24131165

  10. Why is it so hard to implement change? A qualitative examination of barriers and facilitators to distribution of naloxone for overdose prevention in a safety net environment.

    PubMed

    Drainoni, Mari-Lynn; Koppelman, Elisa A; Feldman, James A; Walley, Alexander Y; Mitchell, Patricia M; Ellison, Jacqueline; Bernstein, Edward

    2016-10-18

    The increase in opioid overdose deaths has become a national public health crisis. Naloxone is an important tool in opioid overdose prevention. Distribution of nasal naloxone has been found to be a feasible, and effective intervention in community settings and may have potential high applicability in the emergency department, which is often the initial point of care for persons at high risk of overdose. One safety net hospital introduced an innovative policy to offer take-home nasal naloxone via a standing order to ensure distribution to patients at risk for overdose. The aims of this study were to examine acceptance and uptake of the policy and assess facilitators and barriers to implementation. After obtaining pre-post data on naloxone distribution, we conducted a qualitative study. The PARiHS framework steered development of the qualitative guide. We used theoretical sampling in order to include the range of types of emergency department staff (50 total). The constant comparative method was initially used to code the transcripts and identify themes; the themes that emerged from the coding were then mapped back to the evidence, context and facilitation constructs of the PARiHS framework. Acceptance of the policy was good but uptake was low. Primary themes related to facilitators included: real-world driven intervention with philosophical, clinician and leadership support; basic education and training efforts; availability of resources; and ability to leave the ED with the naloxone kit in hand. Barriers fell into five general categories: protocol and policy; workflow and logistical; patient-related; staff roles and responsibilities; and education and training. The actual implementation of a new innovation in healthcare delivery is largely driven by factors beyond acceptance. Despite support and resources, implementation was challenging, with low uptake. While the potential of this innovation is unknown, understanding the experience is important to improve uptake

  11. Overdose rescues by trained and untrained participants and change in opioid use among substance-using participants in overdose education and naloxone distribution programs: a retrospective cohort study

    PubMed Central

    2014-01-01

    Background One approach to preventing opioid overdose, a leading cause of premature, preventable mortality, is to provide overdose education and naloxone distribution (OEND). Two outstanding issues for OEND implementation include 1) the dissemination of OEND training from trained to untrained community members; and 2) the concern that OEND provides active substance users with a false sense of security resulting in increased opioid use. Methods To compare overdose rescue behaviors between trained and untrained rescuers among people reporting naloxone rescue kit use; and determine whether heroin use changed after OEND, we conducted a retrospective cohort study among substance users in the Massachusetts OEND program from 2006 to 2010. We used chi square and t-test statistics to compare the differences in overdose management characteristics among overdoses managed by trained versus untrained participants. We employed Wilcoxon signed rank test to compare median difference among two repeated measures of substance use among participants with drug use information collected more than once. Results Among 4,926 substance-using participants, 295 trained and 78 untrained participants reported one or more rescues, resulting in 599 rescue reports. We found no statistically significant differences in help-seeking (p = 0.41), rescue breathing (p = 0.54), staying with the victim (p = 0.84) or in the success of naloxone administration (p = 0.69) by trained versus untrained rescuers. We identified 325 OEND participants who had drug use information collected more than once. We found no significant overall change in the number of days using heroin in past 30 days (decreased 38%, increased 35%, did not change 27%, p = 0.52). Conclusion Among 4926 substance users who participated in OEND, 373(7.6%) reported administering naloxone during an overdose rescue. We found few differences in behavior between trained and untrained overdose rescuers. Prospective studies will be needed to

  12. Preincisional and postoperative epidural morphine, ropivacaine, ketamine, and naloxone treatment for postoperative pain management in upper abdominal surgery.

    PubMed

    Lai, Hou-Chuan; Hsieh, Chung-Bao; Wong, Chih-Shung; Yeh, Chun-Chang; Wu, Zhi-Fu

    2016-09-01

    Previous studies have shown that preincisional epidural morphine, bupivacaine, and ketamine combined with epidural anesthesia (EA) and general anesthesia (GA) provided pre-emptive analgesia for upper abdominal surgery. Recent studies reported that ultralow-dose naloxone enhanced the antinociceptive effect of morphine in rats. This study investigated the benefits of preincisional and postoperative epidural morphine + ropivacaine + ketamine + naloxone (M + R + K + N) treatment for achieving postoperative pain relief in upper abdominal surgery. Eighty American Society of Anesthesiology I-II patients scheduled for major upper abdominal surgery were allocated to four groups in a randomized, single-blinded study. All patients received combined GA and EA with a continuous epidural infusion of 2% lidocaine (6-8 mL/h) 30 minutes after pain regimen. After GA induction, in Group I, an epidural pain control regimen (total 10 mL) was administered using 1% lidocaine (8 mL) + morphine (2 mg) + ropivacaine (20 mg; M + R); in Group II, 1% lidocaine 8 (mL) + morphine (2 mg) + ropivacaine (20 mg) + ketamine (20 mg; M + R + K); in Group III, 1% lidocaine (8 mL) + morphine (2 mg) + ropivacaine (20 mg) + naloxone (2 μg; M + R + N); and in Group IV, 1% lidocaine (8 mL) + morphine (2 mg) + ropivacaine (20 mg) + ketamine (20 mg) + naloxone (2 μg; M + R + K + N), respectively. All patients received patient-controlled epidural analgesia (PCEA) with different pain regimens to control subsequent postoperative pain for 3 days following surgery. During the 3-day period following surgery, PCEA consumption (mL), numerical rating scale (NRS) score while cough/moving, and analgesic-related adverse effects were recorded. Total PCEA consumption for the 3-day observation period was 161.5±17.8 mL, 103.2±21.7 mL, 152.4±25.6 mL, and 74.1±16.9 mL for Groups I, II, III, and IV, respectively. (p < 0.05). The cough/moving NRS

  13. Effectiveness and cost-effectiveness of unsupervised buprenorphine-naloxone for the treatment of heroin dependence in a randomized waitlist controlled trial.

    PubMed

    Dunlop, Adrian J; Brown, Amanda L; Oldmeadow, Christopher; Harris, Anthony; Gill, Anthony; Sadler, Craig; Ribbons, Karen; Attia, John; Barker, Daniel; Ghijben, Peter; Hinman, Jennifer; Jackson, Melissa; Bell, James; Lintzeris, Nicholas

    2017-05-01

    Access to opioid agonist treatment can be associated with extensive waiting periods with significant health and financial burdens. This study aimed to determine whether patients with heroin dependence dispensed buprenorphine-naloxone weekly have greater reductions in heroin use and related adverse health effects 12-weeks after commencing treatment, compared to waitlist controls and to examine the cost-effectiveness of this strategy. An open-label waitlist RCT was conducted in an opioid treatment clinic in Newcastle, Australia. Fifty patients with DSM-IV-TR heroin dependence (and no other substance dependence) were recruited. The intervention group (n=25) received take-home self-administered sublingual buprenorphine-naloxone weekly (mean dose, 22.7±5.7mg) and weekly clinical review. Waitlist controls (n=25) received no clinical intervention. The primary outcome was heroin use (self-report, urine toxicology verified) at weeks four, eight and 12. The primary cost-effectiveness outcome was incremental cost per additional heroin-free-day. Outcome data were available for 80% of all randomized participants. Across the 12-weeks, treatment group heroin use was on average 19.02days less/month (95% CI -22.98, -15.06, p<0.0001). A total 12-week reduction in adjusted costs including crime of $A5,722 (95% CI 3299, 8154) in favor of treatment was observed. Excluding crime, incremental cost per heroin-free-day gained from treatment was $A18.24 (95% CI 4.50, 28.49). When compared to remaining on a waitlist, take-home self-administered buprenorphine-naloxone treatment is associated with significant reductions in heroin use for people with DSM-IV-TR heroin dependence. This cost-effective approach may be an efficient strategy to enhance treatment capacity. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  14. Caged Naloxone Reveals Opioid Signaling Deactivation Kinetics

    PubMed Central

    Banghart, Matthew R.; Shah, Ruchir C.; Lavis, Luke D.

    2013-01-01

    The spatiotemporal dynamics of opioid signaling in the brain remain poorly defined. Photoactivatable opioid ligands provide a means to quantitatively measure these dynamics and their underlying mechanisms in brain tissue. Although activation kinetics can be assessed using caged agonists, deactivation kinetics are obscured by slow clearance of agonist in tissue. To reveal deactivation kinetics of opioid signaling we developed a caged competitive antagonist that can be quickly photoreleased in sufficient concentrations to render agonist dissociation effectively irreversible. Carboxynitroveratryl-naloxone (CNV-NLX), a caged analog of the competitive opioid antagonist NLX, was readily synthesized from commercially available NLX in good yield and found to be devoid of antagonist activity at heterologously expressed opioid receptors. Photolysis in slices of rat locus coeruleus produced a rapid inhibition of the ionic currents evoked by multiple agonists of the μ-opioid receptor (MOR), but not of α-adrenergic receptors, which activate the same pool of ion channels. Using the high-affinity peptide agonist dermorphin, we established conditions under which light-driven deactivation rates are independent of agonist concentration and thus intrinsic to the agonist-receptor complex. Under these conditions, some MOR agonists yielded deactivation rates that are limited by G protein signaling, whereas others appeared limited by agonist dissociation. Therefore, the choice of agonist determines which feature of receptor signaling is unmasked by CNV-NLX photolysis. PMID:23960100

  15. Naloxone Administration for Suspected Opioid Overdose: An Expanded Scope of Practice by a Basic Life Support Collegiate-Based Emergency Medical Services Agency

    ERIC Educational Resources Information Center

    Jeffery, Ryan M.; Dickinson, Laura; Ng, Nicholas D.; DeGeorge, Lindsey M.; Nable, Jose V.

    2017-01-01

    Opioid abuse is a growing and significant public health concern in the United States. Naloxone is an opioid antagonist that can rapidly reverse the respiratory depression associated with opioid toxicity. Georgetown University's collegiate-based emergency medical services (EMS) agency recently adopted a protocol, allowing providers to administer…

  16. A cluster-analytic profiling of heroin-dependent patients based on level, clinical adequacy, and patient-desired adjustment of buprenorphine dosage during buprenorphine-naloxone maintenance treatment in sixteen Spanish centers.

    PubMed

    Alcaraz, Saul; González-Saiz, Francisco; Trujols, Joan; Vergara-Moragues, Esperanza; Siñol, Núria; Pérez de Los Cobos, José

    2018-06-01

    Buprenorphine dosage is a crucial factor influencing outcomes of buprenorphine treatment for heroin use disorders. Therefore, the aim of the present study is to identify naturally occurring profiles of heroin-dependent patients regarding individualized management of buprenorphine dosage in clinical practice of buprenorphine-naloxone maintenance treatment. 316 patients receiving buprenorphine-naloxone maintenance treatment were surveyed at 16 Spanish centers during the stabilization phase of this treatment. Patients were grouped using cluster analysis based on three key indicators of buprenorphine dosage management: dose, adequacy according to physician, and adjustment according to patient. The clusters obtained were compared regarding different facets of patient clinical condition. Four clusters were identified and labeled as follows (buprenorphine average dose and percentage of participants in each cluster are given in brackets): "Clinically Adequate and Adjusted to Patient Desired Low Dosage" (2.60 mg/d, 37.05%); "Clinically Adequate and Adjusted to Patient Desired High Dosage" (10.71 mg/d, 29.18%); "Clinically Adequate and Patient Desired Reduction of Low Dosage" (3.38 mg/d, 20.0%); and "Clinically Inadequate and Adjusted to Patient Desired Moderate Dosage" (7.55 mg/d, 13.77%). Compared to patients from the other three clusters, participants in the latter cluster reported more frequent use of heroin and cocaine during last week, lower satisfaction with buprenorphine-naloxone as a medication, higher prevalence of buprenorphine-naloxone adverse effects and poorer psychological adjustment. Our results show notable differences between clusters of heroin-dependent patients regarding buprenorphine dosage management. We also identified a group of patients receiving clinically inadequate buprenorphine dosage, which was related to poorer clinical condition. Copyright © 2018 Elsevier B.V. All rights reserved.

  17. A maternal "junk-food" diet reduces sensitivity to the opioid antagonist naloxone in offspring postweaning.

    PubMed

    Gugusheff, Jessica R; Ong, Zhi Yi; Muhlhausler, Beverly S

    2013-03-01

    Perinatal exposure to a maternal "junk-food" diet has been demonstrated to increase the preference for palatable diets in adult offspring. We aimed to determine whether this increased preference could be attributed to changes in μ-opioid receptor expression within the mesolimbic reward pathway. We report here that mRNA expression of the μ-opioid receptor in the ventral tegmental area (VTA) at weaning was 1.4-fold (males) and 1.9-fold (females) lower in offspring of junk-food (JF)-fed rat dams than in offspring of dams fed a standard rodent diet (control) (P<0.05). Administration of the opioid antagonist naloxone to offspring given a palatable diet postweaning significantly reduced fat intake in control offspring (males: 7.7 ± 0.7 vs. 5.4 ± 0.6 g/kg/d; females: 6.9 ± 0.3 vs. 3.9 ± 0.5 g/kg/d; P<0.05), but not in male JF offspring (8.6 ± 0.6 vs. 7.1 ± 0.5 g/kg/d) and was less effective at reducing fat intake in JF females (42.2 ± 6.0 vs. 23.1 ± 4.1% reduction, P<0.05). Similar findings were observed for total energy intake. Naloxone treatment did not affect intake of standard rodent feed in control or JF offspring. These findings suggest that exposure to a maternal junk-food diet results in early desensitization of the opioid system which may explain the increased preference for junk food in these offspring.

  18. Alberta's provincial take-home naloxone program: A multi-sectoral and multi-jurisdictional response to overdose.

    PubMed

    Freeman, Lisa K; Bourque, Stacey; Etches, Nick; Goodison, Karin; O'Gorman, Claire; Rittenbach, Kay; Sikora, Christopher A; Yarema, Mark

    2017-11-09

    Alberta is a prairie province located in western Canada, with a population of approximately 4.3 million. In 2016, 363 Albertans died from apparent drug overdoses related to fentanyl, an opioid 50-100 times more toxic than morphine. This surpassed the number of deaths from motor vehicle collisions and homicides combined. Naloxone is a safe, effective, opioid antagonist that may quickly reverse an opioid overdose. In July 2015, a committee of community-based harm reduction programs in Alberta implemented a geographically restricted take-home naloxone (THN) program. The successes and limitations of this program demonstrated the need for an expanded, multi-sectoral, multi-jurisdictional response. The provincial health authority, Alberta Health Services (AHS), used previously established incident command system processes to coordinate implementation of a provincial THN program. Alberta's provincial THN program was implemented on December 23, 2015. This collaborative program resulted in a coordinated response across jurisdictional levels with wide geographical reach. Between December 2015 and December 2016, 953 locations, including many community pharmacies, registered to dispense THN kits, 9572 kits were distributed, and 472 reversals were reported. The provincial supply of THN kits more than tripled from 3000 to 10 000. Alberta was uniquely poised to deliver a large, province-wide, multi-sectoral and multi-jurisdictional THN program as part of a comprehensive response to increasing opioid-related morbidity and mortality. The speed at which AHS was able to roll out the program was made possible by work done previously and the willingness of multiple jurisdictions to work together to build on and expand the program.

  19. The involvement of CRF1 receptor within the basolateral amygdala and dentate gyrus in the naloxone-induced conditioned place aversion in morphine-dependent mice.

    PubMed

    Valero, E; Gómez-Milanés, I; Almela, P; Ribeiro Do Couto, B; Laorden, M L; Milanés, M V; Núñez, C

    2018-06-08

    Drug withdrawal-associated aversive memories trigger relapse to drug-seeking behavior. Corticotrophin-releasing factor (CRF) is an important mediator of the reinforcing properties of drugs of abuse. However, the involvement of CRF1 receptor (CRF1R) in aversive memory induced by opiate withdrawal has yet to be elucidated. We used the conditioned-place aversion (CPA) paradigm to evaluate the role of CRF1R on opiate withdrawal memory acquisition, along with plasticity-related processes that occur after CPA within the basolateral amygdala (BLA) and dentate gyrus (DG). Male mice were rendered dependent on morphine and injected acutely with naloxone before paired to confinement in a naloxone-associated compartment. The CPA scores as well as the number of TH-positive neurons (in the NTS-A2 noradrenergic cell group), and the expression of the transcription factors Arc and pCREB (in the BLA and DG) were measured with and without CRF1R blockade. Mice subjected to conditioned naloxone-induced morphine withdrawal robustly expressed CPA. Pre-treatment with the selective CRF1R antagonist CP-154,526 before naloxone conditioning session impaired morphine withdrawal-induced aversive memory acquisition. CP-154,526 also antagonized the enhanced number of TH-positive neurons in the NTS-A2 that was seen after CPA. Increased Arc expression and Arc-pCREB co-localization were seen in the BLA after CPA, which was not modified by CP-154,526. In the DG, CPA was accompanied by a decrease of Arc expression and no changes in Arc-pCREB co-localization, whereas pre-treatment with CP-154,526 induced an increase in both parameters. These results indicate that CRF-CRF1R pathway could be a critical factor governing opiate withdrawal memory storage and retrieval and might suggest a role for TH-NA pathway in the effects of withdrawal on memory. Our results might indicate that the blockade of CRF1R could represent a promising pharmacological treatment strategy approach for the attenuation of the relapse

  20. The effects of oxotremorine, epibatidine, atropine, mecamylamine and naloxone in the tail-flick, hot-plate, and formalin tests in the naked mole-rat (Heterocephalus glaber).

    PubMed

    Dulu, Thomas D; Kanui, Titus I; Towett, Philemon K; Maloiy, Geoffrey M; Abelson, Klas S P

    2014-01-01

    The naked mole-rat (Heterocephalus glaber) is a promising animal model for the study of pain mechanisms, therefore a thorough characterization of this species is essential. The aim of the present study was to establish the naked mole-rat as a model for studying the cholinergic receptor system in antinociception by investigating the involvement of muscarinic, nicotinic and opioid receptors in nociceptive tests in this species. The effects of systemic administration of the muscarinic receptor agonist oxotremorine and the nicotinic receptor agonist epibatidine were investigated in the tail-flick, the hot-plate, and the formalin tests. The effects of co-administration of the muscarinic receptor antagonist atropine, the nicotinic receptor antagonist mecamylamine, and the opioid receptor antagonist naloxone were also investigated. Oxotremorine and epibatidine induced a significant, dose-dependent antinociceptive effect in the tail-flick, hot-plate, and formalin tests, respectively. The effects of oxotremorine and epibatidine were blocked by atropine and mecamylamine, respectively. In all three nociceptive tests, naloxone in combination with oxotremorine or epibatidine enhanced the antinociceptive effects of the drugs. The present study demonstrated that stimulation of muscarinic and nicotinic receptors produces antinociceptive effects in the naked-mole rat. The reversal effect of atropine and mecamylamine suggests that this effect is mediated by cholinergic receptors. As naloxone increases the antinociceptive effects of cholinergic agonists, it is suggested that the cholinergic antinociception acts via a gateway facilitated by opioid receptor blockage; however, the precise interaction between these receptor systems needs further investigation.

  1. [Competitive study of the effects of naloxone and of almitrine on fentanyl analgesia in the anesthetized dog: effects on the muzzle opening reflex and blood gases].

    PubMed

    Dauthier, C; Gaudy, J H; Willer, J C

    1980-01-01

    The search for a technique making it possible to dissociate the analgesia and ventilatory depression of central analgesics led to a comparison of the effects of naloxone, a specific morphinomimetic antagonist, with almitrine, a ventilatory stimulant with a peripheral action, on muzzle opening reflex and blood gases. Five male dogs (Beagles, aged one year), anaesthetised with Alfetesine were treated separately with the two drugs used alone and after fentanyl analgesia (injection of fractionnated doses up to the threshold of apnoea). The association of the two drugs was also tested in tyhe dog after analgesia. The parameters studied were muzzle opening reflex, as an indication of analgesia, and blood gases, and were observed for 45 minutes, including 15 minutes control. 1 - The intravenous injection of 1,2 mg of naloxone had the effect of increasing the surface area of muscle potentials with a maximum of 7 per cent (p 0.001) at the 15 th minute. By contrast, no significant change in blood gases was seen. In the same dogs given fentanyl analgesia, naloxone not only reversed respiratory depression but had a stimulatory effect on MOR reaching 7 per cent (p 0.001) at the 30 th minute. 2 - The effects of 1 mg.kg-1 of almitrine were characterised by a fall in MOR for a period equal to that of the study and a minimum of 7.8 per cent (p 0.001) at the 20 th minute. At the same time, marked ventilatory stimulation was seen. PO2 rose by 22.7 per cent (p 0.02) at the 5 th minute. PCO2 fell during the 30 minutes studied with a minimum of 39.6 per cent (p 0.01) at the 20 th minute. Almitrine did not antagonise the depression of MOR caused by fentanyl but reversed the respiratory depression of the analgesic, increasing PO2 by 26 per cent (p 0.01) and decreasing PCO2 by 25.7 per cent (p 0.01). 3 - The combination of both drugs cancelled out the abolition of the reflex by fentanyl then facilitated it up to 24.7 per cent (p 0.001) in comparison with the animal not receiving any

  2. Budgetary impact of the utilization of buprenorphine/naloxone sublingual film and tablet for Medicaid in the United States.

    PubMed

    Asche, Carl V; Clay, Emilie; Kharitonova, Elizaveta; Zah, Vladimir; Ruby, Jane; Aballéa, Samuel

    2015-01-01

    The buprenorphine/naloxone combination for the treatment of opioid dependence is available in a film or tablet formulation. Recent retrospective studies demonstrated that treatment with the sublingual film formulation is associated with improved treatment retention and lower healthcare costs. In March 2013, generic buprenorphine/naloxone tablets were approved in the US. A budget impact model was built to compare healthcare expenditures for different market shares of sublingual film and tablet. A Markov model was developed to track a cohort of opioid dependent patients treated with sublingual film or tablet through the following treatment phases: initiation, maintenance, discontinuation, off-treatment and reinitiation. Transition probabilities and costs for each phase were estimated from the MarketScan Medicaid database for the period between 1 March 2010 and 30 June 2012. The total expenditure for the plan and expenditure per plan member per month were predicted over 5 years. Two market share scenarios were considered: 1) sublingual film is progressively replaced by generic tablet (current situation) and 2) the sublingual film holds a market share of 100%. Predicted total costs over 5 years were $6400 million when the sublingual film holds a market share of 100% (as per Scenario 2) which is lower than when sublingual film is progressively replaced by generic tablet (current situation as per Scenario 1) by $64 million. These savings were mostly driven by inpatient care ($56 million saved over 5 years), followed by emergency room care ($27 million) and pharmaceutical costs ($24 million). Costs of outpatient care attenuated the difference as they were predicted to be higher by $44 million in Scenario 2. The reduction in total cost per member per month reached $0.027 in the fifth year. Results were most sensitive to price rebates and to the probability of non-psychiatric hospitalization. While using the sublingual film formulation for more patients treated with

  3. Effect of naloxone on plasma insulin, insulin-like growth factor I, and its binding protein 1 in patients with polycystic ovarian disease.

    PubMed

    Laatikainen, T; Anttila, L; Suikkari, A M; Ruutiainen, K; Erkkola, R; Seppälä, M

    1990-09-01

    Insulin and insulin-like growth factors (IGFs) stimulate ovarian steroidogenesis, and hyperinsulinemia is often accompanied by hyperandrogenemia in women with polycystic ovarian disease (PCOD). Because opioid peptides are involved in the regulation of insulin secretion, we studied the effect of naloxone-induced opiate receptor blockade on the circulating levels of insulin, IGF-I, and IGF binding protein 1 (IGFBP-1) in 13 nonobese and 7 obese PCOD patients and in 6 healthy subjects. In obese PCOD patients, the mean basal insulin concentration was significantly higher and the IGFBP-1 concentration lower than in nonobese PCOD patients. Plasma IGF-I levels were elevated both in obese and nonobese PCOD patients. After an intravenous bolus of 10 mg naloxone, no significant changes were found in the circulating insulin or IGF-I levels, whereas IGFBP-1 levels decreased in nonobese PCOD patients and remained low in obese PCOD patients. No significant decrease was found in healthy subjects. These results suggest that, in addition to insulin, endogenous opioids are involved in the regulation of serum IGFBP-1 level.

  4. Diversion and injection of buprenorphine-naloxone film two years post-introduction in Australia.

    PubMed

    Larance, Briony; Mattick, Richard; Ali, Robert; Lintzeris, Nicholas; Jenkinson, Rebecca; White, Nancy; Kihas, Ivana; Cassidy, Rosemary; Degenhardt, Louisa

    2016-01-01

    We report 2 years of post-marketing surveillance of the diversion and injection of buprenorphine-naloxone (BNX) film following its introduction in 2011. Interviews were conducted with people who inject drugs regularly (PWID) (2004-2013), opioid substitution therapy clients (2013, n = 492) and key experts (n = 44). Key outcomes were unsanctioned removal of supervised doses, diversion, injection and street price. Prevalence of past 6-month injection among PWID was adjusted for background availability of opioid substitution therapy medications using sales data. Among out-of-treatment PWID, the levels of regular (weekly+) BNX film injection were comparable to methadone and BNX tablets, and lower than mono-buprenorphine, adjusting for background availability. Fewer BNX film clients [3%; 95% (CI) 1-5] regularly injected their medication than mono-buprenorphine clients (25%; 95% CI 11-39), but at levels equivalent to those among methadone (3%; 95% CI 1-6) and BNX tablet clients (2%; 95% CI 0-6). Key experts perceived BNX film needed less supervised dosing time as it dissolved rapidly and was harder to remove from the mouth than sublingual tablets; however, removal of supervised doses was higher among BNX film clients (15%; 95% CI: 10-20) than methadone clients (3%; 95% CI 1-6), and not significantly different from BNX tablet (11%; 95% CI 2-21) and mono-buprenorphine clients (31%; 95% CI 16-46). Two years post-introduction, levels of BNX film diversion and injection remained comparable with those for methadone and BNX tablets, and lower than mono-buprenorphine. We found no evidence that BNX film has lower non-adherence and diversion than the tablet formulation. [Larance B, Mattick R, Ali R, Lintzeris N, Jenkinson R, White N, Kihas I, Cassidy R, Degenhardt L. Diversion and injection of buprenorphine-naloxone film two years post-introduction in Australia. Drug Alcohol Rev 2015]. © 2015 Australasian Professional Society on Alcohol and other Drugs.

  5. Persistence and healthcare utilization associated with the use of buprenorphine/naloxone film and tablet formulation therapy in adults with opioid dependence.

    PubMed

    Clay, Emilie; Khemiri, Amine; Zah, Vladimir; Aballéa, Samuel; Ruby, Jane; Asche, Carl V

    2014-09-01

    Buprenorphine/naloxone film was developed to improve retention in treatment and reduce public health risks over the tablet formulation for opioid dependence. To compare patient persistence and resource utilization between formulations for the treatment of opioid dependence. A longitudinal, retrospective cohort analysis was conducted to compare persistence and healthcare costs in a private US insurance claims database. Previously untreated patients, who initiated treatment with buprenorphine/naloxone following the introduction of the film, were classified in two groups according to the initial prescription. Persistence was defined as the proportion of patients continuing treatment for at least 6 months. Resource utilization and related costs were calculated over the 6- and 12-month periods after treatment initiation. Film and tablet groups included 2796 and 1510 patients enrolled over 9.76 and 13.76 months on average, respectively, from initiation of treatment. Patient characteristics were similar between groups. Mean prescribed doses were 14.62 and 14.26 mg/day in film and tablet groups. Among patients enrolled for at least 6 months from the initial treatment, persistence rates were 63.78% with film vs 58.13% with tablet. Time to treatment discontinuation was longer in the film group, with a hazard ratio of 0.818 (p = 0.0005, 95% CI = [0.730;0.916]) adjusted for baseline characteristics. Patients treated with film had significantly more outpatient visits (+4%, p = 0.0185) and lower probability to be hospitalized (-17%, p = 0.0158), resulting in lower total healthcare costs over the 12-month period after initiation (-27%, p < 0.0001). Patients treated with the film formulation of buprenorphine/naloxone appeared to stay longer on treatment, have a lower probability of hospital admission, and lower health care costs compared to patients treated with the tablet. This study, based on insurance claims data, has the advantage of reflecting real-world practice, but one

  6. International patent applications for non-injectable naloxone for opioid overdose reversal: Exploratory search and retrieve analysis of the PatentScope database.

    PubMed

    McDonald, Rebecca; Danielsson Glende, Øyvind; Dale, Ola; Strang, John

    2018-02-01

    Non-injectable naloxone formulations are being developed for opioid overdose reversal, but only limited data have been published in the peer-reviewed domain. Through examination of a hitherto-unsearched database, we expand public knowledge of non-injectable formulations, tracing their development and novelty, with the aim to describe and compare their pharmacokinetic properties. (i) The PatentScope database of the World Intellectual Property Organization was searched for relevant English-language patent applications; (ii) Pharmacokinetic data were extracted, collated and analysed; (iii) PubMed was searched using Boolean search query '(nasal OR intranasal OR nose OR buccal OR sublingual) AND naloxone AND pharmacokinetics'. Five hundred and twenty-two PatentScope and 56 PubMed records were identified: three published international patent applications and five peer-reviewed papers were eligible. Pharmacokinetic data were available for intranasal, sublingual, and reference routes. Highly concentrated formulations (10-40 mg mL -1 ) had been developed and tested. Sublingual bioavailability was very low (1%; relative to intravenous). Non-concentrated intranasal spray (1 mg mL -1 ; 1 mL per nostril) had low bioavailability (11%). Concentrated intranasal formulations (≥10 mg mL -1 ) had bioavailability of 21-42% (relative to intravenous) and 26-57% (relative to intramuscular), with peak concentrations (dose-adjusted C max  = 0.8-1.7 ng mL -1 ) reached in 19-30 min (t max ). Exploratory analysis identified intranasal bioavailability as associated positively with dose and negatively with volume. We find consistent direction of development of intranasal sprays to high-concentration, low-volume formulations with bioavailability in the 20-60% range. These have potential to deliver a therapeutic dose in 0.1 mL volume. [McDonald R, Danielsson Glende Ø, Dale O, Strang J. International patent applications for non-injectable naloxone for opioid overdose reversal

  7. Sensitivity of neuronal nicotinic acetylcholine receptors to the opiate antagonists naltrexone and naloxone: receptor blockade and up-regulation.

    PubMed

    Almeida, Luis E F; Pereira, Edna F R; Camara, Adriana L; Maelicke, Alfred; Albuquerque, Edson X

    2004-04-19

    In HEK293 cells stably expressing alpha4beta2 nAChRs, naltrexone, but not naloxone, blocked alpha4beta2 nAChRs via an open-channel blocking mechanism. In primary hippocampal cultures, naltrexone inhibited alpha7 nAChRs up-regulated by nicotine, and in organotypic hippocampal cultures naltrexone caused a time-dependent up-regulation of functional alpha7 nAChRs that was detected after removal of the drug. These results indicate that naltrexone could be used as a smoking cessation aid.

  8. Buprenorphine Implants for Treatment of Opioid Dependence: Randomized Comparison to Placebo and Sublingual Buprenorphine/Naloxone

    PubMed Central

    Rosenthal, Richard N.; Ling, Walter; Casadonte, Paul; Vocci, Frank; Bailey, Genie L.; Kampman, Kyle; Patkar, Ashwin; Chavoustie, Steven; Blasey, Christine; Sigmon, Stacey; Beebe, Katherine L.

    2015-01-01

    Aims To evaluate safety and efficacy of buprenorphine implants (BI) versus placebo implants (PI) for the treatment of opioid dependence. A secondary aim compared BI to open-label sublingual buprenorphine/naloxone tablets (BNX). Design Randomized, double-blind, placebo-controlled trial. Subjects received either 4 buprenorphine implants (80 mg/implant) (n=114), 4 placebo implants (n=54), or open-label BNX (12–16 mg/d) (n=119). Setting 20 addiction treatment centers. Participants Adult outpatients (ages 18 to 65) with DSM-IV-TR opioid dependence. Measurements The primary efficacy endpoint was the percent of urine samples negative for opioids collected from weeks 1 to 24, examined as a cumulative distribution function (CDF). Findings The BI CDF was significantly different from placebo (P<.0001). Mean (95% CI) proportions of urines negative for opioids were: BI: 31.2% (25.3, 37.1) and PI: 13.4% (8.3, 18.6). BI subjects had a higher study completion rate relative to placebo (64% vs. 26%, P<.0001), lower clinician-rated (P<.0001) and patient-rated (P<.0001) withdrawal, lower patient-ratings of craving (P<.0001), and better subjects’ (P=.031) and clinicians’ (P=.022) global ratings of improvement. BI also resulted in significantly lower cocaine use (P=.0016). Minor implant-site reactions were comparable in the buprenorphine (27.2% [31/114]) and placebo groups (25.9% [14/54]). BI were non-inferior to BNX on percent urines negative for opioids [mean (95% CI): 33.5 (27.3, 39.6); CI for the difference of proportions, (−10.7, 6.2)]. Conclusions Compared with placebo, buprenorphine implants result in significantly less frequent opioid use, and are non-inferior to sublingual buprenorphine/naloxone tablets. PMID:23919595

  9. Buprenorphine implants for treatment of opioid dependence: randomized comparison to placebo and sublingual buprenorphine/naloxone.

    PubMed

    Rosenthal, Richard N; Ling, Walter; Casadonte, Paul; Vocci, Frank; Bailey, Genie L; Kampman, Kyle; Patkar, Ashwin; Chavoustie, Steven; Blasey, Christine; Sigmon, Stacey; Beebe, Katherine L

    2013-12-01

    To evaluate the safety and efficacy of buprenorphine implants (BI) versus placebo implants (PI) for the treatment of opioid dependence. A secondary aim compared BI to open-label sublingual buprenorphine/naloxone tablets (BNX). Randomized, double-blind, placebo-controlled trial. Subjects received either four buprenorphine implants (80 mg/implant) (n = 114), four placebo implants (n = 54) or open-label BNX (12-16 mg/day) (n = 119). Twenty addiction treatment centers. Adult out-patients (ages 18-65) with DSM-IV-TR opioid dependence. The primary efficacy end-point was the percentage of urine samples negative for opioids collected from weeks 1 to 24, examined as a cumulative distribution function (CDF). The BI CDF was significantly different from placebo (P < 0.0001). Mean [95% confidence interval (CI)] proportions of urines negative for opioids were: BI = 31.2% (25.3, 37.1) and PI = 13.4% (8.3, 18.6). BI subjects had a higher study completion rate relative to placebo (64 versus 26%, P < 0.0001), lower clinician-rated (P < 0.0001) and patient-rated (P < 0.0001) withdrawal, lower patient-ratings of craving (P < 0.0001) and better subjects' (P = 0.031) and clinicians' (P = 0.022) global ratings of improvement. BI also resulted in significantly lower cocaine use (P = 0.0016). Minor implant-site reactions were comparable in the buprenorphine [27.2% (31 of 114)] and placebo groups [25.9% (14 of 54)]. BI were non-inferior to BNX on percentage of urines negative for opioids [mean (95% CI) = 33.5 (27.3, 39.6); 95% CI for the difference of proportions = (-10.7, 6.2)]. Compared with placebo, buprenorphine implants result in significantly less frequent opioid use and are non-inferior to sublingual buprenorphine/naloxone tablets. © 2013 Society for the Study of Addiction.

  10. Decline in Buprenorphine/Naloxone Prescriptions in a State Medicaid Population Following Formulary Conversion from Suboxone to Bunavail.

    PubMed

    Soper, Richard; Appajosyula, Sireesh; Deximo, Christina

    2018-04-01

    A large, statewide, fee-for-service Medicaid plan recently (October 2015) executed a complete switch from sublingual buprenorphine-naloxone [(SLBN), Suboxone ® ] to buccal buprenorphine-naloxone [(BBN), Bunavail ® ] on its preferred drug formulary. This complete formulary switch provided an opportunity to assess dynamic changes in prescribing patterns, patient/physician acceptance, and indices of potential misuse/diversion. For the period January 1, 2015 through December 31, 2016, two datasets were analyzed: prescriptions and associated costs for buprenorphine-naloxone (BN) products and urine toxicology test results for patients in the Medicaid plan. The dataset comprised 1370 unique providers ordering 643,225 prescriptions for opioid addiction therapy. Patient and order volumes, and the rate of monthly positive laboratory values for opioid molecules and cocaine were reviewed. A targeted survey of physicians treating opioid-dependent patients with state Medicaid plan coverage was also conducted. Upon plan conversion to BBN, there was a rapid increase in monthly BBN prescriptions mirrored by a rapid decrease in SLBN prescriptions. Peak in BBN prescriptions (2633 in November 2015) was approximately 60% lower than peak in SLBN prescriptions (6531 in July 2015). An unexpected finding was a 68% reduction of the overall BN market, indicating that many BN prescriptions were abandoned. The reduction was associated with quarterly cost savings to the Medicaid plan of approximately $3.5 million. Toxicology results indicated a reduction in drug positivity (defined as positivity for cocaine and/or any opioids except buprenorphine and methadone) from 13-16% in 2015 to less than 10% in 2016. Heroin positivity decreased from approximately 9% in December 2015 to an average of less than 1% during the last quarter of 2016, while positivity for norbuprenorphine, the major metabolite of buprenorphine, showed a marked increase in 2016 vs 2015. Among physicians who responded to the

  11. Comparative Trial to Study the Effectiveness of Clonidine Hydrochloride and Buprenorphine-Naloxone in Opioid Withdrawal – A Hospital Based Study

    PubMed Central

    Farhat, Samina; Rather, Yasir Hassan; Abbas, Zaffar

    2015-01-01

    Objectives: Prevalence of opioid addiction has alarmingly increased over the recent years. In South Asian region alone there are more than 10 million opioid abusers amounting to 2% of world population. Detoxification remains to be the first step for the successful treatment of opioid addiction. The present study was carried out to compare the relative efficacy and safety of buprenorphine –naloxone and clonidine hydrochloride in the detoxification of opioid-dependents. Materials and Methods: Present trial was conducted at De- addiction centre of Institute of Mental and Neurosciences (IMNS), GMC Srinagar. Fifty four (54) treatment seeking subjects, 15-50 years of age, fulfilling DSM-1V TR (American Psychiatric association`s Mental Disorders-1V text revision) criteria for opioid dependence were included and randomized into two groups. The groups received either clonidine hydrochloride (Group A) or buprenorphine- naloxone (Bup-Nax) (Group B) for the duration of 10 days. The efficacy of the two drugs in controlling the opioid withdrawal was evaluated by Clinical Opioid Withdrawal Scale (COWS) and their effect on the desire for the abused substance was measured by Visual Analogue Scale (VAS). The safety of the two drugs was measured by taking the side effect profile of the two compared drugs into consideration. Results: There was significant difference of COWS-score between the two groups which was evident from day 3 (14.85 ± 3.43 vs. 11.67 ± 2.40, p<0.005) and continued till day 6 (2.56 ± 1.40 vs. 0.30 ± 0.61, p<0.005), for Group A and group B respectively. The effect of two drugs in controlling the craving for the abused substance also showed significant difference from day 2 (66.30 ± 10.80 vs. 47.40 ± 12.90, p<0.005) till day 5 (7.78 ± 6.41 vs. 1.85 ± 6.22, p<0.005), for Group A and Group B respectively. Conclusion: Administration of buprenorphine-naloxone was more efficient in reducing the signs and symptoms of opioid withdrawal and in controlling the

  12. Activation of serotonin 5-HT(2C) receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in heroin-treated mice.

    PubMed

    Wu, Xian; Pang, Gang; Zhang, Yong-Mei; Li, Guangwu; Xu, Shengchun; Dong, Liuyi; Stackman, Robert W; Zhang, Gongliang

    2015-10-21

    Abuse and dependence to heroin has evolved into a global epidemic as a significant clinical and societal problem with devastating consequences. Repeated exposure to heroin can induce long-lasting behavioral sensitization and withdrawal. Pharmacological activation of 5-HT2C receptors (5-HT2CRs) suppresses psychostimulant-induced drug-seeking and behavioral sensitization. The present study examined the effect of a selective 5-HT2CR agonist lorcaserin on behavioral sensitization and naloxone-precipitated withdrawal symptoms in heroin-treated mice. Male mice received heroin (1.0 mg/kg, s.c.) twice a day for 3 days and then drug treatment was suspended for 5 days. On day 9, a challenge dose of heroin (1.0 mg/kg) was administered to examine the expression of behavioral sensitization. Lorcaserin administered during the development, withdrawal or expression stage suppressed heroin-induced behavioral sensitization on day 9. Another cohort of mice received increasing doses of heroin over a 4.5-day period. Lorcaserin, or the positive control clonidine (an α2-adrenoceptor agonist) suppressed naloxone-precipitated withdrawal symptoms in heroin-treated mice. These findings suggest that activation of 5-HT2CRs suppresses behavioral sensitization and withdrawal in heroin-treated mice. Thus, pharmacological activation of 5-HT2CRs may represent a new avenue for the treatment of heroin addiction. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  13. Activation of serotonin 5-HT2C receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in heroin-treated mice

    PubMed Central

    Li, Guangwu; Xu, Shengchun; Dong, Liuyi; Stackman, Robert W.; Zhang, Gongliang

    2015-01-01

    Abuse and dependence to heroin has evolved into a global epidemic as a significant clinical and societal problem with devastating consequences. Repeated exposure to heroin can induce long-lasting behavioral sensitization and withdrawal. Pharmacological activation of 5-HT2C receptors (5-HT2CRs) suppresses psychostimulant-induced drug-seeking and behavioral sensitization. The present study examined the effect of a selective 5-HT2CR agonist lorcaserin on behavioral sensitization and naloxone-precipitated withdrawal symptoms in heroin-treated mice. Male mice received heroin (1.0 mg/kg, s.c.) twice a day for 3 days and then drug treatment was suspended for 5 days. On day 9, a challenge dose of heroin (1.0 mg/kg) was administered to examine the expression of behavioral sensitization. Lorcaserin administered during the development, withdrawal or expression stage suppressed heroin-induced behavioral sensitization on day 9. Another cohort of mice received increasing doses of heroin over a 4.5-day period. Lorcaserin, or the positive control clonidine (an α2-adrenoceptor agonist) suppressed naloxone-precipitated withdrawal symptoms in heroin-treated mice. These findings suggest that activation of 5-HT2CRs suppresses behavioral sensitization and withdrawal in heroin-treated mice. Thus, pharmacological activation of 5-HT2CRs may represent a new avenue for the treatment of heroin addiction. PMID:26375926

  14. Examining the effect of the CaMKII inhibitor administration in the locus coeruleus on the naloxone-precipitated morphine withdrawal signs in rats.

    PubMed

    Navidhamidi, M; Semnanian, S; Javan, M; Goudarzvand, M; Rohampour, K; Azizi, H

    2012-01-15

    Drug addiction is an occurrence with physiological, psychological, and social outcomes. Repeated drug exposure causes neuronal adaptations and dependency. It has been shown that CaMKIIα enzyme contributes to morphine dependency. The locus coeruleus nucleus has been implied in the morphine withdrawal syndrome. This research focuses on the behavioral and molecular adaptations that occur in the locus coeruleus neurons in response to the chronic morphine exposure. Adult male Wistar rats were injected by morphine sulfate (10 mg/kg/s.c.) at an interval of 12 h for a period of nine subsequent days. On the tenth day, naloxone (1 mg/kg/i.p.) was injected 2 h after the morphine administration. Somatic withdrawal signs were investigated for 30 min. We concluded that the inhibition of CaMKIIα by administration of KN-93, the specific inhibitor of this enzyme, significantly attenuated some of the withdrawal signs. In molecular method, the expression of CaMKIIα protein has been enhanced in locus coeruleus of the morphine dependent rats. These findings indicate that CaMKIIα may be involved in the modulation of the naloxone-induced withdrawal syndrome, and treatment with KN-93 may have some effects on this system. Copyright © 2011 Elsevier B.V. All rights reserved.

  15. Cost-effectiveness analysis of oxycodone with naloxone versus oxycodone alone for the management of moderate-to-severe pain in patients with opioid-induced constipation in Canada.

    PubMed

    Goeree, Ron; Goeree, Jeff

    2016-01-01

    Approximately 20-30% of Canadians suffer from chronic pain. Guidelines for the management of chronic pain support the use of controlled-release (CR) opioids to treat chronic pain. Although effective in managing chronic pain, oxycodone is associated with high rates of opioid-induced constipation (OIC). The cost-effectiveness of a combination of oxycodone for the management of pain and naloxone for the relief of OIC has not previously been evaluated for Canada. A decision analytic model was developed to estimate the cost-utility of combination oxycodone/naloxone compared to oxycodone alone in four populations. Drug costs for managing pain and healthcare costs related to managing OIC were included in the analysis and the primary measure of effectiveness was quality adjusted life years (QALYs) derived from OIC rates observed in clinical trials. The analysis was conducted from a healthcare system perspective, used a 1-year time horizon, and results were expressed in 2015 Canadian dollars. In all four patient populations, there was a trade-off between slightly higher total expected costs for Targin treated patients compared to oxycodone treated patients, but also improved clinical benefits in terms of reduced OIC, which resulted in higher QALYs for patients. Although analgesic costs were found to be slightly higher for Targin treated patients, Targin also resulted in cost offsets to the healthcare system in terms of less rescue laxative drug use and other resources required for the management of OIC. The resulting 1-year cost-utility of Targin compared to oxycodone ranged from $2178-$7732 per QALY gained in the base case analysis, and it was found that these cost-utility results remained robust and at low values throughout a series of one-way deterministic analyses of uncertainty. The clinical effectiveness of oxycodone/naloxone in managing pain and OIC compared to CR oxycodone alone resulted in low cost-utility estimates.

  16. Dipyridamole stress myocardial perfusion by computed tomography in patients with left bundle branch block.

    PubMed

    Cabeda, Estêvan Vieira; Falcão, Andréa Maria Gomes; Soares, José; Rochitte, Carlos Eduardo; Nomura, César Higa; Ávila, Luiz Francisco Rodrigues; Parga, José Rodrigues

    2015-12-01

    Functional tests have limited accuracy for identifying myocardial ischemia in patients with left bundle branch block (LBBB). To assess the diagnostic accuracy of dipyridamole-stress myocardial computed tomography perfusion (CTP) by 320-detector CT in patients with LBBB using invasive quantitative coronary angiography (QCA) (stenosis ≥ 70%) as reference; to investigate the advantage of adding CTP to coronary computed tomography angiography (CTA) and compare the results with those of single photon emission computed tomography (SPECT) myocardial perfusion scintigraphy. Thirty patients with LBBB who had undergone SPECT for the investigation of coronary artery disease were referred for stress tomography. Independent examiners performed per-patient and per-coronary territory assessments. All patients gave written informed consent to participate in the study that was approved by the institution's ethics committee. The patients' mean age was 62 ± 10 years. The mean dose of radiation for the tomography protocol was 9.3 ± 4.6 mSv. With regard to CTP, the per-patient values for sensitivity, specificity, positive and negative predictive values, and accuracy were 86%, 81%, 80%, 87%, and 83%, respectively (p = 0.001). The per-territory values were 63%, 86%, 65%, 84%, and 79%, respectively (p < 0.001). In both analyses, the addition of CTP to CTA achieved higher diagnostic accuracy for detecting myocardial ischemia than SPECT (p < 0.001). The use of the stress tomography protocol is feasible and has good diagnostic accuracy for assessing myocardial ischemia in patients with LBBB.

  17. Comparison of Naloxone and Thyrotropin-Releasing Hormone in the Treatment of Experimental Spinal Injury: Endogenous Opioids and Experimental Spinal Injury.

    DTIC Science & Technology

    1983-09-30

    BETHESDA ND A I FADEN 38 SEP 83 UNCLASSIFIED MPR-2509 FG 6/15 NL EIihlllIEllllI EIIhlEEE~llllE E/I/I/IEE/IlhI EIIIEEEEEEIIE = " W lo 111.2.0 1111IL25 LA 11_L...blood flow related to the release of endogenous opioi 1 ,,;. I LCV;0,,;’ ’ W i-’, ; . .- I:I, opiate receptor antagonist naloxone improve,; 1,ou- spinal...34iorl-one (TRH), which acts in part as a physiologic antaT-, iL endogenous opicii’ -;’’,tems, also significantly" i -rov s bloo (l Fo., .-,nd netir

  18. The NAPRESSIM trial: the use of low-dose, prophylactic naloxone infusion to prevent respiratory depression with intrathecally administered morphine in elective hepatobiliary surgery: a study protocol and statistical analysis plan for a randomised controlled trial.

    PubMed

    Cosgrave, David; Galligan, Marie; Soukhin, Era; McMullan, Victoria; McGuinness, Siobhan; Puttappa, Anand; Conlon, Niamh; Boylan, John; Hussain, Rabia; Doran, Peter; Nichol, Alistair

    2017-12-29

    Intrathecally administered morphine is effective as part of a postoperative analgesia regimen following major hepatopancreaticobiliary surgery. However, the potential for postoperative respiratory depression at the doses required for effective analgesia currently limits its clinical use. The use of a low-dose, prophylactic naloxone infusion following intrathecally administered morphine may significantly reduce postoperative respiratory depression. The NAPRESSIM trial aims to answer this question. 'The use of low-dose, prophylactic naloxone infusion to prevent respiratory depression with intrathecally administered morphine' trial is an investigator-led, single-centre, randomised, double-blind, placebo-controlled, double-arm comparator study. The trial will recruit 96 patients aged > 18 years, undergoing major open hepatopancreaticobiliary resections, who are receiving intrathecally administered morphine as part of a standard anaesthetic regimen. It aims to investigate whether the prophylactic administration of naloxone via intravenous infusion compared to placebo will reduce the proportion of episodes of respiratory depression in this cohort of patients. Trial patients will receive an infusion of naloxone or placebo, commenced within 1 h of postoperative extubation continued until the first postoperative morning. The primary outcome is the rate of respiratory depression in the intervention group as compared to the placebo group. Secondary outcomes include pain scores, rates of nausea and vomiting, pruritus, sedation scores and adverse outcomes. We will also employ a novel, non-invasive, respiratory minute volume monitor (ExSpiron 1Xi, Respiratory Motion, Inc., 411 Waverley Oaks Road, Building 1, Suite 150, Waltham, MA, USA) to assess the monitor's accuracy for detecting respiratory depression. The trial aims to provide a clear management plan to prevent respiratory depression after the intrathecal administration of morphine, and thereby improve patient safety

  19. Development and validation of a sensitive LC/MS/MS method for the simultaneous determination of naloxone and its metabolites in mouse plasma.

    PubMed

    Jiang, Hongliang; Wang, Yurong; Shet, Manjunath S; Zhang, Yang; Zenke, Duane; Fast, Douglas M

    2011-09-01

    A rapid, specific, and reliable LC-MS/MS based bioanalytical method was developed and validated for the simultaneous determination of naloxone (NLX) and its two metabolites, 6β-naloxol (NLL) and naloxone-3β-D-glucuronide (NLG) in mouse plasma. The optimal chromatographic behavior of these analytes was achieved on an Aquasil C18 column (50 mm × 2.1 mm, 5 μm) using reversed phase chromatography. The total LC analysis time per injection was 2.5 min with a flow rate of 1.0 mL/min with gradient elution. Sample preparation via protein precipitation with acetonitrile in a 96-well format was applied for analyses of these analytes. The analytes were monitored by electrospray ionization in positive ion multiple reaction monitoring (MRM) mode. Modification of collision energy besides chromatographic separation was applied to further eliminate interference peaks for NLL and NLG. The method validation was conducted over the curve range of 0.200/0.400/0.500 to 100/200/250 ng/mL for NLX/NLL/NLG, respectively, using 0.0250 mL of plasma sample. The intra- and inter-day precision and accuracy of the quality control samples at low, medium, and high concentration levels showed ≤ 6.5% relative standard deviation (RSD) and -8.3 to -2.5% relative error (RE). The method was successfully applied to determine the concentrations of NLX, NLL, and NLG in incurred mouse plasma samples. Copyright © 2011 Elsevier B.V. All rights reserved.

  20. Elevation of naloxone-sensitive /sup 3/H-dihydromorphine binding in hippocampal formation of genetically epilepsy-prone rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Savage, D.D.; Mills, S.A.; Jobe, P.C.

    1988-01-01

    /sup 3/H-Dihydromorphine (DHM) binding sites were measured in the brain of non-epileptic control and GEPR rats using in vitro autoradiographic techniques. The number of naloxone-sensitive /sup 3/H-DHM binding sites was increased 38-57% in the pyramidal cell layer of ventral hippocampal CA/sub 3/ and CA/sub 1/ of GEPR-3 and GEPR-9 rats compared to non-epileptic controls. No significant differences in /sup 3/H-DHM binding were observed in dorsal hippocampal formation, lateral entorhinal cortex, lateral geniculate or cerebellum. The results suggest that an increase in the number of opioid receptors in ventral hippocampus of GEPR rats may be one factor contributing to the enhancedmore » sensitivity of GEPR-9 rats to the proconvulsant effects of morphine.« less

  1. Poly(DL-lactide)-b-poly(N,N-dimethylamino-2-ethyl methacrylate): synthesis, characterization, micellization behavior in aqueous solutions, and encapsulation of the hydrophobic drug dipyridamole.

    PubMed

    Karanikolopoulos, Nikos; Zamurovic, Miljana; Pitsikalis, Marinos; Hadjichristidis, Nikos

    2010-02-08

    We synthesized a series of well-defined poly(dl-lactide)-b-poly(N,N-dimethylamino-2-ethyl methacrylate) (PDLLA-b-PDMAEMA) amphiphilic diblock copolymers by employing a three-step procedure: (a) ring-opening polymerization (ROP) of dl-lactide using n-decanol and stannous octoate, Sn(Oct)(2), as the initiating system, (b) reaction of the PDLLA hydroxyl end groups with bromoisobutyryl bromide, and (c) atom transfer radical polymerization, ATRP, of DMAEMA with the newly created bromoisobutyryl initiating site. The aggregation behavior of the prepared block copolymers was investigated by dynamic light scattering and zeta potential measurements at 25 degrees C in aqueous solutions of different pH values. The hydrophobic drug dipyridamole was efficiently incorporated into the copolymer aggregates in aqueous solutions of pH 7.40. High partition coefficient values were determined by fluorescence spectroscopy.

  2. Brief versus extended counseling along with buprenorphine/naloxone for HIV-infected opioid dependent patients.

    PubMed

    Tetrault, Jeanette M; Moore, Brent A; Barry, Declan T; O'Connor, Patrick G; Schottenfeld, Richard; Fiellin, David A; Fiellin, Lynn E

    2012-12-01

    Untreated opioid dependence adversely affects HIV outcomes. Integrating buprenorphine/naloxone into HIV treatment settings is feasible; however, the optimal level of counseling has not been established. We conducted a 12-week randomized clinical trial of physician management (PM) versus PM plus enhanced medical management (EMM) in 47 subjects. At 12 weeks, there were no differences between the two groups in percentage of opioid negative urines (63.6% PM vs. 69.0% PM+EMM, p=.5), maximum duration of continuous abstinence (4.9 weeks PM vs. 5.2 weeks PM+EMM, p=.8) or retention (80% PM vs. 59% PM+EMM, p=.1). The percentage of subjects with detectable HIV viral loads decreased from 58% at baseline to 40% at 12 weeks across both groups (p=.02 for time) with no between group differences (p=.84 and p=.27 for the interaction). Providing more extensive counseling beyond PM is feasible in an HIV clinic, but we are unable to detect an improvement in outcomes associated with these services. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. Successful management of drug-induced hypercapnic acidosis with naloxone and noninvasive positive pressure ventilation.

    PubMed

    Agrafiotis, Michalis; Tryfon, Stavros; Siopi, Demetra; Chassapidou, Georgia; Galanou, Artemis; Tsara, Venetia

    2015-02-01

    A 74-year-old man was referred to our hospital due to deteriorating level of consciousness and desaturation. His Glasgow Coma Scale was 6, and his pupils were constricted but responded to light. Chest radiograph was negative for significant findings. Arterial blood gas evaluation on supplemental oxygen revealed severe acute on chronic respiratory acidosis: pH 7.15; PCO2, 133 mm Hg; PO2,64 mm Hg; and HCO3, 31 mmol/L. He regained full consciousness (Glasgow Coma Scale, 15) after receiving a 0.4 mg dose of naloxone, but because of persistent severe respiratory acidosis (pH 7.21; PCO2, 105 mm Hg), he was immediately commenced on noninvasive positive pressure ventilation (NIV) displaying a remarkable improvement in arterial blood gas values within the next few hours. However, in the days that followed, he remained dependent on NIV, and he was finally discharged on a home mechanical ventilation prescription. In cases of drug-induced respiratory depression, NIV should be regarded as an acceptable treatment, as it can provide ventilatory support without the increased risks associated with invasive mechanical ventilation.

  4. Injecting buprenorphine-naloxone film: Findings from an explorative qualitative study.

    PubMed

    White, Nancy; Flaherty, Ian; Higgs, Peter; Larance, Briony; Nielsen, Suzanne; Degenhardt, Louisa; Ali, Robert; Lintzeris, Nicholas

    2015-11-01

    Experiences of buprenorphine-naloxone (BNX) sublingual film injection are not well documented or understood. We examined how people who inject BNX film seek and share information about this practice, document the methods used to prepare BNX film for injection, and report participants' experiences of this practice. Interviews were (n = 16) conducted with people who indicated that they had injected BNX film since its introduction onto the Australian market. Semistructured interviews were recorded and transcribed. NVivo10 program (QSR International) was used to analyse the data using qualitative description methodology. Participants largely reported similar BNX film preparation techniques, although the texture of BNX film during preparation to inject was reported to be unusual (gluggy), and there were many varied accounts associated with the amount of water used. Physical harms reported as associated with injecting BNX film were described (including local and systemic issues); participants reported injecting the film to enhance its immediate effects, yet generally reported that sublingual administration provided longer-lasting effects. Understanding knowledge acquisition about injecting new formulations of opioid substitution therapy is crucial in developing more effective harm-reduction strategies. Dissemination by peer networks to those who are currently or planning to inject BNX film regarding the 'gelatine like' texture when mixing, using only cold water and double filtering is important to ensure safer injecting practices. Findings from this study highlight the importance of peer networks for the dissemination of harm-reduction information. Introduction of new formulations internationally requires more qualitative studies to inform safer practices. © 2015 Australasian Professional Society on Alcohol and other Drugs.

  5. Analysis of buprenorphine/naloxone dosing impact on treatment duration, resource use and costs in the treatment of opioid-dependent adults: a retrospective study of US public and private health care claims.

    PubMed

    Khemiri, Amine; Kharitonova, Elizaveta; Zah, Vladimir; Ruby, Jane; Toumi, Mondher

    2014-09-01

    The buprenorphine/naloxone combination is used to treat the chronic relapsing disorder of opioid dependence. Adequate dosing levels are important to control cravings, prevent withdrawal syndrome, and maintain patients in treatment. The objective of this study was to estimate the impact of dosing on treatment persistence, resource utilization, and total direct health care costs. A retrospective cohort analysis was performed using administrative claims extracted from the MarketScan and Clinformatics databases from January 2007 to June and November 2012. Patients initiating treatment with buprenorphine/naloxone were classified into 2 groups based on the prescribed average dose over the entire treatment period and matched by multiple criteria. The threshold for differentiating the dosing groups was set at 15 and 15.7 mg/day for publicly and privately insured patients, respectively. Resource utilization and related costs were calculated over the 12-month period after the treatment initiation. Patient characteristics at baseline were considerably different between the privately and publicly insured patients. Publicly insured patients were slightly younger (33.1 vs 34.3 years old for privately insured) and had a higher prevalence of mental disorders (70.9% vs 64.9%). In both groups, patients treated with higher doses (> 15 mg and > 15.7 mg per day for publicly and privately insured patients, respectively) had lower risk of discontinuation (public: 11% lower; private: 9% lower) and lower probability of a psychiatric hospitalization than patients treated with lower doses (public: 17% lower; private: 41% lower). Total costs were comparable between the 2 groups (public: $14 600; private: $21 000) despite the expected higher cost of pharmacy in the higher-dose group. Treatment with higher doses of buprenorphine/naloxone was associated with a longer time to treatment discontinuation, less resource use, and lower total medical costs despite higher pharmacy acquisition cost.

  6. Activation of serotonin 5-HT2C receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in morphine-dependent mice

    PubMed Central

    Zhang, Gongliang; Wu, Xian; Zhang, Yong-Mei; Liu, Huan; Jiang, Qin; Pang, Gang; Tao, Xinrong; Dong, Liuyi; Stackman, Robert W.

    2015-01-01

    Opioid abuse and dependence have evolved into an international epidemic as a significant clinical and social problem with devastating consequences. Repeated exposure to the opioid, for example morphine, can induce profound, long-lasting behavioral sensitization and physical dependence, which are thought to reflect neuroplasticity in neural circuitry. Central serotonin (5-HT) neurotransmission participates in the development of dependence on and the expression of withdrawal from morphine. Serotonin 5-HT2C receptor (5-HT2CR) agonists suppress psychostimulant nicotine or cocaine-induced behavioral sensitization and drug-seeking behavior; however, the impact of 5-HT2CR agonists on behaviors relevant to opioid abuse and dependence has not been reported. In the present study, the effects of 5-HT2CR activation on the behavioral sensitization and naloxone-precipitated withdrawal symptoms were examined in mice underwent repeated exposure to morphine. Male mice received morphine (10 mg/kg, s.c.) to develop behavioral sensitization. Lorcaserin, a 5-HT2CR agonist, prevented the induction and expression, but not the development, of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine-dependence. Pretreatment of lorcaserin, or the positive control clonidine (an alpha 2-adrenoceptor agonist), ameliorated the naloxone-precipitated withdrawal symptoms. SB 242084, a selective 5-HT2CR antagonist, prevented the lorcaserin-mediated suppression of behavioral sensitization and withdrawal. Chronic morphine treatment was associated with an increase in the expression of 5-HT2CR protein in the ventral tegmental area, locus coeruleus and nucleus accumbens. These findings suggest that 5-HT2CR can modulate behavioral sensitization and withdrawal in morphine-dependent mice, and the activation of 5-HT2CR may represent a new avenue for the treatment of opioid addiction. PMID:26432939

  7. Stability of Acetazolamide, Baclofen, Dipyridamole, Mebeverine Hydrochloride, Propylthiouracil, Quinidine Sulfate, and Topiramate Oral Suspensions in SyrSpend SF PH4.

    PubMed

    Ferreira, Anderson de Oliveira; Polonini, Hudson; da Silva, Sharlene Loures; Aglio, Natália Cristina Buzinari; Abreu, Jordana; Fernandes, Brandão Marcos Antônio

    2017-01-01

    The objective of this study was to evaluate the stability of 7 commonly used active pharmaceutical ingredients compounded in oral suspensions using an internationally used suspending vehicle (SyrSpend SF PH4): acetazolamide 25.0 mg/mL, baclofen 10.0 mg/mL, dipyridamole 10.0 mg/mL, mebeverine hydrochloride 10.0 mg/mL, propylthiouracil 5.0 mg/mL, quinidine sulfate 10.0 mg/mL, and topiramate 5.0 mg/mL. All suspensions were stored both at controlled refrigerated (2°C to 8°C) and room temperature (20°C to 25°C). Stability was assessed by measuring the percentage recovery at varying time points throughout a 90-day period. Active pharmaceutical ingredient quantification was performed by ultraviolet (UV) high-performance liquid chromatography, via a stability-indicating method. Given the percentage of recovery of the active pharmaceutical ingredients within the suspensions, the beyond-use date of the final products (active pharmaceutical ingredient + vehicle) was at least 90 days for all suspensions with regards to both temperatures. This suggests that SyrSpend SF PH4 is suitable for compounding active pharmaceutical ingredients from different pharmacological classes. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

  8. Naloxone-blocked depriming effect of anxiolytic selank on apomorphine-induced behavioral manifestations of hyperfunction of dopamine system.

    PubMed

    Meshavkin, V K; Kost, N V; Sokolov, O Yu; Zolotarev, Yu A; Myasoedov, N F; Zozulya, A A

    2006-11-01

    Peptide anxiolytic selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) applied intraperitoneally in doses of 0.01, 0.1, 1.0, and 10.0 mg/kg to mice reduces behavioral manifestations of dopaminergic system induced by apomorphine in the verticalization test. This effect was comparable to that of atypical antipsychotic olanzapine in near-therapeutic doses (0.1 and 1.0 mg/kg, intraperitoneally) and was blocked with nonselective opioid receptor antagonist naloxone (10 mg/kg, intraperitoneally). Radioreceptor assay showed that selank did not displace nonselective D2-dopamine receptor antagonist (3)H-spiperone (EC50>100 microM) and delta- and micro-opioid receptor ligand 3H-DADLE (EC50>40 microM) from specific binding sites on rat brain membranes. It is hypothesized that the revealed behavioral effect of selank is mediated by its modulating effect on the endogenous opioid system and specifically, by its effect on activity of enkephalin-degrading enzymes.

  9. Analysis of structure of hyperfine poly(3-hydroxybutyrate) fibers (PHB) for controlled drug delivery

    NASA Astrophysics Data System (ADS)

    Olkhov, A. A.; Kosenko, R. Yu; Markin, V. S.; Zykova, A. K.; Pantyukhov, P. V.; Karpova, S. G.; Iordanskii, A. L.

    2017-12-01

    Hyperfine fibers based on biodegradable poly (3-hydroxybutyrate) with encapsulated drug substance (dipyridamol) were obtained by using electrospinning method. Addition of dipyridamol has a significant effect on geometrical shape and structure of microfibers as well as total porosity of fibrous material. Observation of fibers using scanning electron microscopy (SEM) method showed that without or at lower dipyridamol content (<3%) fibers consisted of interleaved ellipsoid and cylindrical fragments. At higher dipyridamol content (3-5%) anomalous ellipsoid structures did not practically form, and fiber’s shape became cylindrical. The totality of morphological and structural characteristics determined the rate of dipyridamol diffusive transports. The simplified model of drug desorption from fibrous matrix was presented. In current work it was showed that the rate-limiting stage of transport was the diffusion of dipyridamol in the bulk of cylindrical fibers.

  10. Analysis of the 2-deoxy-D-glucose-induced vagal stimulation of gastric secretion and gastrin release in dogs using methionine-enkephalin, morphine and naloxone.

    PubMed

    Anderson, W; Molina, E; Rentz, J; Hirschowitz, B I

    1982-09-01

    Gastric acid and pepsin secreted in 3 hr and antral gastrin released in response to vagal excitation induced by 2-deoxy-D-glucose (2DG), 625 mumol/kg i.v., were studied in six conscious trained gastric fistula dogs. During a 2-hr infusion, Met-enkephalin (96 nmol/kg/hr; delta receptor) reduced the 2DG response by 50%; when the enkephalin was stopped there was a rapid rebound to peak values. Met-enkephalin also blocked the release of gastrin in the first 15 min. By itself, Met-enkephalin did not stimulate secretion and slightly depressed gastrin. By contrast, morphine (96 nmol/kg/hr; mu receptor) augmented and sustained the 2DG gastric acid secretory response. This effect was blocked by naloxone. Morphine alone caused a small rise in serum gastrin after 90 min, followed by a delayed gastric acid secretion of about 30% of the peak 2DG response. Naloxone, a mu opiate antagonist (mu/delta, 27:1), also inhibited the 2DG gastric secretory response by about 50% and augmented the Met-enkephalin inhibition of secretion without blocking either the secretory rebound or the effect on gastrin release. None of the three opiates changed the direct cholinergic gastric secretory or gastrin-releasing effects of bethanechol. Thus, vagal stimulation of the stomach involves pathways which can be influenced by both mu and delta opiates, with apparently opposite effects, proximal to the level of acetylcholine action on the gastric mucosa. The central and peripheral control points in the activation of the stomach via the vagus which are sensitive to opiates have yet to be located and explained.

  11. Predictors of attrition with buprenorphine/naloxone treatment in opioid dependent youth.

    PubMed

    Warden, Diane; Subramaniam, Geetha A; Carmody, Thomas; Woody, George E; Minhajuddin, Abu; Poole, Sabrina A; Potter, Jennifer; Fishman, Marc; Bogenschutz, Michael; Patkar, Ashwin; Trivedi, Madhukar H

    2012-09-01

    In opioid dependent youth there is substantial attrition from medication-assisted treatment. If youth at risk for attrition can be identified at treatment entry or early in treatment, they can be targeted for interventions to help retain them in treatment. Opioid dependent adolescents and young adults (n=152), aged 15-21, were randomized to 12 weeks (BUP, n=74) or 2 weeks of detoxification (DETOX, n=78) with buprenorphine/naloxone (Bup/Nal), both in combination with 12 weeks of psychosocial treatment. Baseline and early treatment related predictors of treatment attrition were identified in each group using bivariate and multivariate logistic regression. In the DETOX group 36% left between weeks 2 and 4, at the end of the dose taper, while in the BUP group only 8% left by week 4. In the BUP group, early adherence to Bup/Nal, early opioid negative urines, use of any medications in the month prior to treatment entry, and lifetime non-heroin opioid use were associated with retention while prior 30-day hallucinogen use was associated with attrition. In the DETOX group, only use of sleep medications was associated with retention although not an independent predictor. A broad range of other pre-treatment characteristics was unrelated to attrition. Prompt attention to those with early non-adherence to medication or an early opioid positive urine, markers available in the first 2 weeks of treatment, may improve treatment retention. Extended Bup/Nal treatment appeared effective in improving treatment retention for youth with opioid dependence across a wide range of demographics, and pre-treatment clinical characteristics. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. Predictors of attrition with buprenorphine/naloxone treatment in opioid dependent youth☆

    PubMed Central

    Warden, Diane; Subramaniam, Geetha A.; Carmody, Thomas; Woody, George E.; Minhajuddin, Abu; Poole, Sabrina A.; Potter, Jennifer; Fishman, Marc; Bogenschutz, Michael; Patkar, Ashwin; Trivedi, Madhukar H.

    2012-01-01

    Background In opioid dependent youth there is substantial attrition from medication-assisted treatment. If youth at risk for attrition can be identified at treatment entry or early in treatment, they can be targeted for interventions to help retain them in treatment. Methods Opioid dependent adolescents and young adults (n=152), aged 15–21, were randomized to 12 weeks (BUP, n=74) or 2 weeks of detoxification (DETOX, n=78) with buprenorphine/naloxone (Bup/Nal), both in combination with 12 weeks of psychosocial treatment. Baseline and early treatment related predictors of treatment attrition were identified in each group using bivariate and multivariate logistic regression. Results In the DETOX group 36% left between weeks 2 and 4, at the end of the dose taper, while in the BUP group only 8% left by week 4. In the BUP group, early adherence to Bup/Nal, early opioid negative urines, use of any medications in the month prior to treatment entry, and lifetime non-heroin opioid use were associated with retention while prior 30-day hallucinogen use was associated with attrition. In the DETOX group, only use of sleep medications was associated with retention although not an independent predictor. A broad range of other pre-treatment characteristics was unrelated to attrition. Conclusions Prompt attention to those with early non-adherence to medication or an early opioid positive urine, markers available in the first 2 weeks of treatment, may improve treatment retention. Extended Bup/ Nal treatment appeared effective in improving treatment retention for youth with opioid dependence across a wide range of demographics, and pre-treatment clinical characteristics. PMID:22626890

  13. Budgetary impact analysis of buprenorphine-naloxone combination (Suboxone®) in Spain

    PubMed Central

    2012-01-01

    Background Opioid addiction is a worldwide problem. Agonist opioid treatment (AOT) is the most widespread and frequent pharmacotherapeutic approach. Methadone has been the most widely used AOT, but buprenorphine, a partial μ-opiod agonist and a κ-opiod antagonist, is fast gaining acceptance. The objective was to assess the budgetary impact in Spain of the introduction of buprenorphine-naloxone (B/N) combination. Methods A budgetary impact model was developed to estimate healthcare costs of the addition of B/N combination to the therapeutic arsenal for treating opioid dependent patients, during a 3-year period under the National Health System perspective. Inputs for the model were obtained from the specialized scientific literature. Detailed information concerning resource consumption (drug cost, logistics, dispensing, medical, psychiatry and pharmacy supervision, counselling and laboratory test) was obtained from a local expert panel. Costs are expressed in euros (€, 2010). Results The number of patients estimated to be prescribed B/N combination was 2,334; 2,993 and 3,589 in the first, second and third year respectively. Total budget is €85,766,129; €79,855,471 and €79,137,502 in the first, second and third year for the scenario without B/N combination. With B/N combination the total budget would be €86,589,210; €80,398,259 and €79,708,964 in the first, second and third year of the analyses. Incremental cost/patient comparing the addition of the B/N combination to the scenario only with methadone is €10.58; €6.98 and €7.34 in the first, second and third year respectively. Conclusion Addition of B/N combination would imply a maximum incremental yearly cost of €10.58 per patient compared to scenario only with methadone and would provide additional benefits. PMID:22828157

  14. The extramedical use and diversion of opioid substitution medications and other medications in prison settings in Australia following the introduction of buprenorphine-naloxone film.

    PubMed

    White, Nancy; Ali, Robert; Larance, Briony; Zador, Deborah; Mattick, Richard P; Degenhardt, Louisa

    2016-01-01

    Around 65% of people incarcerated in prisons in Australia, America and Europe have a history of drug dependence, sometimes treated with opioid substitution treatment (OST) medications. Studies report that those in treatment in prison do engage in some level of diversion to others, whether on a voluntary or coerced basis. We aimed to examine the use of prescribed and non-prescribed OST medications by those in prisons, especially buprenorphine-naloxone film (BNX-F); the extent of non-adherence and diversion and reasons for such practices; and the impact of the introduction of BNX-F into the prison system. Mixed methods study drawing on: (i) structured interviews with current OST clients (n = 60) who reported being incarcerated in the 12 months prior to being interviewed and (ii) qualitative interviews with key experts working in corrections and prison (or justice) health settings. The majority were prescribed OST medications in prison, with 25% removing all or part of their supervised dose on at least one occasion, and 44% reporting use of non-prescribed medications. Some reported intravenous use (14% injected). One-third of OST recipients reported selling/sharing OST medications with others in prison. The introduction of BNX-F into the prison system saw different diversion methods used and removal from dosing within prison. Despite prison being a highly regulated and controlled environment, some level of diversion and sharing of psychoactive medication occurs among prisoners. The buprenorphine formulations used in OST present particular challenges with respect to supervised dosing in this setting. [White N, Ali R, Larance B, Zador D, Mattick RP, Degenhardt L. The extramedical use and diversion of opioid substitution medications and other medications in prison settings in Australia following the introduction of buprenorphine-naloxone film. Drug Alcohol Rev 2015;●●:●●-●●]. © 2015 Australasian Professional Society on Alcohol and other Drugs.

  15. Assessing causality in drug policy analyses: How useful are the Bradford Hill criteria in analysing take-home naloxone programs?

    PubMed

    Olsen, Anna; McDonald, David; Lenton, Simon; Dietze, Paul M

    2018-05-01

    The Bradford Hill criteria for assessing causality are useful in assembling evidence, including within complex policy analyses. In this paper, we argue that the implementation of take-home naloxone (THN) programs in Australia and elsewhere reflects sensible, evidence-based public health policy, despite the absence of randomised controlled trials. However, we also acknowledge that the debate around expanding access to THN would benefit from a careful consideration of causal inference and health policy impact of THN program implementation. Given the continued debate around expanding access to THN, and the relatively recent access to new data from implementation studies, two research groups independently conducted Bradford Hill analyses in order to carefully consider causal inference and health policy impact. Hill's criteria offer a useful analytical tool for interpreting current evidence on THN programs and making decisions about the (un)certainty of THN program safety and effectiveness. © 2017 Australasian Professional Society on Alcohol and other Drugs.

  16. False-positive defects on exercise 99mTc-sestamibi SPECT imaging, but not on dipyridamole 99mTc-sestamibi SPECT imaging, in a patient with right bundle branch block (RBBB).

    PubMed

    Javadi, Hamid; Jallalat, Sara; Semnani, Shahriar; Mogharrabi, Mehdi; Nabipour, Iraj; Abbaszadeh, Moloud; Assadi, Majid

    2013-01-01

    False-positive findings with myocardial perfusion imaging (MPI) have frequently been identified in the presence of left bundle branch block (LBBB) and tend to lower the accuracy of MPI in individuals with normal coronary angiographs. Pharmacologic stress is recognized as the preferred method for MPI in patients with LBBB. In contrast, very few studies have evaluated the effect of right bundle branch block (RBBB) on MPI, and there is no consensus regarding the selection of pharmacologic versus exercise stress during MPI for the RBBB patient. In this study, we present a 45-year-old man with RBBB, who has a normal coronary artery angiography, but who showed abnormal myocardial perfusion with exercise MPI, and normal perfusion on dipyridamole MPI. The aim of the study is to stimulate awareness that the stress method selected for patients with RBBB can potentially interfere with the accuracy of the data.

  17. Naloxone and the Inner City Youth Experience (NICYE): a community-based participatory research study examining young people's perceptions of the BC take home naloxone program.

    PubMed

    Mitchell, Keren; Durante, S Elise; Pellatt, Katrina; Richardson, Chris G; Mathias, Steve; Buxton, Jane A

    2017-06-07

    Take home naloxone (THN) programs reduce mortality by training bystanders to respond to opioid overdoses. Clinical observation by the health care team at the Inner City Youth (ICY) program indicated that young adults appeared to enthusiastically participate in the THN program and developed improved relationships with staff after THN training. However, we found a dearth of literature exploring the experiences of young adults with THN programs. This study set out to address this gap and identify suggestions from the young adults for program improvement. The primary research question was "How do street-involved young people experience the THN Program in Vancouver, BC?" The study was undertaken at the ICY Program. Two peer researchers with lived experience of THN were recruited from ICY and were involved in all phases of the study. The peer researchers and a graduate student facilitated two focus groups and five individual interviews with ICY program participants using a semi-structured interview guide. Audio recordings were transcribed verbatim. The cut-up-and-put-in-folders approach was used to identify emerging themes. The themes that emerged were perceptions of risk, altruism, strengthening relationship with staff, access to training, empowerment, and confidence in ability to respond, and suggestions for youth-friendly training. These themes were then situated within the framework of the health belief model to provide additional context. Participants viewed themselves as vulnerable to overdose and spoke of the importance of expanding access to THN training. Following training, participants reported an increase in internal locus of control, an improved sense of safety among the community of people who use drugs, improved self-esteem, and strengthened relationships with ICY staff. Overall, participants found THN training engaging, which appeared to enhance participation in other ICY programming. Young people perceived THN training as a positive experience that

  18. Intravenous nicotine self-administration in rats: effects of mecamylamine, hexamethonium and naloxone.

    PubMed

    DeNoble, Victor J; Mele, Paul C

    2006-03-01

    The rate and pattern of lever pressing were studied in 18 rats during 24-h sessions in which responding resulted in intravenous infusions of nicotine. There were four indications of the positive reinforcing effect of nicotine: (1) a greater number of lever presses when nicotine was response-contingent compared to when saline was available; (2) a greater number of responses on the lever resulting in an infusion of nicotine than on the control lever; (3) systematic decreases in the number of contingent nicotine infusions when nicotine was delivered noncontingently; and (4) systematic changes in the frequency of lever pressing as a function of dose. Under a fixed ratio 1 (FR 1) schedule, the number of infusions first increased and then decreased as the dose of nicotine was decreased (64, 32, 16, and 8 microg/kg infusion) and nicotine intake (mg/kg every 24 h) was directly related to the infusion dose. As the FR size was increased from 1 to 6, the number of lever presses increased and the number of infusions (32 microg/kg) remained stable. At FR values greater than 6, both the number of lever presses and infusions decreased. Presession injections of mecamylamine (0.75, 1.5, and 3.0 mg/kg, s.c.) decreased the number of infusions in a dose-related manner. Presession injections of hexamethonium (1.5 and 3.0 mg/kg, s.c.) or naloxone (0.75, 1.5, and 3.0 mg/kg, s.c.) did not alter the within- or between-session patterns of nicotine self-administration. Under the conditions of the present experiment, nicotine served as an effective reinforcer and the behavior was shown to be sensitive to both FR size and infusion dose. In addition, the results suggest that nicotine self-administration involves central nicotinic receptors and that opioid receptor antagonism has no effect on nicotine's reinforcing effects in rats.

  19. High-dose cisplatin with dipyridamole in advanced non-small cell lung cancer. A Grupo Oncológico Cooperativo del Sur study.

    PubMed

    Vallejo, C T; Rabinovich, M G; Perez, J E; Rodriguez, R; Machiavelli, M R; Leone, B A; Romero, A D; Lacava, J A; Cuevas, M A; Langhi, M J

    1995-06-01

    From March 1991 to October 1992, 41 patients with advanced non-small cell lung cancer (NSCLC) (20 stage IIIB and 21 stage IV) received a regimen consisting of cisplatin (CP) 100 mg/m2 i.v. days 1 and 8, and dipyridamole (DPD) 100 mg p.o. 75 minutes before CP, and then at hours 6, 12, and 18 as first-line chemotherapy. Cycles were repeated every 28 days for a total of 3. Median age was 56 years (range: 40-70). All patients had a performance status 0 to 1 and a weight loss < or = 10%. Squamous-cell carcinoma was diagnosed in 19 patients; adenocarcinoma in 16, and large-cell carcinoma in 6. A total of 37 patients were fully evaluable for response, whereas 39 were assessable for toxicity. No complete responses were observed: 5 patients (14%) achieved partial response; 23 patients (62%) showed no change, and progressive disease was observed in 9 (24%). The median time to treatment failure was 4 months, whereas median survival was 8 months. The average dose intensity received at the end of the third course of therapy was 46 mg/m2/week. There were no drug-related deaths. Toxicity was mild to moderate, with a high incidence of ototoxicity (54%) and emesis (67%). In conclusion, these results failed to demonstrate any significant advantage from a high-dose CP regimen modulated by DPD in patients with advanced NSCLC.

  20. Effect of methylnaltrexone and naloxone on esophageal motor function in man.

    PubMed

    Scarpellini, E; Pauwels, A; Vos, R; Rommel, N; Tack, J

    2017-03-01

    Endogenous opioids (EO) acting on μ-opiod receptors in central and enteric nervous system (ENS) control gastrointestinal motility but it is still unclear whether EO in ENS may control esophageal function in man, thus we will study the effects of methylnaltrexone (MNTX), a peripherally selective, and naloxone (NA), a non-selective μ-opiod receptor antagonist, on esophageal motility in healthy subjects. Fifteen HV (6 M; 34.1 ± 0.6 years; BMI: 22.1 ± 0.1 kg/m 2 ) underwent three esophageal high-resolution manometry impedance (HRiM) studies with 10 saline swallows administered every 30 minutes: drug was administered after 30 minutes (MNTX subcutaneously/NA or saline intravenously), a solid meal after 90 minutes; measurements continued for 120 minutes postprandially. Methylnaltrexone did not significantly decrease the upper esophageal sphincter (UES) percentage of relaxation preprandially (72.5 ± 5 vs 66.9 ± 4.6 and 73 ± 3.8%, ANOVA between placebo, MNTX and NA, P=NS) and postprandially (60 minutes: 68.2 ± 5.6 vs 61 ± 5.5 and 67.1 ± 5.6%; 120 minutes: 68 ± 5.9 vs 59.3 ± 5.2 and 67.7 ± 4.7%; ANOVA between placebo, MNTX and NA, P=NS). MNTX and NA did not significantly alter preprandial and postprandial LES resting pressures and integrated relaxation pressure (ANOVA between placebo, MNTX and NA, all P=NS). Peak front velocity and distal contractile integral were not altered pre- and postprandially by MNTX and NA (ANOVA between placebo, MNTX and NA, P=NS). Transient lower esophageal sphincter relaxations (TLESRs') number was not altered by MNTX and NA (ANOVA between placebo, MNTX and NA, all P=NS). The peripheral selective and non-selective μ-opioid receptor antagonists MNTX and NA, respectively, do not alter TLESRs occurrence and esophageal peristalsis. © 2017 John Wiley & Sons Ltd.

  1. Anti-nociceptive effects of calcitonin gene-related peptide in nucleus raphe magnus of rats: an effect attenuated by naloxone.

    PubMed

    Huang, Y; Brodda-Jansen, G; Lundeberg, T; Yu, L C

    2000-08-04

    The present study investigated the role of calcitonin gene-related peptide (CGRP) on nociception in nucleus raphe magnus (NRM) and the interaction between CGRP and opioid peptides in NRM of rats. CGRP-like immunoreactivity was found at a concentration of 6.0+/-0. 77 pmol/g in NRM tissue of ten samples of rats, suggesting that it may contribute to physiological responses orchestrated by the NRM. The hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation increased significantly after intra-NRM administration of 0.5 or 1 nmol of CGRP in rats, but not 0.25 nmol. The anti-nociceptive effect induced by CGRP was antagonized by following intra-NRM injection of 1 nmol of the CGRP receptor antagonist CGRP8-37. Furthermore, the CGRP-induced anti-nociceptive effect was attenuated by following intra-NRM administration of 6 nmol of naloxone. The results indicate that CGRP and its receptors play an important role in anti-nociception, and there is a possible interaction between CGRP and opioid peptides in NRM of rats.

  2. Naloxone effects on extinction of ethanol- and cocaine-induced conditioned place preference in mice.

    PubMed

    Font, Laura; Houck, Christa A; Cunningham, Christopher L

    2017-09-01

    Previous studies found that naloxone (NLX) facilitated choice extinction of ethanol conditioned place preference (CPP) using long (60 min) test sessions, but there is little information on the variables determining this effect. These studies examined repeated exposure to NLX during extinction of ethanol- or cocaine-induced CPP using both short and long tests. DBA/2J mice were injected with NLX (0 or 10 mg/kg) before three 10- or 60-min choice extinction tests (experiment 1). All mice received a final 60-min test without NLX. Post-test NLX was given in experiment 2. Experiment 3 tested whether NLX would affect a forced extinction procedure. Experiment 4 tested its effect on extinction of cocaine-induced CPP. Pre-test (but not post-test) injections of NLX-facilitated choice extinction of ethanol CPP at both test durations. Pre-test NLX also facilitated forced extinction. However, pre-test NLX had no effect on choice extinction of cocaine CPP. Extinction test duration is not critical for engaging the opioid system during ethanol CPP extinction (experiment 1). Moreover, NLX's effect does not depend on CPP expression during extinction, just exposure to previously conditioned cues (experiment 3). The null effect of post-test NLX eliminates a memory consolidation interpretation (experiment 2) and the failure to alter cocaine CPP extinction argues against alteration of general learning or memory processes (experiment 4). Overall, these data suggest that the endogenous opioid system mediates a conditioned motivational effect that normally maintains alcohol-induced seeking behavior, which may underlie the efficacy of opiate antagonists in the treatment of alcoholism.

  3. The influences of temperature and naloxone on the antinociceptive activity of Corchorus olitorius L. in mice.

    PubMed

    Zakaria, Z A; Safarul, M; Valsala, R; Sulaiman, M R; Fatimah, C A; Somchit, M N; Mat Jais, A M

    2005-07-01

    A series of preliminary studies was carried out to evaluate the antinociceptive (pain relief) activity of the aqueous extract of Corchorus olitorius L. leaves (COAE) and to determine the influence of temperature and opioid receptors on COAE activity using the abdominal constriction and hot plate tests in mice. COAE, at concentrations of 10, 25, 50, 75, and 100%, showed both peripheral and central antinociception that are non-concentration- and concentration-dependent respectively. The peripheral activity was clearly observed at a concentration of 25% and diminished at a concentration of 100%, while the central activity was observed at all the concentrations of COAE used. Furthermore, the insignificant results obtained indicated that this peripheral activity (at concentrations of 25 and 50%) was comparable to that of morphine (0.8 mg/kg). Pre-heating COAE at a temperature of 80 degrees C and 100 degrees C, or 60 degrees C and 80 degrees C was found to enhance its peripheral and central antinociception respectively. Pre-treatment with naloxone (10 mg/kg), a general opioid receptor antagonist, for 5 min, followed by COAE, was found to completely block its peripheral, but not central, antinociceptive activity. Based on this observation, we conclude that the antinociceptive activity exhibited by C. olitorius is enhanced by the increase in temperature and may be mediated peripherally, but not centrally, at least in part, via an opioid receptor.

  4. Effect of preoperative antiplatelet drugs on vascular prostacyclin synthesis.

    PubMed

    Karwande, S V; Weksler, B B; Gay, W A; Subramanian, V A

    1987-03-01

    Patients undergoing aortocoronary bypass using autogenous saphenous veins were randomly divided into three comparable groups. Group 1 (n = 10) acted as a control, Group 2 (n = 14) received 80 mg of aspirin at midnight before the operation, and Group 3 (n = 12) received 80 mg of aspirin and 75 mg of dipyridamole at midnight and an additional 75-mg dose of dipyridamole at 6 AM. The purpose was to determine which regimen would maximally inhibit platelet function without depressing vascular prostacyclin synthesis. Serum thromboxane A2, saphenous vein wall and aortic wall prostacyclin, platelet aggregation, and bleeding time were measured in all patients. None was restarted on a regimen of aspirin or dipyridamole postoperatively. Aspirin alone and in combination with dipyridamole significantly inhibited thromboxane A2 and platelet aggregation in all treated patients but spared venous prostacyclin synthesis. Aortic prostacyclin synthesis was partially inhibited in both treated groups. Chest tube drainage was comparable in all three groups. These results indicate that the combination of aspirin and dipyridamole offers no measurable advantage over aspirin alone in the perioperative period.

  5. An investigation into the crystallization tendency/kinetics of amorphous active pharmaceutical ingredients: A case study with dipyridamole and cinnarizine.

    PubMed

    Baghel, Shrawan; Cathcart, Helen; Redington, Wynette; O'Reilly, Niall J

    2016-07-01

    Amorphous drug formulations have great potential to enhance solubility and thus bioavailability of BCS class II drugs. However, the higher free energy and molecular mobility of the amorphous form drive them towards the crystalline state which makes them unstable. Accurate determination of the crystallization tendency/kinetics is the key to the successful design and development of such systems. In this study, dipyridamole (DPM) and cinnarizine (CNZ) have been selected as model compounds. Thermodynamic fragility (mT) was measured from the heat capacity change at the glass transition temperature (Tg) whereas dynamic fragility (mD) was evaluated using methods based on extrapolation of configurational entropy to zero [Formula: see text] , and heating rate dependence of Tg [Formula: see text] . The mean relaxation time of amorphous drugs was calculated from the Vogel-Tammann-Fulcher (VTF) equation. Furthermore, the correlation between fragility and glass forming ability (GFA) of the model drugs has been established and the relevance of these parameters to crystallization of amorphous drugs is also assessed. Moreover, the crystallization kinetics of model drugs under isothermal conditions has been studied using Johnson-Mehl-Avrami (JMA) approach to determine the Avrami constant 'n' which provides an insight into the mechanism of crystallization. To further probe into the crystallization mechanism, the non-isothermal crystallization kinetics of model systems were also analysed by statistically fitting the crystallization data to 15 different kinetic models and the relevance of model-free kinetic approach has been established. The crystallization mechanism for DPM and CNZ at each extent of transformation has been predicted. The calculated fragility, glass forming ability (GFA) and crystallization kinetics are found to be in good correlation with the stability prediction of amorphous solid dispersions. Thus, this research work involves a multidisciplinary approach to

  6. Patient- and clinician-reported satisfaction with pharmacological stress agents for single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI).

    PubMed

    Hudgens, Stacie; Breeze, Janis; Spalding, James

    2013-01-01

    The objective of this study was to compare clinician and patient measures of satisfaction with two pharmacological stress agents (PSA), regadenoson and dipyridamole, used in Single Photon Emission Computed Tomography (SPECT) Myocardial Perfusion Imaging (MPI). This observational study included patients who had undergone SPECT MPI with regadenoson or dipyridamole, as well as the clinician/clinical technologist who performed the test. Mean scores for individual item and domain scores of the main outcome measures were computed as well as the effect sizes (ES) of the mean difference in scores between treatment groups. Statistical significance of the mean item and domain score differences were assessed via Mann-Whitney tests. Two self-report questionnaires which had beeb previously developed and validated: Patient Satisfaction/Preference Questionnaire (PSPQ) and Clinician Satisfaction/Preference Questionnaire (CSPQ). A total of 87 patients (68 received regadenoson, 19 received dipyridamole) and nine clinicians/clinical technologists took part in the study. Patients had a mean age of 66.8 ± 12.2 years, and 56.3% were male. Compared to dipyridamole, use of regadenoson was associated with greater clinician satisfaction on all items and domains of the CSPQ (p < 0.001 for all comparisons). Among patients, regadenoson was associated with less bother and greater satisfaction than dipyridamole for all items on the PSPQ. These patients reported less stinging at the injection site (ES = -0.66) and less nervousness during injection (ES = -0.60). The PSPQ found that regadenoson patients were more satisfied with their PSA than dipyridamole patients in all areas. This study utilized a relatively small sample size of dipyridamole patients and lacked an adenosine group. A broader sampling of professionals would also help demonstrate generalizability. Both patients and clinicians reported higher satisfaction with regadenoson compared to dipyridamole for SPECT-MPI. Clinicians were

  7. Buprenorphine/naloxone treatment practices in Malaysia: Results of national surveys of physicians and patients.

    PubMed

    Vicknasingam, B; Dazali, M N M; Singh, D; Schottenfeld, R S; Chawarski, M C

    2015-07-01

    Medication assisted treatment with buprenorphine/naloxone (Bup/Nx), including prescribing and dispensing practices of general practitioners (GPs) in Malaysia and their patients' experiences with this treatment have not been systematically examined. The current study surveyed GPs providing Bup/Nx treatment and patients receiving office-based Bup/Nx treatment in Malaysia. Two cross-sectional surveys of GPs (N=115) providing outpatient Bup/Nx maintenance treatment and of patients (N=253) currently receiving Bup/Nx treatment throughout peninsular Malaysia. Physicians prescribed Bup/Nx dosages in the range of 2-4mg daily for 70% of patients and conducted urine testing in the past month on approximately 16% of their patients. In the patient survey, 79% reported taking daily Bup/Nx doses of 2mg or less; 82% reported that no urine toxicology testing had been conducted on them in the past month, 36% had an opiate positive urine test at the time of the survey, 43% reported illicit opiate use, 15% reported injection of heroin and 22% reported injection of Bup/Nx in the past month. Low daily Bup/Nx doses, lack of behavioral monitoring or counseling, and high rates of continued drug use, including injection of drugs and medications during Bup/Nx treatment in Malaysia, indicate continuing problems with implementation and less than optimal treatment effectiveness. High cost of Bup/Nx in Malaysia may deter patients from seeking treatment and contribute to taking low Bup/Nx dosages. Improved training of physicians and establishing standards for Bup/Nx dosing, routine toxicology testing, and counseling may be needed to improve care and treatment response. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  8. Predictors of Abstinence: NIDA Multi-site Buprenorphine/Naloxone Treatment Trial in Opioid Dependent Youth

    PubMed Central

    Subramaniam, Geetha A.; Warden, Diane; Minhajuddin, Abu; Fishman, Marc J.; Stitzer, Maxine L.; Adinoff, Bryon; Trivedi, Madhukar; Weiss, Roger; Potter, Jennifer; Poole, Sabrina A.; Woody, George E.

    2013-01-01

    Objective To examine predictors of opioid abstinence in buprenorphine/naloxone (Bup/Nal) assisted psychosocial treatment for opioid dependent youth Method Secondary analyses of data from 152 youth (ages 15–21) randomly assigned to 12 weeks of extended Bup/Nal therapy or up to 2 weeks of Bup/Nal detoxification, both with weekly individual and group drug counseling. Logistic regression models were constructed to identify baseline and during-treatment predictors of opioid positive urines (OPU) at week-12. Predictors were selected based on significance or trend toward significance (i.e. p<0.1) and backward stepwise selection was used, controlling for treatment group, to produce final independent predictors at p ≤ 0.05. Results Youth presenting to treatment with past 30-day injection drug use (IDU) and more active medical/psychiatric problems were less likely to have a week-12 OPU. Those with early treatment opioid abstinence (i.e. weeks 1 and 2); and those who received additional non-study treatments during the study were less likely to have a week-12 OPU; and those not completing 12 weeks of treatment were more likely to have an OPU. Conclusions Youth with advanced illness (i.e. reporting IDU and additional health problems), and those receiving ancillary treatments to augment study treatment were more likely to have lower opioid use. Treatment success in the first 2 weeks and completion of 12 weeks of treatment were associated with lower rates of OPU. These findings suggest that youth with advanced illness respond well to Bup/Nal treatment, and identify options for tailoring treatment for opioid-dependent youth presenting at community-based settings. PMID:22024000

  9. Suboxone (buprenorphine/naloxone) as an agonist opioid treatment in Spain: a budgetary impact analysis.

    PubMed

    Martínez-Raga, José; González Saiz, Francisco; Pascual, César; Casado, Miguel A; Sabater Torres, Francisco J

    2010-01-01

    To evaluate the economic impact of buprenorphine/naloxone (B/N) as an agonist opioid treatment for opiate dependence. A budgetary impact analysis model was designed to calculate the annual costs (drugs and associated costs) to the Spanish National Healthcare System of methadone versus B/N. Data for the model were obtained from official databases and expert panel opinion. It was estimated that 86,017 patients would be in an agonist opioid treatment program each of the 3 years of the study. No increase in the number of patients is expected with the introduction of B/N combination. The budgetary impact (drugs and associated costs) for agonist opiate treatment in the first year of the study would be 89.53 million EUR. In the first year of B/N use, the budgetary impact would rise by 4.39 million EUR (4.6% of the total impact), with an incremental cost of 0.79 million EUR (0.9% of the total impact). The budgetary increase would be 0.6% (0.48 million EUR increase) and 0.6% (0.49 million EUR increase) in the second and third years of use, respectively. The mean cost per patient in the first year with and without B/N would be EUR 1,050 and 1,041, respectively. The most influential variables in the sensitivity analysis were logistics and production costs of methadone and the percentage use of B/N. With an additional cost of only EUR 9 per patient, B/N is an efficient addition to the therapeutic arsenal in the drug treatment of opiate dependence, particularly when considering clinical aspects of novel pharmacotherapy. Copyright 2009 S. Karger AG, Basel.

  10. Stakeholder perceptions and operational barriers in the training and distribution of take-home naloxone within prisons in England.

    PubMed

    Sondhi, Arun; Ryan, George; Day, Ed

    2016-02-03

    The aim of the study was to assess potential barriers and challenges to the implementation of take-home naloxone (THN) across ten prisons in one region of England. Qualitative interviews deploying a grounded theory approach were utilised over a 12- to 18-month period that included an on-going structured dialogue with strategic and operational prison staff from the ten prisons and other key stakeholders (n = 17). Prisoner perceptions were addressed through four purposive focus groups belonging to different establishments (n = 26). Document analysis also included report minutes and access to management information and local performance reports. The data were thematically interpreted using visual mapping techniques. The distribution and implementation of THN in a prison setting was characterised by significant barriers and challenges. As a result, four main themes were identified: a wide range of negative and confused perceptions of THN amongst prison staff and prisoners; inherent difficulties with the identification and engagement of eligible prisoners; the need to focus on individual prison processes to enhance the effective distribution of THN; and the need for senior prison staff engagement. The distribution of THN within a custodial setting requires consideration of a number of important factors which are discussed.

  11. Withdrawal from Buprenorphine/Naloxone and Maintenance with a Natural Dopaminergic Agonist: A Cautionary Note.

    PubMed

    Blum, Kenneth; Oscar-Berman, Marlene; Femino, John; Waite, Roger L; Benya, Lisa; Giordano, John; Borsten, Joan; Downs, William B; Braverman, Eric R; Loehmann, Raquel; Dushaj, Kristina; Han, David; Simpatico, Thomas; Hauser, Mary; Barh, Debmalya; McLaughlin, Thomas

    2013-04-23

    While numerous studies support the efficacy of methadone and buprenorphine for the stabilization and maintenance of opioid dependence, clinically significant opioid withdrawal symptoms occur upon tapering and cessation of dosage. We present a case study of a 35 year old Caucasian female (Krissie) who was prescribed increasing dosages of prescription opioids after carpel tunnel surgery secondary to chronic pain from reflex sympathetic dystrophy and fibromyalgia. Over the next 5 years, daily dosage requirements increased to over 80 mg of Methadone and 300 ug/hr Fentanyl transdermal patches, along with combinations of 12-14 1600 mcg Actig lollipop and oral 100 mg Morphine and 30 mg oxycodone 1-2 tabs q4-6hr PRN for breakthrough pain. Total monthly prescription costs including supplemental benzodiazepines, hypnotics and stimulants exceeded $50,000. The patient was subsequently transferred to Suboxone® in 2008, and the dosage was gradually tapered until her admission for inpatient detoxification with KB220Z a natural dopaminergic agonist. We carefully documented her withdrawal symptoms when she precipitously stopped taking buprenorphine/naloxone and during follow-up while taking KB220Z daily. We also genotyped the patient using a reward gene panel including (9 genes 18 alleles): DRD 2,3,4; MOA-A; COMT; DAT1; 5HTTLLR; OPRM1; and GABRA3. At 432 days post Suboxone® withdrawal the patient is being maintained on KB220Z, has been urine tested and is opioid free. Genotyping data revealed a moderate genetic risk for addiction showing a hypodopaminergic trait. This preliminary case data suggest that the daily use of KB220Z could provide a cost effective alternative substitution adjunctive modality for Suboxone®. We encourage double-blind randomized -placebo controlled studies to test the proposition that KB220Z may act as a putative natural opioid substitution maintenance adjunct.

  12. Beta-endorphin and islet hormone release in type-2 diabetes mellitus the effects of normoglycemia, enkephalin, naloxone and somatostatin.

    PubMed

    Giugliano, D; Cozzolino, D; Salvatore, T; Ceriello, A; Giunta, R; Torella, R; D'Onofrio, F

    1987-01-01

    The present study was aimed at characterizing the effects of beta-endorphin on plasma glucose, insulin and glucagon plasma levels in subjects with type-2 diabetes mellitus. Infusion of 0.5 mg/h human beta-endorphin produced significant and simultaneous increments in both insulin and glucagon concentrations and decreased plasma glucose levels (-18 +/- 4 mg/dl, 60 min level, p less than 0.01). When the same diabetics were rendered euglycemic by an insulin infusion (1 mU/kg/min), beta-endorphin did not produce the expected decrease in plasma glucose concentrations nor raise plasma insulin levels; only the response of glucagon was preserved. Normal subjects were rendered hyperglycemic by an intravenous glucose infusion to match the plasma glucose levels of diabetic subjects. In this condition, beta-endorphin produced a significant increase of insulin concentrations, whereas glucagon remained suppressed. The intravenous administration of the long-acting met-enkephalin analogue DAMME (0.25 mg) blunted the hormonal responses to the subsequent beta-endorphin infusion in diabetic patients, although the inhibition was short-lived (30-40 min). Naloxone (5 mg), an opiate antagonist, did not produce any significant change in the insulin and glucagon responses to beta-endorphin, while somatostatin (0.25 mg/h) completely abolished the hormonal responses to the opioid.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. Preparation and in vitro-in vivo evaluation of none gastric resident dipyridamole (DIP) sustained-release pellets with enhanced bioavailability.

    PubMed

    Xu, Lishuang; Luo, Yanfei; Feng, Jia; Xu, Ming; Tao, Xiaoguang; He, Haibing; Tang, Xing

    2012-01-17

    The objective of this study was to develop none gastric resident sustained-release pellets loaded with dipyridamole with a high bioavailability. Two different kinds of core pellets, one containing citric acid as a pH-modifier (CAP) and, the other without pH-modifier (NCAP) were prepared by extrusion-spheronization and then coated with mixtures of enteric soluble and insoluble polymers (referred to as CAP(1) and NCAP(1)) or insoluble polymer alone (referred to as CAP(2) and NCAP(2)). The relative bioavailability of the sustained-release pellets was studied in fasted beagle dogs after oral administration using a commercially available immediate release tablet (IRT) as a reference. The in vitro release, in vivo absorption and in vitro-in vivo correlation were also evaluated. Results revealed that the plasma drug concentrations after administration of CAP(2), NCAP(1) and NCAP(2) were undetectable, indicating that the drug release was almost zero from the preparations throughout the gastro-intestinal tract. The C(max), T(max) and AUC((0→24)) of CAP(1) were 0.78 ± 0.23 (μg/ml), 3.80 ± 0.30 (h), and 6.74 ± 0.47 (μg/mlh), respectively. While the corresponding values were 2.23 ± 0.32 (μg/ml), 3.00 ± 0.44 (h) and 9.42 ± 0.69 (μg/mlh) for IRT. The relative bioavailability of CAP(1) was 71.55% compared with IRT. By combined incorporation of a pH-modifier into the core of pellets to modify the inner micro-environment and employing mixtures of enteric soluble and insoluble polymers as a retarding layer, drugs with high solubility in stomach and limited solubility in small intestine, such as DIP, could be successfully formulated as sustained release preparations with no pH-dependence in drug release and enhanced bioavailability. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Cost-effectiveness of extended buprenorphine-naloxone treatment for opioid-dependent youth: data from a randomized trial.

    PubMed

    Polsky, Daniel; Glick, Henry A; Yang, Jianing; Subramaniam, Geetha A; Poole, Sabrina A; Woody, George E

    2010-09-01

    The objective is to estimate cost, net social cost and cost-effectiveness in a clinical trial of extended buprenorphine-naloxone (BUP) treatment versus brief detoxification treatment in opioid-dependent youth. Economic evaluation of a clinical trial conducted at six community out-patient treatment programs from July 2003 to December 2006, who were randomized to 12 weeks of BUP or a 14-day taper (DETOX). BUP patients were prescribed up to 24 mg per day for 9 weeks and then tapered to zero at the end of week 12. DETOX patients were prescribed up to 14 mg per day and then tapered to zero on day 14. All were offered twice-weekly drug counseling. 152 patients aged 15-21 years. Data were collected prospectively during the 12-week treatment and at follow-up interviews at months 6, 9 and 12. The 12-week out-patient study treatment cost was $1514 (P < 0.001) higher for BUP relative to DETOX. One-year total direct medical cost was only $83 higher for BUP (P = 0.97). The cost-effectiveness ratio of BUP relative to DETOX was $1376 in terms of 1-year direct medical cost per quality-adjusted life year (QALY) and $25,049 in terms of out-patient treatment program cost per QALY. The acceptability curve suggests that the cost-effectiveness ratio of BUP relative to DETOX has an 86% chance of being accepted as cost-effective for a threshold of $100,000 per QALY. Extended BUP treatment relative to brief detoxification is cost effective in the US health-care system for the outpatient treatment of opioid-dependent youth.

  15. MK-801, but not naloxone, attenuates high-dose dextromethorphan-induced convulsive behavior: Possible involvement of the GluN2B receptor.

    PubMed

    Tran, Hai-Quyen; Chung, Yoon Hee; Shin, Eun-Joo; Tran, The-Vinh; Jeong, Ji Hoon; Jang, Choon-Gon; Nah, Seung-Yeol; Yamada, Kiyofumi; Nabeshima, Toshitaka; Kim, Hyoung-Chun

    2017-11-01

    Dextromethorphan (DM) is a dextrorotatory isomer of levorphanol, a typical morphine-like opioid. When administered at supra-antitussive doses, DM produces psychotoxic and neurotoxic effects in humans. Although DM abuse has been well-documented, few studies have examined the effects of high-dose DM. The present study aimed to explore the effects of a single high dose of DM on mortality and seizure occurrence. After intraperitoneal administration with a high dose of DM (80mg/kg), Sprague-Dawley rats showed increased seizure occurrence and intensity. Hippocampal expression levels of N-methyl-d-aspartate (NMDA) receptor subunits (GluN1naloxone, did not affect DM-induced neurotoxicity. Moreover, pretreatment with a highly specific GluN2B subunit inhibitor, traxoprodil, was selectively effective in preventing DM-induced c-Fos expression and apoptotic changes. These results suggest that high-dose DM produces convulsive behaviors by activating GluN2B/NMDA signaling that leads to pro-apoptotic changes. Copyright © 2017. Published by Elsevier Inc.

  16. Sublingual Buprenorphine/Naloxone for Chronic Pain in At-Risk Patients: Development and Pilot Test of a Clinical Protocol

    PubMed Central

    Rosenblum, Andrew; Cruciani, Ricardo A.; Strain, Eric C; Cleland, Charles M.; Joseph, Herman; Magura, Stephen; Marsch, Lisa A; McNicholas, Laura F; Savage, Seddon R; Sundaram, Arun; Portenoy, Russell K.

    2013-01-01

    Objective Sublingual buprenorphine/naloxone (Bup/Nx) is approved for addiction treatment and may be useful for pain management, particularly in opioid-treated pain patients with nonadherence behaviors. The transition of opioid-treated pain patients to buprenorphine carries the risk of precipitated withdrawal and increased pain. This study convened pain and addiction specialists to develop and pilot a clinical protocol for safe transitioning to Bup/Nx. Design The protocol was revised three times based on outside expert review and pilot study observations. The pilot was conducted with a prospective cohort of 12 patients with moderate to severe chronic pain, who were receiving long-term opioid therapy with any full μ-agonist drug, and had exhibited one or more aberrant drug-related behaviors. Patients were followed up for 3 to 6 months with the expectation that they would experience few adverse events and report lower pain severity. Results The three patients on the highest baseline opioid dose (equivalent to 303–450 mg of oral morphine) and the three on the lowest doses (≤20 mg) had early adverse events (AEs) when switched to Bup/Nx and did not complete the trial. Of the remaining six, one withdrew due to AEs; one responded well, then withdrew; and four completed a three-month trial. A mixed effects model controlling for dropouts found that average and worst pain significantly decreased after the switch to Bup/Nx (both p < .01). Conclusion Based on this experience, the protocol recommends Bup/Nx for pain only when baseline opioid doses are within bounds that reduce AEs at transition and incorporates dose flexibility to further reduce risks. This protocol warrants further testing. PMID:23264315

  17. Naloxone

    MedlinePlus

    ... Abuse and Mental Illness Recovery and Recovery Support School and Campus Health Specific Populations State and Local Government Partnerships Suicide Prevention Trauma and Violence Tribal Affairs Underage Drinking Veterans and Military Families ...

  18. Cost-effectiveness of long-term outpatient buprenorphine-naloxone treatment for opioid dependence in primary care.

    PubMed

    Schackman, Bruce R; Leff, Jared A; Polsky, Daniel; Moore, Brent A; Fiellin, David A

    2012-06-01

    Primary care physicians with appropriate training may prescribe buprenorphine-naloxone (bup/nx) to treat opioid dependence in US office-based settings, where many patients prefer to be treated. Bup/nx is off patent but not available as a generic. We evaluated the cost-effectiveness of long-term office-based bup/nx treatment for clinically stable opioid-dependent patients compared to no treatment. A decision analytic model simulated a hypothetical cohort of clinically stable opioid-dependent individuals who have already completed 6 months of office-based bup/nx treatment. Data were from a published cohort study that collected treatment retention, opioid use, and costs for this population, and published quality-of-life weights. Uncertainties in estimated monthly costs and quality-of-life weights were evaluated in probabilistic sensitivity analyses, and the economic value of additional research to reduce these uncertainties was also evaluated. Bup/nx, provider, and patient costs in 2010 US dollars, quality-adjusted life years (QALYs), and incremental cost-effectiveness (CE) ratios ($/QALY); costs and QALYs are discounted at 3% annually. In the base case, office-based bup/nx for clinically stable patients has a CE ratio of $35,100/QALY compared to no treatment after 24 months, with 64% probability of being < $100,000/QALY in probabilistic sensitivity analysis. With a 50% bup/nx price reduction the CE ratio is $23,000/QALY with 69% probability of being < $100,000/QALY. Alternative quality-of-life weights result in CE ratios of $138,000/QALY and $90,600/QALY. The value of research to reduce quality-of-life uncertainties for 24-month results is $6,400 per person eligible for treatment at the current bup/nx price and $5,100 per person with a 50% bup/nx price reduction. Office-based bup/nx for clinically stable patients may be a cost-effective alternative to no treatment at a threshold of $100,000/QALY depending on assumptions about quality-of-life weights. Additional

  19. Opioid overdose prevention training with naloxone, an adjunct to basic life support training for first-year medical students.

    PubMed

    Berland, Noah; Fox, Aaron; Tofighi, Babak; Hanley, Kathleen

    2017-01-01

    Opioid overdose deaths have reached epidemic proportions in the United States. This problem stems from both licit and illicit opioid use. Prescribing opioids, recognizing risky use, and initiating prevention, including opioid overdose prevention training (OOPT), are key roles physicians play. The American Heart Association (AHA) modified their basic life support (BLS) algorithms to consider naloxone in high-risk populations and when a pulse is appreciated; however, the AHA did not provide OOPT. The authors' intervention filled this training deficiency by teaching medical students opioid overdose resuscitation with a Train-the-Trainer model as part of mandatory BLS training. The authors introduced OOPT, following a Train-the-Trainer model, into the required basic life support (BLS) training for first-year medical students at a single medical school in a large urban area. The authors administered pre- and post-evaluations to assess the effects of the training on opioid overdose knowledge, self-reported preparedness to respond to opioid overdoses, and attitudes towards patients with substance use disorders (SUDs). In the fall 2014, 120 first-year medical students received OOPT. Seventy-three students completed both pre- and posttraining evaluations. Improvements in knowledge about and preparedness to respond to opioid overdoses were statistically significant (P < .01) and large (Cohen's D = 2.70 and Cohen's D = 2.10, respectively). There was no statistically significant change in attitudes toward patients with SUDs. The authors demonstrated the effectiveness of OOPT as an adjunct to BLS in increasing knowledge about and preparedness to respond to opioid overdoses; improving attitudes toward patients with SUDs likely requires additional intervention. The authors will characterize knowledge and preparedness durability, program sustainability, and long-term changes in attitudes in future evaluations. These results support dissemination of OOPT as a part of BLS training

  20. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial

    PubMed Central

    Lee, Joshua D; Nunes, Edward V; Novo, Patricia; Bachrach, Ken; Bailey, Genie L; Bhatt, Snehal; Farkas, Sarah; Fishman, Marc; Gauthier, Phoebe; Hodgkins, Candace C; King, Jacquie; Lindblad, Robert; Liu, David; Matthews, Abigail G; May, Jeanine; Peavy, K Michelle; Ross, Stephen; Salazar, Dagmar; Schkolnik, Paul; Shmueli-Blumberg, Dikla; Stablein, Don; Subramaniam, Geetha; Rotrosen, John

    2018-01-01

    Summary Background Extended-release naltrexone (XR-NTX), an opioid antagonist, and sublingual buprenorphine-naloxone (BUP-NX), a partial opioid agonist, are pharmacologically and conceptually distinct interventions to prevent opioid relapse. We aimed to estimate the difference in opioid relapse-free survival between XR-NTX and BUP-NX. Methods We initiated this 24 week, open-label, randomised controlled, comparative effectiveness trial at eight US community-based inpatient services and followed up participants as outpatients. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 opioid use disorder, and had used non-prescribed opioids in the past 30 days. We stratified participants by treatment site and opioid use severity and used a web-based permuted block design with random equally weighted block sizes of four and six for randomisation (1:1) to receive XR-NTX or BUP-NX. XR-NTX was monthly intramuscular injections (Vivitrol; Alkermes) and BUP-NX was daily self-administered buprenorphine-naloxone sublingual film (Suboxone; Indivior). The primary outcome was opioid relapse-free survival during 24 weeks of outpatient treatment. Relapse was 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use. This trial is registered with ClinicalTrials.gov, NCT02032433. Findings Between Jan 30, 2014, and May 25, 2016, we randomly assigned 570 participants to receive XR-NTX (n=283) or BUP-NX (n=287). The last follow-up visit was Jan 31, 2017. As expected, XR-NTX had a substantial induction hurdle: fewer participants successfully initiated XR-NTX (204 [72%] of 283) than BUP-NX (270 [94%] of 287; p<0·0001). Among all participants who were randomly assigned (intention-to-treat population, n=570) 24 week relapse events were greater for XR-NTX (185 [65%] of 283) than for BUP-NX (163 [57%] of 287; hazard ratio [HR] 1·36, 95% CI 1·10–1·68), most or all of this

  1. Reinforcement of wheel running in BALB/c mice: role of motor activity and endogenous opioids.

    PubMed

    Vargas-Pérez, Héctor; Sellings, Laurie H L; Paredes, Raúl G; Prado-Alcalá, Roberto A; Díaz, José-Luis

    2008-11-01

    The authors investigated the effect of the opioid antagonist naloxone on wheel-running behavior in Balb/c mice. Naloxone delayed the acquisition of wheel-running behavior, but did not reduce the expression of this behavior once acquired. Delayed acquisition was not likely a result of reduced locomotor activity, as naloxone-treated mice did not exhibit reduced wheel running after the behavior was acquired, and they performed normally on the rotarod test. However, naloxone-blocked conditioned place preference for a novel compartment paired previously with wheel running, suggesting that naloxone may delay wheel-running acquisition by blocking the rewarding or reinforcing effects of the behavior. These results suggest that the endogenous opioid system mediates the initial reinforcing effects of wheel running that are important in acquisition of the behavior.

  2. The Opioid Crisis and the Physician's Role in Contributing to its Resolution: Step One--Prevention of Overdoses.

    PubMed

    Wolfe, Susan; Bouffard, Dennis L; Modesto-Lowe, Vania

    2016-01-01

    The escalation of opioid prescriptions, associated misuse, and related mortality continues to pose public health challenges in the United States. Data from the Centers for Disease Control and Prevention (CDC) indicates that opioid overdose death rates remain high, suggesting the need for improved access to, and use of naloxone to save lives. In this context, community-based overdose initiatives have trained laypersons to identify overdose and administer naloxone for reversal. Although there have been efforts to encourage physicians to prescribe naloxone to patients at-risk for opioid overdose, the rate of prescribing remains suboptimal. This article outlines the epidemiology of overdoses, discusses naloxone distribution programs and myths surrounding its use, and reviews relevant legislative developments in Connecticut and proper counseling of patients and families to encourage broader education and prescribing of naloxone.

  3. Excitatory and inhibitory effects of opiates in the rat vas deferens: a dual mechanism of opiate action.

    PubMed

    Jacquet, Y F

    1980-10-03

    Both natural (-)-morphine and its unnatural enantiomer (+)-morphine exert an excitatory action on electrically stimulated contractions of rat vas deferens. Preexposure to (-)-morphine results in cross-tolerance to the inhibitory action of beta-endorphin. (-)-Naloxone and its stereoisomer (+)-naloxone also exert an excitatory action, but only (-)-naloxone bocks the inhibtory action of beta-endorphin. Thus morphine exerts a dual action on a peripheral organ: one an inhibitory action mediated by the stereospecific endorphin receptor that is blocked stereospecifically by naloxone, the other an excitatory action mediated by a nonstereospecific receptor that is not blocked by naloxone. The opiate abstinence syndrome is seen as due to the unmasking of the excitatory action of opiates when its concomitant inhibitory influence is removed by selective blockade by naloxone or weakened by selective tolerance. The view that the rat vas deferens is devoid of morphine receptors is now seen as arising from a reverse example of morphine's dual action: the masking of the inhibitory action of morphine by its concomitant and more potent excitatory action.

  4. The introduction of buprenorphine-naloxone film in opioid substitution therapy in Australia: Uptake and issues arising from changing buprenorphine formulations.

    PubMed

    Larance, Briony; Dietze, Paul; Ali, Robert; Lintzeris, Nicholas; White, Nancy; Jenkinson, Rebecca; Degenhardt, Louisa

    2015-11-01

    Buprenorphine-naloxone (BNX) film for opioid dependence treatment was introduced in Australia in 2011. A key difference in State policy approaches saw transfer from BNX tablets to BNX film mandated in South Australia (SA) with New South Wales (NSW) and Victoria (VIC) having less stringent policies. This study examined (i) how initiations and transfers were implemented, (ii) the profile and predictors of adverse effects as self-reported by BNX film clients, and (iii) dosing issues. Survey of 334 buprenorphine (BPN), BNX tablet and BNX film clients and semi-structured interviews with 39 key experts (KEs) in 2012. Comparisons are made between clients interviewed in SA versus NSW and VIC combined. Among the 180 current BNX film clients, 23% started treatment on BNX film, 18% requested a transfer to BNX film and 59% (n = 106) reported their clinic/prescriber recommended transfer to BNX film. Among clients who were offered but refused a transfer to BNX film (n = 66), the most common reason was 'I am happy with my current treatment and do not see a reason to change' (53%). Some opioid substitution therapy clients and KE viewed transfers as 'forced' (i.e. no choice of buprenorphine formulation). Multivariable regression showed residing in SA (vs. NSW/VIC) and a shorter length of current treatment episode were associated with more BNX film-attributed adverse effects but clinic/prescriber-recommended transfer was not. The introduction of BNX film in Australia varied across States. A perception of restricted choice in medication may have undermined initial acceptance in SA. © 2015 Australasian Professional Society on Alcohol and other Drugs.

  5. Distinctive Trajectories of Opioid Use Over an Extended Follow-up of Patients in a Multisite Trial on Buprenorphine + Naloxone and Methadone.

    PubMed

    Hser, Yih-Ing; Huang, David; Saxon, Andrew J; Woody, George; Moskowitz, Andrew L; Matthews, Abigail G; Ling, Walter

    Uncovering heterogeneities in longitudinal patterns (trajectories) of opioid use among individuals with opioid use disorder can increase our understanding of disease progression and treatment responses to improve care. The present study aims to identify distinctive opioid use trajectories and factors associated with these patterns among participants randomized to treatment with methadone (MET) or buprenorphine + naloxone (BUP). Growth mixture modeling was applied to identify distinctive opioid use trajectories among 795 opioid users after their enrollment in a multisite trial during 2006 to 2009, with follow-up interviews conducted during 2011 to 2014. Four distinctive trajectories were identified based on opioid use over the follow-up period: low use (42.0%), high use (22.3%), increasing use (17.1%), and decreasing use (18.6%). Greater odds of being in the high use group (relative to low use) was associated with Hispanics (relative to African American, odds ratio [OR] 3.21), injection drug use (OR 2.12), higher mental health functioning at baseline (OR 1.23), location on the West Coast (vs East Coast, OR 2.15), and randomization to BUP (relative to MET, OR 1.53). High use and increasing use groups had greater severity in problems related to drug, employment, legal, and social/family relationships, and worsened mental health functioning at follow-up. Participation in treatment significantly accounted for both within and between-group differences in opioid use. Continued treatment is necessary to reduce risk for opioid use and related adverse consequences, particularly among individuals (eg, injecting drug) at risk for consistently high level of opioid use.

  6. The Role of Pituitary Beta-Endorphin in the Attenuation of Nociception

    DTIC Science & Technology

    1986-08-28

    204 X TABLES Table # Title 1 Effects of naloxone, fentanyl , diazepam and placebo on plasma norepinephrine levels (pgjml). 2 Lack of...the clinical CRH study. 4 Experimental design and sampling schedule for the clinical dexamethasone study. 5 Effects of naloxone (NAL), fentanyl ...FEN), diazepam (DZP) and placebo (PLBO) on circulating levels of iB-END. 6 7 8 9 10 11 12 Effects of naloxone (NAL), fentanyl (FEN), diazepam

  7. Can the chronic administration of the combination of buprenorphine and naloxone block dopaminergic activity causing anti-reward and relapse potential?

    PubMed

    Blum, Kenneth; Chen, Thomas J H; Bailey, John; Bowirrat, Abdalla; Femino, John; Chen, Amanda L C; Simpatico, Thomas; Morse, Siobhan; Giordano, John; Damle, Uma; Kerner, Mallory; Braverman, Eric R; Fornari, Frank; Downs, B William; Rector, Cynthia; Barh, Debmayla; Oscar-Berman, Marlene

    2011-12-01

    Opiate addiction is associated with many adverse health and social harms, fatal overdose, infectious disease transmission, elevated health care costs, public disorder, and crime. Although community-based addiction treatment programs continue to reduce the harms of opiate addiction with narcotic substitution therapy such as methadone maintenance, there remains a need to find a substance that not only blocks opiate-type receptors (mu, delta, etc.) but also provides agonistic activity; hence, the impetus arose for the development of a combination of narcotic antagonism and mu receptor agonist therapy. After three decades of extensive research, the federal Drug Abuse Treatment Act 2000 (DATA) opened a window of opportunity for patients with addiction disorders by providing increased access to options for treatment. DATA allows physicians who complete a brief specialty-training course to become certified to prescribe buprenorphine and buprenorphine/naloxone (Subutex, Suboxone) for treatment of patients with opioid dependence. Clinical studies indicate that buprenorphine maintenance is as effective as methadone maintenance in retaining patients in substance abuse treatment and in reducing illicit opioid use. With that stated, we must consider the long-term benefits or potential toxicity attributed to Subutex or Suboxone. We describe a mechanism whereby chronic blockade of opiate receptors, in spite of only partial opiate agonist action, may ultimately block dopaminergic activity causing anti-reward and relapse potential. While the direct comparison is not as yet available, toxicity to buprenorphine can be found in the scientific literature. In considering our cautionary note in this commentary, we are cognizant that, to date, this is what we have available, and until such a time when the real magic bullet is discovered, we will have to endure. However, more than anything else this commentary should at least encourage the development of thoughtful new strategies to target

  8. Can the chronic administration of the combination of buprenorphine and naloxone block dopaminergic activity causing anti-reward and relapse potential?

    PubMed Central

    Blum, Kenneth; Chen, Thomas JH; Bailey, John; Bowirrat, Abdulla; Femino, John; Chen, Amanda LC; Simpatico, Thomas; Morse, Siobhan; Giordano, John; Damle, Uma; Kerner, Mallory; Braverman, Eric R.; Fornari, Frank; Downs, B.William; Rector, Cynthia; Barh, Debmayla; Oscar-Berman, Marlene

    2013-01-01

    Opiate addiction is associated with many adverse health and social harms, fatal overdose, infectious disease transmission, elevated health care costs, public disorder, and crime. Although community-based addiction treatment programs continue to reduce the harms of opiate addiction with narcotic substitution therapy such as methadone maintenance, there remains a need to find a substance that not only blocks opiate-type receptors (mu, delta, etc.) but also provides agonistic activity; hence the impetus arose for the development of a combination of narcotic antagonism and mu receptor agonist therapy. After three decades of extensive research the federal Drug Abuse Treatment Act 2000 (DATA) opened a window of opportunity for patients with addiction disorders by providing increased access to options for treatment. DATA allows physicians who complete a brief specialty-training course to become certified to prescribe buprenorphine and buprenorphine/naloxone (Subutex, Suboxone) for treatment of patients with opioid dependence. Clinical studies indicate buprenorphine maintenance is as effective as methadone maintenance in retaining patients in substance abuse treatment and in reducing illicit opioid use. With that stated, we must consider the long-term benefits or potential toxicity attributed to Subutex or Suboxone. We describe a mechanism whereby chronic blockade of opiate receptors, in spite of only partial opiate agonist action, may ultimately block dopaminergic activity causing anti-reward and relapse potential. While the direct comparison is not as yet available, toxicity to buprenorphine can be found in the scientific literature. In considering our cautionary note in this commentary, we are cognizant that to date this is what we have available, and until such a time when the real magic bullet is discovered, we will have to endure. However, more than anything else this commentary should at least encourage the development of thoughtful new strategies to target the

  9. Topical review on the abuse and misuse potential of tramadol and tilidine in Germany.

    PubMed

    Radbruch, Lukas; Glaeske, Gerd; Grond, Stefan; Münchberg, Frank; Scherbaum, Norbert; Storz, Elisabeth; Tholen, Kathrin; Zagermann-Muncke, Petra; Zieglgänsberger, Walter; Hoffmann-Menzel, Helmut; Greve, Hendrik; Cremer-Schaeffer, Peter

    2013-01-01

    Tramadol and tilidine (in combination with naloxone) are used as weak opioid analgesics in Germany. Tramadol is not scheduled in the German Narcotic Drugs Act. Tilidine is scheduled, whereas Tilidine in fixed combinations with naloxone is exempt from some of the provisions of the Narcotic Drugs Act. Recent reports on misuse of both substances led to an evaluation of their potential for misuse, abuse, and dependency by the expert advisory committee established by the German Federal Government, resident at the Federal Institute for Drugs and Medical Devices. A subcommittee formulated key questions and identified available data sources for each of these questions. Additional information was solicited where necessary, including a survey among a panel of pharmacists, a survey in an addiction clinic, analysis of prescription patterns, and information from the boards of pharmacists of the federal states and the Federal Bureau of Criminal Investigation. Analgesic efficiency in the treatment of acute and chronic pain has been proven for both tramadol and tilidine/naloxone. For tramadol, high evidence has been confirmed in systematic reviews, and tramadol is listed in national and international guidelines on acute and chronic pain management. Animal and human studies found a low potential for misuse, abuse, and dependency for both substances. Information from 2 tramadol safety databases allowed calculation of the incidence of abuse or dependency as 0.21 and 0.12 cases per million defined daily dosages (DDDs), with lower incidences in recent years. For tilidine/naloxone, the incidence was calculated as 0.43 cases per million DDDs for oral solution and 0.18 for slow-release tablets. In an online survey among German pharmacies as well as in the reports from state pharmacy boards, fraud attempts were repeated more frequently with tilidine/naloxone than with tramadol in the last 2 years. The Federal Bureau of Criminal Investigations reported prescription fraud only with tilidine/naloxone

  10. Opioid systems in the response to inflammatory pain: sustained blockade suggests role of kappa- but not mu-opioid receptors in the modulation of nociception, behaviour and pathology.

    PubMed

    Millan, M J; Colpaert, F C

    1991-01-01

    One day after intraplantar inoculation of Mycobacterium butyricum into the right hind-paw, unilaterally inflamed and control rats were implanted subcutaneously with osmotic mini-pumps delivering naloxone at 0.16 or 3.0 mg/kg/h or vehicle. As determined three days after implantation, 0.16 mg/kg/h of naloxone completely antagonized the antinociceptive action of the mu-agonist, morphine, but did not affect antinociception evoked by the kappa-agonist, U69,593. In contrast, at 3.0 mg/kg/h, naloxone blocked both morphine- and U69,593-induced antinociception. Thus, 0.16 mg/kg ("low dose") and 3.0 mg/kg ("high dose") of naloxone block mu, or mu- plus kappa-opioid receptors, respectively. Pumps were removed one week following their implantation. Inoculation was associated with a sustained hyperalgesia of the inflamed paw to noxious pressure, and elevation in resting core temperature, a loss of body weight, hypophagia, hypodipsia and a reduction in mobility. These parameters were differentially modified by the high as compared to the low dose of naloxone. Two days following implantation of pumps delivering the high dose of naloxone, the hyperalgesia of the inflamed paw was potentiated: by six days, this effect was lost. Further, one day after removal of pumps yielding the high dose, the inflamed paw showed a normalization of thresholds, that is a "rebound antinociception". One day later, this effect had subsided. In distinction, at no time did the low dose of naloxone modify nociceptive thresholds. The high dose of naloxone enhanced the reduction in body weight and food intake shown by unilaterally inflamed rats whereas the low dose was ineffective. Neither dose affected the reduction in water intake or hypothermia of unilaterally inflamed animals. The high dose of naloxone reduced the mobility of unilaterally inflamed rats whereas the low dose was ineffective. Finally, by 10 days following pump removal, pathology had transferred to the contralateral paw. In rats which had

  11. Adenosine formation and release from neonatal-rat heart cells in culture.

    PubMed Central

    Meghji, P; Holmquist, C A; Newby, A C

    1985-01-01

    The incorporation of [3H]adenosine (10 microM) into neonatal-rat heart cell nucleotides was inhibited in a concentration-dependent manner, such that 50% inhibition was obtained with 0.75 microM-dipyridamole, 0.26 microM-hexobendine or 0.22 microM-dilazep. Adenosine formation was accelerated 2.5-fold to 2.1 +/- 0.3 nmol/10(7) cells in 10 min when cells were incubated with a combination of 30 mM-2-deoxyglucose and 2 micrograms of oligomycin/ml. Of the newly formed adenosine, 6 +/- 2% was in the cells. Dipyridamole, hexobendine or dilazep (10 microM) increased the amount of adenosine in the cells and decreased that in the medium such that 45-50% of the newly formed adenosine was in the cells. Antibodies which inhibited ecto-5'-nucleotidase by 98.7 +/- 0.3% did not alter the rate of adenosine formation or its distribution between cells and medium. We conclude that adenosine was formed in the cytoplasm during catabolism of cellular ATP and was released via the dipyridamole-sensitive symmetric nucleoside transporter. PMID:2996488

  12. Leishmania major: effect of protein kinase A and phosphodiesterase activity on infectivity and proliferation of promastigotes.

    PubMed

    Malki-Feldman, Laura; Jaffe, Charles L

    2009-09-01

    Effect of modulators on protein kinase A (PKA) activity, promastigote growth and their ability to infect peritoneal macrophages was monitored. PKA inhibitors reduced [Protein Kinase Inhibitor (PKI) - 56%; H89 - 54.5%] kemptide phosphorylation by Leishmania major promastigote lysates, while activators increased phosphorylation (8-CPT-cAMP - 88%; Sp-cAMPS-AM - 152%). Activation was specifically inhibited by PKI. Phosphodiesterase inhibitors also increased kemptide phosphorylation (dipyridamole - 171%; rolipram - 106%; and 3-isobutyl-1-methyl-xanthine - 154%). Parasite proliferation was significantly retarded (200 nM H89; 100 microM myristoylated-PKI) or completely inhibited (500 nM H89) by culturing with PKA inhibitors. Incubation with dipyridamole or Sp-cAMPS-AM also inhibited proliferation. Brief treatment (2h) with either H89, myristoylated-PKI, dipyridamole or Sp-cAMPS-AM reduced initial macrophage infection at days 1 and 2 (>40%) and on day 3 (>78% only for 100 microM myr-PKI). Characterization of leishmanial cAMP mediated signal transduction pathways will serve as the basis for the new drug design.

  13. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Boettcher, M.; Czernin, J.; Sun, K.

    The {beta}{sub 1} receptor blockade reduces cardiac work and may thereby lower myocardial blood flow (MBF) at rest. The effect of {beta}{sub 1} receptor blockade on hyperemic MBF is unknown. To evaluate the effect of selective {beta}{sub 1} receptor blockade on MBF at rest and during dipyridamole induced hyperemia, 10 healthy volunteers (8 men, 2 women, mean age 24 {+-} 5 yr) were studied using {sup 13}N-ammonia PET (two-compartment model) under control conditions and again during metoprolol (50 mg orally 12 hr and 1 hr before the study). The resting rate pressure product (6628 {+-} 504 versus 5225 {+-} 807)more » and heart rate (63 {+-} 6-54 {plus_minus} 5 bpm) declined during metoprolol (p < 0.05). Similarly, heart rate and rate pressure product declined from the baseline dipyridamole study to dipyridamole plus metoprolol (p < 0.05). Resting MBF declined in proportion to cardiac work by approximately 20% from 0.61 {+-} 0.09-0.51 {+-} 0.10 ml/g/min (p < 0.05). In contrast, hyperemic MBF increased when metoprolol was added to dipyridamole (1.86 {plus_minus} 0.27 {+-} 0.45 ml/g/min; p<0.05). The decrease in resting MBF together with the increase in hyperemic MBF resulted in a significant increase in the myocardial flow reserve during metoprolol (3.14 {+-} 0.80-4.61 {+-} 0.68; p<0.01). The {beta}{sub 1} receptor blockade increases coronary vasodilatory capacity and myocardial flow reserve. However, the mechanisms accounting for this finding remain uncertain. 32 refs., 2 figs., 2 tabs.« less

  14. Nicotine enhancement and reinforcer devaluation: Interaction with opioid receptors.

    PubMed

    Kirshenbaum, Ari P; Suhaka, Jesse A; Phillips, Jessie L; Voltolini de Souza Pinto, Maiary

    In rats, nicotine enhances responding maintained by non-pharmacological reinforcers, and discontinuation of nicotine devalues those same reinforcers. The goal of this study was to assess the interaction of nicotine and opioid receptors and to evaluate the degree to which nicotine enhancement and nicotine-induced devaluation are related to opioid activation. Nicotine (0.4mg/kg), or nicotine plus naloxone (0.3 or 3.0mg/kg), was delivered to rats prior to progressive ratio (PR) schedule sessions in which sucrose was used as a reinforcer. PR-schedule responding was assessed during ten daily sessions of drug delivery, and for three post-dosing days/sessions. Control groups for this investigation included a saline-only condition, and naloxone-only (0.3 or 3.0mg/kg) conditions. When administered in conjunction with nicotine, both naloxone doses attenuated nicotine enhancement of the sucrose reinforcer, and the combination of the larger dose of naloxone (3.0mg/kg) with nicotine produced significant impairments in sucrose reinforced responding. When administered alone, neither dose of naloxone (0.3 & 3.0mg/kg) significantly altered responding in comparison to saline. Furthermore, when dosing was discontinued after ten once-daily doses, all nicotine groups (nicotine-only and nicotine+naloxone combination) demonstrated significant decreases in sucrose reinforcement compared to the saline group. Although opioid antagonism attenuated reinforcement enhancement by nicotine, it did not prevent reinforcer devaluation upon discontinuation of nicotine dosing, and the higher dose of naloxone (3.0mg/kg) produced decrements upon discontinuation on its own in the absence of nicotine. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Gastric pentadecapeptide BPC 157 counteracts morphine-induced analgesia in mice.

    PubMed

    Boban Blagaic, A; Turcic, P; Blagaic, V; Dubovecak, M; Jelovac, N; Zemba, M; Radic, B; Becejac, T; Stancic Rokotov, D; Sikiric, P

    2009-12-01

    Previously, the gastric pentadecapeptide BPC 157, (PL 14736, Pliva) has been shown to have several beneficial effects, it exert gastroprotective, anti-inflammatory actions, stimulates would healing and has therapeutic value in inflammatory bowel disease. The present study aimed to study the effect of naloxone and BPC 157 on morphine-induced antinociceptive action in hot plate test in the mouse. It was found that naloxone and BPC 157 counteracted the morphine (16 mg/kg s.c.) - analgesia. Naloxone (10 mg/kg s.c.) immediately antagonised the analgesic action and the reaction time returned to the basic values, the development of BPC 157-induced action (10 pg/kg, 10 ng/kg, 10 microg/kg i.p.) required 30 minutes. When haloperidol, a central dopamine-antagonist (1 mg/kg i.p.), enhanced morphine-analgesia, BPC 157 counteracted this enhancement and naloxone reestablished the basic values of pain reaction. BPC 157, naloxone, and haloperidol per se failed to exert analgesic action. In summary, interaction between dopamine-opioid systems was demonstrated in analgesia, BPC 157 counteracted the haloperidol-induced enhancement of the antinociceptive action of morphine, indicating that BPC acts mainly through the central dopaminergic system.

  16. Endogenous opioids inhibit oxytocin release during nicotine-stimulated secretion of vasopressin in man.

    PubMed

    Seckl, J R; Johnson, M; Shakespear, C; Lightman, S L

    1988-05-01

    The effects of the opioid antagonist naloxone on the vasopressin (AVP) and oxytocin (OT) responses to nicotine were studied in male non-smokers (21-30 years old). Either saline (n = 6) or naloxone (4 mg bolus + 6 mg/h, n = 6) was infused i.v. during the study. After 60 min infusion the subjects smoked one high-nicotine content cigarette. Naloxone infusion for 60 min did not alter basal plasma AVP or OT levels. Smoking led to a significant rise in plasma vasopressin in both saline and naloxone-infused subjects (P less than 0.05). There was no significant difference in the plasma AVP response to smoking between the two groups. Saline-infused subjects did not show any change in plasma OT in response to smoking. Naloxone infusion was associated with a significant rise in OT from 1.3 +/- 0.1 pmol/l to 4.3 +/- 2.4 pmol/l 5 min after smoking (P less than 0.05). We conclude that there is endogenous opioid-mediated inhibition of OT which prevents its release when AVP is secreted in response to nicotine in man.

  17. Lack of mixed agonist-antagonist properties of [Gln8-Gly31]-beta h-EP-Gly-Gly-NH2 and [Arg9,19,24,28,29]-beta h-EP in the rat vas deferens neuroeffector junction: studies with naloxone, beta-funaltrexamine and ICI 174,864.

    PubMed

    Valenzuela, R; Li, C H; Huidobro-Toro, J P

    1989-02-01

    The 1-27 truncated fragment of beta h-endorphin (beta h-EP) as well as [Gln8,Gly31]-beta h-EP-Gly-Gly-NH2 or [Arg9,19,24,28,29]-beta h-EP exhibited opiate agonist activity in the rat vas deferens bioassay; the potency of these peptides was 3 to 6 times less than that of beta h-EP. None of these compounds exhibited any degree of antagonism towards the inhibitory action of beta h-EP. Naloxone antagonized and reversed the inhibitory action of beta h-EP and its analogues though with varying potencies. The apparent naloxone-pA2 value for beta h-EP was 8.94; that for [Gln8-Gly31]-beta h-EP-Gly-Gly-NH2 was 8.08 and that for [Arg9,19,24,28,29]-beta h-EP was 8.38. beta-Funaltrexamine (beta-FNA) potently antagonized the inhibitory action of beta h-EP following non-equilibrium kinetics. Tissue preincubation with 10 nM beta-FNA for 60 min followed by extensive washing caused a 10-fold increase in the beta h-EP IC50. However, 10 nM beta-FNA caused only a 1.2 increase in the IC50 of [Gln8,Gly31]-beta h-EP-Gly-Gly-NH2 and a 4.1-fold increase in the IC50 of [Arg9,19,24,28,29]-beta h-EP. In contrast, preincubation of the tissue with 3 microM ICI 174,864 did not modify the potency of beta h-EP or its structural analogues. However, a 60 min pretreatment with 10 microM beta-FNA followed by the addition of 3 microM ICI 174,864 revealed a further decrease in the potency of the opiopeptins compared with tissues exposed to beta-FNA alone or ICI 174,864 alone. In conclusion, the inhibitory action of these peptides is remarkably sensitive to beta-FNA antagonism; in addition the peptides act as pure opiate agonists in marked contrast with the agonist-antagonist properties described in the CNS.

  18. Combining clinical and thallium data optimizes preoperative assessment of cardiac risk before major vascular surgery

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Eagle, K.A.; Coley, C.M.; Newell, J.B.

    1989-06-01

    STUDY OBJECTIVE: To determine whether clinical markers and preoperative dipyridamole-thallium imaging are both useful in predicting ischemic events after vascular surgery. Two hundred fifty-four consecutive patients were referred to a nuclear cardiology laboratory before surgery. Forty-four patients had surgery cancelled or postponed after clinical evaluation and dipyridamole-thallium imaging. Surgery was not confirmed for ten. Two hundred patients receiving prompt vascular surgery were the study group. Thirty patients (15%) had early postoperative cardiac ischemic events, with cardiac death in 6 (3%) and nonfatal myocardial infarction in 9 (4.5%). Logistic regression identified five clinical predictors (Q waves, history of ventricular ectopic activity,more » diabetes, advanced age, angina) and two dipyridamole-thallium predictors of postoperative events. Of patients with none of the clinical variables (n = 64), only 2 (3.1%; 95% CI, 0% to 8%) had ischemic events with no cardiac deaths. Ten of twenty (50%; 95% CI, 29% to 71%) patients with three or more clinical markers had events. Eighteen of one hundred sixteen (15.5%; 95% CI, 7% to 21%) patients with either 1 or 2 clinical predictors had events. Within this group, 2 of 62 (3.2%; 95% CI, 0% to 8%) patients without thallium redistribution had events compared with 16 events in 54 patients (29.6%; 95% CI, 16% to 44%) with thallium redistribution. The multivariate model using both clinical and thallium variables showed significantly higher specificity at equivalent sensitivity levels than models using either clinical or thallium variables alone. Preoperative dipyridamole-thallium imaging appears most useful to stratify vascular patients determined to be at intermediate risk by clinical evaluation.« less

  19. Reduced coronary flow and resistance reserve in primary scleroderma myocardial disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Nitenberg, A.; Foult, J.M.; Kahan, A.

    1986-08-01

    The maximum coronary vasodilator capacity after intravenous dipyridamole (0.14 mg X kg-1 X min-1 X 4 minutes) was studied in seven patients with primary scleroderma myocardial disease and compared to that of seven control subjects. Hemodynamic data and left ventricular angiographic data were not different in the two groups. The coronary flow reserve was evaluated by the dipyridamole/basal coronary sinus blood flow ratio (D/B CSBF) and the coronary resistance reserve by the dipyridamole/basal coronary resistance ratio (D/B CR). Coronary reserve was greatly impaired in the group with primary scleroderma myocardial disease: D/B CSBF was lower than in the control groupmore » (2.54 +/- 1.37 vs 4.01 +/- 0.56, respectively; p less than 0.05) and D/B CR was higher than in the control group (0.47 +/- 0.25 vs 0.23 +/- 0.04, respectively; p less than 0.05). Such a decreased coronary flow and resistance reserve in patients with primary scleroderma myocardial disease was not explained by an alteration of left ventricular function. It may be an important contributing factor in the pathogenesis of primary scleroderma myocardial disease.« less

  20. 77 FR 3777 - Draft and Revised Draft Guidances for Industry Describing Product-Specific Bioequivalence...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-25

    ... Potassium (multiple RLDs) Aripiprazole Aspirin; Butalbital; Caffeine (multiple RLDs) Aspirin; Dipyridamole Aspirin; Oxycodone Aspirin; Butalbital; Caffeine; Codeine Phosphate Atovaquone Auranofin Azelaic Acid...

  1. Opioid modulation of ingestive behaviors in woodchucks and racoons.

    PubMed

    Nizielski, S E; Morley, J E; Gosnell, B A; Seal, U S; Levine, A S

    1985-02-01

    We have examined the effect on feeding of opioid blockade with naloxone in two species which demonstrate a marked seasonality in their feeding patterns, the racoon (Procyon lotor) and the woodchuck (Marmota monax). Naloxone suppressed food intake in the woodchuck which is a true hibernator. Naloxone failed to suppress food intake in the racoon and, in fact, enhanced intake of a preferred sucrose solution. In the racoon, ir-dynorphine concentrations were extremely high in the hypothalamus compared to the values obtained in rats and woodchucks. We suggest that possible explanations for the lack of responsiveness to opiates in racoons may be their extremely high daily food intake relatively to body mass when compared to woodchucks and rats and the high levels of ir-dynorphin may be sufficient to overcome the inhibitory effect of naloxone. These studies stress the occurrence of species diversity in the response to opioid antagonism.

  2. Suppression of transmission of nociceptive impulses by morphine

    PubMed Central

    Duggan, A.W.; Hall, J.G.; Headley, P.M.

    1977-01-01

    1 In spinal cats anaesthetized with α-chloralose, a study was made of the effects of morphine and naloxone, administered electrophoretically from micropipettes, on the responses of dorsal horn neurones to noxious (raising of skin temperature above 45°C) and innocuous (deflection of hairs) peripheral stimuli. 2 Administered near cell bodies, morphine reduced the nociceptive responses of only 2 of 37 cells. Excitation occurred more commonly than depression and abnormalities in action potentials were commonly observed following ejection of morphine. None of these effects of morphine was antagonized by electrophoretically applied naloxone. 3 Administered in the substantia gelatinosa from one micropipette while recording responses of deeper neurones with a second micropipette, morphine reduced the nociceptive responses of 15 of 19 neurones. Firing in response to deflection of hairs was not reduced by morphine. Depression of nociceptive responses by morphine was long lasting (>20 minutes). Naloxone ejected into the substantia gelatinosa or given intravenously in doses as low as 0.1 mg/kg antagonized the effects of morphine. The effectiveness of this dose of intravenous naloxone suggests that the concentrations of morphine in the substantia gelatinosa which reduced nociceptive responses were not unlike those present after analgesic doses of systemic morphine. Naloxone alone, and excitant and depressant amino acids ejected into the substantia gelatinosa had little effect on cell firing. 4 Both the selective action of morphine on nociceptive responses and the reversal of this action by intravenous naloxone suggest that the opiate receptor present in the substantia gelatinosa is relevant to analgesia produced by opiates given systemically. PMID:199311

  3. The role of endogenous opiates in athletic amenorrhea.

    PubMed

    Samuels, M H; Sanborn, C F; Hofeldt, F; Robbins, R

    1991-03-01

    We hypothesized that menstrual disturbances in female athletes arise from opioid-induced abnormalities in gonadotropin and/or prolactin (PRL) secretion. To investigate this hypothesis, we measured luteinizing hormone, follicle-stimulating hormone, and PRL levels in eumenorrheic and amenorrheic athletes during thyrotropin-releasing hormone and gonadotropin-releasing hormone tests at baseline, after naloxone infusions, after exercise to exhaustion, and after similar exercise during naloxone infusions. Contrary to our hypothesis, amenorrheic runners did not have significant alterations in basal, postexercise, or stimulated hormone levels compared with eumenorrheic runners. In addition, opioid blockade by naloxone did not enhance gonadotropin release by amenorrheic athletes.

  4. Differential involvement of 3', 5'-cyclic adenosine monophosphate-dependent protein kinase in regulation of Fos and tyrosine hydroxylase expression in the heart after naloxone induced morphine withdrawal.

    PubMed

    Almela, Pilar; Cerezo, Manuela; González-Cuello, A; Milanés, M Victoria; Laorden, M Luisa

    2007-01-01

    We previously demonstrated that morphine withdrawal induced hyperactivity of the heart by the activation of noradrenergic pathways innervating the left and right ventricle, as evaluated by noradrenaline (NA) turnover and Fos expression. We investigated whether cAMP-dependent protein kinase (PKA) plays a role in this process by estimating changes in PKA immunoreactivity and the influence of inhibitor of PKA on Fos protein expression, tyrosine hydroxylase (TH) immunoreactivity levels and NA turnover in the left and right ventricle. Dependence on morphine was induced by a 7-day s.c. implantation of morphine pellets. Morphine withdrawal was precipitated on day 8 by an injection of naloxone (5 mg/kg). When opioid withdrawal was precipitated, an increase in PKA immunoreactivity and phospho-CREB (cyclic AMP response element protein) levels were observed in the heart. Moreover, morphine withdrawal induces Fos expression, an enhancement of NA turnover and an increase in the total TH levels. When the selective PKA inhibitor HA-1004 was infused, concomitantly with morphine pellets, it diminished the increase in NA turnover and the total TH levels observed in morphine-withdrawn rats. However, this inhibitor neither modifies the morphine withdrawal induced Fos expression nor the increase of nonphosphorylated TH levels. The present findings indicate that an up-regulated PKA-dependent transduction pathway might contribute to the activation of the cardiac catecholaminergic neurons in response to morphine withdrawal and suggest that Fos is not a target of PKA at heart levels.

  5. Medically assisted recovery from opiate dependence within the context of the UK drug strategy: methadone and Suboxone (buprenorphine-naloxone) patients compared.

    PubMed

    McKeganey, Neil; Russell, Christopher; Cockayne, Lucinda

    2013-01-01

    The focus of drug policy in the UK has shifted markedly in the past 5 years to move beyond merely emphasising drug abstinence towards maximising individuals' opportunities for recovery. The UK government continues to recognise the prescribing of narcotic medications indicated for opiate dependence as a key element of these individuals' recovery journey. This article describes a small, naturalistic comparison of the efficacy of the two most commonly prescribed opiate substitute medications in the UK--methadone hydrochloride (methadone oral solution) and Suboxone (buprenorphine-naloxone sublingual tablets)--for reducing current heroin users' (n = 34) days of heroin use, and preventing short-term abstainers (n = 37) from relapsing to regular heroin use. All patients had been prescribed either methadone or Suboxone for maintenance for 6 months prior to intake. Results showed that when controlling for a number of patient-level covariates, both methadone and Suboxone significantly reduced current users' days of heroin use between the 90 days prior to intake and at the 8-month follow-up, with Suboxone yielding a significantly larger magnitude reduction in heroin use days than methadone. Methadone and Suboxone were highly and equally effective for preventing relapse to regular heroin use, with all but 3 of 37 (91.9%) patients who were abstinent at intake reporting past 90-day point prevalence heroin abstinence at the 8-month follow-up. Overall, prescribing methadone or Suboxone for eight continuous months was highly effective for initiating abstinence from heroin use, and for converting short-term abstinence to long-term abstinence. However, the study design, which was based on a relatively small sample size and was not able randomise patients to medication and so could not control for the effects of potential prognostic factors inherent within each patient group, means that these conclusions can only be made tentatively. These positive but preliminary indications of the

  6. Development of an Incarceration-Specific Overdose Prevention Video: "Staying Alive on the Outside"

    ERIC Educational Resources Information Center

    Green, Traci C.; Bowman, Sarah E.; Ray, Madeline; McKenzie, Michelle; Lord, Sarah E.; Rich, Josiah D.

    2015-01-01

    Objectives: The first 2 weeks following release from prison are associated with extraordinary risk of fatal drug overdose. However, bystanders can reverse opioid overdoses using rescue breathing and naloxone, an overdose antidote. We reviewed overdose prevention and naloxone administration training videos for incarceration specific and behaviour…

  7. Reduction of myocardial blood flow reserve in idiopathic dilated cardiomyopathy without overt heart failure and its relation with functional indices: an echo-Doppler and positron emission tomography study.

    PubMed

    Morales, Maria-Aurora; Neglia, Danilo; L'Abbate, Antonio

    2008-08-01

    Myocardial blood flow during pharmacological vasodilatation is depressed in patients with idiopathic dilated cardiomyopathy even the in absence of overt heart failure; the extent of myocardial blood flow abnormalities is not predictable by left ventricular ejection fraction (LVEF) and diastolic dimensions. To assess whether myocardial blood flow impairment in idiopathic dilated cardiomyopathy without overt heart failure can be related to Doppler-derived dP/dt and to echocardiographically determined left ventricular end systolic stress - which is linked to myocardial blood flow reserve in advanced disease. Twenty-six patients, New York Heart Association Class I-II, (LVEF 37.4 +/- 1.4%, left ventricular diastolic dimensions 62.6 +/- 0.9 mm) underwent resting/dipyridamole [13N]NH3 flow positron emission tomography and an ultrasonic study. Regional myocardial blood flow values (ml/min per g) were computed from positron emission tomography data in 13 left ventricular (LV) myocardial regions and averaged to provide mean myocardial blood flow and myocardial blood flow reserve, defined as dipyridamole/resting mean myocardial blood flow ratio. Resting myocardial blood flow was 0.686 +/- 0.045, dipyridamole myocardial blood flow 1.39 +/- 0.15 and myocardial blood flow reserve 2.12 +/- 0.2, lower than in controls (P < 0.01). The ratio dP/dt was directly related to dipyridamole myocardial blood flow and myocardial blood flow reserve (r = 0.552 and 0.703, P < 0.005 and P < 0.0001); no relation was found between myocardial blood flow and LVEF left ventricular diastolic dimensions, and left ventricular end systolic stress. In idiopathic dilated cardiomyopathy patients without overt heart failure, the extent of myocardial blood flow reserve impairment is related to dP/dt but not to more classical indices of left ventricular function.

  8. Validation of early image acquisitions following Tc-99 m sestamibi injection using a semiconductors camera of cadmium-zinc-telluride.

    PubMed

    Meyer, Celine; Weinmann, Pierre

    2017-08-01

    Cadmium-zinc-telluride (CZT) cameras allow to decrease significantly the acquisition time of myocardial perfusion imaging (MPI), but the duration of the examination is still long. Therefore, this study was performed to test the feasibility of early imaging following injection of Tc-99 m sestamibi using a CZT camera. Seventy patients underwent both an early and a delayed image acquisition after exercise stress test (n = 30), dipyridamole stress test (n = 20), and at rest (n = 20). After injection of Tc-99 m sestamibi, the early image acquisition started on average within 5 minutes for the exercise and rest groups, and 3 minutes 30 seconds for the dipyridamole group. Two independent observers evaluated image quality and extracardiac uptake on four-point scales. The difference between early and later images for each patient was scored on a five-point scale. The image quality and extracardiac uptake of early and delayed image acquisitions were not different for the three groups (P > .05). There was no significant difference between early and delayed image acquisitions in the exercise, dipyridamole, and rest groups, respectively, in 63%, 40%, and 80% of cases. In the exercise group and rest group, a defect was only present in early MPI, respectively, in 13% and 20% of cases. A defect was only present in delayed images in 10% of cases in the exercise group and in 45% of cases in the dipyridamole group. There was no difference between early and later image acquisitions in terms of quality. This protocol reduces the length of the procedure for the patient. Beginning with early image acquisitions may help to overcome the artifacts that are observed at the delayed time.

  9. Lack of respiratory depression in paracetamol-codeine combination overdoses.

    PubMed

    Heppell, Simon P E; Isbister, Geoffrey K

    2017-06-01

    Codeine containing analgesics are commonly taken in overdose, but the frequency of respiratory depression is unknown. We investigated whether paracetamol-codeine combination overdoses caused respiratory depression more than paracetamol alone. We reviewed deliberate self-poisoning admissions with paracetamol (>2 g) and paracetamol-codeine combinations presenting to a tertiary toxicology unit (1987-2013). Demographic information, clinical effects, treatment (naloxone, length of stay [LOS], mechanical ventilation) were extracted from a prospective database. Primary outcome was naloxone requirement or ventilation for respiratory depression. From 4488 presentations, 1376 admissions were included with paracetamol alone (929), paracetamol-codeine combinations (346) or paracetamol-codeine-doxylamine combinations (101) without co-ingestants. Median age was 23 years (12-89 years); 1002 (73%) were female. Median dose was 12 g (interquartile range [IQR]: 7.5-20 g). Median LOS was 16 h (IQR: 6.5-27 h) and 564 (41%) were given acetylcysteine. Significantly larger paracetamol doses were ingested and more acetylcysteine given in paracetamol alone versus paracetamol combination overdoses. Seven out of 1376 patients were intubated or received naloxone (0.5%; 95% CI: 0.2-1.1%), three intubated, three given naloxone and one both. Three out of 929 patients ingesting paracetamol alone (0.3%; 95% CI: 0.1-1%) required intubation or naloxone, compared to two out of 346 ingesting paracetamol-codeine combinations (0.6%; 95% CI: 0.1-2.3%; absolute difference, 0.26%; 95% CI: -0.7-1.2%; P = 0.62). Two out of 101 patients ingesting paracetamol-codeine-doxylamine combinations (2%; 95% CI: 0.3-8%) required intubation or naloxone. Four patients were intubated for reasons other than respiratory depression: hepatotoxicity (2), retrieval (1), no data (1). Two out of 929 (0.2%) paracetamol alone overdoses had a Glasgow coma score < 9 compared to three out of 346 (0.9%) in the paracetamol

  10. The different roles of opioid receptors in the inhibitory effects induced by sacral dorsal root ganglion stimulation on nociceptive and nonnociceptive conditions in cats.

    PubMed

    Wang, Zhaoxia; Liao, Limin; Deng, Han; Li, Xing; Chen, Guoqing; Liao, Xiwen

    2018-06-04

    To examine the roles of opioid receptors in the inhibition of nociceptive and nonnociceptive bladder reflexes by sacral dorsal root ganglion (DRG) stimulation in cats. Hook electrodes were placed in the right S1 and S2 DRG of cats. The bladders were infused with physiologic saline or 0.25% acetic acid (AA). Naloxone (0.1, 0.3, and 1 mg/kg), an opioid receptor antagonist, was administered intravenously. S1 or S2 DRG stimulation was applied before and after administering the drug. Multiple cystometrograms were performed to determine the effects of DRG stimulation and opioid receptors on the micturition reflex under nociceptive and non-nociceptive conditions. AA significantly (P < 0.01) reduced bladder capacity (BC). DRG stimulation at threshold (T) and 1.5 T significantly increased BC of the saline control under nociceptive and non-nociceptive conditions. When saline was infused, naloxone (0.1-1 mg/kg) significantly (P < 0.01) reduced BC; however, naloxone did not change BC during AA irritation. During saline infusion, naloxone (0.3 and 1 mg/kg) partly blocked S1 DRG stimulation-induced inhibition but had only a slight effect on S2 DRG stimulation. During AA infusion, naloxone (0.3 and 1 mg/kg) only partially blocked S1 DRG stimulation at T intensity but not during 1.5 T stimulation. However, no doses of naloxone significantly affected S2 DRG stimulation. Opioid receptors play a role in sacral DRG stimulation on non-nociceptive condition but are not involved in the inhibitory effect of stimulation in nociceptive conditions. © 2018 Wiley Periodicals, Inc.

  11. Intravenous Narcotic Antagonists in Ambulatory Oral Surgery

    PubMed Central

    Greenfield, William; Granada, Margarito G.

    1975-01-01

    Results of a study indicate that significant respiratory depression can be produced by the intravenous administration of narcotics in the anesthetic management of oral surgery patients. Naloxone hydrochloride reversed this reaction in all instances. Naloxone is a unique narcotic antagonist in that it does not possess agonistic properties of its own, it is effective in reversing respiratory depression resulting from all commonly used narcotics and narcotic antagonists, it causes no undesirable side effects, and it acts as a placebo when administered to a patient who has not had a narcotic. The use of naloxone should be considered when a potent narcotic is administered to an ambulatory patient. PMID:19598479

  12. Naloxone Nasal Spray

    MedlinePlus

    ... emergency medical treatment to reverse the life-threatening effects of a known or suspected opiate (narcotic) overdose. ... called opiate antagonists. It works by blocking the effects of opiates to relieve dangerous symptoms caused by ...

  13. Evidence of validity and reliability of the Opiate Dosage Adequacy Scale (ODAS) in a sample of heroin addicted patients in buprenorphine/naloxone maintenance treatment.

    PubMed

    González-Saiz, Francisco; Lozano Rojas, Oscar; Trujols, Joan; Alcaraz, Saul; Siñol, Núria; Pérez de Los Cobos, José

    2018-02-01

    The Opiate Dosage Adequacy Scale (ODAS) is a clinical tool to individually measure the "adequacy" of opioid doses in patients on maintenance treatment. The aim of this paper is to provide evidence for the validity and reliability of the ODAS in a sample of patients in buprenorphine/naloxone (B/N) maintenance treatment. Cross-sectional study of a convenience sample of B/N-treated patients (n = 316) from four Autonomous Communities in Spain. Participants completed a battery of instruments to assess the following: buprenorphine dose adequacy; heroin dependence severity; psychological adjustment; and patient-desired adjustment of buprenorphine dose. Exploratory Factor Analysis identified four factors from the ODAS that together account for 85.4% of the total variance: "Heroin craving and use"; "Overmedication"; "Objective opiate withdrawal symptoms (OWS)" and 'Subjective OWS'. Compared to patients with an "inadequate" B/N dose (ODAS), patients with "adequate" doses had less heroin use in the last week (0.01 vs. 0.40; t = -2.73; p < 0.01, 95% CI: -0.67, -0.10), less severe heroin dependence (2.20 vs. 5.26, t = -5.14, p < 0.001; 95% CI: -4.23, -1.88), less psychological distress (3.00 vs. 6.31, t = -4.37, p < 0.001; 95% CI: -4.80, -1.81), and greater satisfaction with their doses (42.1% vs. 13.6%, χ 2  = 14.44, p < 0.01). Cronbach's alpha coefficient was 0.76 (0.81, 0.92, 0.94, and 0.93, respectively, for the four factor dimensions). These findings support the validity and reliability of the ODAS as a tool to measure and assess buprenorphine dose adequacy in the context of an opioid dependency treatment program. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Why are some people who have received overdose education and naloxone reticent to call Emergency Medical Services in the event of overdose?

    PubMed

    Koester, Stephen; Mueller, Shane R; Raville, Lisa; Langegger, Sig; Binswanger, Ingrid A

    2017-10-01

    Overdose Education and Naloxone Distribution (OEND) training for persons who inject drugs (PWID) underlines the importance of summoning emergency medical services (EMS). To encourage PWID to do so, Colorado enacted a Good Samaritan law providing limited immunity from prosecution for possession of a controlled substance and/or drug paraphernalia to the overdose victim and the witnesses who in good faith provide emergency assistance. This paper examines the law's influence by describing OEND trained PWIDs' experience reversing overdoses and their decision about calling for EMS support. Findings from two complementary studies, a qualitative study based on semi-structured interviews with OEND trained PWID who had reversed one or more overdoses, and an on-going fieldwork-based project examining PWIDs' self-identified health concerns were triangulated to describe and explain participants' decision to call for EMS. In most overdose reversals described, no EMS call was made. Participants reported several reasons for not doing so. Most frequent was the fear that despite the Good Samaritan law, a police response would result in arrest of the victim and/or witness for outstanding warrants, or sentence violations. Fears were based on individual and collective experience, and reinforced by the city of Denver's aggressive approach to managing homelessness through increased enforcement of misdemeanors and the imposition of more recent ordinances, including a camping ban, to control space. The city's homeless crisis was reflected as well in the concern expressed by housed PWID that an EMS intervention would jeopardize their public housing. Results suggest that the immunity provided by the Good Samaritan law does not address PWIDs' fear that their current legal status as well as the victim's will result in arrest and incarceration. As currently conceived, the Good Samaritan law does not provide immunity for PWIDs' already enmeshed in the criminal justice system, or PWID fearful of

  15. Anti-Clotting Agents Explained

    MedlinePlus

    ... becomes potentially life-threatening. Anti platelet agents, including aspirin , clopidogrel, dipyridamole and ticlopidine, work by inhibiting the production of thromboxane. Aspirin is highly recommended for preventing a first stroke, ...

  16. Hydrogen-rich saline attenuates anxiety-like behaviors in morphine-withdrawn mice.

    PubMed

    Wen, Di; Zhao, Peng; Hui, Rongji; Wang, Jian; Shen, Qianchao; Gong, Miao; Guo, Hongyan; Cong, Bin; Ma, Chunling

    2017-05-15

    Hydrogen therapy is a new medical approach for a wide range of diseases. The effects of hydrogen on central nervous system-related diseases have recently become increasingly appreciated, but little is known about whether hydrogen affects the morphine withdrawal process. This study aims to investigate the potential effects of hydrogen-rich saline (HRS) administration on naloxone-precipitated withdrawal symptoms and morphine withdrawal-induced anxiety-like behaviors. Mice received gradually increasing doses (25-100 mg/kg, i.p.) of morphine over 3 days. In the naloxone-precipitated withdrawal procedure, the mice were treated with three HRS (20 μg/kg, i.p.) injections, and naloxone (1 mg/kg, i.p.) was given 30 min after HRS administration. Body weight, jumping behavior and wet-dog shakes were immediately assessed. In the spontaneous withdrawal procedure, the mice were treated with HRS (20 μg/kg, i.p.) every 8-h. Mice underwent naloxone-precipitated or spontaneous withdrawal were tested for anxiety-like behaviors in the elevated plus-maze (EPM) and light/dark box (L/D box) paradigm, respectively. In addition, the levels of plasma corticosterone were measured. We found that HRS administration significantly reduced body weight loss, jumping behavior and wet-dog shakes in mice underwent naloxone-precipitated withdrawal, and attenuated anxiety-like behaviors in the EPM and L/D box tests after naloxone-precipitated withdrawal or a 2-day spontaneous withdrawal period. Hypo-activity or motor impairment after HRS administration was not observed in the locomotion tests. Furthermore, HRS administration significantly decreased the levels of corticosterone in morphine-withdrawn mice. These are the first findings to indicate that hydrogen might ameliorate withdrawal symptoms and exert an anxiolytic-like effect in morphine-withdrawal mice. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. New opioid receptor antagonist: Naltrexone-14-O-sulfate synthesis and pharmacology.

    PubMed

    Zádor, Ferenc; Király, Kornél; Váradi, András; Balogh, Mihály; Fehér, Ágnes; Kocsis, Dóra; Erdei, Anna I; Lackó, Erzsébet; Zádori, Zoltán S; Hosztafi, Sándor; Noszál, Béla; Riba, Pál; Benyhe, Sándor; Fürst, Susanna; Al-Khrasani, Mahmoud

    2017-08-15

    Opioid antagonists, naloxone and naltrexone have long been used in clinical practice and research. In addition to their low selectivity, they easily pass through the blood-brain barrier. Quaternization of the amine group in these molecules, (e.g. methylnaltrexone) results in negligible CNS penetration. In addition, zwitterionic compounds have been reported to have limited CNS access. The current study, for the first time gives report on the synthesis and the in vitro [competition binding, G-protein activation, isolated mouse vas deferens (MVD) and mouse colon assay] pharmacology of the zwitterionic compound, naltrexone-14-O-sulfate. Naltrexone, naloxone, and its 14-O-sulfate analogue were used as reference compounds. In competition binding assays, naltrexone-14-O-sulfate showed lower affinity for µ, δ or κ opioid receptor than the parent molecule, naltrexone. However, the μ/κ opioid receptor selectivity ratio significantly improved, indicating better selectivity. Similar tendency was observed for naloxone-14-O-sulfate when compared to naloxone. Naltrexone-14-O-sulfate failed to activate [ 35 S]GTPγS-binding but inhibit the activation evoked by opioid agonists (DAMGO, Ile 5,6 deltorphin II and U69593), similarly to the reference compounds. Schild plot constructed in MVD revealed that naltrexone-14-O-sulfate acts as a competitive antagonist. In mouse colon, naltrexone-14-O-sulfate antagonized the inhibitory effect of morphine with lower affinity compared to naltrexone and higher affinity when compared to naloxone or naloxone-14-O-sulfate. In vivo (mouse tail-flick test), subcutaneously injected naltrexone-14-O-sulfate antagonized morphine's antinociception in a dose-dependent manner, indicating it's CNS penetration, which was unexpected from such zwitter ionic structure. Future studies are needed to evaluate it's pharmacokinetic profile. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Factors associated with knowledge of a Good Samaritan Law among young adults who use prescription opioids non-medically.

    PubMed

    Evans, Tristan I; Hadland, Scott E; Clark, Melissa A; Green, Traci C; Marshall, Brandon D L

    2016-07-26

    To date, no studies have examined the extent of knowledge and perceptions of Good Samaritan Laws (GSLs) among young adults who engage in non-medical prescription opioid (NMPO) use. We sought to determine awareness of and factors associated with knowledge of Rhode Island's Good Samaritan Law (RIGSL) among young adult NMPO users. We compared the sociodemographic and overdose-related characteristics of participants who were aware and unaware of the RIGSL and determined independent correlates of knowledge of the RIGSL via modified stepwise logistic regression. Among 198 eligible participants, 15.7 % were black, 62.1 % white, and 20.7 % mixed or other race. The mean age was 24.5 (SD = 3.2) and 129 (65.2 %) were male. Fewer than half (45.5 %) were aware of the RIGSL; nonetheless, the majority (95.5 %) reported a willingness to call 911 in the event of an overdose. Knowledge of the RIGSL was associated with older age, white race, a history of incarceration, a history of injection drug use, lifetime heroin use, ever witnessing or experiencing an overdose, having heard of naloxone, knowledge of where to obtain naloxone, and experience administering naloxone (all p < 0.05). In the final explanatory regression model, lifetime injection drug use, having heard of naloxone, and knowledge of where to obtain naloxone were independently associated with awareness of the RIGSL. Fewer than half of NMPO users surveyed knew of the RIGSL. Targeted harm reduction education is needed to address a vulnerable population of NMPO users who have not initiated injection drug use and are unaware of naloxone. Additional research is needed to determine how the effectiveness of GSLs could be improved to prevent overdose deaths among young adults.

  19. Inhibitory effect of harmane on morphine-dependent Guinea pig ileum.

    PubMed

    Aricioglu, Feyza; Utkan, Tijen

    2003-12-01

    Studies on the occurrence and properties of b-carbolines structurally related to harmala alkaloids have gained attention since it was hypothesized that some of these compounds play a role in processes of substance abuse and dependence. This study investigates the effects of harmane on naloxone-precipitated withdrawal syndrome in morphine-dependent guinea pig ileum. Segments of ilea from starved male guinea pigs were obtained and fixed at a resting tension of 1 g in an organ bath containing 10(-6) M morphine in Tyrode solution at 37 degrees C, which was bubbled with 95% O(2) and 5% CO(2). Tissues were incubated in 10(-6) M morphine containing Tyrode solution for 4 hours before harmane was added. Naloxone and harmane had no effect on naive ilea. Naloxone (10(-6) M) contracted morphine-dependent ilea. Harmane significantly inhibited the contractile response to naloxone in a dose-dependent manner (10(-7) M = 24%; 10(-6) M = 49.3%; 10(-5) = 70%). These results suggest that harmane may have beneficial effects on morphine withdrawal syndrome.

  20. Effects of opioid peptides on thermoregulation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Clark, W.G.

    1981-11-01

    In a given species, injected opioid peptides usually cause changes in temperature similar to those caused by nonpeptide opioids. The main effect in those species most studied, the cat, rat, and mouse, is an increase in the level about which body temperature is regulated; there is a coordinated change in the activity of thermoregulatory effectors such that hyperthermia is produced in both hot and cold environments. Larger doses may depress thermoregulation, thereby causing body temperature to decrease in the cold. Elicitation of different patterns of response over a range of environmental temperatures and studies with naloxone and naltrexone indicate thatmore » stimulation of a number of different receptors by both peptide and nonpeptide opioids can evoke thermoregulatory responses. ..beta..-Endorphin is readily antagonized by naloxone whereas methionine-enkephalin can act on naloxone-insensitive receptors. Moreover, synthetic peptide analogs do not necessarily evoke the same response as does the related endogenous peptide. The lack of effect of naloxone on body temperature of subjects housed at usual laboratory temperature or on pyrogen-induced increases in body temperature indicates that an action of endogenous peptides on naloxone-sensitive receptors plays little, if any, role in normal thermoregulation or in fever. However, there is some evidence that such an action may be involved in responses to restraint or ambient temperature-induced stress. Further evaluation of possible physiological roles of endogenous opioid peptides will be facilitated when specific antagonists at other types of opioid receptors become available.« less

  1. Multiple Fentanyl Overdoses - New Haven, Connecticut, June 23, 2016.

    PubMed

    Tomassoni, Anthony J; Hawk, Kathryn F; Jubanyik, Karen; Nogee, Daniel P; Durant, Thomas; Lynch, Kara L; Patel, Rushaben; Dinh, David; Ulrich, Andrew; D'Onofrio, Gail

    2017-02-03

    On the evening of June 23, 2016, a white powder advertised as cocaine was purchased off the streets from multiple sources and used by an unknown number of persons in New Haven, Connecticut. During a period of less than 8 hours, 12 patients were brought to the emergency department (ED) at Yale New Haven Hospital, experiencing signs and symptoms consistent with opioid overdose. The route of intoxication was not known, but presumed to be insufflation ("snorting") in most cases. Some patients required doses of the opioid antidote naloxone exceeding 4 mg (usual initial dose = 0.1-0.2 mg intravenously), and several patients who were alert after receiving naloxone subsequently developed respiratory failure. Nine patients were admitted to the hospital, including four to the intensive care unit (ICU); three required endotracheal intubation, and one required continuous naloxone infusion. Three patients died. The white powder was determined to be fentanyl, a drug 50 times more potent than heroin, and it included trace amounts of cocaine. The episode triggered rapid notification of public health and law enforcement agencies, interviews of patients and their family members to trace and limit further use or distribution of the fentanyl, immediate naloxone resupply and augmentation for emergency medical services (EMS) crews, public health alerts, and plans to accelerate naloxone distribution to opioid users and their friends and families. Effective communication and timely, coordinated, collaborative actions of community partners reduced the harm caused by this event and prevented potential subsequent episodes.

  2. International Workshop on Neuroimmunomodulation (2nd) Held in Dubrovnik (Yugoslavia) on 1-6 June 1986.

    DTIC Science & Technology

    1986-09-18

    systemically with doses of reaction) were sharply reduced. Histo- naltrexone or naloxone and subsequently logically, the infiltration of the dermis...challenged with a lethal dose of antigen. with polymorphonuclear (Arthus reaction) Both naloxone and naltrexone were found and mononuclear cells (delayed...for Integrative Biomedical Research, Eb- roendocrine cell type present in low num- matingen, Switzerland) reported on the bers in the spleen, lymph

  3. Myocardial Blood Volume Is Associated with Myocardial Oxygen Consumption: An Experimental Study with CMR in a Canine Model

    PubMed Central

    McCommis, Kyle S.; Zhang, Haosen; Goldstein, Thomas A.; Misselwitz, Bernd; Abendschein, Dana R.; Gropler, Robert J.; Zheng, Jie

    2009-01-01

    OBJECTIVES To evaluate the feasibility of cardiovascular MR (CMR) to determine regional myocardial perfusion and O2 metabolism, and assess the role of myocardial blood volume (MBV) on oxygen supply. BACKGROUND Coronary artery disease presents as an imbalance of myocardial oxygen supply and demand. We have developed relevant CMR methods to determine the relationship of myocardial blood flow (MBF) and MBV to oxygen consumption (MVO2) during pharmacologic hyperemia. METHODS Twenty-one mongrel dogs were studied with varying stenosis severities imposed on the proximal left anterior descending (LAD) coronary artery. MBF and MBV were determined by CMR first-pass perfusion, while the oxygen extraction fraction (OEF) and MVO2 were determined by the myocardial Blood-Oxygen-Level-Dependent (BOLD) effect and Fick’s law, respectively. MR imaging was performed at rest, and during either dipyridamole-induced vasodilation or dobutamine-induced hyperemia. Regional differences in myocardial perfusion and oxygenation were then evaluated. RESULTS Dipyridamole and dobutamine both led to 145–200% increases in MBF and 50–80% increases in MBV in normal perfused myocardium. As expected, MVO2 increased more significantly with dobutamine (~175%) than dipyridamole (~40%). Coronary stenosis resulted in an attenuation of MBF, MBV, and MVO2 in both the LAD-subtended stenosis region and the left circumflex subtended remote region. Liner regression analysis showed that MBV reserve appears to be more correlated with MVO2 reserve during dobutamine stress than MBF reserve, particularly in the stenotic regions. Conversely, MBF reserve appears to be more correlated with MVO2 reserve during dipyridamole, although neither of these differences was significant. CONCLUSIONS Noninvasive evaluation of both myocardial perfusion and oxygenation by CMR facilitates direct monitoring of regional myocardial ischemia and provides a valuable tool for better understanding microvascular pathophysiology. These

  4. Hepatotoxicity in a 52-week randomized trial of short-term versus long-term treatment with buprenorphine/naloxone in HIV-negative injection opioid users in China and Thailand.

    PubMed

    Lucas, Gregory M; Young, Alicia; Donnell, Deborah; Richardson, Paul; Aramrattana, Apinun; Shao, Yiming; Ruan, Yuhua; Liu, Wei; Fu, Liping; Ma, Jun; Celentano, David D; Metzger, David; Jackson, J Brooks; Burns, David

    2014-09-01

    Buprenorphine/naloxone (BUP/NX), an effective treatment for opioid dependence, has been implicated in hepatic toxicity. However, as persons taking BUP/NX have multiple hepatic risk factors, comparative data are needed to quantify the risk of hepatoxicity with BUP/NX. We compared rates of alanine aminotransferase (ALT) elevation≥grade 3 (ALT≥5.1 times the upper limit of normal) and graded bilirubin elevations in HIV-negative opioid injectors randomized to long-term (52 weeks) or short-term (18 days) medication assisted treatment (LT-MAT and ST-MAT, respectively) with BUP/NX in a multisite trial conducted in China and Thailand. ALT and bilirubin were measured at baseline, 12, 26, 40 and 52 weeks, times temporally remote from BUP/NX exposure in the ST-MAT participants. Among1036 subjects with at least one laboratory follow-up measurement, 76 (7%) participants experienced ALT elevation≥grade 3. In an intent-to-treat analysis, the risk of ALT events was similar in participants randomized to LT-MAT compared with ST-MAT (adjusted hazard ratio 1.25, 95% confidence interval 0.79 to 1.98). This finding was supported by an as-treated analysis, in which actual exposure to BUP/NX was considered. Hepatitis C seroconversion during follow-up was strongly associated with ALT events. Bilirubin elevations≥grade 2 occurred in 2% of subjects, with no significant difference between arms. Over 52-week follow-up, the risk of hepatotoxicity was similar in opioid injectors receiving brief and prolonged treatment with BUP/NX. These data suggest that most hepatotoxic events observed during treatment with BUP/NX are due to other factors. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  5. Picrotoxin-induced seizures modified by morphine and opiate antagonists.

    PubMed

    Thomas, J; Nores, W L; Kenigs, V; Olson, G A; Olson, R D

    1993-07-01

    The effects of naloxone, Tyr-MIF-1, and MIF-1 on morphine-mediated changes in susceptibility to picrotoxin-induced seizures were studied. Rats were pretreated with naloxone, MIF-1, Tyr-MIF-1, or saline. At 15-min intervals, they received a second pretreatment of morphine or saline and then were tested for seizures following a convulsant dose of picrotoxin. Several parameters of specific categories of seizures were scored. Morphine increased the number of focal seizure episodes, duration of postseizure akinesis, and incidence of generalized clonic seizures. Naloxone tended to block the morphine-mediated changes in susceptibility. Tyr-MIF-1 had effects similar to naloxone on duration of postseizure immobility but tended to potentiate the effects of morphine on focal seizure episodes. The effects of morphine and the opiate antagonists on focal seizure episodes and postseizure duration suggest the general involvement of several types of opiate receptors in these picrotoxin-induced behaviors. However, the observation of antagonistic effects for Tyr-MIF-1 on immobility but agonistic effects for focal seizures suggests that the type of effect exerted by opiate agents may depend upon other neuronal variables.

  6. [The effects of caffeine on the respiratory depression by morphine].

    PubMed

    Kasaba, T; Takeshita, M; Takasaki, M

    1997-12-01

    The effects of intravenous administration of caffeine on the discharge of the phrenic nerve were studied following vagotomy in 7 pentobarbital anesthetized mechanically ventilated rats. Morphine (0.4 mg.kg-1.min-1) was administered until the respiratory rate decreased to about half of the baseline respiratory rate. In those state, we first administered caffeine (20 mg.kg-1), intravenously and then administered naloxone (0.02 mg) intravenously. The increase of inspiratory time from 0.49 +/- 0.16 to 2.01 +/- 0.47 s by morphine recovered to 0.86 +/- 0.38 s by caffeine and 0.50 +/- 0.22 s by naloxone. Expiratory time did not change during each drug administration. The decrease of respiratory rate from 46.6 +/- 5.9 to 20.6 +/- 4.1 breaths.min-1 by morphine recovered to 39.6 +/- 6.1 breaths.min-1 by caffeine and 47.6 +/- 4.6 breaths.min-1 by naloxone. Amplitude of integrated phrenic nerve discharge increased to 117 +/- 32% by caffeine and 156 +/- 39% by naloxone compared to the baseline. These results suggest that caffeine acts as a respiratory stimulant on the respiratory depression by morphine.

  7. A comparison of the effects of morphine, enkephalin, kyotorphin and D-phenylalanine on rat central neurones.

    PubMed Central

    Stone, T. W.

    1983-01-01

    1 Morphine, Met-enkephalin, kyotorphin and D-phenylalanine have been applied by microiontophoresis to neurones in the globus pallidus and cerebral cortex of rats anaesthetized with urethane. 2 In the pallidum, most cells were inhibited by all the agonists, with a high correspondence between cells inhibited by Met-enkephalin and D-phenylalanine and by Met-enkephalin and kyotorphin. Whereas responses to Met-enkephalin were readily antagonized by naloxone, responses to kyotorphin and D-phenylalanine were not. 3 In the cerebral cortex a high proportion of cells was excited by all four agonists and antagonism by naloxone was less consistent than in pallidum. 4 It is concluded that the naloxone-reversible analgesic effects of kyotorphin and D-phenylalanine may be mediated indirectly, rather through an activation of opiate receptors. PMID:6871550

  8. A comparison of the effects of morphine, enkephalin, kyotorphin and D-phenylalanine on rat central neurones.

    PubMed

    Stone, T W

    1983-05-01

    1 Morphine, Met-enkephalin, kyotorphin and D-phenylalanine have been applied by microiontophoresis to neurones in the globus pallidus and cerebral cortex of rats anaesthetized with urethane. 2 In the pallidum, most cells were inhibited by all the agonists, with a high correspondence between cells inhibited by Met-enkephalin and D-phenylalanine and by Met-enkephalin and kyotorphin. Whereas responses to Met-enkephalin were readily antagonized by naloxone, responses to kyotorphin and D-phenylalanine were not. 3 In the cerebral cortex a high proportion of cells was excited by all four agonists and antagonism by naloxone was less consistent than in pallidum. 4 It is concluded that the naloxone-reversible analgesic effects of kyotorphin and D-phenylalanine may be mediated indirectly, rather through an activation of opiate receptors.

  9. A Systematic, Intensive Statistical Investigation of Data from the Comprehensive Analysis of Reported Drugs (CARD) for Compliance and Illicit Opioid Abstinence in Substance Addiction Treatment with Buprenorphine/naloxone.

    PubMed

    Blum, Kenneth; Han, David; Modestino, Edward J; Saunders, Scott; Roy, A Kennison; Jacobs, W; Inaba, Darryl S; Baron, David; Oscar-Berman, Marlene; Hauser, Mary; Badgaiyan, Rajendra D; Smith, David E; Femino, John; Gold, Mark S

    2018-01-28

    Buprenorphine and naloxone (bup/nal), a combination partial mu receptor agonist and low-dose delta mu antagonist, is presently recommended and used to treat opioid-use disorder. However, a literature review revealed a paucity of research involving data from urine drug tests that looked at compliance and abstinence in one sample. Statistical analysis of data from the Comprehensive Analysis of Reported Drugs (CARD) was used to assess compliance and abstinence during treatment in a large cohort of bup/nal patients attending chemical-dependency programs from eastern USA in 2010 and 2011. Part 1: Bup/nal was present in 93.4% of first (n = 1,282; p <.0001) and 92.4% of last (n = 1,268; p <.0001) urine samples. Concomitantly, unreported illicit drugs were present in 47.7% (n = 655, p =.0261) of samples. Patients who were compliant to the bup/nal prescription were more likely than noncompliant patients to be abstinent during treatment (p =.0012; odds ratio = 1.69 with 95% confidence interval (1.210, 2.354). Part 2: An analysis of all samples collected in 2011 revealed a significant improvement in both compliance (p < 2.2 × 10 -16 ) and abstinence (p < 2.2 × 10 -16 ) during treatment. Conclusion/Importance: While significant use of illicit opioids during treatment with bup/nal is present, improvements in abstinence and high compliance during maintenance-assisted therapy programs may ameliorate fears of diversion in comprehensive programs. Expanded clinical datasets, the treatment modality, location, and year of sampling are important covariates, for further studies. The potential for long-term antireward effects from bup/nal use requires consideration in future investigations.

  10. Inhibition of B16-BL6 melanoma growth in mice by methionine-enkephalin.

    PubMed

    Murgo, A J

    1985-08-01

    The antitumor effect of methionine-enkephalin [( Met]enkephalin) was demonstrated in C57BL/6J mice inoculated with B16-BL6 melanoma cells. Local subcutaneous tumor growth was inhibited with a 50-micrograms dose daily for 7 or 14 days. The antitumor effect of [Met]enkephalin was inhibited by the administration of the opioid receptor antagonist naloxone. Naloxone alone had no significant effect on tumor growth.

  11. Prehospital Use of Ketamine in Battlefield Analgesia 2012-03

    DTIC Science & Technology

    2012-03-08

    15 mg PO once a day - Tylenol , 650-mg bilayer caplet, 2 PO every 8 hours b. Unable to fight: Note: Have naloxone readily...possible after the wound is sustained. - Mobic, 15 mg PO once a day - Tylenol , 650-mg bilayer caplet, 2 PO every 8 hours b. Unable to fight... Tylenol , 650-mg bilayered caplet, 2 PO every 8 hours b. Unable to fight: Note: Have naloxone readily available whenever

  12. Prehospital Use of Ketamine in Battlefield Analgesia

    DTIC Science & Technology

    2012-03-08

    15 mg PO once a day - Tylenol , 650-mg bilayer caplet, 2 PO every 8 hours b. Unable to fight: Note: Have naloxone readily...possible after the wound is sustained. - Mobic, 15 mg PO once a day - Tylenol , 650-mg bilayer caplet, 2 PO every 8 hours b. Unable to fight... Tylenol , 650-mg bilayered caplet, 2 PO every 8 hours b. Unable to fight: Note: Have naloxone readily available whenever

  13. High-throughput screening for modulators of ACVR1 transcription: discovery of potential therapeutics for fibrodysplasia ossificans progressiva

    PubMed Central

    Cappato, Serena; Tonachini, Laura; Giacopelli, Francesca; Tirone, Mario; Galietta, Luis J. V.; Sormani, Martina; Giovenzana, Anna; Spinelli, Antonello E.; Canciani, Barbara; Brunelli, Silvia; Ravazzolo, Roberto

    2016-01-01

    ABSTRACT The ACVR1 gene encodes a type I receptor of bone morphogenetic proteins (BMPs). Activating mutations in ACVR1 are responsible for fibrodysplasia ossificans progressiva (FOP), a rare disease characterized by congenital toe malformation and progressive heterotopic endochondral ossification leading to severe and cumulative disability. Until now, no therapy has been available to prevent soft-tissue swelling (flare-ups) that trigger the ossification process. With the aim of finding a new therapeutic strategy for FOP, we developed a high-throughput screening (HTS) assay to identify inhibitors of ACVR1 gene expression among drugs already approved for the therapy of other diseases. The screening, based on an ACVR1 promoter assay, was followed by an in vitro and in vivo test to validate and characterize candidate molecules. Among compounds that modulate the ACVR1 promoter activity, we selected the one showing the highest inhibitory effect, dipyridamole, a drug that is currently used as a platelet anti-aggregant. The inhibitory effect was detectable on ACVR1 gene expression, on the whole Smad-dependent BMP signaling pathway, and on chondrogenic and osteogenic differentiation processes by in vitro cellular assays. Moreover, dipyridamole reduced the process of heterotopic bone formation in vivo. Our drug repositioning strategy has led to the identification of dipyridamole as a possible therapeutic tool for the treatment of FOP. Furthermore, our study has also defined a pipeline of assays that will be useful for the evaluation of other pharmacological inhibitors of heterotopic ossification. PMID:27125279

  14. The opioid receptor pharmacology of GSK1521498 compared to other ligands with differential effects on compulsive reward-related behaviours.

    PubMed

    Kelly, Eamonn; Mundell, Stuart J; Sava, Anna; Roth, Adelheid L; Felici, Antonio; Maltby, Kay; Nathan, Pradeep J; Bullmore, Edward T; Henderson, Graeme

    2015-01-01

    The novel opioid receptor antagonist, GSK1421498, has been shown to attenuate reward-driven compulsive behaviours, such as stimulant drug seeking or binge eating, in animals and humans. Here, we report new data on the receptor pharmacology of GSK121498, in comparison to naltrexone, naloxone, 6-β-naltrexol and nalmefene. To determine whether the novel opioid antagonist, GSK1521498, is an orthosteric or allosteric antagonist at the μ opioid receptor (MOPr) and whether it has neutral antagonist or inverse agonist properties. A combination of radioligand binding assays and [(35)S]GTPγS binding assays was employed. GSK1521498 completely displaced [(3)H]naloxone binding to MOPr and did not alter the rate of [(3)H]naloxone dissociation from MOPr observations compatible with it binding to the orthosteric site on MOPr. GSK1521498 exhibited inverse agonism when MOPr was overexpressed but not when the level of MOPr expression was low. In parallel studies under conditions of high receptor expression density, naloxone, naltrexone, 6-β-naltrexol and nalmefene exhibited partial agonism, not inverse agonism as has been reported previously for naloxone and naltrexone. In brain tissue from mice receiving a prolonged morphine pre-treatment, GSK1521498 exhibited slight inverse agonism. Differences between GSK1521498 and naltrexone in their effects on compulsive reward seeking are arguably linked to the more selective and complete MOPr antagonism of GSK1521498 versus the partial MOPr agonism of naltrexone. GSK1521498 is also pharmacologically differentiated by its inverse agonist efficacy at high levels of MOPr expression, but this may be less likely to contribute to behavioural differentiation at patho-physiological levels of expression.

  15. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Conroy, W.G.

    Structural relatedness between the variable region of anti-ligand antibodies and opioid binding sites allowed the generation of anti-idiotypic antibodies which recognized opioid receptors. The IgG{sub 3}k antibodies which bound to opioid receptors were obtained when an anti-morphine antiserum was the idiotype. Both antibodies bound to opioid receptors, but only one of these blocked the binding of ({sup 3}H)naloxone. The antibody which did not inhibit the binding of ({sup 3}H)naloxone was itself displaced from the receptor by opioid ligands. The unique binding properties displayed by this antibody indicated that anti-idiotypic antibodies are not always a perfect image of the original ligand,more » and therefore may be more useful than typical ligands as probes for the receptor. An auto-anti-idiotypic technique was successfully used to obtain anti-opioid receptor antibodies. Another IgG{sub 3}k antibody that blocked the binding of ({sup 3}H)naloxone to rat brain opioid receptors was obtained when a mouse was immunized with naloxone conjugated to bovine serum albumin. These data confirmed that an idiotype-anti-idiotype network which can generate an anti-receptor antibody normally functions when an opioid ligand is introduced into an animal in an immunogenic form.« less

  16. Opioid system of the brain and ethanol.

    PubMed

    Gogichadze, M; Mgaloblishvili-Nemsadze, M; Oniani, N; Emukhvary, N; Basishvili, T

    2009-04-01

    Influence of blocking of opioid receptors with concomitant intraperitoneal injections of Naloxone (20 mg/kg) (non-selective antagonist of opioid system) on the outcomes of anesthetic dose of ethanol (4,25 ml /kg 25% solution) was investigated in the rats. The sleep-wakefulness cycle (SWC) was used as a model for identification of the effects. Alterations of the SWC structure adequately reflect the neuro-chemical changes, which may develop during pharmacological and non-pharmacological impact. Administration of anesthetic dose of ethanol evoked considerable modification of spontaneous EEG activity of the neocortex. The EEG activity was depressed and full inhibition of spinal reflexes and somatic muscular relaxation did occur. During EEG depression regular SWC did not develop. All phases of SWC were reduced. The disturbances of SWC, such as decrease of slow wave sleep and paradoxical sleep duration and increase of wakefulness, remained for several days. At concomitant administration of Naloxone and ethanol, duration of EEG depression decreased significantly. Generation of normal SWC was observed on the same experimental day. However, it should be noted that complete abolishment of ethanol effects by Naloxone was not observed. The results obtained suggest that Naloxone partially blocks ethanol depressogenic effects and duration of this effect is mediated by GABA-ergic system of the brain.

  17. Suppression of guinea pig ileum induced contractility by plasma albumin of hibernators

    USGS Publications Warehouse

    Bruce, David S.; Ambler, Douglas L.; Henschel, Timothy M.; Oeltgen, Peter R.; Nilekani, Sita P.; Amstrup, Steven C.

    1992-01-01

    Previous studies suggest that hibernation may be regulated by internal opioids and that the putative “hibernation induction trigger” (HIT) may itself be an opioid. This study examined the effect of plasma albumin (known to bind HIT) on induced contractility of the guinea pig ileum muscle strip. Morphine (400 nM) depressed contractility and 100 nM naloxone restored it. Ten milligrams of lyophilized plasma albumin fractions from hibernating ground squirrels, woodchucks, black bears, and polar bears produced similar inhibition, with partial reversal by naloxone. Five hundredths mg of d-Ala2-d-Leu5-enkephalin (DADLE) also inhibited contractility and naloxone reversed it. Conclusions are that hibernating individuals of these species contain an HIT substance that is opioid in nature and summer animals do not; an endogenous opioid similar to leu-enkephalin may be the HIT compound or give rise to it.

  18. In Vitro Screening of Opiod Antagonist Effectiveness

    DTIC Science & Technology

    2018-04-01

    with a co-administration of acrylfentanyl and naloxone. Reversibility of acrylfentanyl was achieved at naloxone concentrations comparable to those of...EC50, EC90, and efficacy values were calculated (Figure 4). These values were compared to those of fentanyl (Table 1). 1 2 3 4 5 6 7 8 9 10 11 12... compare that to the metabolic rate of the reversal agent, itself. Metabolic clearance data, when combined with a potency and competition assay

  19. Prise en charge des troubles de consommation d’opioïdes en première ligne

    PubMed Central

    Srivastava, Anita; Kahan, Meldon; Nader, Maya

    2017-01-01

    Résumé Objectif Conseiller les médecins quant aux options thérapeutiques à recommander à des populations précises de patients : approche axée sur l’abstinence, traitement d’entretien par la buprénorphine-naloxone ou traitement d’entretien par la méthadone. Sources d’information Une recherche sur PubMed a été effectuée, et on a relevé dans les publications les données sur l’efficacité, l’innocuité et le profil d’effets indésirables de l’approche axée sur l’abstinence, du traitement par la buprénorphine-naloxone et du traitement par la méthadone. Les études d’observation et interventionnelles ont été incluses. Message principal La méthadone et la buprénorphine-naloxone sont substantiellement plus efficaces que l’approche axée sur l’abstinence. La méthadone présente un taux de rétention plus élevé que la buprénorphine-naloxone, alors que la buprénorphine-naloxone présente un risque plus faible de surdose. Les médecins devraient recommander le traitement par la méthadone ou la buprénorphine-naloxone plutôt que l’approche axée sur l’abstinence, et ce, à tous les groupes de patients (données de niveau I). La méthadone est préférable à la buprénorphine-naloxone chez les patients qui présentent un risque élevé d’abandon, comme les usagers d’opioïdes par injection (données de niveau I). Les jeunes et les femmes enceintes qui font usage d’opioïdes par injection devraient aussi recevoir la méthadone d’abord (données de niveau III). Si la buprénorphine-naloxone est prescrite en premier, il faut faire passer rapidement le patient à la méthadone si les symptômes de sevrage, les fortes envies ou la consommation d’opioïdes persistent malgré une dose optimale de buprénorphine-naloxone (données de niveau II). La buprénorphine-naloxone est recommandée chez les usagers d’opioïdes sur ordonnance par voie orale socialement stables, surtout s’ils ont un emploi ou si leurs

  20. Endogenous opioid mechanisms partially mediate P2X3/P2X2/3-related antinociception in rat models of inflammatory and chemogenic pain but not neuropathic pain.

    PubMed

    McGaraughty, Steve; Honore, Prisca; Wismer, Carol T; Mikusa, Joseph; Zhu, Chang Z; McDonald, Heath A; Bianchi, Bruce; Faltynek, Connie R; Jarvis, Michael F

    2005-09-01

    P2X3/P2X2/3 receptors have emerged as important components of nociception. However, there is limited information regarding the neurochemical systems that are affected by antagonism of the P2X3/P2X2/3 receptor and that ultimately contribute to the ensuing antinociception. In order to determine if the endogenous opioid system is involved in this antinociception, naloxone was administered just prior to the injection of a selective P2X3/P2X2/3 receptor antagonist, A-317491, in rat models of neuropathic, chemogenic, and inflammatory pain. Naloxone (1-10 mg kg(-1), i.p.), dose-dependently reduced the antinociceptive effects of A-317491 (1-300 micromol kg(-1), s.c.) in the CFA model of thermal hyperalgesia and the formalin model of chemogenic pain (2nd phase), but not in the L5-L6 spinal nerve ligation model of neuropathic allodynia. In comparison experiments, the same doses of naloxone blocked or attenuated the actions of morphine (2 or 8 mg kg(-1), s.c.) in each of these behavioral models. Injection of a peripheral opioid antagonist, naloxone methiodide (10 mg kg(-1), i.p.), did not affect A-317491-induced antinociception in the CFA and formalin assays, suggesting that the opioid component of this antinociception occurred within the CNS. Furthermore, this utilization of the central opioid system could be initiated by antagonism of spinal P2X3/P2X2/3 receptors since the antinociceptive actions of intrathecally delivered A-317491 (30 nmol) in the formalin model were reduced by both intrathecally (10-50 nmol) and systemically (10 mg kg(-1), i.p.) administered naloxone. This utilization of the opioid system was not specific to A-317491 since suramin-, a nonselective P2X receptor antagonist, induced antinociception was also attenuated by naloxone. In in vitro studies, A-317491 (3-100 microM) did not produce any agonist response at delta opioid receptors expressed in NG108-15 cells. A-317491 had been previously shown to be inactive at the kappa and mu opioid receptors

  1. Morphine, Endogenous Opioid Peptides, and Reproduction in the Male Rhesus Monkey

    DTIC Science & Technology

    1983-05-18

    receptors are both antagonized at high dose levels, while at low doses , naloxone antagonizes only u-receptors (Kosterlitz, 1980). Studies of a...found witli the 20 ug/kg dose . As in the case of testosterone at the same dose , the LH pretreatment levels measured were unusually low (600 ng/dl vs...concentration of the dose of an- tagonist required to reduce agonistic potency by one-half. Due to differences in affinity, naloxone at low dose levels

  2. Peptide and non-peptide opioid-induced hyperthermia in rabbits

    NASA Technical Reports Server (NTRS)

    Kandasamy, S. B.; Williams, B. A.

    1983-01-01

    The intracerebroventricular administration of prototype nonpeptide opioid receptor (mu, kappa, and sigma) agonists, morphine, ketocyclazocine, and N-allyl-normetazocine was found to induce hyperthermia in rabbits. The similar administration of peptide opioids like beta-endorphin (BE), methionine-enkephalin (ME), and its synthetic analogue D-ala2-methionine-enkephalinamide (DAME) was also found to cause hyperthermia. Results indicate that only the liver-like transport system is important to the ventricular inactivation of BE and DAME. Prostaglandins and norepinephrine were determined not to be involved in peptide and nonpeptide opioid-induced hyperthermia. In addition, cAMP was not required since a phosphodiesterase inhibitor, theophylline, did not accentuate the hyperthermia due to peptide and nonpeptide opioids. Naloxone-sensitive receptors were found to be involved in the induction of hyperthermia by morphine, BE, ME, and DAME since naloxone attenuated them. However, the hyperthermic response to ketocyclazocine and N-allyl-normetazocine was not antagonized by naloxone.

  3. Anti-arrhythmic activities of opioid agonists and antagonists and their stereoisomers.

    PubMed Central

    Sarne, Y.; Flitstein, A.; Oppenheimer, E.

    1991-01-01

    1. A series of opioid agonists, antagonists and their (+)-stereoisomers were tested for antiarrhythmic activity in the rat coronary artery occlusion model. 2. Naloxone (0.01-2 mg kg-1) significantly reduced the incidence and severity of cardiac arrhythmias, in accordance with previous published studies. 3. The non-opioid stereoisomer, (+)-naloxone, was equipotent with naloxone against occlusion-induced arrhythmia. 4. Similar non-stereospecific antiarrhythmic effects were induced by another opioid antagonist, Win 44,441-3 and its stereoisomer Win 44,441-2. 5. The opioid agonists, morphine and levorphanol, protected against occlusion-induced arrhythmia as did the opioid antagonists, and the (+)-stereoisomer, dextrorphan, was equipotent to levorphanol. 6. It is concluded that the antiarrhythmic effects of opioid drugs are not mediated by opioid receptors. A direct effect on ionic currents in cardiac muscle is suggested as the mechanism of opioid antiarrhythmic activity. PMID:1364840

  4. Fatal Fentanyl: One Pill Can Kill.

    PubMed

    Sutter, Mark E; Gerona, Roy R; Davis, M Thais; Roche, Bailey M; Colby, Daniel K; Chenoweth, James A; Adams, Axel J; Owen, Kelly P; Ford, Jonathan B; Black, Hugh B; Albertson, Timothy E

    2017-01-01

    The current national opioid epidemic is a public health emergency. We have identified an outbreak of exaggerated opioid toxicity caused by fentanyl adulterated tablets purchased on the street as hydrocodone/acetaminophen. Over an 8-day period in late March 2016, a total of 18 patients presented to our institution with exaggerated opioid toxicity. The patients provided a similar history: ingesting their "normal dose" of hydrocodone/acetaminophen tablets but with more pronounced symptoms. Toxicology testing and analysis was performed on serum, urine, and surrendered pills. One of the 18 patients died in hospital. Five patients underwent cardiopulmonary resuscitation, one required extracorporeal life support, three required intubation, and two received bag-valve-mask ventilation. One patient had recurrence of toxicity after 8 hours after naloxone discontinuation. Seventeen of 18 patients required boluses of naloxone, and four required prolonged naloxone infusions (26-39 hours). All 18 patients tested positive for fentanyl in the serum. Quantitative assays conducted in 13 of the sera revealed fentanyl concentrations of 7.9 to 162 ng/mL (mean = 52.9 ng/mL). Pill analysis revealed fentanyl amounts of 600-6,900 μg/pill. The pills are virtually indistinguishable from authentic hydrocodone/acetaminophen tablets and are similar in weight. To date, our county has reported 56 cases of fentanyl opioid toxicity, with 15 fatalities. In our institution, the outbreak has stressed the capabilities and resources of the emergency department and intensive care units. A serious outbreak of exaggerated opioid toxicity caused by fentanyl-adulterated tablets purchased on the street as hydrocodone/acetaminophen is under way in California. These patients required higher dosing and prolonged infusions of naloxone. Additionally, observation periods off naloxone were extended due to delayed, recurrent toxicity. The outbreak has serious ramifications for public health and safety, law

  5. Safety of a Brief Emergency Department Observation Protocol for Patients With Presumed Fentanyl Overdose.

    PubMed

    Scheuermeyer, Frank X; DeWitt, Christopher; Christenson, Jim; Grunau, Brian; Kestler, Andrew; Grafstein, Eric; Buxton, Jane; Barbic, David; Milanovic, Stefan; Torkjari, Reza; Sahota, Indy; Innes, Grant

    2018-03-09

    Fentanyl overdoses are increasing and few data guide emergency department (ED) management. We evaluate the safety of an ED protocol for patients with presumed fentanyl overdose. At an urban ED, we used administrative data and explicit chart review to identify and describe consecutive patients with uncomplicated presumed fentanyl overdose (no concurrent acute medical issues) from September to December 2016. We linked regional ED and provincial vital statistics databases to ascertain admissions, revisits, and mortality. Primary outcome was a composite of admission and death within 24 hours. Other outcomes included treatment with additional ED naloxone, development of a new medical issue while in the ED, and length of stay. A prespecified subgroup analysis assessed low-risk patients with normal triage vital signs. There were 1,009 uncomplicated presumed fentanyl overdose, mainly by injection. Median age was 34 years, 85% were men, and 82% received out-of-hospital naloxone. One patient was hospitalized and one discharged patient died within 24 hours (combined outcome 0.2%; 95% confidence interval [CI] 0.04% to 0.8%). Sixteen patients received additional ED naloxone (1.6%; 95% CI 1.0% to 2.6%), none developed a new medical issue (0%; 95% CI 0% to 0.5%), and median length of stay was 173 minutes (interquartile range 101 to 267). For 752 low-risk patients, no patients were admitted or developed a new issue, and one died postdischarge; 3 (0.4%; 95% CI 0.01% to 1.3%) received ED naloxone. In our cohort of ED patients with uncomplicated presumed fentanyl overdose-typically after injection-deterioration, admission, mortality, and postdischarge complications appear low; the majority can be discharged after brief observation. Patients with normal triage vital signs are unlikely to require ED naloxone. Copyright © 2018 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.

  6. Contrasting cardiovascular properties of the µ-opioid agonists morphine and methadone in the rat.

    PubMed

    Tung, Kenneth H; Angus, James A; Wright, Christine E

    2015-09-05

    Morphine and methadone share the property of μ-opioid receptor agonism yet have markedly different cardiovascular actions suggesting additional properties are at play. We investigated the i.v. dose-response relationships of the opioids on cardiovascular metameters in anaesthetised rats in the absence or presence of H1- and H2-receptor antagonism and the μ-opioid antagonist naloxone. In vitro tissue assays were employed to define more clearly cardiac and vascular mechanisms of action. Morphine (9, 30, 90mg/kg i.v.) decreased heart rate (HR) and mean arterial pressure (MAP) - responses that were blocked by naloxone pretreatment (10mg/kg i.v.). In contrast, methadone (3, 10, 30mg/kg i.v.) caused dramatic short-lived (1-3min) bradycardia, hypotension and lengthening of the QT interval before stabilising 5min after i.v. dosing. Only the steady-state responses of HR and MAP were blocked by naloxone. Mepyramine (10mg/kg i.v.) and cimetidine (100mg/kg i.v.) also blocked the naloxone-sensitive components. In isolated small mesenteric arteries precontracted by K(+) 62mM or endothelin-1, methadone (1-30μM) relaxed vessels while morphine (1-100μM) had no effect. Pretreatment with naloxone (10μM), indomethacin (30μM) or nitro-l-arginine (100μM) did not affect the relaxation to methadone. In rat isolated left atria, morphine and methadone inhibited inotropic responses at high concentrations (100μM). In rat papillary muscle and right atria, methadone was more than 30 times more potent at lengthening the refractory period and slowing the atrial rate than morphine. We conclude that methadone is a potent vasodilator agent, possibly through blocking L-type calcium channels. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Neuropeptides and seizures.

    PubMed

    Snead, O C

    1986-11-01

    There are four lines of evidence for or against a role of neuropeptides in epilepsy: Administration of a variety of opiate agonists into the ventricles or brain of animals produces a constellation of electrical and behavioral changes, seemingly receptor-specific, both sensitive to the specific opiate antagonist naloxone as well as certain anticonvulsant drugs. The primary reservation concerning these data in terms of their relevance to epilepsy regards the fact that the peptides are exogenously administered in relatively high doses. Hence, these data may reflect neurotoxic effects of peptides rather than physiologic function. A variety of opiate agonists are anticonvulsant and naloxone shortens the postictal state in some experimental seizure models. One could attempt to reconcile these data with those in No. 1 by hypothesizing that the spikes and behavioral changes examined in the latter experimental parodynes represented a sort of isolated model of the postictal state. Naloxone has little effect in clinical epilepsy. These data are far from conclusive for two reasons. First, few patients have been studied. Second, because of the issue of opiate receptor heterogeneity and the high doses of naloxone needed experimentally to block non-mu opiate effects, the doses of naloxone used clinically to date are too low to rule out possible delta- or epsilon-mediated effects. The negative clinical data are illustrative of the dangers and difficulties of extrapolating data generated in animal models of seizures to the human condition. ACTH, a peptide that is derived from the same precursor molecule as beta-endorphin, is clearly an effective anticonvulsant in certain childhood seizure states. However, whether this is due to a direct or indirect (that is, cortisol) effect on brain is far from clear. Paradoxically, in contradistinction to other data concerning pro- and anticonvulsant properties of various opioid peptides, there is no animal model of infantile spasms to help

  8. Opioid analgesia on the battlefield: a retrospective review of data from Operation HERRICK.

    PubMed

    Lewis, Pip; Wright, C; Hooper, C

    2018-04-06

    Acute pain secondary to trauma is commonly encountered on the battlefield. The use of morphine to manage pain during combat has been well established since the 19th century. Despite this, there is relatively little research on analgesia use in this environment. This study aims to review the use and complications of morphine and other opioids during Operation HERRICK. A database search of the Joint Theatre Trauma Registry was completed looking for all incidences of morphine, fentanyl or naloxone use from February 2007 to September 2014. Microsoft Excel was used to analyse the results. Opioid analgesia was administered to 5801 casualties. Morphine was administered 6742 times to 3808 patients. Fentanyl was administered 9672 times to 4318 patients. Naloxone was used 18 times on 14 patients, giving a complication rate of 0.24%. Opioid doses prior to naloxone administration range from 0 to 72 mg of morphine and from 0 to 100 mcg of fentanyl. Four casualties (two local civilians and two coalition forces) received naloxone despite no recorded opioids being administered. Opium abuse was prevalent among the local population in Afghanistan, and this could explain the rationale behind two local national casualties receiving naloxone without any documented opioids being given. The use of opioids in a battlefield environment is extremely safe. Complication rates are similar to previously published data which is reassuring. The efficacy of different opioids was not covered by this study, and further analysis is required, particularly following the introduction of oral transmucosal fentanyl citrate and the availability of novel non-opioid analgesics. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  9. Blockade of Endocannabinoid Hydrolytic Enzymes Attenuates Precipitated Opioid Withdrawal Symptoms in MiceS⃞

    PubMed Central

    Ramesh, Divya; Ross, Gracious R.; Schlosburg, Joel E.; Owens, Robert A.; Abdullah, Rehab A.; Kinsey, Steven G.; Long, Jonathan Z.; Nomura, Daniel K.; Sim-Selley, Laura J.; Cravatt, Benjamin F.; Akbarali, Hamid I.

    2011-01-01

    Δ9-Tetrahydrocannbinol (THC), the primary active constituent of Cannabis sativa, has long been known to reduce opioid withdrawal symptoms. Although THC produces most of its pharmacological actions through the activation of CB1 and CB2 cannabinoid receptors, the role these receptors play in reducing the variety of opioid withdrawal symptoms remains unknown. The endogenous cannabinoids, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), activate both cannabinoid receptors but are rapidly metabolized by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The objective of this study was to test whether increasing AEA or 2-AG, via inhibition of their respective hydrolytic enzymes, reduces naloxone-precipitated morphine withdrawal symptoms in in vivo and in vitro models of opioid dependence. Morphine-dependent mice challenged with naloxone reliably displayed a profound withdrawal syndrome, consisting of jumping, paw tremors, diarrhea, and weight loss. THC and the MAGL inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) dose dependently reduced the intensity of most measures through the activation of CB1 receptors. JZL184 also attenuated spontaneous withdrawal signs in morphine-dependent mice. The FAAH inhibitor N-(pyridin-3-yl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)benzyl)-piperdine-1-carboxamide (PF-3845) reduced the intensity of naloxone-precipitated jumps and paw flutters through the activation of CB1 receptors but did not ameliorate incidence of diarrhea or weight loss. In the final series of experiments, we investigated whether JZL184 or PF-3845 would attenuate naloxone-precipitated contractions in morphine-dependent ilea. Both enzyme inhibitors attenuated the intensity of naloxone-induced contractions, although this model does not account mechanistically for the autonomic withdrawal responses (i.e., diarrhea) observed in vivo. These results indicate

  10. Mindfulness-Meditation-Based Pain Relief Is Not Mediated by Endogenous Opioids

    PubMed Central

    Adler-Neal, Adrienne L.; Wells, Rebecca E.; Stagnaro, Emily; May, Lisa M.; Eisenach, James C.; McHaffie, John G.; Coghill, Robert C.

    2016-01-01

    Mindfulness meditation, a cognitive practice premised on sustaining nonjudgmental awareness of arising sensory events, reliably attenuates pain. Mindfulness meditation activates multiple brain regions that contain a high expression of opioid receptors. However, it is unknown whether mindfulness-meditation-based analgesia is mediated by endogenous opioids. The present double-blind, randomized study examined behavioral pain responses in healthy human volunteers during mindfulness meditation and a nonmanipulation control condition in response to noxious heat and intravenous administration of the opioid antagonist naloxone (0.15 mg/kg bolus + 0.1 mg/kg/h infusion) or saline placebo. Meditation during saline infusion significantly reduced pain intensity and unpleasantness ratings when compared to the control + saline group. However, naloxone infusion failed to reverse meditation-induced analgesia. There were no significant differences in pain intensity or pain unpleasantness reductions between the meditation + naloxone and the meditation + saline groups. Furthermore, mindfulness meditation during naloxone produced significantly greater reductions in pain intensity and unpleasantness than the control groups. These findings demonstrate that mindfulness meditation does not rely on endogenous opioidergic mechanisms to reduce pain. SIGNIFICANCE STATEMENT Endogenous opioids have been repeatedly shown to be involved in the cognitive inhibition of pain. Mindfulness meditation, a practice premised on directing nonjudgmental attention to arising sensory events, reduces pain by engaging mechanisms supporting the cognitive control of pain. However, it remains unknown if mindfulness-meditation-based analgesia is mediated by opioids, an important consideration for using meditation to treat chronic pain. To address this question, the present study examined pain reports during meditation in response to noxious heat and administration of the opioid antagonist naloxone and placebo saline

  11. Effects of antithrombotic drugs in patients with left ventricular thrombi: assessment with indium-111 platelet imaging and two-dimensional echocardiography

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Stratton, J.R.; Ritchie, J.L.

    Patients with left ventricular thrombi not caused by recent myocardial infarction were prospectively studied by indium-111 platelet imaging and two-dimensional echocardiography to determine the reproducibility of these techniques and the short-term effects of sulfinpyrazone (200 mg four times daily), aspirin (325 mg three times daily) plus dipyridamole (75 mg three times daily), and full-dose warfarin. At baseline, all patients underwent indium-111 platelet imaging and echocardiography, and the results were positive for thrombus. In six patients on no antithrombotic drug therapy, repeat platelet scans and echocardiographic studies at 6.0 +/- 3.3 weeks remained positive and were unchanged. In seven patients studiedmore » on sulfinpyrazone, three platelet scans became negative, two became equivocal, and two were unchanged; the presence and size of thrombus was constant by echocardiography in all seven patients. Of the six patients studied on aspirin plus dipyridamole, one platelet scan became negative, those of three became equivocal, and two were unchanged; all echocardiographic findings remained positive, but one patient had decreased thrombus size. Among four warfarin-treated patients, three had resolution of platelet deposition and one was unchanged; by echocardiography, thrombus resolved in one patient, was decreased in size in one, and was unchanged in two. We conclude that, in the absence of antithrombotic drug therapy, platelet imaging and echocardiographic findings are stable in patients with left ventricular thrombi not caused by recent myocardial infarction. Sulfinpyrazone, aspirin plus dipyridamole, and warfarin all interrupt platelet deposition in some patients with chronic left ventricular thrombi.« less

  12. Understanding abuse of buprenorphine/naloxone film versus tablet products using data from ASI-MV® substance use disorder treatment centers and RADARS® System Poison Centers.

    PubMed

    Butler, Stephen F; Black, Ryan A; Severtson, Stevan Geoffrey; Dart, Richard C; Green, Jody L

    2018-01-01

    The objectives were to examine the abuse prevalence and route-of-administration (ROA) profiles of sublingual buprenorphine/naloxone combination (BNX) film in comparison with the BNX tablet and to identify clinically-relevant subgroups of patients or geographic patterns. Between Q1 2015 through Q3 2015, data were collected from two major surveillance systems: (1) assessment of individuals in substance use disorder (SUD) treatment collected from the National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO®) ASI-MV® system and (2) intentional abuse/misuse exposures in the RADARS® System Poison Center Program. Poisson regression models were tailored to each system's data characteristics by population (all SUD treatment patients, US census) and adjusted for prescription volume. Effects of gender, race, age and US region as well as ROA profile were examined. For the ASI-MV study, 45,695 assessments of unique adults evaluated for substance use problems were collected. The abuse rate unadjusted for prescription volume of BNX tablet formulation was 2.64 cases/100 ASI-MV respondents versus 7.01 cases for the film formulation (RR=0.390, p<0.001). Prescription-adjusted abuse, however, was greater for the tablet version (0.47 abuse cases/100 ASI-MV respondents/100,000 dosage units compared with 0.38 for the film) (RR=1.25, p<0.001). Results among the US population from the RADARS System Poison Center Program data revealed a similar pattern; population rates for film abuse (0.0364) were greater than for tablet (0.0161), while prescription-adjusted rates were greater for tablet (0.2114) than for film (0.1703) per 100,000 prescriptions. ASI-MV ROA analyses indicated less abuse of the film by any alternate route, insufflation or injection than the tablet. Poison center data found more injection of tablets than film, although insufflation was not significantly different. On a prescription-adjusted basis, overall abuse of the BNX tablet is greater than that of

  13. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lewis, M.E.; Khachaturian, H.; Watson, S.J.

    Using adjacent section autoradiography-immunocytochemistry, the distribution of (TH)naloxone binding sites was studied in relation to neuronal systems containing (Leu)enkephalin, dynorphin A, or beta-endorphin immunoreactivity in rat brain. Brain sections from formaldehyde-perfused rats show robust specific binding of (TH)naloxone, the pharmacological (mu-like) properties of which appear unaltered. In contrast, specific binding of the delta ligand (TH)D-Ala2,D-Leu5-enkephalin was virtually totally eliminated as a result of formaldehyde perfusion. Using adjacent section analysis, the authors have noted associations between (TH)naloxone binding sites and one, two, or all three opioid systems in different brain regions; however, in some areas, no apparent relationship could be observed.more » Within regions, the relationship was complex. The complexity of the association between (TH)naloxone binding sites and the multiple opioid systems, and previous reports of co-localization of mu and kappa receptors in rat brain, are inconsistent with a simple-one-to-one relationship between a given opioid precursor and opioid receptor subtype. Instead, since differential processing of the three precursors gives rise to peptides of varying receptor subtype potencies and selectivities, the multiple peptide-receptor relationships may point to a key role of post-translational processing in determining the physiological consequences of opioid neurotransmission.« less

  14. Noni (Morinda citrifolia L.) fruit extract attenuates the rewarding effect of heroin in conditioned place preference but not withdrawal in rodents

    PubMed Central

    Narasingam, Megala; Pandy, Vijayapandi; Mohamed, Zahurin

    2016-01-01

    The present study was designed to investigate the effect of a methanolic extract of Morinda citrifolia Linn. fruit (MMC) on the rewarding effect of heroin in the rat conditioned place preference (CPP) paradigm and naloxone-precipitated withdrawal in mice. In the first experiment, following a baseline preference test (preconditioning score), the rats were subjected to conditioning trials with five counterbalanced escalating doses of heroin versus saline followed by a preference test conducted under drug-free conditions (post-conditioning score) using the CPP test. Meanwhile, in the second experiment, withdrawal jumping was precipitated by naloxone administration after heroin dependence was induced by escalating doses for 6 days (3×/ day). The CPP test results revealed that acute administration of MMC (1, 3, and 5 g/kg body weight (bw), p.o.), 1 h prior to the CPP test on the 12th day significantly reversed the heroin-seeking behavior in a dose-dependent manner, which was similar to the results observed with a reference drug, methadone (3 mg/kg bw, p.o.). On the other hand, MMC (0.5, 1, and 3 g/kg bw, p.o.) did not attenuate the heroin withdrawal jumps precipitated by naloxone. These findings suggest that the mechanism by which MMC inhibits the rewarding effect of heroin is distinct from naloxone-precipitated heroin withdrawal. PMID:26744024

  15. Noni (Morinda citrifolia L.) fruit extract attenuates the rewarding effect of heroin in conditioned place preference but not withdrawal in rodents.

    PubMed

    Narasingam, Megala; Pandy, Vijayapandi; Mohamed, Zahurin

    2016-05-20

    The present study was designed to investigate the effect of a methanolic extract of Morinda citrifolia Linn. fruit (MMC) on the rewarding effect of heroin in the rat conditioned place preference (CPP) paradigm and naloxone-precipitated withdrawal in mice. In the first experiment, following a baseline preference test (preconditioning score), the rats were subjected to conditioning trials with five counterbalanced escalating doses of heroin versus saline followed by a preference test conducted under drug-free conditions (post-conditioning score) using the CPP test. Meanwhile, in the second experiment, withdrawal jumping was precipitated by naloxone administration after heroin dependence was induced by escalating doses for 6 days (3×/ day). The CPP test results revealed that acute administration of MMC (1, 3, and 5 g/kg body weight (bw), p.o.), 1 h prior to the CPP test on the 12th day significantly reversed the heroin-seeking behavior in a dose-dependent manner, which was similar to the results observed with a reference drug, methadone (3 mg/kg bw, p.o.). On the other hand, MMC (0.5, 1, and 3 g/kg bw, p.o.) did not attenuate the heroin withdrawal jumps precipitated by naloxone. These findings suggest that the mechanism by which MMC inhibits the rewarding effect of heroin is distinct from naloxone-precipitated heroin withdrawal.

  16. Is the polar bear (Ursus maritimus) a hibernator? Continued studies on opioids and hibernation

    USGS Publications Warehouse

    Bruce, David S.; Darling, Nancy K.; Seeland, Katheleen J.; Oeltgen, Peter R.; Nilekani, Sita P.; Amstrup, Steven C.

    1990-01-01

    Polar bear behavior and biochemistry suggest they may have the ability to hibernate year-round, even though this species is not considered to be a true hibernator. This observation, plus the discovery of a hibernation-induced trigger (HIT) in the blood of black bears, prompted the examination of polar bear blood collected thoughout the year for evidence ofr HIT, and to determine if it displayed opioid activity, as black bear blood does. A bioassay was conducted by injected summer 13-lined ground squirrels with serum collected from polar bears at different seasons. One group of squirrels was previously implanted with osmotic pumps containing naloxone. The rest had pumps containing saline. Squirrels with saline pumps all hibernated significantly more than those with naloxone, except the group receiving blood from a November polar bear, observed to be highly active and hyperphagic. An in vitro study, using guinea pig ileum, showed that 400 nM morphine inhibited induced contractions and 100 nM naloxone reversed the inhibition. Ten mg of winter polar bear serum albumin fraction (to which HIT binds in ground squirrels and woodchucks) had a similar inhibiting effect, but naloxone, even at 4,000 nM, didn't reverse it. It is concluded that polar bear contains HIT, that it has an opioid effct, but may not itself be an opioid.

  17. L-type calcium channel blockade attenuates morphine withdrawal: in vivo interaction between L-type calcium channels and corticosterone.

    PubMed

    Esmaeili-Mahani, Saeed; Fathi, Yadollah; Motamedi, Fereshteh; Hosseinpanah, Farhad; Ahmadiani, Abolhassan

    2008-02-01

    Both opioids and calcium channel blockers could affect hypothalamic-pituitary-adrenal (HPA) axis function. Nifedipine, as a calcium channel blocker, can attenuate the development of morphine dependence; however, the role of the HPA axis in this effect has not been elucidated. We examined the effect of nifedipine on the induction of morphine dependency in intact and adrenalectomized (ADX) male rats, as assessed by the naloxone precipitation test. We also evaluated the effect of this drug on HPA activity induced by naloxone. Our results showed that despite the demonstration of dependence in both groups of rats, nifedipine is more effective in preventing of withdrawal signs in ADX rats than in sham-operated rats. In groups that received morphine and nifedipine concomitantly, naloxone-induced corticosterone secretion was attenuated. Thus, we have shown the involvement of the HPA axis in the effect of nifedipine on the development of morphine dependency and additionally demonstrated an in vivo interaction between the L-type Ca2+ channels and corticosterone.

  18. Use of radiotelemetry to evaluate respiratory depression produced by chronic methadone administration.

    PubMed

    Lewanowitsch, Tanya; White, Jason M; Irvine, Rodney J

    2004-01-26

    Illicit and therapeutic opioid administration can result in overdose due to opioid-induced respiratory depression. Research investigating the respiratory depressant effects of opioids has been limited due to difficulties associated with acquiring long-term respiratory data. This study examined the novel use of radiotelemetry to measure respiratory rate, heart rate, locomotor activity and blood pressure in rats treated chronically with methadone. Over 4 days of treatment, respiratory rate decreased, but partial tolerance appeared to develop during active (night) periods. Decreased heart rate was observed during the night periods and tolerance appeared to develop to this effect. Activity and blood pressure did not change with treatment. The effects of naloxone hydrochloride and naloxone methiodide administration on the methadone-treated rats were also examined and both antagonists increased respiratory rate and heart rate, with only naloxone hydrochloride producing significant increases in activity. Radiotelemetry offers a means of evaluating drug effects on respiratory rate continually in ambulatory, unstressed animals.

  19. Behavioral and electrographic effects of opioids on kindled seizures in rats.

    PubMed

    Caldecott-Hazard, S; Shavit, Y; Ackermann, R F; Engel, J; Frederickson, R C; Liebeskind, J C

    1982-11-18

    Our laboratory previously suggested that opioid peptides are released by an amygdaloid kindled seizure and may affect the elicitation of a subsequent seizure. The present study examined the effects of morphine, naloxone, enkephalin analogues, and conditions of morphine tolerance and withdrawal on the severity and duration of a series of amygdaloid kindled seizures. The results suggest two distinct opiate/opioid actions on seizures. The first is an anticonvulsant effect on the behavioral manifestations of seizures. This effect is seen following a high dose (50 mg/kg) of morphine or a low dose (6 mg/kg) of enkephalin analogue (LY146104), and is reversed by naloxone. The second is a naloxone-reversible prolonging effect of the high dose of morphine on the electrographic components of the seizures. Receptor affinities of these various opiate/opioid drugs suggest that these two actions are mediated by different receptors which appear not to include high affinity mu receptors.

  20. Opiate modification of amygdaloid-kindled seizures in rats.

    PubMed

    Stone, W S; Eggleton, C E; Berman, R F

    1982-05-01

    Male Long-Evans rats were stereotaxically implanted bilaterally with bipolar electrodes in the central amygdala. Rats were then kindled once daily for 1 sec until 3 consecutive Stage V [25] kindled seizures were elicited. On the following day, animals were injected (IP) with either saline, naloxone (10 mg/kg), naltrexone (10mg/kg) or morphine sulfate (10 mg/kg) and again stimulated at the kindling stimulation parameters. Saline injected animals continued to show long bilateral AD's and behaviors (i.e., forelimb clonus, rearing, falling) typical of Stage V kindled animals. In contrast, rats injected with naloxone or naltrexone showed reduced behavioral seizures. Potentiation of post-ictal spiking by morphine in amygdaloid-kindled rats was also observed supporting previous reports [7,21]. In a second experiment, the reduction of kindled seizure serverity by naloxone was systematically replicated. It is concluded that opiates can significantly modify amygdaloid-kindled seizures, and that brain endorphins may play a role in the development or maintenance of an amygdaloid-kindled seizure focus.

  1. Effect of agmatine on the development of morphine dependence in rats: potential role of cAMP system

    PubMed Central

    Aricioglu, Feyza; Means, Andrea; Regunathan, Soundar

    2010-01-01

    Agmatine is an endogenous amine derived from arginine that potentiates morphine analgesia and blocks symptoms of naloxone-precipitated morphine withdrawal in rats. In this study, we sought to determine whether treatment with agmatine during the development of morphine dependence inhibits the withdrawal symptoms and that the effect is mediated by cAMP system. Exposure of rats to morphine for 7 days resulted in marked naloxone-induced withdrawal symptoms and agmatine treatment along with morphine significantly decreasing the withdrawal symptoms. The levels of cAMP were markedly increased in morphine-treated rat brain slices when incubated with naloxone and this increase was significantly reduced in rats treated with morphine and agmatine. The induction of tyrosine hydroxylase after morphine exposure was also reduced in locus coeruleus when agmatine was administered along with morphine. We conclude that agmatine reduces the development of dependence to morphine and that this effect is probably mediated by the inhibition of cAMP signaling pathway during chronic morphine exposure. PMID:15541421

  2. The Effect of Opioid Receptor Blockade on the Neural Processing of Thermal Stimuli

    PubMed Central

    Schoell, Eszter D.; Bingel, Ulrike; Eippert, Falk; Yacubian, Juliana; Christiansen, Kerrin; Andresen, Hilke; May, Arne; Buechel, Christian

    2010-01-01

    The endogenous opioid system represents one of the principal systems in the modulation of pain. This has been demonstrated in studies of placebo analgesia and stress-induced analgesia, where anti-nociceptive activity triggered by pain itself or by cognitive states is blocked by opioid antagonists. The aim of this study was to characterize the effect of opioid receptor blockade on the physiological processing of painful thermal stimulation in the absence of cognitive manipulation. We therefore measured BOLD (blood oxygen level dependent) signal responses and intensity ratings to non-painful and painful thermal stimuli in a double-blind, cross-over design using the opioid receptor antagonist naloxone. On the behavioral level, we observed an increase in intensity ratings under naloxone due mainly to a difference in the non-painful stimuli. On the neural level, painful thermal stimulation was associated with a negative BOLD signal within the pregenual anterior cingulate cortex, and this deactivation was abolished by naloxone. PMID:20811582

  3. Separation of opioid from nonopioid mediation of affect in neonatal rats: nonopioid mechanisms mediate maternal contact influences.

    PubMed

    Blass, E M; Fillion, T J; Weller, A; Brunson, L

    1990-08-01

    A causal distinction is established in infant Norway rats between opioid- and nonopioid-mediated determinants of behavior. Contact influences are shown to be mediated by nonopioid pathways, whereas gustatory influences are shown to be opioid mediated. Specifically, naltrexone (0.5 and 1.0 mg/kg) did not at all diminish quieting exerted by contact with an anesthetized dam but completely reversed the quieting effects of morphine in isolated rats. Naloxone (5 mg/kg) did not affect the latencies with which nondeprived or 8-hr deprived rats 9, 12, 15, and 18 days of age attached to the nipples of anesthetized dams, nor did naloxone (5 and 10 mg/kg) cause any systematic change in nipple attachment in 10- and 18-day-old rats that had been deprived of their dam for either 0, 8, or 24 hr. In a 3rd experiment, naloxone (5 mg/kg) did not significantly reduce milk intake by 9-, 12-, 15-, or 18-day-old rats from the nipple when milk letdown was induced by oxytocin. Moreover, naloxone (5 and 10 mg/kg) did not reduce milk intake in Day-10 rats that, while suckling, received milk via a cannula placed in the posterior portion of the tongue at the level of the intermolar eminence or in rats that obtained milk directly from their awake mother. In contrast, milk intake was significantly reduced by naltrexone (0.25-1.0 mg/kg) in Day-10 rats that obtained milk (a) by licking it off a saturated substrate or (b) through an indwelling cannula located in the anterior portion of the lower jaw. (Milk delivered at this placement is thought to engage feeding systems by its taste and texture.) In a final set of experiments in Day-10 rats, intake of milk delivered via anterior jaw cannulae was reduced by naloxone (5 and 10 mg/kg) in rats that were either isolated, in contact with an anesthetized dam, or attached to her nipples. On the basis of resistance to naloxone and naltrexone administration, these experiments demonstrate that behavioral influences of the tactile (and possibly olfactory

  4. Syzygium cumini is more effective in preventing the increase of erythrocytic ADA activity than phenolic compounds under hyperglycemic conditions in vitro.

    PubMed

    De Bona, Karine S; Bonfanti, Gabriela; Bitencourt, Paula E R; Cargnelutti, Lariane O; da Silva, Priscila S; da Silva, Thainan P; Zanette, Régis A; Pigatto, Aline S; Moretto, Maria B

    2014-06-01

    Syzygium cumini (S. cumini) is a plant known for its antidiabetic properties. The aim of this study was to evaluate the effect of Sc aqueous leaf extract (ASc) on adenosine deaminase (ADA) activity in erythrocytes (RBCs) exposed to high glucose concentrations (30 mM) in vitro. We also investigated the effects of the main phenolic compounds found in ASc (gallic acid, rutin, and chlorogenic acid) and the effects of insulin, caffeine, and dipyridamole, which are substances involved in the adenosine metabolism, on ADA activity in vitro. Blood samples were obtained from healthy volunteers and a suspension of RBCs was used for the determination of ADA activity. The results showed that: (1) the effect of ASc on ADA activity was more significant than the combination of phenolic compounds; (2) insulin, caffeine, or dipyridamole prevented high glucose increase of ADA activity at doses as low as 50 μU/mL, 25 μM, and 1 μM, respectively; (3) the inhibitory effect caused by ASc on erythrocyte ADA activity remained practically the same after the combination of the extract with insulin or caffeine; (4) when RBCs were exposed to ASc plus dipyridamole, this chemical attenuated the effect of ASc on ADA activity, suggesting an antagonism or a competition with ASc by the same site of action. Therefore, ASc was more effective in preventing the increase in ADA activity than phenolic compounds, suggesting that ASc may collaborate to improve endothelial dysfunction, antioxidant, anti-inflammatory, and antithrombotic properties of adenosine by affecting its metabolism. The results of this study help to provide evidence of the empirically supported benefits of the use of S. cumini in diabetes.

  5. Opioid systems in the lateral hypothalamus regulate feeding behavior through orexin and GABA neurons.

    PubMed

    Ardianto, C; Yonemochi, N; Yamamoto, S; Yang, L; Takenoya, F; Shioda, S; Nagase, H; Ikeda, H; Kamei, J

    2016-04-21

    The hypothalamus controls feeding behavior. Since central opioid systems may regulate feeding behavior, we examined the role of μ-, δ- and κ-opioid receptors in the lateral hypothalamus (LH), the hunger center, in feeding behavior of mice. Non-selective (naloxone; 3 mg/kg, s.c.) and selective μ- (β-funaltrexamine, β-FNA; 10 mg/kg, s.c.), δ- (naltrindole; 3 mg/kg, s.c.) and κ- (norbinaltorphimine, norBNI; 20 mg/kg, s.c.) opioid receptor antagonists significantly decreased food intake in food-deprived mice. The injection of naloxone (20 μg/side) into the LH significantly decreased food intake whereas the injection of naloxone (20 μg/side) outside of the LH did not affect food intake. The injection of β-FNA (2 μg/side), naltrindole (1 μg/side) or norBNI (2 μg/side) into the LH significantly decreased food intake. Furthermore, all these antagonists significantly decreased the mRNA level of preproorexin, but not those of other hypothalamic neuropeptides. In addition, the injection of the GABAA receptor agonist muscimol (5 μg/side) into the LH significantly decreased food intake, and this effect was abolished by the GABAA receptor antagonist bicuculline (50 μg/side). Muscimol (1mg/kg, i.p.) decreased the mRNA level of preproorexin in the hypothalamus. Naloxone (3mg/kg, s.c.) significantly increased the GABA level in the LH and both bicuculline and the GABA release inhibitor 3-mercaptopropionic acid (3-MP, 5 μg/side) attenuated the inhibitory effect of naloxone on feeding behavior. 3-MP also attenuated the effects of β-FNA and norBNI, but not that of naltrindole. These results show that opioid systems in the LH regulate feeding behavior through orexin neurons. Moreover, μ- and κ-, but not δ-, opioid receptor antagonists inhibit feeding behavior by activating GABA neurons in the LH. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  6. [Behavioural studies during the gestational-lactation period in morphine treated rats].

    PubMed

    Sobor, Melinda; Timár, Júlia; Riba, Pál; Király, Kornél P; Al-Khrasani, Mahmoud; Gyarmati, Zsuzsanna; Fürst, Zsuzsanna

    2013-12-01

    Opioids impair the maternal behaviour of experimental animals. The effect of morphine on maternal behaviour in rat dams treated chronically with morphine during the whole pregnancy and lactation has not been yet analysed systematically. The aim of our work was to investigate the behavioural effects of moderate dose morphine administered constantly in the whole perinatal period in rats. Nulliparous female rats were treated with 10 mg/kg morphine s.c. once daily, from the day of mating. Maternal behaviour was observed, the effects of acute morphine treatment on the maternal behaviour and whether this effect could be antagonised by naloxone were also investigated. Physical and other behavioural (anxiety-like signals in elevated plus maze, changes in locomotor activity) withdrawal signs precipitated by naloxone were registered. After weaning sensitivity to the rewarding effect of morphine was measured by conditioned place preference and to the aversive effect of naloxone by conditioned place aversion tests. Antinociceptive test on tail-flick apparatus was performed to investigate the changes in morphine antinociceptive effects due to chronic morphine treatment. Maternal behaviour was significantly impaired in morphine-treated dams. This effect of morphine lasted c.a. 2-3 hours a day, it showed dose-dependency and was enhanced in MO-treated group (sensitisation). Only weak physical and no other behavioural (anxiety-like behaviour or hypolocomotion) withdrawal signs were precipitated by naloxone. The positive reinforcing effect of morphine and aversive effect of naloxone were markedly increased on conditioned place paradigm. Significant antinociceptive tolerance was not seen. Although human drug abuse can be hardly modelling under experimental circumstances, our constant, relatively moderate dose morphine treatment administered once daily during the whole pregnancy and lactation resulted in several subtle behavioural changes in dams. In perinatally opioid

  7. Mindfulness-Meditation-Based Pain Relief Is Not Mediated by Endogenous Opioids.

    PubMed

    Zeidan, Fadel; Adler-Neal, Adrienne L; Wells, Rebecca E; Stagnaro, Emily; May, Lisa M; Eisenach, James C; McHaffie, John G; Coghill, Robert C

    2016-03-16

    Mindfulness meditation, a cognitive practice premised on sustaining nonjudgmental awareness of arising sensory events, reliably attenuates pain. Mindfulness meditation activates multiple brain regions that contain a high expression of opioid receptors. However, it is unknown whether mindfulness-meditation-based analgesia is mediated by endogenous opioids. The present double-blind, randomized study examined behavioral pain responses in healthy human volunteers during mindfulness meditation and a nonmanipulation control condition in response to noxious heat and intravenous administration of the opioid antagonist naloxone (0.15 mg/kg bolus + 0.1 mg/kg/h infusion) or saline placebo. Meditation during saline infusion significantly reduced pain intensity and unpleasantness ratings when compared to the control + saline group. However, naloxone infusion failed to reverse meditation-induced analgesia. There were no significant differences in pain intensity or pain unpleasantness reductions between the meditation + naloxone and the meditation + saline groups. Furthermore, mindfulness meditation during naloxone produced significantly greater reductions in pain intensity and unpleasantness than the control groups. These findings demonstrate that mindfulness meditation does not rely on endogenous opioidergic mechanisms to reduce pain. Endogenous opioids have been repeatedly shown to be involved in the cognitive inhibition of pain. Mindfulness meditation, a practice premised on directing nonjudgmental attention to arising sensory events, reduces pain by engaging mechanisms supporting the cognitive control of pain. However, it remains unknown if mindfulness-meditation-based analgesia is mediated by opioids, an important consideration for using meditation to treat chronic pain. To address this question, the present study examined pain reports during meditation in response to noxious heat and administration of the opioid antagonist naloxone and placebo saline. The results

  8. Comparison of tizanidine and morphine with regard to tolerance-developing ability to antinociceptive action.

    PubMed

    Nabeshima, T; Yamada, S; Sugimoto, A; Matsuno, K; Kameyama, T

    1986-10-01

    The antinociceptive, tolerance-developing and anti-withdrawal activities of tizanidine [5-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3-benzo-thiadiazole] were investigated by comparing its effects with those of morphine and clonidine in tail-flick-, hot plate-, acetic acid-induced writhing-, and naloxone-precipitated withdrawal jumping-tests. The antinociceptive action of tizanidine was not altered by naloxone, while that of morphine was antagonized. Tolerance to the tizanidine-induced antinociceptive action and to motor incoordination was developed by successive administration of tizanidine. In the tizanidine-tolerant mice, the antinociceptive action of morphine was significantly decreased, but not sleeping time induced by pentobarbital. The action of tizanidine was not modified in the morphine-tolerant mice. Tizanidine failed to induce morphine-withdrawal jumping and to inhibit naloxone-precipitated withdrawal jumping in the morphine-dependent mice. Cross tolerance to the antinociceptive action induced by tizanidine and clonidine was developed. These results suggest that alpha 2-adrenoreceptors may be involved in the action mechanism of tizanidine, but not opioid receptors. Functional tolerance to tizanidine action may be developed by successive administration of tizanidine.

  9. Addiction-prone Lewis but not Fischer rats develop compulsive running that coincides with downregulation of nerve growth factor inducible-B and neuron-derived orphan receptor 1.

    PubMed

    Werme, M; Thorén, P; Olson, L; Brené, S

    1999-07-15

    We have examined the effects of chronic voluntary running for 30 d on the levels of nerve growth factor inducilble-B (NGFI-B) and neuron-derived orphan receptor 1 (NOR1) mRNAs in Fischer and Lewis rats. The aim was to compare the addiction-prone Lewis rat strain to the Fischer strain in a plausible model for natural reward. The Lewis strain ran markedly more than the Fischer strain, as indicated by the length of running per day when given free access to running wheels. Both strains progressively increased their amount of daily running. By day 14, Lewis rats had reached a maximal level corresponding to 10 km/d, which slowly decreased to approximately 8 km/d. Fischer rats ran considerably less, averaging approximately 1. 5 km/d by day 30. After 30 d of running, levels of mRNA encoding NGFI-B and Nor1 were decreased in cerebral cortex in Lewis but not Fischer rats. The downregulation of NGFI-B mRNA in Lewis rats could not be attenuated by the opioid receptor antagonist naloxone. Instead, naloxone by itself downregulated NGFI-B in striatum and cerebral cortex in both strains. In contrast, naloxone had no effect on Nor1 mRNA levels, although the running-induced downregulation of Nor1 was, in most cases, attenuated by naloxone. Data from the present study suggest that the same genetic factors contributing to the drug addiction-prone behavior of Lewis rats also control the excessive running behavior and that this coincides with downregulation of transcription factors of the NGFI-B family.

  10. Self-identification of nonpharmaceutical fentanyl exposure following heroin overdose

    PubMed Central

    Griswold, Matthew K.; Chai, Peter R.; Krotulski, Alex J.; Friscia, Melissa; Chapman, Brittany; Boyer, Edward W.; Logan, Barry K.; Babu, Kavita M.

    2018-01-01

    Objective To compare user self-identification of nonpharmaceutical fentanyl exposure with confirmatory urine drug testing in emergency department (ED) patients presenting after heroin overdose. Methods This was a cross-sectional study of adult ED patients who presented after a heroin overdose requiring naloxone administration. Participants provided verbal consent after which they were asked a series of questions regarding their knowledge, attitudes and beliefs toward heroin and non-pharmaceutical fentanyl. Participants also provided urine samples, which were analyzed using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry to identify the presence of fentanyl, heroin metabolites, other clandestine opioids, common pharmaceuticals and drugs of abuse. Results Thirty participants were enrolled in the study period. Ten participants (33%) had never required naloxone for an overdose in the past, 20 participants (67%) reported recent abstinence, and 12 participants (40%) reported concomitant cocaine use. Naloxone was detected in all urine drug screens. Heroin or its metabolites were detected in almost all samples (93.3%), as were fentanyl (96.7%) and its metabolite, norfentanyl (93.3%). Acetylfentanyl was identified in nine samples (30%) while U-47700 was present in two samples (6.7%). Sixteen participants self-identified fentanyl in their heroin (sensitivity 55%); participants were inconsistent in their qualitative ability to identify fentanyl in heroin. Conclusions Heroin users presenting to the ED after heroin overdose requiring naloxone are unable to accurately identify the presence of nonpharmaceutical fentanyl in heroin. Additionally, cutting edge drug testing methodologies identified fentanyl exposures in 96.7% of our patients, as well as unexpected clandestine opioids (like acetylfentanyl and U-47700). PMID:28681615

  11. Potency of three opiate antagonists to reverse the inhibitory activity of dynorphin, enkephalins and opioid-like alkaloids on the guinea pig ileum.

    PubMed

    Yoshimura, K; Huidobro-Toro, J P; Way, E L

    1982-10-15

    To test the hypothesis that dynorphin is a K-opiate agonist acting on the myenteric plexus, the potency of two benzomorphan antagonists (Win 44, 441 and Mr 2266) to block the inhibitory action of dynorphin, enkephalins and opioid alkaloids was determined on the longitudinal muscle preparation of the guinea pig ileum. The effectiveness of these antagonists was compared to that of naloxone. Antagonistic potency was established by calculating the apparent antagonist dissociation constant, Ke, as derived from Schild plots. Win 44, 441 and Mr 2266 were about 7-8 times more potent than naloxone against dynorphin, dynorphin-(1-13) or ethylketocyclazocine. Although the Ke obtained with Win 44, 441 or Mr 2266 against dynorphin or ethylketocyclazocine were significantly lower than those of naloxone, the values obtained for these antagonists did not differ significantly in the case of each of these agonists. With respect to the antagonism of the enkephalins or normorphine, Win 44, 441 was the most potent antagonist. Its Ke value for the enkephalins was 2.5-3 times lower than those for dynorphin or ethylketocyclazocine and in comparison to naloxone, Win 44, 441 was about 5 times more potent. Although Mr 2266 was a potent antagonist of dynorphin, ethylketocyclazocine, the enkephalins or normorphine, it showed no selectivity of action. The fact that the 3 opiate antagonists evidenced similar Ke values for dynorphin and ethylketocyclazocine, but different ones for the enkephalins or normorphine supports the conclusion that dynorphin activates preferentially K- but not mu-opiate receptors in the myenteric plexus.

  12. Opiates modulate insulin action in vivo in dogs.

    PubMed

    Werther, G A; Joffe, S; Artal, R; Sperling, M A

    1984-01-01

    To investigate the influence of opiates on insulin action in vivo, we induced mild physiological hyperinsulinaemia (15-20 mU/l) in five trained conscious dogs in the absence or presence of ongoing infusion with the opiate agonist D-met2-pro5-enkephalinamide (DMPE, 0.5 micrograms X kg-1 X min-1), or the opiate antagonist naloxone (1.25 mg followed by 1 microgram X kg-1 X min-1). The effects on glucose production and glucose utilization were measured by isotope dilution using 3-3H-glucose. Glucose fell similarly over 30 min in response to insulin in controls (0.021 +/- 0.003 mmol X l-1 X min-1), and both the DMPE and naloxone studies (0.016 +/- 0.002 mmol X l-1 X min-1 and 0.017 +/- 0.003 mmol X l-1 X min-1, respectively). In control dogs, insulin lowered glucose by transiently suppressing production by 0.028 +/- 0.006 mmol X kg-1 X min-1 at 20-30 min without changing utilization. In contrast, in both the DMPE and naloxone studies insulin lowered glucose by markedly raising utilization at 20 min by 0.094 +/- 0.017 and 0.139 +/- 0.022 mmol X kg-1 X min-1, respectively. Furthermore, insulin failed to suppress production in both DMPE and naloxone studies and, as plasma glucose fell, production rose in both treatment groups at 20 min by 0.045 +/- 0.012 and 0.089 +/- 0.022 mmol X kg-1 X min-1 respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. Self-identification of nonpharmaceutical fentanyl exposure following heroin overdose.

    PubMed

    Griswold, Matthew K; Chai, Peter R; Krotulski, Alex J; Friscia, Melissa; Chapman, Brittany; Boyer, Edward W; Logan, Barry K; Babu, Kavita M

    2018-01-01

    To compare user self-identification of nonpharmaceutical fentanyl exposure with confirmatory urine drug testing in emergency department (ED) patients presenting after heroin overdose. This was a cross-sectional study of adult ED patients who presented after a heroin overdose requiring naloxone administration. Participants provided verbal consent after which they were asked a series of questions regarding their knowledge, attitudes and beliefs toward heroin and nonpharmaceutical fentanyl. Participants also provided urine samples, which were analyzed using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry to identify the presence of fentanyl, heroin metabolites, other clandestine opioids, common pharmaceuticals and drugs of abuse. Thirty participants were enrolled in the study period. Ten participants (33%) had never required naloxone for an overdose in the past, 20 participants (67%) reported recent abstinence, and 12 participants (40%) reported concomitant cocaine use. Naloxone was detected in all urine drug screens. Heroin or its metabolites were detected in almost all samples (93.3%), as were fentanyl (96.7%) and its metabolite, norfentanyl (93.3%). Acetylfentanyl was identified in nine samples (30%) while U-47700 was present in two samples (6.7%). Sixteen participants self-identified fentanyl in their heroin (sensitivity 55%); participants were inconsistent in their qualitative ability to identify fentanyl in heroin. Heroin users presenting to the ED after heroin overdose requiring naloxone are unable to accurately identify the presence of nonpharmaceutical fentanyl in heroin. Additionally, cutting edge drug testing methodologies identified fentanyl exposures in 96.7% of our patients, as well as unexpected clandestine opioids (like acetylfentanyl and U-47700).

  14. Effects of acupuncture on vasopressin-induced emesis in conscious dogs.

    PubMed

    Tatewaki, Makoto; Strickland, Carmen; Fukuda, Hiroyuki; Tsuchida, Daisuke; Hoshino, Etsuo; Pappas, Theodore N; Takahashi, Toku

    2005-02-01

    Although acupuncture has a significant clinical benefit, the mechanism of acupuncture remains unclear. Vasopressin, a posterior pituitary hormone, is involved in nausea and vomiting in humans and dogs. To investigate the antiemetic effects of acupuncture on vasopressin-induced emesis, gastroduodenal motor activity and the frequency of retching and vomiting were simultaneously recorded in conscious dogs. In seven dogs, four force transducers were implanted on the serosal surfaces of the gastric body, antrum, pylorus, and duodenum. Gastroduodenal motility was continuously monitored throughout the experiment. Vasopressin was intravenously infused at a dose of 0.1 U x kg(-1) x min(-1) for 20 min. Electroacupuncture (EA, 1-30 Hz) at pericardium-6 (PC6), bladder-21 (BL21), or stomach-36 (ST36) was performed before, during, and after the vasopressin infusion. To investigate whether the opioid pathway is involved in EA-induced antiemetic effects, naloxone (a central and peripheral opioid receptor antagonist) or naloxone methiodide (a peripheral opioid receptor antagonist) was administered before, during, and after EA and vasopressin infusion. Intravenous infusion of vasopressin induced retching and vomiting in all dogs tested. Retrograde peristaltic contractions occurred before the onset of retching and vomiting. EA (10 Hz) at PC6 significantly reduced the number of episodes of retching and vomiting. EA at PC6 also suppressed retrograde peristaltic contractions. In contrast, EA at BL21 or ST36 had no antiemetic effects. The antiemetic effect of EA was abolished by pretreatment with naloxone but not naloxone methiodide. It is suggested that the antiemetic effect of acupuncture is mediated via the central opioid pathway.

  15. Combined abuse of clonidine and amitriptyline in a patient on buprenorphine maintenance treatment.

    PubMed

    Seale, J Paul; Dittmer, Trent; Sigman, Erika J; Clemons, Holly; Johnson, J Aaron

    2014-01-01

    Buprenorphine/naloxone maintenance therapy is often prescribed in primary care to treat opioid dependence. Previous reports have described concomitant abuse of opioids and clonidine. In this case, a primary care patient on buprenorphine/naloxone maintenance therapy demonstrating altered mental status, hallucinations, falls, and rebound hypertension was found to be concomitantly abusing clonidine and amitryptyline, which share metabolic pathways with buprenorphine. Clinicians should be aware of patients' combining amitryptyline, clonidine, and gabapentin with buprenorphine to achieve a mood altering state, avoid co-prescribing them if possible, and maintain communication with pharmacies and other providers when they are prescribed.

  16. Combined Abuse of Clonidine and Amitriptyline in a Patient on Buprenorphine Maintenance Treatment

    PubMed Central

    Dittmer, Trent; Sigman, Erika J.; Clemons, Holly; Johnson, J. Aaron

    2014-01-01

    Buprenorphine/naloxone maintenance therapy is often prescribed in primary care to treat opioid dependence. Previous reports have described concomitant abuse of opioids and clonidine. In this case, a primary care patient on buprenorphine/naloxone maintenance therapy demonstrating altered mental status, hallucinations, falls, and rebound hypertension was found to be concomitantly abusing clonidine and amitryptyline, which share metabolic pathways with buprenorphine. Clinicians should be aware of patients' combining amitryptyline, clonidine, and gabapentin with buprenorphine to achieve a mood altering state, avoid co-prescribing them if possible, and maintain communication with pharmacies and other providers when they are prescribed. PMID:25314340

  17. Crosstalk between the equilibrative nucleoside transporter ENT2 and alveolar Adora2b adenosine receptors dampens acute lung injury

    PubMed Central

    Eckle, Tobias; Hughes, Kelly; Ehrentraut, Heidi; Brodsky, Kelley S.; Rosenberger, Peter; Choi, Doo-Sup; Ravid, Katya; Weng, Tingting; Xia, Yang; Blackburn, Michael R.; Eltzschig, Holger K.

    2013-01-01

    The signaling molecule adenosine has been implicated in attenuating acute lung injury (ALI). Adenosine signaling is terminated by its uptake through equilibrative nucleoside transporters (ENTs). We hypothesized that ENT-dependent adenosine uptake could be targeted to enhance adenosine-mediated lung protection. To address this hypothesis, we exposed mice to high-pressure mechanical ventilation to induce ALI. Initial studies demonstrated time-dependent repression of ENT1 and ENT2 transcript and protein levels during ALI. To examine the contention that ENT repression represents an endogenous adaptive response, we performed functional studies with the ENT inhibitor dipyridamole. Dipyridamole treatment (1 mg/kg; EC50=10 μM) was associated with significant increases in ALI survival time (277 vs. 395 min; P<0.05). Subsequent studies in gene-targeted mice for Ent1 or Ent2 revealed a selective phenotype in Ent2−/− mice, including attenuated pulmonary edema and improved gas exchange during ALI in conjunction with elevated adenosine levels in the bronchoalveolar fluid. Furthermore, studies in genetic models for adenosine receptors implicated the A2B adenosine receptor (Adora2b) in mediating ENT-dependent lung protection. Notably, dipyridamole-dependent attenuation of lung inflammation was abolished in mice with alveolar epithelial Adora2b gene deletion. Our newly identified crosstalk pathway between ENT2 and alveolar epithelial Adora2b in lung protection during ALI opens possibilities for combined therapies targeted to this protein set.—Eckle, T., Hughes, K., Ehrentraut, H., Brodsky, K. S., Rosenberger, P., Choi, D.-S., Ravid, K., Weng, T., Xia, Y., Blackburn, M. R., Eltzschig, H. K. Crosstalk between the equilibrative nucleoside transporter ENT2 and alveolar Adora2b adenosine receptors dampens acute lung injury. PMID:23603835

  18. Noninvasive radioisotopic technique for detection of platelet deposition in mitral valve prostheses and quantitation of visceral microembolism in dogs

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Dewanjee, M.K.; Fuster, V.; Rao, S.A.

    1983-05-01

    A noninvasive technique has been developed in the dog model for imaging, with a gamma camera, the platelet deposition on Bjoerk-Shiley mitral valve prostheses early postoperatively. At 25 hours after implantation of the prosthesis and 24 hours after intravenous administration of 400 to 500 microCi of platelets labeled with indium-111, the platelet deposition in the sewing ring and perivalvular cardiac tissue can be clearly delineated in a scintiphotograph. An in vitro technique was also developed for quantitation of visceral microemboli in brain, lungs, kidneys, and other tissues. Biodistribution of the labeled platelets was quantitated, and the tissue/blood radioactivity ratio wasmore » determined in 22 dogs in four groups: unoperated normal dogs, sham-operated dogs, prosthesis-implanted dogs, and prosthesis-implanted dogs treated with dipyridamole before and aspirin and dipyridamole immediately after operation. Fifteen to 20% of total platelets were consumed as a consequence of the surgical procedure. On quantitation, we found that platelet deposition on the components of the prostheses was significantly reduced in prosthesis-implanted animals treated with dipyridamole and aspirin when compared with prosthesis-implanted, untreated dogs. All prosthesis-implanted animals considered together had a twofold to fourfold increase in tissue/blood radioactivity ratio in comparison with unoperated and sham-operated animals, an indication that the viscera work as filters and trap platelet microemboli that are presumably produced in the region of the mitral valve prostheses. In the dog model, indium-111-labeled platelets thus provide a sensitive marker for noninvasive imaging of platelet deposition on mechanical mitral valve prostheses, in vitro evaluation of platelet microembolism in viscera, in vitro quantitation of surgical consumption of platelets, and evaluation of platelet-inhibitor drugs.« less

  19. Analysis of structure and dynamics of superfine polyhydroxybutyrate fibers for targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Olkhov, A.; Kucherenko, E.; Pantyukhov, P.; Zykova, A.; Karpova, S.; Iordanskii, A.

    2017-02-01

    Creation of polymer matrix systems for targeted drug delivery into a living organism is a challenging problem of modern treatment of various diseases and injuries. Poly-3-hydroxybutyrate (PHB) is commonly used for development of therapeutic systems. The aim of this article is to examine the changes in structure and morphology of fibers in presence of dipyridamole (DPD) as model drug for controlled release. It was found that addition of dipyridamole led to disappearance of spindle-shaped nodules on fibers of PHB in comparison with pure PHB. The research of thermophysical parameters showed that specific melting enthalpy (and the degree of crystallinity) of PHB fibers increased with the addition of DPD. With the increasing of DPD content in PHB fibers, more perfect and equilibrium crystal structure was formed. According to analysis of intercrystalline regions of PHB fibers, it was found that as the crystallinity of PHB in intergranular regions rose, the corresponding decrease of radical rotation speed was observed. It was concluded that fibers of PHB can be used for creating therapeutic systems for targeted and prolonged drug delivery.

  20. Pharmacologic Profile of Naloxegol, a Peripherally Acting µ-Opioid Receptor Antagonist, for the Treatment of Opioid-Induced Constipation

    PubMed Central

    Floettmann, Eike; Sostek, Mark; Payza, Kemal; Eldon, Michael

    2017-01-01

    Opioid-induced constipation (OIC) is a common side effect of opioid pharmacotherapy for the management of pain because opioid agonists bind to µ-opioid receptors in the enteric nervous system (ENS). Naloxegol, a polyethylene glycol derivative of naloxol, which is a derivative of naloxone and a peripherally acting µ-opioid receptor antagonist, targets the physiologic mechanisms that cause OIC. Pharmacologic measures of opioid activity and pharmacokinetic measures of central nervous system (CNS) penetration were employed to characterize the mechanism of action of naloxegol. At the human µ-opioid receptor in vitro, naloxegol was a potent inhibitor of binding (Ki = 7.42 nM) and a neutral competitive antagonist (pA2 - 7.95); agonist effects were <10% up to 30 μM and identical to those of naloxone. The oral doses achieving 50% of the maximal effect in the rat for antagonism of morphine-induced inhibition of gastrointestinal transit and morphine-induced antinociception in the hot plate assay were 23.1 and 55.4 mg/kg for naloxegol and 0.69 and 1.14 mg/kg by for naloxone, respectively. In the human colon adenocarcinoma cell transport assay, naloxegol was a substrate for the P-glycoprotein transporter, with low apparent permeability in the apical to basolateral direction, and penetrated the CNS 15-fold slower than naloxone in a rat brain perfusion model. Naloxegol-derived radioactivity was poorly distributed throughout the rat CNS and was eliminated from most tissues within 24 hours. These findings corroborate phase 3 clinical studies demonstrating that naloxegol relieves OIC-associated symptoms in patients with chronic noncancer pain by antagonizing the µ-opioid receptor in the ENS while preserving CNS-mediated analgesia. PMID:28336575

  1. Opiate modulation of monoamines in the chick forebrain: possible role in emotional regulation?

    PubMed

    Baldauf, K; Braun, K; Gruss, M

    2005-02-05

    Numerous studies have shown that the opiate system is crucially involved in emotionally guided behavior. In the present study, we focussed on the medio-rostral neostriatum/hyperstriatum ventrale (MNH) of the chick forebrain. This avian prefrontal cortex analogue is critically involved in auditory filial imprinting, a well-characterized juvenile emotional learning event. The high density of mu-opiate receptors expressed in the MNH led to the hypothesis that mu-opiate receptor-mediated processes may modulate the glutamatergic, dopaminergic, and/or serotonergic neurotransmission within the MNH and thereby have a critical impact on filial imprinting. Using microdialysis and pharmaco-behavioral approaches in young chicks, we demonstrated that: the systemic application of the mu-opiate receptor antagonist naloxone (5, 50 mg/kg) significantly increased extracellular levels of 5-HIAA and HVA; the systemic application of the specific mu-opiate receptor agonist DAGO (5 mg/kg) increased the levels of HVA and taurine, an effect that was antagonized by simultaneously applied naloxone (5 mg/kg); the local application of DAGO (1 mM) had no effects on 5-HIAA, HVA, glutamate, and taurine, however, the effects of systemically injected naloxone (5 mg/kg) were abolished by simultaneously applied DAGO (1 mM); the systemic application of naloxone (5 mg/kg) increased distress behavior (measured as the duration of distress vocalization during separation from the peer group). These results are in line with our hypothesis that the mu-opiate receptor-mediated modulation of serotonergic and dopaminergic neurotransmission alters the emotional and motivational status of the animal and thereby may play a modulatory role during filial imprinting in the newborn animal. 2004 Wiley Periodicals, Inc

  2. Opioid modulation of reflex versus operant responses following stress in the rat.

    PubMed

    King, C D; Devine, D P; Vierck, C J; Mauderli, A; Yezierski, R P

    2007-06-15

    In pre-clinical models intended to evaluate nociceptive processing, acute stress suppresses reflex responses to thermal stimulation, an effect previously described as stress-induced "analgesia." Suggestions that endogenous opioids mediate this effect are based on demonstrations that stress-induced hyporeflexia is enhanced by high dose morphine (>5 mg/kg) and is reversed by naloxone. However, reflexes and pain sensations can be modulated differentially. Therefore, in the present study direct comparisons were made of opioid agonist and antagonist actions, independently and in combination with acute restraint stress in Long Evans rats, on reflex lick-guard (L/G) and operant escape responses to nociceptive thermal stimulation (44.5 degrees C). A high dose of morphine (>8 mg/kg) was required to reduce reflex responding, but a moderate dose of morphine (1 mg/kg) significantly reduced escape responding. The same moderate dose (and also 5 mg/kg) of morphine significantly enhanced reflex responding. Naloxone (3 mg/kg) significantly enhanced escape responding but did not affect L/G responding. Restraint stress significantly suppressed L/G reflexes (hyporeflexia) but enhanced escape responses (hyperalgesia). Stress-induced hyperalgesia was significantly reduced by morphine and enhanced by naloxone. In contrast, stress-induced hyporeflexia was blocked by both naloxone and 1 mg/kg of morphine. Thus, stress-induced hyperalgesia was opposed by endogenous opioid release and by administration of morphine. Stress-induced hyporeflexia was dependent upon endogenous opioid release but was counteracted by a moderate dose of morphine. These data demonstrate a differential modulation of reflex and operant outcome measures by stress and by separate or combined opioid antagonism or administration of morphine.

  3. A preliminary study comparing methadone and buprenorphine in patients with chronic pain and coexistent opioid addiction.

    PubMed

    Neumann, Anne M; Blondell, Richard D; Jaanimägi, Urmo; Giambrone, Amanda K; Homish, Gregory G; Lozano, Jacqueline R; Kowalik, Urszula; Azadfard, Mohammadreza

    2013-01-01

    Patients with opioid addiction who receive prescription opioids for treatment of nonmalignant chronic pain present a therapeutic challenge. Fifty-four participants with chronic pain and opioid addiction were randomized to receive methadone or buprenorphine/naloxone. At the 6-month follow-up examination, 26 (48.1%) participants who remained in the study noted a 12.75% reduction in pain (P = 0.043), and no participants in the methadone group compared to 5 in the buprenorphine group reported illicit opioid use (P = 0.039). Other differences between the two conditions were not found. Long-term, low-dose methadone or buprenorphine/naloxone treatment produced analgesia in participants with chronic pain and opioid addiction.

  4. Opioidergic mechanisms are not involved in the antihyperalgesic effects of carbamazepine and oxcarbazepine.

    PubMed

    Stepanovic-Petrovic, Radica M; Tomic, M A; Vuckovic, S M; Ugresic, N D; Prostran, M S; Boskovic, B

    2007-04-01

    The mechanisms of the analgesic action of carbamazepine and oxcarbazepine, in particular the role of opioid receptors, have not been established precisely. The systemic effects of naloxone, an opioid receptor antagonist, on the antihyperalgesic effects of carbamazepine and oxcarbazepine were examined in the model of inflammatory hyperalgesia induced by the intraplantar (i.pl.) administration of concanavaline A (Con A, 0.8 mg/paw) into the rat hind paw. Naloxone (3 mg/kg; i.p.) did not alter the antihyperalgesic effects of either carbamazepine or oxcarbazepine. These results indicate that the opioid system of pain modulation does not play a significant role in the antihyperalgesic effects of carbamazepine and oxcarbazepine.

  5. Targinact--opioid pain relief without constipation?

    PubMed

    2010-12-01

    Targinact (Napp Pharmaceuticals Ltd) is a modified-release combination product containing the strong opioid oxycodone plus the opioid antagonist naloxone. It is licensed for "severe pain, which can be adequately managed only with opioid analgesics".1 The summary of product characteristics (SPC) states that "naloxone is added to counteract opioid-induced constipation by blocking the action of oxycodone at opioid receptors locally in the gut". Advertising for the product claims "better pain relief", "superior GI [gastrointestinal] tolerability" and "improved quality of life" "compared to previous treatment in a clinical practice study (n=7836)". Here we consider whether Targinact offers advantages over using strong opioids plus laxatives where required.

  6. Palonosetron and Hydroxyzine Pre-treatment Reduces the Objective Signs of Experimentally-Induced Acute Opioid Withdrawal in Humans: A Double-Blinded, Randomized, Placebo-Controlled Crossover Study

    PubMed Central

    Erlendson, Matthew; D'Arcy, Nicole; Encisco, Ellen; Yu, Jeff; Rincon-Cruz, Lorena; Peltz, Gary; Clark, J. David

    2017-01-01

    Background Treatments for reducing opioid withdrawal are limited and prone to problematic side effects. Laboratory studies, clinical observations, and limited human trial data suggest 5-HT3-receptor antagonists and antihistamines may be effective. Objectives This double-blind, crossover, placebo-controlled study employing an acute physical dependence model evaluated whether (i) treatment with a 5-HT3-receptor antagonist (palonosetron) would reduce opioid withdrawal symptoms, and (ii) co-administration of an antihistamine (hydroxyzine) would enhance any treatment effect. Methods At timepoint T=0, healthy (non-opioid dependent, non-substance abuser) male volunteers (N=10) were pre-treated with either a) placebo, b) palonosetron IV (0.75 mg), or c) palonosetron IV (0.75 mg) and hydroxyzine PO (100 mg) in a crossover study design. This was followed at T=30 by intravenous morphine (10mg/70kg). At T=165, 10mg/70kg naloxone IV was given to precipitate opioid withdrawal. The objective opioid withdrawal score (OOWS) and subjective opioid withdrawal score (SOWS) were determined 5 and 15 minutes after naloxone administration (T=170, 180, respectively). Baseline measurements were recorded at T=-30 and T=-15. Results Comparison of average baseline OOWS scores with OOWS scores obtained fifteen minutes after naloxone was significant (p=0.0001). Scores from fifteen minutes post-naloxone infusion showed significant differences in OOWS scores between treatment groups: placebo, 3.7 ± 2.4; palonosetron, 1.5± 0.97; and palonosetron with hydroxyzine, 0.2 ± .1333. Conclusions Pretreatment with palonosetron significantly reduced many signs of experimental-induced opioid withdrawal. Co-administration with hydroxyzine further reduced opioid withdrawal severity. These results suggest that 5-HT3 receptor antagonists, alone or in combination with an antihistamine, may be useful in the treatment of opioid withdrawal. PMID:27712113

  7. Dark chocolate receptors: epicatechin-induced cardiac protection is dependent on delta-opioid receptor stimulation.

    PubMed

    Panneerselvam, Mathivadhani; Tsutsumi, Yasuo M; Bonds, Jacqueline A; Horikawa, Yousuke T; Saldana, Michelle; Dalton, Nancy D; Head, Brian P; Patel, Piyush M; Roth, David M; Patel, Hemal H

    2010-11-01

    Epicatechin, a flavonoid, is a well-known antioxidant linked to a variety of protective effects in both humans and animals. In particular, its role in protection against cardiovascular disease has been demonstrated by epidemiologic studies. Low-dose epicatechin, which does not have significant antioxidant activity, is also protective; however, the mechanism by which low-dose epicatechin induces this effect is unknown. Our laboratory tested the hypothesis that low-dose epicatechin mediates cardiac protection via opioid receptor activation. C57BL/6 mice were randomly assigned to 1 of 10 groups: control, epicatechin, naloxone (nonselective opioid receptor antagonist), epicatechin + naloxone, naltrindole (δ-specific opioid receptor antagonist), epicatechin + naltrindole, norbinaltorphimine (nor-BNI, κ-specific opioid receptor antagonist), epicatechin + nor-BNI, 5-hydroxydecanoic acid [5-HD, ATP-sensitive potassium channel antagonist], and epicatechin + 5-HD. Epicatechin (1 mg/kg) or other inhibitors (5 mg/kg) were administered by oral gavage or intraperitoneal injection, respectively, daily for 10 days. Mice were subjected to 30 min coronary artery occlusion followed by 2 h of reperfusion, and infarct size was determined via planimetry. Whole heart homogenates were assayed for downstream opioid receptor signaling targets. Infarct size was significantly reduced in epicatechin- and epicatechin + nor-BNI-treated mice compared with control mice. This protection was blocked by naloxone, naltrindole, and 5-HD. Epicatechin and epicatechin + nor-BNI increased the phosphorylation of Src, Akt, and IκBα, while simultaneously decreasing the expression of c-Jun NH(2)-terminal kinase and caspase-activated DNase. All signaling effects are consistent with opioid receptor stimulation and subsequent cardiac protection. Naloxone, naltrindole, and 5-HD attenuated these effects. In conclusion, epicatechin acts via opioid receptors and more specifically through the δ-opioid receptor to

  8. Pharmacologic Profile of Naloxegol, a Peripherally Acting µ-Opioid Receptor Antagonist, for the Treatment of Opioid-Induced Constipation.

    PubMed

    Floettmann, Eike; Bui, Khanh; Sostek, Mark; Payza, Kemal; Eldon, Michael

    2017-05-01

    Opioid-induced constipation (OIC) is a common side effect of opioid pharmacotherapy for the management of pain because opioid agonists bind to µ -opioid receptors in the enteric nervous system (ENS). Naloxegol, a polyethylene glycol derivative of naloxol, which is a derivative of naloxone and a peripherally acting µ -opioid receptor antagonist, targets the physiologic mechanisms that cause OIC. Pharmacologic measures of opioid activity and pharmacokinetic measures of central nervous system (CNS) penetration were employed to characterize the mechanism of action of naloxegol. At the human µ -opioid receptor in vitro, naloxegol was a potent inhibitor of binding ( K i = 7.42 nM) and a neutral competitive antagonist (p A 2 - 7.95); agonist effects were <10% up to 30 μ M and identical to those of naloxone. The oral doses achieving 50% of the maximal effect in the rat for antagonism of morphine-induced inhibition of gastrointestinal transit and morphine-induced antinociception in the hot plate assay were 23.1 and 55.4 mg/kg for naloxegol and 0.69 and 1.14 mg/kg by for naloxone, respectively. In the human colon adenocarcinoma cell transport assay, naloxegol was a substrate for the P-glycoprotein transporter, with low apparent permeability in the apical to basolateral direction, and penetrated the CNS 15-fold slower than naloxone in a rat brain perfusion model. Naloxegol-derived radioactivity was poorly distributed throughout the rat CNS and was eliminated from most tissues within 24 hours. These findings corroborate phase 3 clinical studies demonstrating that naloxegol relieves OIC-associated symptoms in patients with chronic noncancer pain by antagonizing the µ -opioid receptor in the ENS while preserving CNS-mediated analgesia. Copyright © 2017 The Author(s).

  9. Hot and Cold Drugs: National Park Service Medication Stability at the Extremes of Temperature.

    PubMed

    Armenian, Patil; Campagne, Danielle; Stroh, Geoff; Ives Tallman, Crystal; Zeng, William Z D; Lin, Thomas; Gerona, Roy R

    2017-01-01

    National Park Service (NPS) Parkmedics provide medical care in austere environments. The objective of this study was to evaluate the stability of specific medications used by Parkmedics at extremes of temperatures likely to be faced in the field. This is a bench research study conducted in the laboratory setting over a 4-week period. Parenteral medications were separated into 4 temperature exposure groups: A) 45°C (hot); B) -20°C (cold); C) hot then cold temperatures alternating weekly; and D) cold then hot temperatures alternating weekly. At study start and the end of each week, three aliquots from each group were sampled to determine the remaining drug concentration through liquid chromatography-quadrupole time-of-flight mass spectrometry (Agilent LC 1260- QTOF/MS 6550). Quantitative analysis was done using Agilent MassHunter Quantitative Analysis software. The mean drug concentration from triplicate aliquots was expressed as percentage of its baseline concentration to monitor the drug's stability during storage. Eight medications were analyzed (atropine, diphenhydramine, fentanyl, hydromorphone, midazolam, morphine, naloxone, ondansetron). Hydromorphone, morphine, and ondansetron showed the greatest stability, at above 90% of original concentration in all study arms. Diphenhydramine, fentanyl and midazolam showed heat independent degradation, degrading the same way regardless of heat exposure. By the end of the study period, 51-56% midazolam remained in all groups. Atropine and naloxone showed heat dependent degradation, degrading more when exposed to heat. Atropine had the most degradation, being undetectable after 4 weeks of heat exposure. We recommend that EMS providers replace atropine, naloxone, diphenhydramine, fentanyl, and midazolam frequently if they are practicing in low call volume or high-temperature environments. Further studies will be needed to determine if re-dosing midazolam, naloxone, and atropine is the appropriate clinical strategy in this

  10. Opioid activation of Toll-Like receptor 4 contributes to drug reinforcement

    PubMed Central

    Hutchinson, M.R.; Northcutt, A.L.; Hiranita, T.; Wang, X.; Lewis, S.; Thomas, J.; van Steeg, K.; Kopajtic, T.A.; Loram, L.; Sfregola, C.; Galer, E.; Miles, N.E.; Bland, S.T.; Amat, J.; Rozeske, R.R.; Maslanik, T.; Chapman, T.; Strand, K.; Fleshner, M.; Bachtell, R.K.; Somogyi, A.A.; Yin, H.; Katz, J.L.; Rice, K.C.; Maier, S.F.; Watkins, L.R.

    2012-01-01

    Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, Toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the non-opioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knockouts of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4 −/− mice had reduced oxycodone-induced p38 and JNK phosphorylation, whilst displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system which amplifies opioid-induced elevations in extracellular dopamine levels and therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward. PMID:22895704

  11. Pharmacogenetic analysis of opioid dependence treatment dose and dropout rate.

    PubMed

    Crist, Richard C; Li, James; Doyle, Glenn A; Gilbert, Alex; Dechairo, Bryan M; Berrettini, Wade H

    2018-01-01

    Currently, no pharmacogenetic tests for selecting an opioid-dependence pharmacotherapy have been approved by the US Food and Drug Administration. Determine the effects of variants in 11 genes on dropout rate and dose in patients receiving methadone or buprenorphine/naloxone (ClinicalTrials.gov Identifier: NCT00315341). Variants in six pharmacokinetic genes (CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4) and five pharmacodynamic genes (HTR2A, OPRM1, ADRA2A, COMT, SLC6A4) were genotyped in samples from a 24-week, randomized, open-label trial of methadone and buprenorphine/naloxone for the treatment of opioid dependence (n = 764; 68.7% male). Genotypes were then used to determine the metabolism phenotype for each pharmacokinetic gene. Phenotypes or genotypes for each gene were analyzed for association with dropout rate and mean dose. Genotype for 5-HTTLPR in the SLC6A4 gene was nominally associated with dropout rate when the methadone and buprenorphine/naloxone groups were combined. When the most significant variants associated with dropout rate were analyzed using pairwise analyses, SLC6A4 (5-HTTLPR) and COMT (Val158Met; rs4860) had nominally significant associations with dropout rate in methadone patients. None of the genes analyzed in the study was associated with mean dose of methadone or buprenorphine/naloxone. This study suggests that functional polymorphisms related to synaptic dopamine or serotonin levels may predict dropout rates during methadone treatment. Patients with the S/S genotype at 5-HTTLPR in SLC6A4 or the Val/Val genotype at Val158Met in COMT may require additional treatment to improve their chances of completing addiction treatment. Replication in other methadone patient populations will be necessary to ensure the validity of these findings.

  12. Functional role of peripheral opioid receptors in the regulation of cardiac spinal afferent nerve activity during myocardial ischemia

    PubMed Central

    Longhurst, John C.

    2013-01-01

    Thinly myelinated Aδ-fiber and unmyelinated C-fiber cardiac sympathetic (spinal) sensory nerve fibers are activated during myocardial ischemia to transmit the sensation of angina pectoris. Although recent observations showed that myocardial ischemia increases the concentrations of opioid peptides and that the stimulation of peripheral opioid receptors inhibits chemically induced visceral and somatic nociception, the role of opioids in cardiac spinal afferent signaling during myocardial ischemia has not been studied. The present study tested the hypothesis that peripheral opioid receptors modulate cardiac spinal afferent nerve activity during myocardial ischemia by suppressing the responses of cardiac afferent nerve to ischemic mediators like bradykinin and extracellular ATP. The nerve activity of single unit cardiac afferents was recorded from the left sympathetic chain (T2–T5) in anesthetized cats. Forty-three ischemically sensitive afferent nerves (conduction velocity: 0.32–3.90 m/s) with receptive fields in the left and right ventricles were identified. The responses of these afferent nerves to repeat ischemia or ischemic mediators were further studied in the following protocols. First, epicardial administration of naloxone (8 μmol), a nonselective opioid receptor antagonist, enhanced the responses of eight cardiac afferent nerves to recurrent myocardial ischemia by 62%, whereas epicardial application of vehicle (PBS) did not alter the responses of seven other cardiac afferent nerves to ischemia. Second, naloxone applied to the epicardial surface facilitated the responses of seven cardiac afferent nerves to epicardial ATP by 76%. Third, administration of naloxone enhanced the responses of seven other afferent nerves to bradykinin by 85%. In contrast, in the absence of naloxone, cardiac afferent nerves consistently responded to repeated application of ATP (n = 7) or bradykinin (n = 7). These data suggest that peripheral opioid peptides suppress the

  13. Randomized controlled pilot trial of naloxone‐on‐release to prevent post‐prison opioid overdose deaths

    PubMed Central

    Parmar, Mahesh K. B.; Strang, John; Choo, Louise; Meade, Angela M.

    2016-01-01

    Abstract Background and Aims Naloxone is an opioid antagonist used for emergency resuscitation following opioid overdose. Prisoners with a history of heroin injection have a high risk of drug‐related death soon after release from prison. The NALoxone InVEstigation (N‐ALIVE) pilot trial (ISRCTN34044390) tested feasibility measures for randomized provision of naloxone‐on‐release (NOR) to eligible prisoners in England. Design. Parallel‐group randomized controlled pilot trial. Setting English prisons. Participants A total of 1685 adult heroin injectors, incarcerated for at least 7 days pre‐randomization, release due within 3 months and more than 6 months since previous N‐ALIVE release. Intervention Using 1 : 1 minimization, prisoners were randomized to receive on release a pack containing either a single ‘rescue’ injection of naloxone or a control pack with no syringe. Measurements Key feasibility outcomes were tested against prior expectations: on participation (14 English prisons; 2800 prisoners), consent (75% for randomization), returned prisoner self‐questionnaires (RPSQs: 207), NOR‐carriage (75% in first 4 weeks) and overdose presence (80%). Findings Prisons (16) and prisoners (1685) were willing to participate [consent rate, 95% confidence interval (CI) = 70–74%]; 218 RPSQs were received; NOR‐carriage (95% CI = 63–79%) and overdose presence (95% CI = 75–84%) were as expected. We randomized 842 to NOR and 843 to control during 30 months but stopped early, because only one‐third of NOR administrations were to the ex‐prisoner. Nine deaths within 12 weeks of release were registered for 1557 randomized participants released before 9 December 2014. Conclusions Large randomized trials are feasible with prison populations. Provision of take‐home emergency naloxone prior to prison release may be a life‐saving interim measure to prevent heroin overdose deaths among ex‐prisoners and the wider population. PMID:27776382

  14. Immediate and long-term effects of opiate antagonists on postictal behaviour following amygdala kindling in the rat.

    PubMed

    Cottrell, G A; Bohus, B

    1987-09-23

    Male Wistar rats implanted with bipolar electrodes in the amygdaloid complex were kindled. Subcutaneous injection of naloxone or naltrexone in low doses--0.12 and 0.24 mg/kg, respectively--dramatically reduced the postictal behavioural depression (BD) at 10 or 60 min. Remarkably, the BD was still reduced one day later. It would appear that the brain mechanisms involved in postictal BD use mu-receptors since BD is quite sensitive to low doses of the preferential antagonists naloxone and naltrexone. The long-term effects, the most novel aspect of these studies, are probably related to immediate effects but could be produced through slow genomic processes or alteration of the response to endogenously released enkephalins.

  15. Pharmacologic intervention as an alternative to exercise stress

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gould, K.L.

    1987-04-01

    Although thallium exercise imaging has served an important role in clinical cardiology, it is significantly limited by suboptimal sensitivity and specificity, particularly in asymptomatic man. The increasing recognition of silent myocardial ischemia, the significant prevalence of coronary artery disease in asymptomatic middle age men, and the frequent occurrence of myocardial infarction without preceding symptoms in 60% of cases emphasizes the need for a more definitive, noninvasive diagnostic test for the presence of coronary artery disease suitable for screening in asymptomatic or symptomatic patients. Intravenous dipyridamole combined with handgrip stress provides a potent stimulus for purposes of diagnostic perfusion imaging. Althoughmore » planar and single photon emission computed tomography (SPECT) imaging also have played an important role, these techniques are seriously hindered by their inability to quantitate radiotracer uptake or image modest differences in maximum relative flow caused by coronary artery stenosis. Accordingly, the combination of dipyridamole-handgrip stress with positron imaging of myocardial perfusion has become a powerful diagnostic tool suitable for routine clinical use. With the availability of generator-produced rubidium-82, dedicated clinically oriented positron cameras, the routine application of positron imaging to clinical cardiology has become feasible. 75 references.« less

  16. Tunable Elastomers with an Antithrombotic Component for Cardiovascular Applications.

    PubMed

    Stahl, Alexander M; Yang, Yunzhi Peter

    2018-05-31

    This study reports the development of a novel family of biodegradable polyurethanes for use as tissue engineered cardiovascular scaffolds or blood-contacting medical devices. Covalent incorporation of the antiplatelet agent dipyridamole into biodegradable polycaprolactone-based polyurethanes yields biocompatible materials with improved thromboresistance and tunable mechanical strength and elasticity. Altering the ratio of the dipyridamole to the diisocyanate linking unit and the polycaprolactone macromer enables control over both the drug content and the polymer cross-link density. Covalent cross-linking in the materials achieves significant elasticity and a tunable range of elastic moduli similar to that of native cardiovascular tissues. Interestingly, the cross-link density of the polyurethanes is inversely related to the elastic modulus, an effect attributed to decreasing crystallinity in the more cross-linked polymers. In vitro characterization shows that the antiplatelet agent is homogeneously distributed in the materials and is released slowly throughout the polymer degradation process. The drug-containing polyurethanes support endothelial cell and vascular smooth muscle cell proliferation, while demonstrating reduced levels of platelet adhesion and activation, supporting their candidacy as promising substrates for cardiovascular tissue engineering. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Intraplantar injection of bergamot essential oil induces peripheral antinociception mediated by opioid mechanism.

    PubMed

    Sakurada, Tsukasa; Mizoguchi, Hirokazu; Kuwahata, Hikari; Katsuyama, Soh; Komatsu, Takaaki; Morrone, Luigi Antonio; Corasaniti, Maria Tiziana; Bagetta, Giacinto; Sakurada, Shinobu

    2011-01-01

    This study investigated the effect of bergamot essential oil (BEO) containing linalool and linalyl acetate as major volatile components in the capsaicin test. The intraplantar injection of capsaicin (1.6 μg) produced a short-lived licking/biting response toward the injected paw. The nociceptive behavioral response evoked by capsaicin was inhibited dose-dependently by intraplantar injection of BEO. Both linalool and linalyl acetate, injected into the hindpaw, showed a significant reduction of nociceptive response, which was much more potent than BEO. Intraperitoneal (i.p.) and intraplantar pretreatment with naloxone hydrochloride, an opioid receptor antagonist, significantly reversed BEO- and linalool-induced antinociception. Pretreatment with naloxone methiodide, a peripherally acting μ-opioid receptor preferring antagonist, resulted in a significant antagonizing effect on antinociception induced by BEO and linalool. Antinociception induced by i.p. or intrathecal morphine was enhanced by the combined injection of BEO or linalool. The enhanced effect of combination of BEO or linalool with morphine was antagonized by pretreatment with naloxone hydrochloride. Our results provide evidence for the involvement of peripheral opioids, in the antinociception induced by BEO and linalool. Combined administration of BEO or linalool acting at the peripheral site, and morphine may be a promising approach in the treatment of clinical pain. Copyright © 2010 Elsevier Inc. All rights reserved.

  18. Effect of environmental enrichment on physical and psychological dependence signs and voluntary morphine consumption in morphine-dependent and morphine-withdrawn rats.

    PubMed

    Hammami-Abrand Abadi, Arezoo; Miladi-Gorji, Hossein; Bigdeli, Imanollah

    2016-04-01

    This study was designed to examine the effect of environmental enrichment during morphine dependency and withdrawal on the severity of naloxone-precipitated withdrawal signs, anxiety, and depressive-like behaviors and voluntary morphine consumption in morphine-dependent rats. The rats were injected with bi-daily doses (10 mg/kg, 12 h intervals) of morphine for 14 days following rearing in a standard environment (SE) or enriched environment (EE) during the development of morphine dependence and withdrawal. Then, rats were tested for withdrawal signs after naloxone injection, anxiety (the elevated plus maze) and depression-related behavior (sucrose preference test), and voluntary consumption of morphine using a two-bottle choice paradigm, in morphine-dependent and morphine-withdrawn rats. The results showed that EE decreased naloxone-precipitated withdrawal signs, but not anxiety or sucrose preference during dependence on morphine. The EE-withdrawn rats showed an increase in the elevated plus maze open arm time and entries and higher levels of sucrose preference than SE rats. Voluntary consumption of morphine was lower in the EE-withdrawn rats than in the SE groups in the second period of drug intake. Thus, exposure to EE reduced the severity of morphine dependence and voluntary consumption of morphine, alongside reductions in anxiety and depression-related behavior in morphine-withdrawn rats.

  19. Management of an oral ingestion of transdermal fentanyl patches: a case report and literature review.

    PubMed

    Faust, Andrew C; Terpolilli, Ralph; Hughes, Darrel W

    2011-01-01

    Purpose. Fentanyl is available as a transdermal system for the treatment of chronic pain in opioid-tolerant patients; however, it carries a black box warning due to both the potency of the product and the potential for abuse. In this report, we describe a case of transbuccal and gastrointestinal ingestion of fentanyl patches and the management of such ingestion. Summary. A 32-year-old man was brought to the emergency department (ED) via emergency medical services for toxic ingestion and suicide attempt. The patient chewed and ingested two illegally purchased transdermal fentanyl patches. In the ED, the patient was obtunded, dizzy and drowsy. Initial vital signs showed the patient to be afebrile and normotensive with a heart rate of 63, respiratory rate of 16, and oxygen saturation of 100% on 2 liters nasal cannula after administration of 2 milligrams of intravenous naloxone. The patient was treated with whole bowel irrigation and continuous intravenous naloxone infusion for approximately 48 hours without complications. Conclusion. Despite numerous case reports describing oral ingestion of fentanyl patches, information on the management of such intoxication is lacking. We report successful management of such a case utilizing whole bowel irrigation along with intravenous push and continuous infusion naloxone.

  20. Management of an Oral Ingestion of Transdermal Fentanyl Patches: A Case Report and Literature Review

    PubMed Central

    Faust, Andrew C.; Terpolilli, Ralph; Hughes, Darrel W.

    2011-01-01

    Purpose. Fentanyl is available as a transdermal system for the treatment of chronic pain in opioid-tolerant patients; however, it carries a black box warning due to both the potency of the product and the potential for abuse. In this report, we describe a case of transbuccal and gastrointestinal ingestion of fentanyl patches and the management of such ingestion. Summary. A 32-year-old man was brought to the emergency department (ED) via emergency medical services for toxic ingestion and suicide attempt. The patient chewed and ingested two illegally purchased transdermal fentanyl patches. In the ED, the patient was obtunded, dizzy and drowsy. Initial vital signs showed the patient to be afebrile and normotensive with a heart rate of 63, respiratory rate of 16, and oxygen saturation of 100% on 2 liters nasal cannula after administration of 2 milligrams of intravenous naloxone. The patient was treated with whole bowel irrigation and continuous intravenous naloxone infusion for approximately 48 hours without complications. Conclusion. Despite numerous case reports describing oral ingestion of fentanyl patches, information on the management of such intoxication is lacking. We report successful management of such a case utilizing whole bowel irrigation along with intravenous push and continuous infusion naloxone. PMID:21629807

  1. A nationwide pharmacy chain responds to the opioid epidemic.

    PubMed

    Shafer, Emily; Bergeron, Nyahne; Smith-Ray, Renae; Robson, Chester; O'Koren, Rachel

    To describe the 3-pronged approach taken by a large national retail pharmacy chain to address the opioid epidemic and associated overdoses. Large national retail pharmacy chain with more than 8200 stores in 50 states. Eight million customer interactions daily through in-store and digital settings. This is a company with a long history of responding to public health crises. Initiated 3 programs to respond to the opioid crisis: 1) provide safe medication disposal kiosks; 2) expand national access to naloxone; and 3) provide education on the risk and avoidance of opioid overdose. Used the RE-AIM framework to evaluate and enhance the quality, speed, and public health impact of the interventions. Not applicable. Early results are safe medication disposal kiosks in more than 43 states, naloxone-dispensing program in 33 states, and patient and support system education using the Opioid Overdose Toolkit from the Substance Abuse and Mental Health Services Administration. The availability of safe drug-disposal kiosks, naloxone dispensing at pharmacies, and patient education are key prevention initiatives to address the opioid epidemic and reduce the increasing national burden of opioid overdose. Early results are quantitatively and qualitatively promising. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  2. Routine Clinical Quantitative Rest Stress Myocardial Perfusion for Managing Coronary Artery Disease: Clinical Relevance of Test-Retest Variability.

    PubMed

    Kitkungvan, Danai; Johnson, Nils P; Roby, Amanda E; Patel, Monika B; Kirkeeide, Richard; Gould, K Lance

    2017-05-01

    Positron emission tomography (PET) quantifies stress myocardial perfusion (in cc/min/g) and coronary flow reserve to guide noninvasively the management of coronary artery disease. This study determined their test-retest precision within minutes and daily biological variability essential for bounding clinical decision-making or risk stratification based on low flow ischemic thresholds or follow-up changes. Randomized trials of fractional flow reserve-guided percutaneous coronary interventions established an objective, quantitative, outcomes-driven standard of physiological stenosis severity. However, pressure-derived fractional flow reserve requires invasive coronary angiogram and was originally validated by comparison to noninvasive PET. The time course and test-retest precision of serial quantitative rest-rest and stress-stress global myocardial perfusion by PET within minutes and days apart in the same patient were compared in 120 volunteers undergoing serial 708 quantitative PET perfusion scans using rubidium 82 (Rb-82) and dipyridamole stress with a 2-dimensional PET-computed tomography scanner (GE DST 16) and University of Texas HeartSee software with our validated perfusion model. Test-retest methodological precision (coefficient of variance) for serial quantitative global myocardial perfusion minutes apart is ±10% (mean ΔSD at rest ±0.09, at stress ±0.23 cc/min/g) and for days apart is ±21% (mean ΔSD at rest ±0.2, at stress ±0.46 cc/min/g) reflecting added biological variability. Global myocardial perfusion at 8 min after 4-min dipyridamole infusion is 10% higher than at standard 4 min after dipyridamole. Test-retest methodological precision of global PET myocardial perfusion by serial rest or stress PET minutes apart is ±10%. Day-to-different-day biological plus methodological variability is ±21%, thereby establishing boundaries of variability on physiological severity to guide or follow coronary artery disease management. Maximum stress

  3. Presence of cardiovascular structural changes in essential hypertensive patients with coronary microvascular disease and effects of long-term treatment.

    PubMed

    Virdis, A; Ghiadoni, L; Lucarini, A; Di Legge, V; Taddei, S; Salvetti, A

    1996-04-01

    In asymptomatic essential hypertensive patients with angiographically normal coronary arteries and without left ventricular hypertrophy, dipyridamole-induced ischemic-like ST segment depression may be a marker of coronary microvascular disease. In this study we evaluated, first, whether this cardiac abnormality is linked to structural or functional vascular abnormalities, and second, the effect of antihypertensive treatment by 12-month administration of the angiotensin converting enzyme (ACE) inhibitor captopril (50 mg twice a day orally). In essential hypertensives with dipypridamole echocardiography stress test (DET) (DET+, n = 8) and without (DET-, n = 8) ST segment depression greater than 0.1 mV during intravenous dipyridamole infusion (0.84 mg/kg over 10 min), we studied the forearm blood flow (FBF, venous plethysmography, mL/100) modifications induced by intrabrachial acetylcholine (Ach) (0.15, 0.45, 1.5, 4.5, 15 micrograms/100 mL/min x 5 min each), an endothelium-dependent vasodilator, and by sodium nitroprusside (SNP) (1, 2, 4 micrograms/100 mL/min x 5 min each), a smooth muscle cell relaxant compound. Minimal forearm vascular resistances (MFVR), an index of arteriolar structural changes, were also calculated. Both Ach and SNP caused greater vasodilation in DET- as compared to DET+ while MFVRs were lower in DET- compared to DET+. After treatment, both DET+ and DET- patients showed a significant and similar reduction in blood pressure and left ventricular mass index, while vasodilation to acetylcholine and sodium nitroprusside was increased only in the DET+ group. In addition, forearm minimal vascular resistances were significantly reduced only in DET+ patients, who showed disappearance of dipyridamole-induced ischemic-like ST segment depression. In conclusion, these data confirm that essential hypertensive patients with microvascular coronary disease are characterized by the presence of structural changes in the forearm vascular bed. Our results also

  4. Prevalence of ex vivo high on-treatment platelet reactivity on antiplatelet therapy after transient ischemic attack or ischemic stroke on the PFA-100(®) and VerifyNow(®).

    PubMed

    Kinsella, Justin A; Tobin, W Oliver; Cox, Dermot; Coughlan, Tara; Collins, Ronan; O'Neill, Desmond; Murphy, Raymond P; McCabe, Dominick J H

    2013-10-01

    The prevalence of ex vivo high on-treatment platelet reactivity (HTPR) to commonly prescribed antiplatelet regimens after transient ischemic attack (TIA) or ischemic stroke is uncertain. Platelet function inhibition was simultaneously assessed with modified light transmission aggregometry (VerifyNow; Accumetrics Inc, San Diego, CA) and with a moderately high shear stress platelet function analyzer (PFA-100; Siemens Medical Solutions USA, Inc, Malvern, PA) in a pilot, cross-sectional study of TIA or ischemic stroke patients. Patients were assessed on aspirin-dipyridamole combination therapy (n = 51) or clopidogrel monotherapy (n = 25). On the VerifyNow, HTPR on aspirin was identified in 4 of 51 patients (8%) on aspirin-dipyridamole combination therapy (≥ 550 aspirin reaction units on the aspirin cartridge). Eleven of 25 (44%) patients had HTPR on clopidogrel (≥ 194 P2Y12 reaction units on the P2Y12 cartridge). On the PFA-100, 21 of 51 patients (41%) on aspirin-dipyridamole combination therapy had HTPR on the collagen-epinephrine (C-EPI) cartridge. Twenty-three of 25 patients (92%) on clopidogrel had HTPR on the collagen-adenosine diphosphate (C-ADP) cartridge. The proportion of patients with antiplatelet HTPR was lower on the VerifyNow than PFA-100 in patients on both regimens (P < .001). The prevalence of ex vivo antiplatelet HTPR after TIA or ischemic stroke is markedly influenced by the method used to assess platelet reactivity. The PFA-100 C-ADP cartridge is not sensitive at detecting the antiplatelet effects of clopidogrel ex vivo. Larger prospective studies with the VerifyNow and with the PFA-100 C-EPI and recently released Innovance PFA P2Y cartridges (Siemens Medical Solutions USA, Inc) in addition to newer tests of platelet function are warranted to assess whether platelet function monitoring predicts clinical outcome in ischemic cerebrovascular disease. Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  5. The panicolytic-like effect of fluoxetine in the elevated T-maze is mediated by serotonin-induced activation of endogenous opioids in the dorsal periaqueductal grey.

    PubMed

    Roncon, Camila M; Biesdorf, Carla; Santana, Rosangela G; Zangrossi, Hélio; Graeff, Frederico G; Audi, Elisabeth A

    2012-04-01

    Serotonin (5-HT), opioids and the dorsal periaqueductal grey (DPAG) have been implicated in the pathophysiology of panic disorder. In order to study 5-HT-opioid interaction, the opioid antagonist naloxone was injected either systemically (1 mg/kg, i.p.) or intra-DPAG (0.2 μg/0.5 μL) to assess its interference with the effect of chronic fluoxetine (10 mg/kg, i.p., daily for 21 days) or of intra-DPAG 5-HT (8 μg/0.5 μL). Drug effects were measured in the one-escape task of the rat elevated T-maze, an animal model of panic. Pretreatment with systemic naloxone antagonized the lengthening of escape latency caused by chronic fluoxetine, considered a panicolytic-like effect that parallels the drug's therapeutic response in the clinics. Pretreatment with naloxone injected intra-DPAG antagonized both the panicolytic effect of chronic fluoxetine as well as that of 5-HT injected intra-DPAG. Neither the performance of the inhibitory avoidance task in the elevated T-maze, a model of generalized anxiety nor locomotion measured in a circular arena was affected by the above drug treatments. These results indicate that the panicolytic effect of fluoxetine is mediated by endogenous opioids that are activated by 5-HT in the DPAG. They also allow reconciliation between the serotonergic and opioidergic hypotheses of panic disorder pathophysiology.

  6. Antinociceptive effect and mechanism of action of isatin, N-methyl isatin and oxopropyl isatin in mice.

    PubMed

    Giorno, Thais Biondino Sardella; Silva, Bárbara Vasconcellos da; Pinto, Angelo da Cunha; Fernandes, Patricia Dias

    2016-04-15

    There has been growing interest in the synthesis of new derivatives from isatin, found in Isatis genus. Our objectives were to characterize the antinociceptive mechanism of action of isatin, N-methyl-isatin (MI) and N-methyl-3-(2-oxopropyl)-3-hydroxy-2-oxindole (MOI). Substances (0.1-10mg/kg, p.o.) were studied in chemical (paw licking induced by formalin, capsaicin or glutamate) or thermal (hot plate) models of nociception. The involvement of several systems was evaluated using different receptor antagonists. All three substances inhibit both phases of formalin-induced licking, increase the area under the curve and MI and MOI have a higher effect than that of morphine (in hot plate). Capsaicin and glutamate-induced licking were also reduced by all three substances. In the hot plate model, the antinociceptive effect of isatin was reduced by naloxone and atropine; naloxone, atropine and L-NAME reduced MI effect while naloxone, atropine, L-NAME, mecamylamine and ondansetron reduced MOI effect. Our results suggest that isatin, MI and MOI: 1) present activity in models of nociception; 2) capsaicin and glutamate receptors seems to participate in the mechanism of action; 3) opioid, cholinergic, serotoninergic, nitrergic and adrenergic systems may be involved, at least in part, in the mechanism of action of some of these substances. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. D-phenylalanine: a putative enkephalinase inhibitor studied in a primate acute pain model.

    PubMed

    Halpern, L M; Dong, W K

    1986-02-01

    D-Phenylalanine, along with morphine, acetylsalicylic acid and zomepirac sodium were evaluated for their antinociceptive actions in monkeys (M. fascicularis) trained to autoregulate nociceptive stimulation using a discrete-trials, aversive-threshold paradigm. Morphine sulfate produced dose-related increases in aversive threshold which were reversible after administration of naloxone (12.5 or 25 micrograms/kg i.m.). D-Phenylalanine (500 mg/kg p.o.) produced a small increase in aversive threshold which was not statistically significant and not naloxone reversible. Acetylsalicylic acid (200 mg/kg p.o.) but not zomepirac sodium (200 mg/kg p.o.) in combination with D-phenylalanine (500 mg/kg) produced a small statistically significant increase in aversive threshold. Our results argue against the hypothesis that D-phenylalanine is responsible for increasing aversive thresholds via opiate receptor mechanisms involving increased activity of enkephalins at synaptic loci. Previous studies by others in rats and mice showed that D-phenylalanine and acetylsalicylic acid produced increases in nociceptive thresholds which were naloxone reversible. Our failure to find opiate receptor mediated analgesia in a primate model with demonstrated opiate receptor selectivity and sensitivity is discussed in terms of previous basic and clinical research indicating an analgesic role for D-phenylalanine. Possible species difference in drug action is discussed in terms of inhibition by D-phenylalanine of carboxy-peptidase-like enkephalin processing enzymes as well as inhibition of carboxypeptidase-like enkephalin degrading enzymes.

  8. Effect of Nimodipine on Morphine-related Withdrawal Syndrome in Rat Model: An Observational Study

    PubMed Central

    Mishra, Pravash Ranjan; Barik, Mayadhar; Ray, Subrata Basu

    2017-01-01

    Objective: To observe the effect of L-type calcium channel blocker like nimodipine on morphine's withdrawal when it was administered continuously along with morphine versus a single bolus dose of nimodipine, which was administered at the end of the experiment before the precipitation of withdrawal reaction in morphine-dependent rats. Materials and Methods: Four groups of adult male Wistar rats were rendered morphine dependent by subcutaneous injections of morphine at a dose of 10 mg/kg for 10 days. Nimodipine 10 mg/kg intraperitoneally (ip) administered to one group once daily before morphine administration in the entire experimental period, and another group received nimodipine only once at the end of the experiment as a single bolus dose 2 mg/kg before the administration of naloxone. Naloxone 3 mg/kg was administered ip to all the groups to precipitate withdrawal reactions. The withdrawal reactions were evaluated and scored as per the Gellert and Holtzman global withdrawal rating scale. Results: Nimodipine when administered as a single bolus dose before naloxone administration in morphine-dependant rats reduced the features of withdrawal reactions more effectively than continuous administration of nimodipine along with morphine throughout the experimental period. Conclusion: We discovered that nimodipine helps in attenuating the severity of morphine withdrawal having potential role encountered during pharmacotherapy with morphine management of opioid dependence, well memory, impairement, cell signaling and phosphorylation of neuron. PMID:28553371

  9. Effect of Nimodipine on Morphine-related Withdrawal Syndrome in Rat Model: An Observational Study.

    PubMed

    Mishra, Pravash Ranjan; Barik, Mayadhar; Ray, Subrata Basu

    2017-01-01

    To observe the effect of L-type calcium channel blocker like nimodipine on morphine's withdrawal when it was administered continuously along with morphine versus a single bolus dose of nimodipine, which was administered at the end of the experiment before the precipitation of withdrawal reaction in morphine-dependent rats. Four groups of adult male Wistar rats were rendered morphine dependent by subcutaneous injections of morphine at a dose of 10 mg/kg for 10 days. Nimodipine 10 mg/kg intraperitoneally (ip) administered to one group once daily before morphine administration in the entire experimental period, and another group received nimodipine only once at the end of the experiment as a single bolus dose 2 mg/kg before the administration of naloxone. Naloxone 3 mg/kg was administered ip to all the groups to precipitate withdrawal reactions. The withdrawal reactions were evaluated and scored as per the Gellert and Holtzman global withdrawal rating scale. Nimodipine when administered as a single bolus dose before naloxone administration in morphine-dependant rats reduced the features of withdrawal reactions more effectively than continuous administration of nimodipine along with morphine throughout the experimental period. We discovered that nimodipine helps in attenuating the severity of morphine withdrawal having potential role encountered during pharmacotherapy with morphine management of opioid dependence, well memory, impairement, cell signaling and phosphorylation of neuron.

  10. Blockade of Opioid Receptors in the Medullary Reticularis Nucleus Dorsalis, but not the Rostral Ventromedial Medulla, Prevents Analgesia Produced by Diffuse Noxious Inhibitory Control in Rats With Muscle Inflammation

    PubMed Central

    de Resende, Marcos A.; Silva, Luis Felipe S.; Sato, Karina; Arendt-Nielsen, Lars; Sluka, Kathleen A.

    2014-01-01

    Diffuse Noxious Inhibitory Controls (DNIC) involves application of a noxious stimulus outside the testing site to produce analgesia. In human subjects with a variety of chronic pain conditions, DNIC is less effective; however, in animal studies, DNIC is more effective after tissue injury. While opioids are involved in DNIC analgesia, the pathways involved in this opioid-induced analgesia are not clear. The aim of the present study was to test the effectiveness of DNIC in inflammatory muscle pain, and to study which brainstem sites mediate DNIC- analgesia. Rats were injected with 3% carrageenan into their gastrocnemius muscle and responses to cutaneous and muscle stimuli were assessed before and after inflammation, and before and after DNIC induced by noxious heat applied to the tail (45°C and 47°C). Naloxone was administered systemically, into rostral ventromedial medulla (RVM), or bilaterally into the medullary reticularis nucleus dorsalis (MdD) prior to the DNIC-conditioning stimuli. DNIC produced a similar analgesic effect in both acute and the chronic phases of inflammation reducing both cutaneous and muscle sensitivity in a dose-dependent manner. Naloxone systemically or microinjected into the MdD prevented DNIC-analgesia, while naloxone into the RVM had no effect on DNIC analgesia. Thus, DNIC analgesia involves activation of opioid receptors in the MdD. PMID:21330219

  11. Mindfulness Meditation Modulates Pain Through Endogenous Opioids.

    PubMed

    Sharon, Haggai; Maron-Katz, Adi; Ben Simon, Eti; Flusser, Yuval; Hendler, Talma; Tarrasch, Ricardo; Brill, Silviu

    2016-07-01

    Recent evidence supports the beneficial effects of mindfulness meditation on pain. However, the neural mechanisms underlying this effect remain poorly understood. We used an opioid blocker to examine whether mindfulness meditation-induced analgesia involves endogenous opioids. Fifteen healthy experienced mindfulness meditation practitioners participated in a double-blind, randomized, placebo-controlled, crossover study. Participants rated the pain and unpleasantness of a cold stimulus prior to and after a mindfulness meditation session. Participants were then randomized to receive either intravenous naloxone or saline, after which they meditated again, and rated the same stimulus. A (3) × (2) repeated-measurements analysis of variance revealed a significant time effect for pain and unpleasantness scores (both P <.001) as well as a significant condition effect for pain and unpleasantness (both P <.2). Post hoc comparisons revealed that pain and unpleasantness scores were significantly reduced after natural mindfulness meditation and after placebo, but not after naloxone. Furthermore, there was a positive correlation between the pain scores following naloxone vs placebo and participants' mindfulness meditation experience. These findings show, for the first time, that meditation involves endogenous opioid pathways, mediating its analgesic effect and growing resilient with increasing practice to external suggestion. This finding could hold promising therapeutic implications and further elucidate the fine mechanisms involved in human pain modulation. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Adenosine uptake is the major effector of extracellular ATP toxicity in human cervical cancer cells

    PubMed Central

    Mello, Paola de Andrade; Filippi-Chiela, Eduardo Cremonese; Nascimento, Jéssica; Beckenkamp, Aline; Santana, Danielle Bertodo; Kipper, Franciele; Casali, Emerson André; Nejar Bruno, Alessandra; Paccez, Juliano Domiraci; Zerbini, Luiz Fernando; Wink, Marcia Rosângela; Lenz, Guido; Buffon, Andréia

    2014-01-01

    In cervical cancer, HPV infection and disruption of mechanisms involving cell growth, differentiation, and apoptosis are strictly linked with tumor progression and invasion. Tumor microenvironment is ATP and adenosine rich, suggesting a role for purinergic signaling in cancer cell growth and death. Here we investigate the effect of extracellular ATP on human cervical cancer cells. We find that extracellular ATP itself has a small cytotoxic effect, whereas adenosine formed from ATP degradation by ectonucleotidases is the main factor responsible for apoptosis induction. The level of P2×7 receptor seemed to define the main cytotoxic mechanism triggered by ATP, since ATP itself eliminated a small subpopulation of cells that express high P2×7 levels, probably through its activation. Corroborating these data, blockage or knockdown of P2×7 only slightly reduced ATP cytotoxicity. On the other hand, cell viability was almost totally recovered with dipyridamole, an adenosine transporter inhibitor. Moreover, ATP-induced apoptosis and signaling—p53 increase, AMPK activation, and PARP cleavage—as well as autophagy induction were also inhibited by dipyridamole. In addition, inhibition of adenosine conversion into AMP also blocked cell death, indicating that metabolization of intracellular adenosine originating from extracellular ATP is responsible for the main effects of the latter in human cervical cancer cells. PMID:25103241

  13. Effects of food restriction on expression of place conditioning and biochemical correlates in rat nucleus accumbens.

    PubMed

    Jung, Caroline; Rabinowitsch, Ariana; Lee, Wei Ting; Zheng, Danielle; de Vaca, Soledad Cabeza; Carr, Kenneth D

    2016-09-01

    When ad libitum-fed rats undergo cocaine place preference conditioning (CPP) but are switched to food restriction for testing, CPP becomes resistant to extinction and correlates with phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 at Ser845 in nucleus accumbens (NAc) core. This study tested whether food restriction increases persistence of morphine CPP and conditioned place aversions (CPA) induced by LiCl and naloxone-precipitated morphine withdrawal. Ad libitum-fed rats were conditioned with morphine (6.0 mg/kg, i.p.), LiCl (50.0/75.0 mg/kg, i.p.), or naloxone (1.0 mg/kg, s.c.) 22 h post-morphine (20.0 mg/kg, s.c.). Half of the subjects were then switched to food restriction. Daily testing resumed 3 weeks later, and brains were harvested when one diet group met extinction criterion. Western analyses probed for pSer845-GluA1, pERK1, and pERK2 in NAc. Food restriction increased persistence of morphine CPP and preference scores correlated with pSer845-GluA1 in NAc core and shell. LiCl CPA was curtailed by food restriction, yet pSer845-GluA1 and pERK2 were elevated in NAc core of food-restricted rats. Food restriction increased persistence of naloxone CPA and elevated pSer845-GluA1 in NAc core and shell, and aversion scores were negatively correlated with pERK1 and pERK2 in NAc core. These results suggest that food restriction prolongs responsiveness to environmental contexts paired with subjective effects of both morphine and morphine withdrawal. A mechanistic scheme, attributing these effects to upregulation of pSer845-GluA1, but subject to override by CPA-specific, pERK2-mediated extinction learning, is explored to accommodate opposite effects of food restriction on LiCl and naloxone CPA.

  14. Neurobiological Aspects of Mindfulness in Pain Autoregulation: Unexpected Results from a Randomized-Controlled Trial and Possible Implications for Meditation Research.

    PubMed

    Esch, Tobias; Winkler, Jeremy; Auwärter, Volker; Gnann, Heike; Huber, Roman; Schmidt, Stefan

    2016-01-01

    Background: Research has demonstrated that short meditation training may yield higher pain tolerance in acute experimental pain. Our study aimed at examining underlying mechanisms of this alleged effect. In addition, placebo research has shown that higher pain tolerance is mediated via endogenous neuromodulators: experimental inhibition of opioid receptors by naloxone antagonized this effect. We performed a trial to discern possible placebo from meditation-specific effects on pain tolerance and attention. Objectives: It was proposed that (i) meditation training will increase pain tolerance; (ii) naloxone will inhibit this effect; (iii) increased pain tolerance will correlate with improved attention performance and mindfulness. Methods: Randomized-controlled, partly blinded trial with 31 healthy meditation-naïve adults. Pain tolerance was assessed by the tourniquet test, attention performance was measured by Attention Network Test (ANT), self-perceived mindfulness by Freiburg Mindfulness Inventory. 16 participants received a 5-day meditation training, focusing on body/breath awareness; the control group ( N = 15) received no intervention. Measures were taken before the intervention and on 3 consecutive days after the training, with all participants receiving either no infusion, naloxone infusion, or saline infusion (blinded). Blood samples were taken in order to determine serum morphine and morphine glucuronide levels by applying liquid chromatography-tandem mass spectrometry analysis. Results: The meditation group produced fewer errors in ANT. Paradoxically, increases in pain tolerance occurred in both groups (accentuated in control), and correlated with reported mindfulness. Naloxone showed a trend to decrease pain tolerance in both groups. Plasma analyses revealed sporadic morphine and/or morphine metabolite findings with no discernable pattern. Discussion: Main objectives could not be verified. Since underlying study goals had not been made explicit to

  15. Pentazocine overdose

    MedlinePlus

    ... have signs of opioid intoxication. Opioids are powerful painkillers. Symptoms may include: Bluish skin color (cyanosis) Breathing ... naloxone (Narcan), an antidote to help reverse the effect of the poison, multiple doses may be needed. ...

  16. Morphine overdose

    MedlinePlus

    ... tests Chest x-ray EKG (electrocardiogram, or heart tracing) Fluids through a vein (IV) Laxative Naloxone, a ... Toxicology Data Network. Morphine. Toxnet.nlm.nih.gov Web site. toxnet.nlm.nih.gov/cgi-bin/sis/ ...

  17. Antidiuretic effect of morphine in the rat: tolerance and physical dependence.

    PubMed Central

    Huidobro, F

    1978-01-01

    1 Injection of rats with morphine or methadone, before they received a water load equivalent to 5% of their body weight, produced a dose-dependent antidiuretic effect. Following the antidiuresis, urine was eliminated with kinetics similar to control untreated rats. 2 The antidiuretic effect of morphine or methadone was blocked by naloxone administered before the opiate, or reversed when given after the opiate. 3 Rats implanted with morphine pellets developed a marked degree of tolerance to the antidiuretic effect of morphine. Tolerance was also obtained on injection of three daily doses of morphine or methadone over two days. 4 Withdrawal symptoms were precipitated by naloxone in rats implanted with pellets of morphine; under these conditions the animals showed a marked reduction in urine production as compared to naive rats. PMID:568501

  18. Agmatine reduces only peripheral-related behavioral signs, not the central signs, of morphine withdrawal in nNOS deficient transgenic mice.

    PubMed

    Aricioglu, Feyza; Paul, Ian A; Regunathan, Soundar

    2004-01-09

    Agmatine inhibits morphine tolerance/dependence and potentiates morphine analgesia. This study was designed to investigate whether neuronal nitric oxide mediates the actions of agmatine in morphine dependence by using mice lacking a functional form of this enzyme. Mice received agmatine just after the morphine pellet implantation for 3 days twice daily or single injection 30 min before naloxone. In both genotypes treated for 3 days with morphine pellets, naloxone administration precipitated clear signs of withdrawal. Both acute and chronic administration of agmatine reduced withdrawal signs in wild type mice and reduced only peripheral signs of morphine dependence in neuronal nitric oxide synthase knockout mice. Withdrawal signs, that are related to central nervous system activity were not affected. These findings indicate that neuronal nitric oxide synthase partly mediates the effects of agmatine in morphine physical dependence.

  19. HIV Treatment Outcomes Among HIV-Infected, Opioid-Dependent Patients Receiving Buprenorphine/Naloxone Treatment within HIV Clinical Care Settings: Results From a Multisite Study

    PubMed Central

    Altice, Frederick L.; Bruce, R. Douglas; Lucas, Gregory M.; Lum, Paula J.; Korthuis, P. Todd; Flanigan, Timothy P.; Cunningham, Chinazo O.; Sullivan, Lynn E.; Vergara-Rodriguez, Pamela; Fiellin, David A.; Cajina, Adan; Botsko, Michael; Nandi, Vijay; Gourevitch, Marc N.; Finkelstein, Ruth

    2012-01-01

    Background Having opioid dependence and HIV infection are associated with poor HIV-related treatment outcomes. Methods HIV-infected, opioid-dependent subjects (N = 295) recruited from 10 clinical sites initiated buprenorphine/naloxone (BUP/NX) and were assessed at baseline and quarterly for 12 months. Primary outcomes included receiving antiretroviral therapy (ART), HIV-1 RNA suppression, and mean changes in CD4 lymphocyte count. Analyses were stratified for the 119 subjects not on ART at baseline. Generalized estimating equations were deployed to examine time-dependent correlates for each outcome. Results At baseline, subjects on ART (N = 176) were more likely than those not on ART (N = 119) to be older, heterosexual, have lower alcohol addiction severity scores, and lower HIV-1 RNA levels; they were less likely to be homeless and report sexual risk behaviors. Subjects initiating BUP/NX (N = 295) were significantly more likely to initiate or remain on ART and improve CD4 counts over time compared with baseline; however, these improvements were not significantly improved by longer retention on BUP/NX. Retention on BUP/NX for three or more quarters was, however, significantly associated with increased likelihood of initiating ART (β = 1.34 [1.18, 1.53]) and achieve viral suppression (β = 1.25 [1.10, 1.42]) for the 64 of 119 (54%) subjects not on ART at baseline compared with the 55 subjects not retained on BUP/NX. In longitudinal analyses, being on ART was positively associated with increasing time of observation from baseline and higher mental health quality of life scores (β = 1.25 [1.06, 1.46]) and negatively associated with being homo- or bisexual (β = 0.55 [0.35, 0.97]), homeless (β = 0.58 [0.34, 0.98]), and increasing levels of alcohol addiction severity (β = 0.17 [0.03, 0.88]). The strongest correlate of achieving viral suppression was being on ART (β = 10.27 [5.79, 18.23]). Female gender (β = 1.91 [1.07, 3.41]), Hispanic ethnicity (β = 2.82 [1.44, 5

  20. Social and structural aspects of the overdose risk environment in St. Petersburg, Russia.

    PubMed

    Green, Traci C; Grau, Lauretta E; Blinnikova, Ksenia N; Torban, Mikhail; Krupitsky, Evgeny; Ilyuk, Ruslan; Kozlov, Andrei; Heimer, Robert

    2009-05-01

    While overdose is a common cause of mortality among opioid injectors worldwide, little information exists on opioid overdoses or how context may influence overdose risk in Russia. This study sought to uncover social and structural aspects contributing to fatal overdose risk in St. Petersburg and assess prevention intervention feasibility. Twenty-one key informant interviews were conducted with drug users, treatment providers, toxicologists, police, and ambulance staff. Thematic coding of interview content was conducted to elucidate elements of the overdose risk environment. Several factors within St. Petersburg's environment were identified as shaping illicit drug users' risk behaviours and contributing to conditions of suboptimal response to overdose in the community. Most drug users live and experience overdoses at home, where family and home environment may mediate or moderate risk behaviours. The overdose risk environment is also worsened by inefficient emergency response infrastructure, insufficient cardiopulmonary or naloxone training resources, and the preponderance of abstinence-based treatment approaches to the exclusion of other treatment modalities. However, attitudes of drug users and law enforcement officials generally support overdose prevention intervention feasibility. Modifiable aspects of the risk environment suggest community-based and structural interventions, including overdose response training for drug users and professionals that encompasses naloxone distribution to the users and equipping more ambulances with naloxone. Local social and structural elements influence risk environments for overdose. Interventions at the community and structural levels to prevent and respond to opioid overdoses are needed for and integral to reducing overdose mortality in St. Petersburg.

  1. Opioid receptor agonists may favorably affect bone mechanical properties in rats with estrogen deficiency-induced osteoporosis.

    PubMed

    Janas, Aleksandra; Folwarczna, Joanna

    2017-02-01

    The results of epidemiological, clinical, and in vivo and in vitro experimental studies on the effect of opioid analgesics on bone are inconsistent. The aim of the present study was to investigate the effect of morphine (an agonist of opioid receptors), buprenorphine (a partial μ opioid receptor agonist and κ opioid receptor antagonist), and naloxone (an antagonist of opioid receptors) on the skeletal system of female rats in vivo. The experiments were carried out on 3-month-old Wistar rats, divided into two groups: nonovariectomized (intact; NOVX) rats and ovariectomized (OVX) rats. The bilateral ovariectomy was performed 7 days before the start of drug administration. Morphine hydrochloride (20 mg/kg/day s.c.), buprenorphine (0.05 mg/kg/day s.c.), or naloxone hydrochloride dihydrate (2 mg/kg/day s.c.) were administered for 4 weeks to NOVX and OVX rats. In OVX rats, the use of morphine and buprenorphine counteracted the development of osteoporotic changes in the skeletal system induced by estrogen deficiency. Morphine and buprenorphine beneficially affected also the skeletal system of NOVX rats, but the effects were much weaker than those in OVX rats. Naloxone generally did not affect the rat skeletal system. The results confirmed the role of opioid receptors in the regulation of bone remodeling processes and demonstrated, in experimental conditions, that the use of opioid analgesics at moderate doses may exert beneficial effects on the skeletal system, especially in estrogen deficiency.

  2. Interaction of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and opioid receptors in spinal cord nociceptive reflexes.

    PubMed

    Ramos-Zepeda, Guillermo; Herrero, Juan F

    2013-08-14

    We previously observed that the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) is a very effective antinociceptive agent on intact but not on spinalized adult rats with inflammation. Since a close connection between opioid and adenosine A1 receptors has been described, we studied a possible relationship between these systems in the spinal cord. CPA-mediated antinociception was challenged by the selective adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dimethylxanthine (CPT) and by the opioid receptor antagonist naloxone on male adult Wistar rats with carrageenan-induced inflammation. Withdrawal reflexes activated by noxious mechanical and electrical stimulation were recorded using the single motor technique in intact and sham-spinalized animals. CPA was very effective in intact and sham spinalized rats but not in spinalized animals. Full reversal of CPA antinociception was observed with i.v. 1mg/kg of naloxone but not with 20mg/kg of CPT i.v. in responses to noxious mechanical and electrical stimulation. CPT fully prevented CPA from any antinociceptive action whereas naloxone did not modify CPA activity. These results suggest a centrally-mediated action, since CPA depressed the wind-up phenomenon which is derived of the activity of spinal cord neurons. The present study provides strong in vivo evidence of an antinociceptive activity mediated by the adenosine A1 receptor system in the spinal cord, linked to an activation of opioid receptors in adult animals with inflammation. © 2013.

  3. Evaluation of 6 remote First Nations community-based buprenorphine programs in northwestern Ontario: Retrospective study.

    PubMed

    Mamakwa, Solomon; Kahan, Meldon; Kanate, Dinah; Kirlew, Mike; Folk, David; Cirone, Sharon; Rea, Sara; Parsons, Pierre; Edwards, Craig; Gordon, Janet; Main, Fiona; Kelly, Len

    2017-02-01

    To evaluate established opioid addiction treatment programs that use traditional healing in combination with buprenorphine-naloxone maintenance treatment in 6 First Nations communities in the Sioux Lookout region of northwestern Ontario. Retrospective cohort study. Six First Nations communities in northwestern Ontario. A total of 526 First Nations participants in opioid-dependence treatment programs. Buprenorphine-naloxone substitution therapy and First Nations healing programming. Retention rates and urine drug screening (UDS) results. Treatment retention rates at 6, 12, and 18 months were 84%, 78%, and 72%, respectively. We estimate that the rate at 24 months will also be more than 70%. The UDS programming varied and was implemented in only 1 community. Initially urine testing was voluntary and it then became mandatory. Screening with either method found the proportion of urine samples with negative results for illicit opioids ranged between 84% and 95%. The program's treatment retention rates and negative UDS results were higher than those reported for most methadone and buprenorphine-naloxone programs, despite a patient population where severe posttraumatic stress disorder is endemic, and despite the programs' lack of resources and addiction expertise. Community-based programs like these overcome the initial challenge of cultural competence. First Nations communities in other provinces should establish their own buprenorphinenaloxone programs, using local primary care physicians as prescribers. Sustainable core funding is needed for programming, long-term aftercare, and trauma recovery for such initiatives. Copyright© the College of Family Physicians of Canada.

  4. Evaluation of 6 remote First Nations community-based buprenorphine programs in northwestern Ontario

    PubMed Central

    Mamakwa, Solomon; Kahan, Meldon; Kanate, Dinah; Kirlew, Mike; Folk, David; Cirone, Sharon; Rea, Sara; Parsons, Pierre; Edwards, Craig; Gordon, Janet; Main, Fiona; Kelly, Len

    2017-01-01

    Abstract Objective To evaluate established opioid addiction treatment programs that use traditional healing in combination with buprenorphine-naloxone maintenance treatment in 6 First Nations communities in the Sioux Lookout region of northwestern Ontario. Design Retrospective cohort study. Setting Six First Nations communities in northwestern Ontario. Participants A total of 526 First Nations participants in opioid-dependence treatment programs. Intervention Buprenorphine-naloxone substitution therapy and First Nations healing programming. Main outcome measures Retention rates and urine drug screening (UDS) results. Results Treatment retention rates at 6, 12, and 18 months were 84%, 78%, and 72%, respectively. We estimate that the rate at 24 months will also be more than 70%. The UDS programming varied and was implemented in only 1 community. Initially urine testing was voluntary and it then became mandatory. Screening with either method found the proportion of urine samples with negative results for illicit opioids ranged between 84% and 95%. Conclusion The program’s treatment retention rates and negative UDS results were higher than those reported for most methadone and buprenorphine-naloxone programs, despite a patient population where severe posttraumatic stress disorder is endemic, and despite the programs’ lack of resources and addiction expertise. Community-based programs like these overcome the initial challenge of cultural competence. First Nations communities in other provinces should establish their own buprenorphinenaloxone programs, using local primary care physicians as prescribers. Sustainable core funding is needed for programming, long-term aftercare, and trauma recovery for such initiatives. PMID:28209683

  5. Systemic morphine blocks the seizures induced by intracerebroventricular (i.c.v.) injections of opiates and opioid peptides.

    PubMed

    Urca, G; Frenk, H

    1982-08-19

    Intracerebroventricular (i.c.v.) injections of the endorphins and of morphine in rats produce highly characteristic, naloxone sensitive, electrographic seizures. In contrast, systemic injections of morphine have been shown to exert a marked anticonvulsant effect. The present study demonstrates that systemic morphine pretreatment can prevent the occurrence of electrographic seizures injected by i.c.v. morphine, Leu-enkephalin and beta-endorphin and that the anti-epileptic effect of morphine can be reversed by naloxone. Male albino rats, previously prepared for chronic i.c.v. injections and EEG recordings, were pretreated with 0--100 mg/kg of intraperitoneal (i.p.) morphine. Thirty five minutes later morphine (520 nmol), Leu-enkephalin (80 nmol) or beta-endorphin (5 nmol) were injected i.c.v. Pretreatment with i.p. morphine blocked the occurrence of seizures induced by morphine and both endogenous opioids. Lower doses of systemic morphine (50 mg/kg) were necessary to block i.c.v. morphine seizures than the dose (100 mg/kg) necessary to block seizures induced by i.c.v. Leu-enkephalin and beta-endorphin. Naloxone (1 mg/kg) administered 25 min following 50 mg/kg of i.p. morphine and preceding the injections of i.c.v. morphine reversed the antiepileptic effect of systemic morphine. These results demonstrate the possible existence of two opiate sensitive systems, one with excitatory-epileptogenic effects and the other possessing inhibitory-antiepileptic properties. The possible relationship between these findings and the known heterogeneity of opiate receptors and opiate actions is discussed.

  6. Opiate-induced seizures: a study of mu and delta specific mechanisms.

    PubMed

    Snead, O C

    1986-08-01

    Two groups of experiments were conducted to determine if morphine- and enkephalin-induced seizures are specifically mediated by the mu and delta receptor, respectively. In the first experiments, designed to assess the ontogeny of mu- or delta-seizures, rats from 6 h to 85 days of age received implanted cortical and depth electrodes as well as an indwelling cannula in the lateral ventricle. Various amounts of the mu-receptor agonists, morphine and morphiceptin, and the delta agonists, D-Ala2-D-Leu5-enkephalin (DADL) and Tyr-D-Ser-Gly-Phe-Leu-Thr (DSLET), were then administered intracerebroventricularly (icv) with continuous EEG monitoring. The second experiments entailed use of the nonspecific opiate antagonist, naloxone, as well as the specific delta antagonist, ICI 154,129, against seizures induced by icv-administered morphine, morphiceptin, DADL, or DSLET. Both morphine and morphiceptin produced electrical seizure activity in rats as young as 5 days after birth. The drugs produced similar seizure activity in terms of electrical morphology, observed behavior, ontogeny, threshold dose, and reversibility with small doses of naloxone. In the pharmacologic experiments, icv naloxone blocked all opiate-induced seizures. ICI 154,129 blocked DSLET seizure, had little effect on enkephalin or DADL seizures, and no effect on morphine or morphiceptin seizures. These data indicate that DSLET seizures are delta-specific but that all other opiate-induced seizures studied may involve multiple opiate receptor-mediated mechanisms.

  7. Injection drug users trained by overdose prevention programs: Responses to witnessed overdoses

    PubMed Central

    Lankenau, Stephen E.; Wagner, Karla D.; Silva, Karol; Kecojevic, Aleksander; Iverson, Ellen; McNeely, Miles; Kral, Alex H.

    2012-01-01

    In response to the growing public health problem of drug overdose, community-based organizations have initiated overdose prevention programs (OPP), which distribute naloxone, an opioid antagonist, and teach overdose response techniques. Injection drug users (IDUs) have been targeted for this intervention due to their high risk for drug overdose. Limited research attention has focused on factors that may inhibit or prevent IDUs who have been trained by OPPs to undertake recommended response techniques when responding to a drug overdose. IDUs (n=30) trained by two OPPs in Los Angeles were interviewed in 2010–11 about responses to their most recently witnessed drug overdose using an instrument containing both open and closed-ended questions. Among the 30 witnessed overdose events, the victim recovered in 29 cases while the outcome was unknown in one case. Participants responded to overdoses using a variety of techniques taught by OPP. Injecting the victim with naloxone was the most common recommended response while other recommended responses included stimulating the victim with knuckles, calling 911, and giving rescue breathing. Barriers preventing participants from employing recommended response techniques in certain circumstances included prior successes using folk remedies to revive a victim, concerns over attracting police to the scene, and issues surrounding access to or use of naloxone. Practical solutions, such as developing booster sessions to augment OPP, are encouraged to increase the likelihood that trained participants respond to a drug overdose with the full range of recommended techniques. PMID:22847602

  8. Ondansetron does not prevent physical dependence in patients taking opioid medications chronically for pain control.

    PubMed

    Chu, Larry F; Rico, Tom; Cornell, Erika; Obasi, Hannah; Encisco, Ellen M; Vertelney, Haley; Gamble, Jamison G; Crawford, Clayton W; Sun, John; Clemenson, Anna; Erlendson, Matthew J; Okada, Robin; Carroll, Ian; Clark, J David

    2018-02-01

    In this study, we investigated the co-administration of ondansetron with morphine, and whether it could prevent the development of physical dependence in patients taking opioids for the treatment of chronic pain. A total of 48 chronic back pain patients (N = 48) participated in this double-blinded, placebo-controlled, randomized study. Patients were titrated onto sustained-release oral morphine and randomized to take 8 mg ondansetron or placebo three times daily concurrently with morphine during the 30-day titration. Following titration, patients underwent Naloxone induced opioid withdrawal. Opioid withdrawal signs and symptoms were then assessed by a blinded research assistant (objective opioid withdrawal score: OOWS) and by the research participant (subjective opioid withdrawal score: SOWS). We observed clinically significant signs of naloxone-precipitated opioid withdrawal in all participants (ΔOOWS = 4.3 ± 2.4, p < 0.0001; ΔSOWS = 14.1 ± 11.7, p < 0.0001), however no significant differences in withdrawal scores were detected between treatment groups. We hypothesized that ondansetron would prevent the development of physical dependence in human subjects when co-administered with opioids, but found no difference in naloxone-precipitated opioid withdrawal scores between ondansetron and placebo treatment groups. These results suggest that further studies are needed to determine if 5HT 3 receptor antagonists are useful in preventing opioid physical dependence. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Absence of opioid stress-induced analgesia in mice lacking beta-endorphin by site-directed mutagenesis.

    PubMed

    Rubinstein, M; Mogil, J S; Japón, M; Chan, E C; Allen, R G; Low, M J

    1996-04-30

    A physiological role for beta-endorphin in endogenous pain inhibition was investigated by targeted mutagenesis of the proopiomelanocortin gene in mouse embryonic stem cells. The tyrosine codon at position 179 of the proopiomelanocortin gene was converted to a premature translational stop codon. The resulting transgenic mice display no overt developmental or behavioral alterations and have a normally functioning hypothalamic-pituitary-adrenal axis. Homozygous transgenic mice with a selective deficiency of beta-endorphin exhibit normal analgesia in response to morphine, indicating the presence of functional mu-opiate receptors. However, these mice lack the opioid (naloxone reversible) analgesia induced by mild swim stress. Mutant mice also display significantly greater nonopioid analgesia in response to cold water swim stress compared with controls and display paradoxical naloxone-induced analgesia. These changes may reflect compensatory upregulation of alternative pain inhibitory mechanisms.

  10. Absence of opioid stress-induced analgesia in mice lacking beta-endorphin by site-directed mutagenesis.

    PubMed Central

    Rubinstein, M; Mogil, J S; Japón, M; Chan, E C; Allen, R G; Low, M J

    1996-01-01

    A physiological role for beta-endorphin in endogenous pain inhibition was investigated by targeted mutagenesis of the proopiomelanocortin gene in mouse embryonic stem cells. The tyrosine codon at position 179 of the proopiomelanocortin gene was converted to a premature translational stop codon. The resulting transgenic mice display no overt developmental or behavioral alterations and have a normally functioning hypothalamic-pituitary-adrenal axis. Homozygous transgenic mice with a selective deficiency of beta-endorphin exhibit normal analgesia in response to morphine, indicating the presence of functional mu-opiate receptors. However, these mice lack the opioid (naloxone reversible) analgesia induced by mild swim stress. Mutant mice also display significantly greater nonopioid analgesia in response to cold water swim stress compared with controls and display paradoxical naloxone-induced analgesia. These changes may reflect compensatory upregulation of alternative pain inhibitory mechanisms. Images Fig. 1 Fig. 2 PMID:8633004

  11. NAGD regimen for the coma of drug-related overdose.

    PubMed

    Rappolt, R T; Gay, G R; Decker, W J; Inaba, D S

    1980-07-01

    A specific arousal therapy with NAGD (Naloxone, Activated Charcoal, Glucagon, Doxapram) is outlined for victims of drug overdose in comatose and semi-comatose states. Several direct benefits accrue if early awakening or lightening of such patients is safely accomplished. There are: 1) elimination of need for prolonged intubation or tracheostomy; 2) patient's ability to tell which drug(s) were taken; 3) excessively frantic and vigorous supportive treatment is obviated; and 4) the overall hospital stay is shortened. The NAGD regimen has been found to effectively, safely, and predictably reverse coma. Therapy consists of: naloxone 0.8 mg to 1.6 mg intravenously; large-bore orogastric tube instillation of 100 gm to 120 gm activated charcoal slurry; glucagon 1 mg to 2 mg intravenously; and, in selected cases, doxapram 1 mg/kg to 2 mg/kg intravenously.

  12. Chemical anesthesia of Northern sea otters (Enhydra lutris): Results of past field studies

    USGS Publications Warehouse

    Monson, Daniel H.; McCormick, C.; Ballachey, Brenda E.

    2001-01-01

    Between 1987 and 1997, we chemically immobilized 597 wild sea otters (Enhydra lutris) in Alaska for the collection of biological samples or for surgical instrumentation. One drug-related sea otter fatality occurred during this time. Fentanyl in combination with diazepam produced consistent, smooth inductions with minimal need for supplemental anesthetics during procedures lasting 30-40 min. Antagonism with naltrexone or naloxone was rapid and complete, although we observed narcotic recycling in sea otters treated with naloxone. For surgical procedures, we recommend a fentanyl target dose of 0.33 mg/kg of body mass and diazepam at 0.11 mg/kg. For nonsurgical biological sample collection procedures, we recommend fentanyl at 0.22 mg/kg and diazepam at 0.07 mg/kg. We advise the use of the opioid antagonist naltrexone at a ratio of 2:1 to the total fentanyl administered during processing.

  13. [Regulation of IL-1beta and IL-8 production by mu-, delta-opiate receptors agonists in vitro].

    PubMed

    Geĭn, S V; Gorshkova, K G; Tendriakova, S P

    2008-07-01

    The beta-endorphin 10(-7-)-10(-11) M in LPS (lypopolisaccharide) presence and in spontaneous cultures promoted the IL-1beta production in mixed leukocyte fraction. LPS-induced IL-8 production in leukocyte fraction was inhibited by beta-endorphin 10(-7), 10(-11) M. The enchasing effect of beta-endorphin on IL-1beta production was not blocked by naloxone and naltrindole. The inhibitory effect of beta-endorphin on IL-8 production was blocked by naloxone and naltrindole. In mononuclear and neutrophile fractions beta-endorphin and delta-agonist DADLE enchased IL-1beta production in spontaneous and LPS-stimulating cultures, when IL-8 production inhibited beta-endorphin and delta-agonist DADLE only in LPS presence. No effect of mu-agonist DAGO were observed on IL-1beta production, whereas LPS-induced IL-8 secretion in neutrophile fraction inhibited by DAGO.

  14. Effects of Naloxone on Stress and Performance

    DTIC Science & Technology

    1987-11-10

    and exercise , to psychological stressors, could produce the same triad of responses in an organism. The triad included enlargement of the adrenal...effects were generated was said to be nonspecifically induced . Selye further described the process of stress as driven by the pituitary-adrenal...as during emotional distress associated with oral examinations, exercise , and surgery (e.g., Moncrief, Weichselbaum, & Elman, 1954; Bayliss, 1955

  15. Endogenous Opiate System and Systematic Desensitization.

    ERIC Educational Resources Information Center

    Egan, Kelly J.; And Others

    1988-01-01

    Administered intravenous infusions to phobic patients prior to systematic desensitization. Saline-infused subjects significantly demonstrated the predicted symptom decrease in response to systematic desensitization, whereas naloxone-infused subjects showed no change. Subject reports and psychophysiological measures of arousal indicated no…

  16. A combination turbidity and supernatant microplate assay to rank-order the supersaturation limits of early drug candidates.

    PubMed

    Morrison, John S; Nophsker, Michelle J; Haskell, Roy J

    2014-10-01

    A unique opportunity exists at the drug discovery stage to overcome inherently poor solubility by selecting drug candidates with superior supersaturation propensity. Existing supersaturation assays compare either precipitation-resistant or precipitation-inhibiting excipients, or higher-energy polymorphic forms, but not multiple compounds or multiple concentrations. Furthermore, these assays lack sufficient throughput and compound conservation necessary for implementation in the discovery environment. A microplate-based combination turbidity and supernatant concentration assay was therefore developed to determine the extent to which different compounds remain in solution as a function of applied concentration in biorelevant media over a specific period of time. Dimethyl sulfoxide stock solutions at multiple concentrations of four poorly soluble, weak base compounds (Dipyridamole, Ketoconazole, Albendazole, and Cinnarizine) were diluted with pH 6.5 buffer as well as FaSSIF. All samples were monitored for precipitation by turbidity at 600 nm over 1 h and the final supernatant concentrations were measured. The maximum supersaturation ratio was calculated from the supersaturation limit and the equilibrium solubility in each media. Compounds were rank-ordered by supersaturation ratio: Ketoconazole > Dipyridamole > Cinnarizine ∼ Albendazole. These in vitro results correlated well with oral AUC ratios from published in vivo pH effect studies, thereby confirming the validity of this approach. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  17. Microvascular autonomic dysfunction may justify false-positive stress myocardial perfusion imaging in patients with liver cirrhosis undergoing liver transplantation.

    PubMed

    Senzolo, M; Bassanello, M; Graziotto, A; Zucchetta, P; Cillo, U; Maraglino, G; Loreno, M; Bellotto, F; Davià, G; Burra, P

    2008-01-01

    Up to 15% of liver transplant candidates have asymptomatic coronary artery diseases, which increase the risk of cardiac complications during and after transplantation. The aim of this study was to prospectively investigate the usefulness of an integrated cardiological approach in cirrhotic patients undergoing liver transplantation. Twenty-four consecutive patients undergoing evaluation for liver transplantation were studied by assessing risk factors for coronary artery diseases, electrocardiogram with QTc interval determination, chest X-ray, echocardiography, 24-hour Holter monitor, myocardial perfusion scintigraphy (99mTc)MIBI-GSPECT at rest and after dipyridamole infusion. Cardiac (123)I-metaiodobenzylguanidine (MIBG) scan and coronarography were performed in patients with myocardial perfusion defects. Twenty three of 24 patients underwent successful liver transplantation; one patient died on the waiting list. Before liver transplantation, 29% of patients were diabetic and 41% were smokers. Eleven of 24 patients had a prolonged QTc interval, and 3/24 had positive myocardioscintigraphy after dipyridamole infusion: in two coronarography was negative, while the (123)I-MIBG washout was altered. No cardiac events were recorded during the short-and long-term follow-up after surgery. Predictive value of positive cardiac (99mTc)MIBI-GSPECT in patients with liver cirrhosis is low, and this may be due to alterations of cardiac microvascular tone as showed by cardiac (123)I-MIBG scan.

  18. End-Systolic Elastance and Ventricular-Arterial Coupling Reserve Predict Cardiac Events in Patients with Negative Stress Echocardiography

    PubMed Central

    Bombardini, Tonino; Costantino, Marco Fabio; Sicari, Rosa; Ciampi, Quirino; Pratali, Lorenza; Picano, Eugenio

    2013-01-01

    Background. A maximal negative stress echo identifies a low-risk subset for coronary events. However, the potentially prognostically relevant information on cardiovascular hemodynamics for heart-failure-related events is unsettled. Aim of this study was to assess the prognostic value of stress-induced variation in cardiovascular hemodynamics in patients with negative stress echocardiography. Methods. We enrolled 891 patients (593 males mean age 63 ± 12, ejection fraction 48 ± 17%), with negative (exercise 172, dipyridamole 482, and dobutamine 237) stress echocardiography result. During stress we assessed left ventricular end-systolic elastance index (E LVI), ventricular arterial coupling (VAC) indexed by the ratio of the E LVI to arterial elastance index (E aI), systemic vascular resistance (SVR), and pressure-volume area (PVA). Changes from rest to peak stress (reserve) were tested as predictors of main outcome measures: combined death and heart failure hospitalization. Results. During a median followup of 19 months (interquartile range 8–36), 50 deaths and 84 hospitalization occurred. Receiver-operating-characteristic curves identified as best predictors E LVI reserve for exercise (AUC = 0.871) and dobutamine (AUC = 0.848) and VAC reserve (AUC = 0.696) for dipyridamole. Conclusions. Patients with negative stress echocardiography may experience an adverse outcome, which can be identified by assessment of E LVI reserve and VAC reserve during stress echo. PMID:24024185

  19. An in vitro methodology for forecasting luminal concentrations and precipitation of highly permeable lipophilic weak bases in the fasted upper small intestine.

    PubMed

    Psachoulias, Dimitrios; Vertzoni, Maria; Butler, James; Busby, David; Symillides, Moira; Dressman, Jennifer; Reppas, Christos

    2012-12-01

    To develop an in vitro methodology for prediction of concentrations and potential precipitation of highly permeable, lipophilic weak bases in fasted upper small intestine based on ketoconazole and dipyridamole luminal data. Evaluate usefulness of methodology in predicting luminal precipitation of AZD0865 and SB705498 based on plasma data. A three-compartment in vitro setup was used. Depending on the dosage form administered in in vivo studies, a solution or a suspension was placed in the gastric compartment. A medium simulating the luminal environment (FaSSIF-V2plus) was initially placed in the duodenal compartment. Concentrated FaSSIF-V2plus was placed in the reservoir compartment. In vitro ketoconazole and dipyridamole concentrations and precipitated fractions adequately reflected luminal data. Unlike luminal precipitates, in vitro ketoconazole precipitates were crystalline. In vitro AZD0865 data confirmed previously published human pharmacokinetic data suggesting that absorption rates are not affected by luminal precipitation. In vitro SB705498 data predicted that significant luminal precipitation occurs after a 100 mg or 400 mg but not after a 10 mg dose, consistent with human pharmacokinetic data. An in vitro methodology for predicting concentrations and potential precipitation in fasted upper small intestine, after administration of highly permeable, lipophilic weak bases in fasted upper small intestine was developed and evaluated for its predictability in regard to luminal precipitation.

  20. Evaluation of the light scattering and the turbidity microtiter plate-based methods for the detection of the excipient-mediated drug precipitation inhibition.

    PubMed

    Petruševska, Marija; Urleb, Uroš; Peternel, Luka

    2013-11-01

    The excipient-mediated precipitation inhibition is classically determined by the quantification of the dissolved compound in the solution. In this study, two alternative approaches were evaluated, one is the light scattering (nephelometer) and other is the turbidity (plate reader) microtiter plate-based methods which are based on the quantification of the compound precipitate. Following the optimization of the nephelometer settings (beam focus, laser gain) and the experimental conditions, the screening of 23 excipients on the precipitation inhibition of poorly soluble fenofibrate and dipyridamole was performed. The light scattering method resulted in excellent correlation (r>0.91) between the calculated precipitation inhibitor parameters (PIPs) and the precipitation inhibition index (PI(classical)) obtained by the classical approach for fenofibrate and dipyridamole. Among the evaluated PIPs AUC100 (nephelometer) resulted in only four false positives and lack of false negatives. In the case of the turbidity-based method a good correlation of the PI(classical) was obtained for the PIP maximal optical density (OD(max), r=0.91), however, only for fenofibrate. In the case of the OD(max) (plate reader) five false positives and two false negatives were identified. In conclusion, the light scattering-based method outperformed the turbidity-based one and could be reliably used for identification of novel precipitation inhibitors. Copyright © 2013 Elsevier B.V. All rights reserved.

  1. Roles of myocardial blood volume and flow in coronary artery disease: an experimental MRI study at rest and during hyperemia

    PubMed Central

    McCommis, Kyle S.; Goldstein, Thomas A.; Abendschein, Dana R.; Misselwitz, Bernd; Pilgram, Thomas; Gropler, Robert J.

    2010-01-01

    Objective To validate fast perfusion mapping techniques in a setting of coronary artery stenosis, and to further assess the relationship of absolute myocardial blood volume (MBV) and blood flow (MBF) to global myocardial oxygen demand. Methods A group of 27 mongrel dogs were divided into 10 controls and 17 with acute coronary stenosis. On 1.5-T MRI, first-pass perfusion imaging with a bolus injection of a blood-pool contrast agent was performed to determine myocardial perfusion both at rest and during either dipyridamole-induced vasodilation or dobutamine-induced stress. Regional values of MBF and MBV were quantified by using a fast mapping technique. Color microspheres and 99mTc-labeled red blood cells were injected to obtain respective gold standards. Results Microsphere-measured MBF and 99mTc-measured MBV reference values correlated well with the MR results. Given the same changes in MBF, changes in MBV are twofold greater with dobutamine than with dipyridamole. Under dobutamine stress, MBV shows better association with total myocardial oxygen demand than MBF. Coronary stenosis progressively reduced this association in the presence of increased stenosis severity. Conclusions MR first-pass perfusion can rapidly estimate regional MBF and MBV. Absolute quantification of MBV may add additional information on stenosis severity and myocardial viability compared with standard qualitative clinical evaluations of myocardial perfusion. PMID:20182731

  2. Neurobiological Aspects of Mindfulness in Pain Autoregulation: Unexpected Results from a Randomized-Controlled Trial and Possible Implications for Meditation Research

    PubMed Central

    Esch, Tobias; Winkler, Jeremy; Auwärter, Volker; Gnann, Heike; Huber, Roman; Schmidt, Stefan

    2017-01-01

    Background: Research has demonstrated that short meditation training may yield higher pain tolerance in acute experimental pain. Our study aimed at examining underlying mechanisms of this alleged effect. In addition, placebo research has shown that higher pain tolerance is mediated via endogenous neuromodulators: experimental inhibition of opioid receptors by naloxone antagonized this effect. We performed a trial to discern possible placebo from meditation-specific effects on pain tolerance and attention. Objectives: It was proposed that (i) meditation training will increase pain tolerance; (ii) naloxone will inhibit this effect; (iii) increased pain tolerance will correlate with improved attention performance and mindfulness. Methods: Randomized-controlled, partly blinded trial with 31 healthy meditation-naïve adults. Pain tolerance was assessed by the tourniquet test, attention performance was measured by Attention Network Test (ANT), self-perceived mindfulness by Freiburg Mindfulness Inventory. 16 participants received a 5-day meditation training, focusing on body/breath awareness; the control group (N = 15) received no intervention. Measures were taken before the intervention and on 3 consecutive days after the training, with all participants receiving either no infusion, naloxone infusion, or saline infusion (blinded). Blood samples were taken in order to determine serum morphine and morphine glucuronide levels by applying liquid chromatography-tandem mass spectrometry analysis. Results: The meditation group produced fewer errors in ANT. Paradoxically, increases in pain tolerance occurred in both groups (accentuated in control), and correlated with reported mindfulness. Naloxone showed a trend to decrease pain tolerance in both groups. Plasma analyses revealed sporadic morphine and/or morphine metabolite findings with no discernable pattern. Discussion: Main objectives could not be verified. Since underlying study goals had not been made explicit to

  3. Characterization and Management of Patients with Heroin versus Nonheroin Opioid Overdoses: Experience at an Academic Medical Center.

    PubMed

    Morizio, Kate M; Baum, Regan A; Dugan, Adam; Martin, Julia E; Bailey, Abby M

    2017-07-01

    To characterize the differences between patients who had heroin and nonheroin opioid overdoses and to determine whether there were any significant differences in their management with regard to the naloxone use. Retrospective cohort study. Large academic medical center. A total of 923 patients admitted to the medical center who were identified for overdose by heroin or other opiate-related narcotics between January 2010 and September 2015; 480 patients experienced a nonheroin opioid overdose event, and 443 patients experienced a heroin overdose event. Patients presenting with heroin overdose tended to be younger and male, with higher rates of hepatitis C virus (HCV) infection compared with those presenting with nonheroin opioid overdose (p<0.05). Patients in the heroin group were also more likely to have a previous overdose event, history of injection drug use, and history of prescription opioid abuse compared with the nonheroin group (p<0.05). Those presenting with heroin overdose were more likely to receive naloxone in the prehospital setting (p<0.05) but were less likely to receive naloxone once admitted (p<0.05). Patients with nonheroin opioid overdoses required more continuous infusions of naloxone (p<0.05) and admission to the intensive care unit (p<0.05). Of all 923 patients, 178 (19.3%) had a repeat admission for any reason, and 70 (7.6%) were readmitted over the course of the study period for another overdose event with the same drug. The proportion of patients presenting with a heroin overdose steadily increased from 2010-2015; the number of patients presenting to the emergency department with nonheroin opioid overdoses steadily decreased. As rates of heroin overdose increased each year, the incidence of HCV infection increased dramatically. This study indicates that the incidence of heroin overdoses has significantly increased over the last several years, and the rates of HCV infection 4-fold since the start of the study period. Patients admitted for

  4. Differential effect of opioid and cannabinoid receptor blockade on heroin-seeking reinstatement and cannabinoid substitution in heroin-abstinent rats

    PubMed Central

    Fattore, L; Spano, MS; Melis, V; Fadda, P; Fratta, W

    2011-01-01

    BACKGROUND AND PURPOSE Opioids and cannabinoids interact in drug addiction and relapse. We investigated the effect of the opioid receptor antagonist naloxone and/or the cannabinoid CB1 receptor antagonist rimonabant on cannabinoid-induced reinstatement of heroin seeking and on cannabinoid substitution in heroin-abstinent rats. EXPERIMENTAL APPROACH Rats were trained to self-administer heroin (30 µg·kg−1 per infusion) under a fixed-ratio 1 reinforcement schedule. After extinction of self-administration (SA) behaviour, we confirmed the effect of naloxone (0.1–1 mg·kg−1) and rimonabant (0.3–3 mg·kg−1) on the reinstatement of heroin seeking induced by priming with the CB1 receptor agonist WIN55,212-2 (WIN, 0.15–0.3 mg·kg−1). Then, in a parallel set of heroin-trained rats, we evaluated whether WIN (12.5 µg·kg−1 per infusion) SA substituted for heroin SA after different periods of extinction. In groups of rats in which substitution occurred, we studied the effect of both antagonists on cannabinoid intake. KEY RESULTS Cannabinoid-induced reinstatement of heroin seeking was significantly attenuated by naloxone (1 mg·kg−1) and rimonabant (3 mg·kg−1) and fully blocked by co-administration of sub-threshold doses of the two antagonists. Moreover, contrary to immediate (1 day) or delayed (90 days) drug substitution, rats readily self-administered WIN when access was given after 7, 14 or 21 days of extinction from heroin, and showed a response rate that was positively correlated with the extinction period. In these animals, cannabinoid intake was increased by naloxone (1 mg·kg−1) and decreased by rimonabant (3 mg·kg−1). CONCLUSIONS AND IMPLICATIONS Our findings extend previous research on the crosstalk between cannabinoid and opioid receptors in relapse mechanisms, which suggests a differential role in heroin-seeking reinstatement and cannabinoid substitution in heroin-abstinent rats. LINKED ARTICLES This article is part of a themed issue on

  5. Could pharmacogenetic data explain part of the interindividual sensitivity to methadone-induced respiratory depression?

    PubMed Central

    Crettol, Séverine; Monnat, Martine; Eap, Chin B

    2007-01-01

    In this issue of Critical Care, Megarbane and colleagues present a case report of methadone-induced respiratory depression and conduct a toxicokinetic/toxicodynamic evaluation. An opioid-dependent patient receiving methadone maintenance treatment (daily dose 70 mg) was found unconscious after ingesting 240 mg methadone and 2 mg flunitrazepam. Significant improvement in consciousness was achieved after an intravenous bolus of 0.3 mg naloxone followed by a continuous infusion of naloxone at 0.3 mg/hour. In patients receiving methadone maintenance treatment, an occasional intake of two to four times the usual daily dose of methadone is not an exceptional occurrence. However, few such patients experience episodes of life-threatening respiratory depression. Here, we discuss whether recent pharmacogenetic data could help us to understand interindividual variability in sensitivity to respiratory depression and, ultimately, to predict which patients are most likely to be affected. PMID:17338832

  6. Opiate-like electroencephalographic and behavioral effects of electroconvulsive shock in rats.

    PubMed

    Tortella, F C; Cowan, A; Belenky, G L; Holaday, J W

    1981-12-03

    Rats were studied (a) after a single transauricular electroshock (acute ECS) and (b) following 10 consecutive once-daily shocks (chronic ECS). ECS produced a generalized convulsion marked by a polyspike EEG seizure. The seizure was followed by a period of postictal depression (PID) characterized by EEG high-voltage synchrony, EMG quietening, and an associated stuporous behavior in the rat. Acute ECS produced a maximal of 33 +/- 8 (S.E.) percent above control in the EEG voltage output during postictus, with the PID lasting 2680 +/- 658 sec. Chronic ECS resulted in a significant enhancement of these acute responses. Pretreating rats with naloxone (0.3-10 mg/kg s.c.) antagonized the postictal effects of acute ECS, but not of chronic ECS. These naloxone-sensitive postictal EEG and behavioral changes appear to reflect a release of endogenous opioid peptides during ictus, a finding consistent with the hypothesis that electroshock activates opioid systems.

  7. The epileptogenic spectrum of opiate agonists.

    PubMed

    Snead, O C; Bearden, L J

    1982-11-01

    The present authors gave mu, delta, kappa, epsilon and sigma opiate receptor agonists intracerebroventricularly to rats both singly and in combination while monitoring the electroencephalogram from cortical and depth electrodes. Dose-response curves were plotted with naloxone against the changes produced by each agonist, and the effect of a number of anticonvulsant drugs on agonist-induced seizures was ascertained. Each opiate agonist produced a different seizure pattern with a different naloxone dose-response curve and anticonvulsant profile. The order of convulsive potency was epsilon greater than delta greater than mu greater than sigma much greater than kappa. Petit mal-like seizure activity was unique to the delta agonist, leucine-enkephalin, while only the mu agonist, morphine produced generalized convulsive seizures. These experiments raise the possibility that opiate systems in the brain may be involved in the pathogenesis of a wide spectrum of seizure disorders.

  8. Comparison of the antinociceptive activities of physostigmine, oxotremorine and morphine in the mouse

    PubMed Central

    Pleuvry, Barbara J.; Tobias, M. A.

    1971-01-01

    1. Morphine, oxotremorine and physostigmine showed antinociceptive activity in mice using the hot plate reaction time test. 2. The action of morphine, but not that of oxotremorine, was antagonized by naloxone and by nalorphine, whereas the effect of physostigmine was unaffected by naloxone and increased by nalorphine. 3. The antinociceptive effects of morphine and of physostigmine were increased by procedures reported to increase the ratio of 5-hydroxytryptamine to dopamine in the brain. It was decreased by procedures reported to cause a fall in brain 5-hydroxytryptamine or a rise in dopamine relative to 5-hydroxytryptamine. 4. The antinociceptive effect of oxotremorine was potentiated by procedures reported to decrease brain noradrenaline and was unaffected by procedures altering brain 5-hydroxytryptamine. 5. The results suggest differences in the mode of action of morphine and physostigmine on the one hand and of oxotremorine on the other. PMID:4261560

  9. Study the Antinociceptive Effect of Intracerebroventricular Injection of Aqueous Extract of Origanum Vulgare Leaves in Rat: Possible Involvement of Opioid System

    PubMed Central

    Pahlavan, Yasaman; Sepehri, Gholamreza; Sheibani, Vahid; Afarinesh khaki, Mohammadreza; Gojazadeh, Morteza; Pahlavan, Bahare; Pahlavan, Fereshteh

    2013-01-01

    Objective(s): The aim of study was to investigate the antinociceptive effect of intracerebroventricular (ICV) microinjection of Origanum vulgare (ORG) extract and possible involvement of opioid receptors. Materials and Methods: Cannula was inserted into left ventricle of male rats. Five days after surgery Tail Flick Latency (TFL) was measured after ICV microinjection of, ORG (1, 3 and 6 µg / rat). Effective dose of ORG was injected ICV in concomitant with morphine (2 mg/kg, IP), naloxone (2 mg / kg, IP) and saline (0.5 µl/rat) and TFL was recorded. Results: The co- administration of ORG extract with morphine showed a significant increase in TFL and naloxone, pretreatment significantly inhibited the antinociceptive activity of ORG and morphine. Conclusion: The aqueous extract of ORG possesses antinociceptive activities in the tail-flick test in a dose dependent manner. ORG - induced antinociception may have been mediated by opioid systems. PMID:24379969

  10. Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study.

    PubMed

    Diener, Hans-Christoph; Sacco, Ralph L; Yusuf, Salim; Cotton, Daniel; Ounpuu, Stephanie; Lawton, William A; Palesch, Yuko; Martin, Reneé H; Albers, Gregory W; Bath, Philip; Bornstein, Natan; Chan, Bernard P L; Chen, Sien-Tsong; Cunha, Luis; Dahlöf, Björn; De Keyser, Jacques; Donnan, Geoffrey A; Estol, Conrado; Gorelick, Philip; Gu, Vivian; Hermansson, Karin; Hilbrich, Lutz; Kaste, Markku; Lu, Chuanzhen; Machnig, Thomas; Pais, Prem; Roberts, Robin; Skvortsova, Veronika; Teal, Philip; Toni, Danilo; VanderMaelen, Cam; Voigt, Thor; Weber, Michael; Yoon, Byung-Woo

    2008-10-01

    The treatment of ischaemic stroke with neuroprotective drugs has been unsuccessful, and whether these compounds can be used to reduce disability after recurrent stroke is unknown. The putative neuroprotective effects of antiplatelet compounds and the angiotensin II receptor antagonist telmisartan were investigated in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial. Patients who had had an ischaemic stroke were randomly assigned in a two by two factorial design to receive either 25 mg aspirin (ASA) and 200 mg extended-release dipyridamole (ER-DP) twice a day or 75 mg clopidogrel once a day, and either 80 mg telmisartan or placebo once per day. The predefined endpoints for this substudy were disability after a recurrent stroke, assessed with the modified Rankin scale (mRS) and Barthel index at 3 months, and cognitive function, assessed with the mini-mental state examination (MMSE) score at 4 weeks after randomisation and at the penultimate visit. Analysis was by intention to treat. The study was registered with ClinicalTrials.gov, number NCT00153062. 20,332 patients (mean age 66 years) were randomised and followed-up for a median of 2.4 years. Recurrent strokes occurred in 916 (9%) patients randomly assigned to ASA with ER-DP and 898 (9%) patients randomly assigned to clopidogrel; 880 (9%) patients randomly assigned to telmisartan and 934 (9%) patients given placebo had recurrent strokes. mRS scores were not statistically different in patients with recurrent stroke who were treated with ASA and ER-DP versus clopidogrel (p=0.38), or with telmisartan versus placebo (p=0.61). There was no significant difference in the proportion of patients with recurrent stroke with a good outcome, as measured with the Barthel index, across all treatment groups. Additionally, there was no significant difference in the median MMSE scores, the percentage of patients with an MMSE score of 24 points or less, the percentage of patients with a drop in MMSE

  11. Social and structural aspects of the overdose risk environment in St. Petersburg, Russia

    PubMed Central

    Grau, Lauretta E.; Blinnikova, Ksenia N.; Torban, Mikhail; Krupitsky, Evgeny; Ilyuk, Ruslan; Kozlov, Andrei; Heimer, Robert

    2009-01-01

    Background While overdose is a common cause of mortality among opioid injectors worldwide, little information exists on opioid overdoses or how context may influence overdose risk in Russia. This study sought to uncover social and structural aspects contributing to fatal overdose risk in St. Petersburg and assess prevention intervention feasibility. Methods Twenty-one key informant interviews were conducted with drug users, treatment providers, toxicologists, police, and ambulance staff. Thematic coding of interview content was conducted to elucidate elements of the overdose risk environment. Results Several factors within St. Petersburg’s environment were identified as shaping illicit drug users’ risk behaviors and contributing to conditions of suboptimal response to overdose in the community. Most drug users live and experience overdoses at home, where family and home environment may mediate or moderate risk behaviors. The overdose risk environment is also worsened by inefficient emergency response infrastructure, insufficient cardiopulmonary or naloxone training resources, and the preponderance of abstinence-based treatment approaches to the exclusion of other treatment modalities. However, attitudes of drug users and law enforcement officials generally support overdose prevention intervention feasibility. Modifiable aspects of the risk environment suggest community-based and structural interventions, including overdose response training for drug users and professionals that encompasses naloxone distribution to the users and equipping more ambulances with naloxone. Conclusion Local social and structural elements influence risk environments for overdose. Interventions at the community and structural levels to prevent and respond to opioid overdoses are needed for and integral to reducing overdose mortality in St. Petersburg. PMID:18774283

  12. Law enforcement attitudes toward overdose prevention and response.

    PubMed

    Green, Traci C; Zaller, Nickolas; Palacios, Wilson R; Bowman, Sarah E; Ray, Madeline; Heimer, Robert; Case, Patricia

    2013-12-01

    Law enforcement is often the first to respond to medical emergencies in the community, including overdose. Due to the nature of their job, officers have also witnessed first-hand the changing demographic of drug users and devastating effects on their community associated with the epidemic of nonmedical prescription opioid use in the United States. Despite this seminal role, little data exist on law enforcement attitudes toward overdose prevention and response. We conducted key informant interviews as part of a 12-week Rapid Assessment and Response (RAR) process that aimed to better understand and prevent nonmedical prescription opioid use and overdose deaths in locations in Connecticut and Rhode Island experiencing overdose "outbreaks." Interviews with 13 law enforcement officials across three study sites were analyzed to uncover themes on overdose prevention and naloxone. Findings indicated support for law enforcement involvement in overdose prevention. Hesitancy around naloxone administration by laypersons was evident. Interview themes highlighted officers' feelings of futility and frustration with their current overdose response options, the lack of accessible local drug treatment, the cycle of addiction, and the pervasiveness of easily accessible prescription opioid medications in their communities. Overdose prevention and response, which for some officers included law enforcement-administered naloxone, were viewed as components of community policing and good police-community relations. Emerging trends, such as existing law enforcement medical interventions and Good Samaritan Laws, suggest the need for broader law enforcement engagement around this pressing public health crisis, even in suburban and small town locations, to promote public safety. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  13. Differential Changes in Expression of Stress- and Metabolic-Related Neuropeptides in the Rat Hypothalamus during Morphine Dependence and Withdrawal

    PubMed Central

    Núnez, Cristina; Zelei, Edina; Polyák, Ágnes; Milanés, M. Victoria

    2013-01-01

    Chronic morphine treatment and naloxone precipitated morphine withdrawal activates stress-related brain circuit and results in significant changes in food intake, body weight gain and energy metabolism. The present study aimed to reveal hypothalamic mechanisms underlying these effects. Adult male rats were made dependent on morphine by subcutaneous implantation of constant release drug pellets. Pair feeding revealed significantly smaller weight loss of morphine treated rats compared to placebo implanted animals whose food consumption was limited to that eaten by morphine implanted pairs. These results suggest reduced energy expenditure of morphine-treated animals. Chronic morphine exposure or pair feeding did not significantly affect hypothalamic expression of selected stress- and metabolic related neuropeptides - corticotropin-releasing hormone (CRH), urocortin 2 (UCN2) and proopiomelanocortin (POMC) compared to placebo implanted and pair fed animals. Naloxone precipitated morphine withdrawal resulted in a dramatic weight loss starting as early as 15–30 min after naloxone injection and increased adrenocorticotrophic hormone, prolactin and corticosterone plasma levels in morphine dependent rats. Using real-time quantitative PCR to monitor the time course of relative expression of neuropeptide mRNAs in the hypothalamus we found elevated CRH and UCN2 mRNA and dramatically reduced POMC expression. Neuropeptide Y (NPY) and arginine vasopressin (AVP) mRNA levels were transiently increased during opiate withdrawal. These data highlight that morphine withdrawal differentially affects expression of stress- and metabolic-related neuropeptides in the rat hypothalamus, while relative mRNA levels of these neuropeptides remain unchanged either in rats chronically treated with morphine or in their pair-fed controls. PMID:23805290

  14. Acetyl-L-carnitine (ALC) administration positively affects reproductive axis in hypogonadotropic women with functional hypothalamic amenorrhea.

    PubMed

    Genazzani, A D; Lanzoni, C; Ricchieri, F; Santagni, S; Rattighieri, E; Chierchia, E; Monteleone, P; Jasonni, V M

    2011-04-01

    Hypothalamic amenorrhea (HA) is characterized by neuroendocrine impairment that, in turn, negatively modulates endocrine function, mainly within the reproductive axis. HA presents with hypo-LH, hypoestrogenism and, until now, a definite therapeutic strategy has not yet been found. The aim of the following study was to test the efficacy of acetyl-L-carnitine (ALC) administration in HA-affected subjects. Twenty-four patients affected by stress-induced HA were divided into two groups according to LH plasma levels: group A, hypo-LH (LH≤3 mIU/ml; no.=16), and group B, normo-LH (LH>3 mIU/ml; no.=8), were treated with ALC (1 g/day, per os) for 16 weeks. Patients underwent baseline hormonal assessment, pulsatility test (for LH and FSH), naloxone test (for LH, FSH and cortisol) both before and after 16 weeks of treatment. Under ALC administration hypo-LH patients showed a significant increase in LH plasma levels (from 1.4±0.3 to 3.1±0.5 mIU/ml, p<0.01) and in LH pulse amplitude (p<0.001). No changes were observed in the normo-LH group. LH response to naloxone was restored under ALC therapy. Maximal LH response and area under the curve under naloxone were significantly increased (p<0.05 and p<0.01, respectively). No changes were observed in the normo-LH patients. Our data support the hypothesis of a specific role of ALC on counteracting the stress-induced abnormalities in hypo-LH patients affected by hypothalamic amenorrhea.

  15. Epoxy fatty acids mediate analgesia in murine diabetic neuropathy.

    PubMed

    Wagner, K; Lee, K S S; Yang, J; Hammock, B D

    2017-03-01

    Neuropathic pain is a debilitating condition with no adequate therapy. The health benefits of omega-3 fatty acids are established, however, the role of docosahexaenoic acid (DHA) in limiting pain has only recently been described and the mechanisms of this action remain unknown. DHA is metabolized into epoxydocosapentanoic acids (EDPs) via cytochrome P450 (CYP450) enzymes which are substrates for the soluble epoxide hydrolase (sEH) enzyme. Here, we tested several hypotheses; first, that the antinociceptive action of DHA is mediated by the EDPs. Second, based on evidence that DHA and CYP450 metabolites elicit analgesia through opioid signalling, we investigated this as a possible mechanism of action. Third, we tested whether the analgesia mediated by epoxy fatty acids had similar rewarding effects as opioid analgesics. We tested diabetic neuropathic wild-type and sEH null mice in a conditioned place preference assay for their response to EDPs, sEHI and antagonism of these treatments with naloxone, a mu-opioid receptor antagonist. The EDPs and sEH inhibitors were efficacious against chronic pain, and naloxone antagonized the action of both EDPs and sEH inhibitors. Despite this antagonism, the sEH inhibitors lacked reward side effects differing from opioids. The EpFA are analgesic against chronic pain differing from opioids which have limited efficacy in chronic conditions. EDPs and sEHI mediate analgesia in modelled chronic pain and this analgesia is blocked by naloxone. However, unlike opioids, sEHI are highly effective in neuropathic pain models and importantly lack rewarding side effects. © 2016 European Pain Federation - EFIC®.

  16. Subcutaneous, intrathecal and periaqueductal grey administration of asimadoline and ICI-204448 reduces tactile allodynia in the rat.

    PubMed

    Caram-Salas, Nadia L; Reyes-García, Gerardo; Bartoszyk, Gerd D; Araiza-Saldaña, Claudia I; Ambriz-Tututi, Mónica; Rocha-González, Héctor I; Arreola-Espino, Rosaura; Cruz, Silvia L; Granados-Soto, Vinicio

    2007-11-14

    The purpose of this study was to assess the possible antiallodynic effect of asimadoline ([N-methyl-N-[1S)-1-phenyl)-2-(13S))-3-hydroxypyrrolidine-1-yl)-ethyl]-2,2-diphenylacetamide HCl]) and ICI-20448 ([2-[3-(1-(3,4-Dichlorophenyl-N-methylacetamido)-2-pyrrolidinoethyl)-phenoxy]acetic acid HCl]), two peripheral selective kappa opioid receptor agonists, after subcutaneous, spinal and periaqueductal grey administration to neuropathic rats. Twelve days after spinal nerve ligation tactile allodynia was observed, along with an increase in kappa opioid receptor mRNA expression in dorsal root ganglion and dorsal horn spinal cord. A non-significant increase in periaqueductal grey was also seen. Subcutaneous (s.c.) administration of asimadoline and ICI-204448 (1-30 mg/kg) dose-dependently reduced tactile allodynia. This effect was partially blocked by s.c., but not intrathecal, naloxone. Moreover, intrathecal administration of asimadoline or ICI-204448 (1-30 mug) reduced tactile allodynia in a dose-dependent manner and this effect was completely blocked by intrathecal naloxone. Microinjection of both kappa opioid receptor agonists (3-30 mug) into periaqueductal grey also produced a naloxone-sensitive antiallodynic effect in rats. Our results indicate that systemic, intrathecal and periaqueductal grey administration of asimadoline and ICI-204448 reduces tactile allodynia. This effect may be a consequence of an increase in kappa opioid receptor mRNA expression in dorsal root ganglion, dorsal horn spinal cord and, to some extent, in periaqueductal grey. Finally, our data suggest that these drugs could be useful to treat neuropathic pain in human beings.

  17. Law enforcement attitudes toward overdose prevention and response

    PubMed Central

    Green, Traci C.; Zaller, Nickolas; Palacios, Wilson R.; Bowman, Sarah E.; Ray, Madeline; Heimer, Robert; Case, Patricia

    2014-01-01

    Background Law enforcement is often the first to respond to medical emergencies in the community, including overdose. Due to the nature of their job, officers have also witnessed first-hand the changing demographic of drug users and devastating effects on their community associated with the epidemic of nonmedical prescription opioid use in the United States. Despite this seminal role, little data exist on law enforcement attitudes toward overdose prevention and response. Methods We conducted key informant interviews as part of a 12-week Rapid Assessment and Response (RAR) process that aimed to better understand and prevent nonmedical prescription opioid use and overdose deaths in locations in Connecticut and Rhode Island experiencing overdose “outbreaks.” Interviews with 13 law enforcement officials across three study sites were analyzed to uncover themes on overdose prevention and naloxone. Results Findings indicated support for law enforcement involvement in overdose prevention. Hesitancy around naloxone administration by laypersons was evident. Interview themes highlighted officers’ feelings of futility and frustration with their current overdose response options, the lack of accessible local drug treatment, the cycle of addiction, and the pervasiveness of easily accessible prescription opioid medications in their communities. Overdose prevention and response, which for some officers included law enforcement-administered naloxone, were viewed as components of community policing and good police-community relations. Conclusion Emerging trends, such as existing law enforcement medical interventions and Good Samaritan Laws, suggest the need for broader law enforcement engagement around this pressing public health crisis, even in suburban and small town locations, to promote public safety. PMID:24051061

  18. Inhibitory actions of methionine-enkephalin and morphine on the cat carotid chemoreceptors.

    PubMed

    McQueen, D S; Ribeiro, J A

    1980-01-01

    1 The effects of intracarotid injections of methionine-enkephalin (Met-enkephalin) and morphine on chemoreceptor activity recorded from the peripheral end of a sectioned carotid sinus nerve have been studied in cats anaesthetized with pentobarbitone. 2 Met-enkephalin caused a rapid, powerful, inhibition of spontaneous chemoreceptor discharge, the intensity and duration of which was dose-dependent. 3 Morphine was a less potent inhibitor of spontaneous chemoreceptor discharge, and the inhibition it evoked was rather variable and tended to be biphasic. Low doses of morphine caused a slight increase in discharge. 4 Naloxone (0.2 mg i.c.) slightly increased spontaneous discharge, greatly reduced the chemo-inhibition caused by morphine, and reduced the inhibitory effect of Met-enkephalin. A higher dose of naloxone (0.8 mg) caused a substantial reduction of the Met-enkephalin effect. 5 Chemo-excitation evoked by intracarotid injections of acetylcholine, CO2-saturated Locke solution, and sodium cyanide were only slightly and somewhat variably reduced following injections of Met-enkephalin, whereas the inhibitory effect of dopamine was potentiated. Following morphine administration, response to acetylcholine and sodium cyanide were reduced slightly, whereas those to CO2 and dopamine were potentiated. 6 Responses to acetylcholine and CO2 were slightly potentiated during infusion of Met-enkephalin (50 micrograms/min, i.c.) and the response to sodium cyanide was slightly reduced. 7 It is concluded that naloxone-sensitive opiate receptors are present in the cat carotid body; when activated they cause inhibition of spontaneous chemoreceptor discharge. The physiological role of these receptors and the identity of any endogenous ligand remains to be established.

  19. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Navarro-Zaragoza, J.; Martínez-Laorden, E.; Mora, L.

    Opioid addiction is associated with cardiovascular disease. However, mechanisms linking opioid addiction and cardiovascular disease remain unclear. This study investigated the role of corticotropin-releasing factor (CRF) 1 receptor in mediating somatic signs and the behavioural states produced during withdrawal from morphine dependence. Furthermore, it studied the efficacy of CRF1 receptor antagonist, CP-154,526 to prevent the cardiac sympathetic activity induced by morphine withdrawal. In addition, tyrosine hydroxylase (TH) phosphorylation pathways were evaluated. Like stress, morphine withdrawal induced an increase in the hypothalamic–pituitary–adrenal (HPA) axis activity and an enhancement of noradrenaline (NA) turnover. Pre-treatment with CRF1 receptor antagonist significantly reduced morphine withdrawal-inducedmore » increases in plasma adrenocorticotropic hormone (ACTH) levels, NA turnover and TH phosphorylation at Ser31 in the right ventricle. In addition, CP-154,526 reduced the phosphorylation of extracellular signal-regulated kinase (ERK) after naloxone-precipitated morphine withdrawal. In addition, CP-154,526 attenuated the increases in body weight loss during morphine treatment and suppressed some of morphine withdrawal signs. Altogether, these results support the idea that cardiac sympathetic pathways are activated in response to naloxone-precipitated morphine withdrawal suggesting that treatment with a CRF1 receptor antagonist before morphine withdrawal would prevent the development of stress-induced behavioural and autonomic dysfunction in opioid addicts. - Highlights: • Morphine withdrawal caused an increase in myocardial sympathetic activity. • ERK regulates TH phosphorylation after naloxone-induced morphine withdrawal. • CRF1R is involved in cardiac adaptive changes during morphine dependence.« less

  20. Misuse of Novel Synthetic Opioids: A Deadly New Trend

    PubMed Central

    Prekupec, Matthew P.; Mansky, Peter A.; Baumann, Michael H.

    2017-01-01

    Novel synthetic opioids (NSOs) include various analogs of fentanyl and newly emerging non-fentanyl compounds. Together with illicitly manufactured fentanyl (IMF), these drugs have caused a recent spike in overdose deaths, whereas deaths from prescription opioids have stabilized. NSOs are used as stand-alone products, as adulterants in heroin, or as constituents of counterfeit prescription medications. During 2015 alone, there were 9580 deaths from synthetic opioids other than methadone. Most of these fatalities were associated with IMF rather than diverted pharmaceutical fentanyl. In opioid overdose cases, where the presence of fentanyl analogs was examined, analogs were implicated in 17% of fatalities. Recent data from law enforcement sources show increasing confiscation of acetylfentanyl, butyrylfentanyl, and furanylfentanyl, in addition to non-fentanyl compounds such as U-47700. Since 2013, deaths from NSOs in the United States were 52 for acetylfentanyl, 40 for butyrylfentanyl, 128 for furanylfentanyl, and 46 for U-47700. All of these substances induce a classic opioid toxidrome, which can be reversed with the competitive antagonist naloxone. However, due to the putative high potency of NSOs and their growing prevalence, it is recommended to forgo the 0.4 mg initial dose of naloxone and start with 2 mg. Because NSOs offer enormous profit potential, and there is strong demand for their use, these drugs are being trafficked by organized crime. NSOs present major challenges for medical professionals, law enforcement agencies, and policymakers. Resources must be distributed equitably to enhance harm reduction though public education, medication-assisted therapies, and improved access to naloxone. PMID:28590391

  1. Extinction of conditioned opiate withdrawal in rats in a two-chambered place conditioning apparatus

    PubMed Central

    Myers, Karyn M.; Bechtholt-Gompf, Anita J.; Coleman, Brian R.; Carlezon, William A.

    2016-01-01

    Conditioned opiate withdrawal contributes to relapse in addicts and can be studied in rats using the opiate withdrawal-induced conditioned place aversion (OW-CPA) paradigm. Attenuation of conditioned withdrawal through extinction may be beneficial in the treatment of addiction. Here we describe a protocol for studying OW-CPA extinction using a two-chambered place conditioning apparatus. Rats are made dependent on morphine through subcutaneous implantation of morphine pellets and then trained to acquire OW-CPA through pairings of one chamber with naloxone-precipitated withdrawal and the other chamber with saline. Extinction training consists of re-exposures to both chambers in the absence of precipitated withdrawal. Rats tested following the completion of training show a decline in avoidance of the formerly naloxone-paired chamber with increasing numbers of extinction training sessions. The protocol takes a minimum of seven days; the exact duration varies with the amount of extinction training, which is determined by the goals of the experiment. PMID:22362157

  2. Exercise induced asthma and endogenous opioids.

    PubMed Central

    Gaillard, R C; Bachman, M; Rochat, T; Egger, D; de Haller, R; Junod, A F

    1986-01-01

    Concentrations of endogenous opioid peptides in the plasma are increased during exercise and these substances have been implicated in the pathogenesis of asthma induced by chloropropramide and alcohol in diabetic patients. This work was undertaken to determine whether exercise induced asthma might be mediated by endogenous opioids. Plasma beta endorphin, met-enkephalin, and adrenocorticotrophic hormone (ACTH) concentrations were measured in five asthmatic patients and five normal volunteers breathing cold air during exercise. In four of the patients the effect of an infusion of naloxone on FEV1 was also measured during exercise induced asthma. Exercise produced acute bronchoconstriction in all asthmatics, characterised by a fall in FEV1; whereas no change occurred in normal subjects. There was no difference in plasma met-enkephalin, beta endorphin, and ACTH concentration between the two groups. Infusion of naloxone neither prevented nor worsened exercise induced asthma. These data suggest that endogenous opioids probably do not play a part in the development of exercise induced asthma. PMID:2944240

  3. Effect of plantar subcutaneous administration of bergamot essential oil and linalool on formalin-induced nociceptive behavior in mice.

    PubMed

    Katsuyama, Soh; Otowa, Akira; Kamio, Satomi; Sato, Kazuma; Yagi, Tomomi; Kishikawa, Yukinaga; Komatsu, Takaaki; Bagetta, Giacinto; Sakurada, Tsukasa; Nakamura, Hitoshi

    2015-01-01

    This study investigated the effect of bergamot essential oil (BEO) or linalool, a major volatile component of BEO, on the nociceptive response to formalin. Plantar subcutaneous injection of BEO or linalool into the ipsilateral hindpaw reduced both the first and late phases of the formalin-induced licking and biting responses in mice. Plantar subcutaneous injection of BEO or linalool into the contralateral hindpaw did not yield an antinociceptive effect, suggesting that the antinociceptive effect of BEO or linalool in the formalin test occurred peripherally. Intraperitoneal and plantar subcutaneous injection pretreatment with naloxone hydrochloride, an opioid receptor antagonist, significantly attenuated both BEO- and linalool-induced antinociception. Pretreatment with naloxone methiodide, a peripherally acting opioid receptor antagonists, also significantly antagonized the antinociceptive effects of BEO and linalool. Our results provide evidence for the involvement of peripheral opioids in antinociception induced by BEO and linalool. These results suggest that activation of peripheral opioid receptors may play an important role in reducing formalin-induced nociception.

  4. Electromechanical coupling in rat basilar artery in response to morphine.

    PubMed

    Waters, A; Harder, D R

    1983-12-01

    Force development, intracellular membrane potential (Em), and voltage vs. current curves were measured in rat basilar artery to help elucidate the mechanism of action of morphine sulfate and a synthetic narcotic, meperidine hydrochloride, on this preparation. Morphine sulfate caused a dose-dependent contraction of these vessels, which was reversible with naloxone. Electrical studies show that morphine may act upon this vascular smooth muscle preparation by decreasing potassium conductance (gk). This hypothesis is supported by the findings that morphine sulfate depolarized these cells and increased the input resistance (rin) determined by the application of rectangular hyperpolarizing and depolarizing current pulses through the microelectrode during impalement and recording of the associated voltage changes (delta V). Meperidine hydrochloride had significantly less effect on this preparation than morphine sulfate. Further studies show that the vehicular medium used for the commercially available preparation of naloxone (viz. the methyl and propyl esters of p-hydroxybenzoic acid in a ratio of 9:1) is, in vitro, a vasodilator of cerebral vascular smooth muscle.

  5. Modulation of deprivation-induced food intake by D-phenylalanine.

    PubMed

    Bodnar, R J; Butler, P D

    1983-09-01

    D-phenylalanine has been shown to possess opiate-like effects upon pain perception. The present study examined whether it would have similar opiate-like effects upon food intake in deprived rats. The first experiment demonstrated that food intake of rats deprived for 24 h prior to injection was significantly reduced for 2 h following a 250 mg/kg dose of D-phenylalanine. However, intake over a 24 h period following injection was significantly increased following a 125 mg/kg dose of D-phenylalanine. The second experiment revealed that 0.3, 1.0, 3.0 and 10.0 mg/kg doses of naloxone dose-dependently reduced intake for 2 h in deprived rats when paired with a vehicle injection. However, the inhibitory actions of the two lower naloxone doses were significantly attenuated when paired with an injection of a 250 mg/kg dose of D-phenylalanine. These results are discussed in terms of whether D-phenylalanine possesses direct or indirect opiate-like effects upon ingestion.

  6. Comparative study on the electrophysiological responses at thalamic level to different analgesic peptides.

    PubMed

    Braga, P C; Biella, G; Tiengo, M; Guidobono, F; Pecile, A; Fraschini, F

    1985-01-01

    Using electrophysiological methods to detect the extracellular activity of single neurons in the thalamus of anaesthetized rats, their response to mechanical and thermal noxious stimuli were assessed before and after administration of 4 analgesic peptides of various types. Dermophin, a peptide extracted from frog's skin, was found to have an opioid-like antinociceptive activity antagonized by naloxone. Caerulein, which has a similar origin, failed to suppress the nociceptive responses of thalamic neurons evoked by peripheral stimuli. Calcitonin, a peptide found at brain level, induced an alteration of the increased firing characteristic of noxious stimuli, and its action was not reversed by naloxone. FK 33-824, a synthetic peptide, induced a morphine-like action when injected i.c.v. at a dosage 1000 times lower than that of morphine on a molar basis. It is concluded that electrophysiological investigations on peptides endowed with analgesic activity contribute greatly to a more precise profile of the peptides as candidate drugs in pain control.

  7. Antinociceptive effect of purine nucleotides.

    PubMed

    Mello, C F; Begnini, J; De-La-Vega, D D; Lopes, F P; Schwartz, C C; Jimenez-Bernal, R E; Bellot, R G; Frussa-Filho, R

    1996-10-01

    The antinociceptive effect of purine nucleotides administered systematically (sc) was determined using the formalin and writhing tests in adult male albino mice. The mechanisms underlying nucleotide-induced antinociception were investigated by preinjecting the animals (sc) with specific antagonists for opioid (naloxone, 1 mg/kg), purinergic P1 (caffeine, 5, 10, of 30 mg/kg); theophylline, 10 mg/kg) or purinergic P2 receptors (suramin, 100 mg/kg; Coomassie blue, 30-300 mg/kg; quinidine, 10 mg/kg). Adenosine, adenosine monophosphate (AMP), diphosphate (ADP) and triphosphate (ATP) caused a reduction in the number of writhes and in the time of licking the formalin-injected paw. Naloxone had no effect on adenosine- or adenine nucleotide-induced antinociception. Caffeine (30 mg/kg) and theophylline (10 mg/kg) reversed the antinociceptive action of adenosine and adenine nucleotide derivatives in both tests. P2 antagonists did not reverse adenine nucleotide-induced antinociception. These results suggest that antinociceptive effect of adenine nucleotides is mediated by adenosine.

  8. Prescription opioid abuse, chronic pain, and primary care: a Co-occurring Disorders Clinic in the chronic disease model.

    PubMed

    Pade, Patricia A; Cardon, Karen E; Hoffman, Richard M; Geppert, Cynthia M A

    2012-12-01

    Abuse of opioids has become a public health crisis. The historic separation between the addiction and pain communities and a lack of training in medical education have made treatment difficult to provide, especially in primary care. The Co-occurring Disorders Clinic (COD) was established to treat patients with co-morbid chronic pain and addiction. This retrospective chart review reports results of a quality improvement project using buprenorphine/naloxone to treat co-occurring chronic non-cancer pain (CNCP) and opioid dependence in a primary care setting. Data were collected for 143 patients who were induced with buprenorphine/naloxone (BUP/NLX) between June 2009 and November 2011. Ninety-three patients (65%) continued to be maintained on the medication and seven completed treatment and were no longer taking any opioid (5%). Pain scores showed a modest, but statistically significant improvement on BUP/NLX, which was contrary to our expectations and may be an important factor in treatment retention for this challenging population. Published by Elsevier Inc.

  9. Ibudilast attenuates astrocyte apoptosis via cyclic GMP signalling pathway in an in vitro reperfusion model

    PubMed Central

    Takuma, K; Lee, E; Enomoto, R; Mori, K; Baba, A; Matsuda, T

    2001-01-01

    We examined the effect of 3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine (ibudilast), which has been clinically used for bronchial asthma and cerebrovascular disorders, on cell viability induced in a model of reperfusion injury. Ibudilast at 10 – 100 μM significantly attenuated the H2O2-induced decrease in cell viability. Ibudilast inhibited the H2O2-induced cytochrome c release, caspase-3 activation, DNA ladder formation and nuclear condensation, suggesting its anti-apoptotic effect. Phosphodiesterase inhibitors such as theophylline, pentoxyfylline, vinpocetine, dipyridamole and zaprinast, which increased the guanosine-3′,5′-cyclic monophosphate (cyclic GMP) level, and dibutyryl cyclic GMP attenuated the H2O2-induced injury in astrocytes. Ibudilast increased the cyclic GMP level in astrocytes. The cyclic GMP-dependent protein kinase inhibitor KT5823 blocked the protective effects of ibudilast and dipyridamole on the H2O2-induced decrease in cell viability, while the cyclic AMP-dependent protein kinase inhibitor KT5720, the cyclic AMP antagonist Rp-cyclic AMPS, the mitogen-activated protein/extracellular signal-regulated kinase inhibitor PD98059 and the leukotriene D4 antagonist LY 171883 did not. KT5823 also blocked the effect of ibudilast on the H2O2-induced cytochrome c release and caspase-3-like protease activation. These findings suggest that ibudilast prevents the H2O2-induced delayed apoptosis of astrocytes via a cyclic GMP, but not cyclic AMP, signalling pathway. PMID:11454657

  10. Tramadol: Effects on sexual behavior in male rats are mainly caused by its 5-HT reuptake blocking effects.

    PubMed

    Olivier, Jocelien D A; Esquivel Franco, Diana C; Oosting, Ronald; Waldinger, Marcel; Sarnyai, Zoltan; Olivier, Berend

    2017-04-01

    Tramadol is a well-known and effective analgesic. Recently it was shown that tramadol is also effective in human premature ejaculation. The inhibitory effect of tramadol on the ejaculation latency is probably due to its mechanism of action as a μ-opioid receptor agonist and noradrenaline/serotonin (5-HT) reuptake inhibitor. In order to test this speculation, we tested several doses of tramadol in a rat model of male sexual behavior and investigated two types of drugs interfering with the μ-opioid and the 5-HT system. First the μ-opioid receptor agonist properties of tramadol were tested with naloxone, a μ-opioid receptor antagonist. Second, the effects of WAY100,635, a 5-HT 1A receptor antagonist, were tested on the behavioral effects of tramadol. Finally the effects of paroxetine, a selective serotonin reuptake inhibitor, combined with naloxone or WAY100,635 treatment, were compared to the effects of tramadol combined with these drugs. Results showed that naloxone, at a sexually inactive dose, could only partially antagonize the inhibitory effect of tramadol. Moreover, low and behaviorally inactive doses of WAY100,635, strongly decreased sexual behavior when combined with a behaviorally inactive dose of tramadol. Finally we showed that the effects of paroxetine on sexual behavior resembled the effects of tramadol, indicating that tramadol's inhibitory effects on sexual behavior are primarily and mainly caused by its SSRI properties and that its μ-opioid receptor agonistic activity only contributes marginally. These findings support the hypothesis that tramadol exerts inhibition of premature ejaculations in men by its 5-HT reuptake inhibiting properties. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Involvement of central opioid systems in human interferon-α induced immobility in the mouse forced swimming test

    PubMed Central

    Makino, Mitsuhiro; Kitano, Yutaka; Komiyama, Chika; Hirohashi, Masaaki; Takasuna, Kiyoshi

    2000-01-01

    We investigated the mechanism by which human interferon-α (IFN-α) increases the immobility time in a forced swimming test, an animal model of depression.Central administration of IFN-α (0.05–50 IU per mouse, i.cist.) increased the immobility time in the forced swimming test in mice in a dose-dependent manner.Neither IFN-β nor -γ possessed any effect under the same experimental conditions.Pre-treatment with an opioid receptor antagonist, naloxone (1 mg kg−1, s.c.) inhibited the prolonged immobility time induced by IFN-α (60 KIU kg−1, i.v. or 50 IU per mouse. i.cist.).Peripheral administration of naloxone methiodide (1 mg kg−1, s.c.), which does not pass the blood–brain barrier, failed to block the effect of IFN-α, while intracisternal administration of naloxone methiodide (1 nmol per mouse) completely blocked.The effect of IFN-α was inhibited by a μ1-specific opioid receptor antagonist, naloxonazine (35 mg kg−1, s.c.) and a μ1/μ2 receptor antagonist, β-FNA (40 mg kg−1, s.c.). A selective δ-opioid receptor antagonist, naltrindole (3 mg kg−1, s.c.) and a κ-opioid receptor antagonist, nor-binaltorphimine (20 mg kg−1, s.c.), both failed to inhibit the increasing effect of IFN-α.These results suggest that the activator of the central opioid receptors of the μ1-subtype might be related to the prolonged immobility time of IFN-α, but δ and κ-opioid receptors most likely are not involved. PMID:10903965

  12. A Subanalgesic Dose of Morphine Eliminates Nalbuphine Anti-analgesia in Postoperative Pain

    PubMed Central

    Gear, Robert W.; Gordon, Newton C.; Hossaini-Zadeh, Mehran; Lee, Janice S.; Miaskowski, Christine; Paul, Steven M.; Levine, Jon D.

    2008-01-01

    The agonist-antagonist kappa-opioid nalbuphine administered for postoperative pain produces greater analgesia in females than in males. In fact, males administered nalbuphine (5 mg) experience pain greater than those receiving placebo, suggesting the existence of an anti-analgesic effect. These sexually dimorphic effects on postoperative pain can be eliminated by co-administration of a fixed ratio of the prototypical opioid receptor antagonist naloxone with nalbuphine, implying a role for opioid receptors in the anti-analgesic as well as analgesic effects of nalbuphine. In the present study, we further evaluated the role of opioid receptors in the sex-specific effects on pain produced by nalbuphine by co-administering a dose of morphine low enough that it does not produce analgesia. Following extraction of bony impacted third molar teeth, nalbuphine (5 mg) was administered alone or in combination with either of two low doses of morphine (2 mg or 4 mg). Both doses of morphine reversed nalbuphine-induced anti-analgesia in males, but only the lower dose (2 mg) reached statistical significance. Neither dose affected nalbuphine-induced analgesia in females, and when administered alone in either males or females, morphine (2 mg) had no analgesic effect. Though not observed in females, the effect of morphine in males argues that, like naloxone, low dose morphine may act as an anti-analgesia opioid receptor antagonist. Perspective Previously we reported that the nalbuphine produces both analgesic and anti-analgesic effects, and that the opioid antagonist naloxone can enhance nalbuphine analgesia by selectively antagonizing the anti-analgesic effect. Here we show that morphine, given in a subanalgesic dose, reverses nalbuphine-induced anti-analgesia in males, perhaps by a similar mechanism. PMID:18201935

  13. Opiate physical dependence and N-methyl-D-aspartate receptors.

    PubMed

    Noda, Yukihiro; Nabeshima, Toshitaka

    2004-10-01

    The present review focused the involvement of N-methyl-D-aspartate (NMDA) receptors in morphine physical dependence. The increased levels of extracellular glutamate, NMDA receptor zeta subunit (NR1) mRNA, NMDA receptor epsilon 1 subunit (NR2A) protein, phosphorylated Ca(2+)/calmodulin kinase II (p-CaMKII) protein, c-fos mRNA, c-Fos protein, are observed in the specific brain areas of mice and/or rats showing signs of naloxone-precipitated withdrawal. In preclinical and clinical studies, a variety of NMDA receptor antagonists and pretreatment with an antisense oligonucleotide of the NR1 have been reported to inhibit the development, expression and/or maintenance of opiate physical dependence. In contrast to data obtained in adult animals, NMDA receptor antagonists are neither effective in blocking the development of opiate dependence nor the expression of opiate withdrawal in neonatal rats. In the NMDA receptor-deficient mice, the NR2A knockout mice show the marked loss of typical withdrawal abstinence behaviors precipitated by naloxone. The rescue of NR2A protein by electroporation into the nucleus accumbens of NR2A knockout mice reverses the loss of abstinence behaviors. The activation of CaMKII and increased expression of c-Fos protein in the brain of animals with naloxone-precipitated withdrawal syndrome are prevented by NMDA receptor antagonists, whereas the increased levels of extracellular glutamate are not prevented by them. These findings indicate that glutamatergic neurotransmission at the NMDA receptor site contributes to the development, expression and maintenance of opiate dependence, and suggest that NMDA receptor antagonists may be a useful adjunct in the treatment of opiate dependence.

  14. Extinction of conditioned opiate withdrawal in rats is blocked by intracerebroventricular infusion of an NMDA receptor antagonist.

    PubMed

    Coleman, Brian R; Carlezon, William A; Myers, Karyn M

    2013-04-29

    Maladaptive conditioned responses (CRs) contribute to psychiatric disorders including anxiety disorders and addiction. Methods of reducing these CRs have been considered as possible therapeutic approaches. One such method is extinction, which involves exposure to CR-eliciting cues in the absence of the event they once predicted. In animal models, extinction reduces both fear and addiction-related CRs, and in humans, extinction-based cue exposure therapy (CET) reduces fear CRs. However, CET is less effective in drug addicts, for reasons that are not clear. Increased understanding of the neurobiology of extinction of drug-related CRs as compared to fear CRs may help illuminate this issue. Here, we examine the N-methyl-d-aspartate (NMDA) receptor-dependence of extinction of conditioned opiate withdrawal in rats. Using a place conditioning paradigm, we trained morphine-dependent rats to associate an environment with naloxone-precipitated withdrawal. We then extinguished that association by returning the rats repeatedly to the environment in the absence of acute withdrawal. In some rats we administered the NMDA receptor antagonist d,l-2-amino-5-phosphovaleric acid (AP5) intracerebroventricularly immediately prior to extinction training. In a subsequent test session, these rats avoided the formerly naloxone-paired environment, similar to rats that had not undergone extinction training. By contrast, rats that received vehicle prior to extinction training did not avoid the formerly naloxone-paired environment. This finding indicates that extinction of a drug-related CR (conditioned opiate withdrawal) is dependent on NMDA receptors, similar to extinction of conditioned fear. The locus of the critical NMDA receptors is unclear but may include basolateral amygdala and/or medial prefrontal cortex. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  15. Glucocorticoid receptors participate in the opiate withdrawal-induced stimulation of rats NTS noradrenergic activity and in the somatic signs of morphine withdrawal.

    PubMed

    Navarro-Zaragoza, Javier; Hidalgo, Juana M; Laorden, M Luisa; Milanés, M Victoria

    2012-08-01

    Recent evidence suggests that glucocorticoid receptor (GR) is a major molecular substrate of addictive properties of drugs of abuse. Hence, we performed a series of experiments to further characterize the role of GR signalling in opiate withdrawal-induced physical signs of dependence, enhanced noradrenaline (NA) turnover in the hypothalamic paraventricular nucleus (PVN) and tyrosine hydroxylase (TH) phosphorylation (activation) as well as GR expression in the nucleus of the solitary tract noradrenergic cell group (NTS-A₂). The role of GR signalling was assessed by i.p. pretreatment of the selective GR antagonist, mifepristone. Rats were implanted with two morphine (or placebo) pellets. Six days later, rats were pretreated with mifepristone or vehicle 30 min before naloxone and physical signs of abstinence, NA turnover, TH activation, GR expression and the hypothalamus-pituitary-adrenocortical axis activity were measured using HPLC, immunoblotting and RIA. Mifepristone alleviated the somatic signs of naloxone-induced opiate withdrawal. Mifepristone attenuated the increase in the NA metabolite, 3-methoxy-4-hydroxyphenylethylen glycol (MHPG), in the PVN, and the enhanced NA turnover observed in morphine-withdrawn rats. Mifepristone antagonized the TH phosphorylation at Ser³¹ and the expression of c-Fos expression induced by morphine withdrawal. Finally, naloxone-precipitated morphine withdrawal induced up-regulation of GR in the NTS. These results suggest that the physical signs of opiate withdrawal, TH activation and stimulation of noradrenergic pathways innervating the PVN are modulated by GR signalling. Overall, the present data suggest that drugs targeting the GR may ameliorate stress and aversive effects associated with opiate withdrawal. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  16. Effects of corticotropin-releasing factor receptor-1 antagonists on the brain stress system responses to morphine withdrawal.

    PubMed

    Navarro-Zaragoza, Javier; Núñez, Cristina; Laorden, M Luisa; Milanés, M Victoria

    2010-05-01

    The role of stress in drug addiction is well established. The negative affective states of withdrawal most probably involve recruitment of brain stress neurocircuitry [e.g., induction of hypothalamo-pituitary-adrenocortical (HPA) axis, noradrenergic activity, and corticotropin-releasing factor (CRF) activity]. The present study investigated t$he role of CRF receptor-1 subtype (CRF1R) on the response of brain stress system to morphine withdrawal. The effects of naloxone-precipitated morphine withdrawal on noradrenaline (NA) turnover in the paraventricular nucleus (PVN), HPA axis activity, signs of withdrawal, and c-Fos expression were measured in rats pretreated with vehicle, CP-154526 [N-butyl-N-ethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine], or antalarmin (selective CRF1R antagonists). Tyrosine hydroxylase-positive neurons expressing CRF1R were seen at the level of the nucleus tractus solitarius-A(2) cell group in both control and morphine-withdrawn rats. CP-154526 and antalarmin attenuated the increases in body weight loss and irritability that were seen during naloxone-induced morphine withdrawal. Pretreatment with CRF1R antagonists resulted in no significant modification of the increased NA turnover at PVN, plasma corticosterone levels, or c-Fos expression that was seen during naloxone-induced morphine withdrawal. However, blockade of CRF1R significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropin levels. These results suggest that the CRF1R subtype may be involved in the behavioral and somatic signs and in adrenocorticotropin release (partially) during morphine withdrawal. However, CRF1R activation may not contribute to the functional interaction between NA and CRF systems in mediating morphine withdrawal-activation of brain stress neurocircuitry.

  17. Changes in Expression of Dopamine, Its Receptor, and Transporter in Nucleus Accumbens of Heroin-Addicted Rats with Brain-Derived Neurotrophic Factor (BDNF) Overexpression.

    PubMed

    Li, Yixin; Xia, Baijuan; Li, Rongrong; Yin, Dan; Liang, Wenmei

    2017-06-09

    BACKGROUND The aim of this study was to explore how changes in the expression of BDNF in MLDS change the effect of BDNF on dopamine (DA) neurons, which may have therapeutic implications for heroin addiction. MATERIAL AND METHODS We established a rat model of heroin addiction and observed changes in the expression of BDNF, DA, dopamine receptor (DRD), dopamine transporter (DAT), and other relevant pathways in NAc. We also assessed the effect of BDNF overexpression in the NAc, behavioral changes of heroin-conditioned place preference (CPP), and naloxone withdrawal in rats with high levels of BDNF. We established 5 adult male rat groups: heroin addiction, lentivirus transfection, blank virus, sham operation, and control. The PCR gene chip was used to study gene expression changes. BDNF lentivirus transfection was used for BDNF overexpression. A heroin CPP model and a naloxone withdrawal model of rats were established. RESULTS Expression changes were found in 20 of the 84 DA-associated genes in the NAc of heroin-addicted rats. Weight loss and withdrawal symptoms in the lentivirus group for naloxone withdrawal was less than in the blank virus and the sham operation group. These 2 latter groups also showed significant behavioral changes, but such changes were not observed in the BDNF lentivirus group before or after training. DRD3 and DAT increased in the NAc of the lentivirus group. CONCLUSIONS BDNF and DA in the NAc are involved in heroin addiction. BDNF overexpression in NAc reduces withdrawal symptoms and craving behavior for medicine induced by environmental cues for heroin-addicted rats. BDNF participates in the regulation of the dopamine system by acting on DRD3 and DAT.

  18. Is systematic training in opioid overdose prevention effective?

    PubMed

    Espelt, Albert; Bosque-Prous, Marina; Folch, Cinta; Sarasa-Renedo, Ana; Majó, Xavier; Casabona, Jordi; Brugal, M Teresa

    2017-01-01

    The objectives were to analyze the knowledge about overdose prevention, the use of naloxone, and the number of fatal overdoses after the implementation of Systematic Training in Overdose Prevention (STOOP) program. We conducted a quasi-experimental study, and held face-to-face interviews before (n = 725) and after (n = 722) implementation of systematic training in two different samples of people who injected opioids attending harm reduction centers. We asked participants to list the main causes of overdose and the main actions that should be taken when witnessing an overdose. We created two dependent variables, the number of (a) correct and (b) incorrect answers. The main independent variable was Study Group: Intervention Group (IG), Comparison Group (CG), Pre-Intervention Group With Sporadic Training in Overdose Prevention (PREIGS), or Pre-Intervention Group Without Training in Overdose Prevention (PREIGW). The relationship between the dependent and independent variables was assessed using a multivariate Poisson regression analysis. Finally, we conducted an interrupted time series analysis of monthly fatal overdoses before and after the implementation of systematic program during the period 2006-2015. Knowledge of overdose prevention increased after implementing systematic training program. Compared to the PREIGW, the IG gave more correct answers (IRR = 1.40;95%CI:1.33-1.47), and fewer incorrect answers (IRR = 0.33;95%CI:0.25-0.44). Forty percent of people who injected opioids who received a naloxone kit had used the kit in response to an overdose they witnessed. These courses increase knowledge of overdose prevention in people who use opioids, give them the necessary skills to use naloxone, and slightly diminish the number of fatal opioid overdoses in the city of Barcelona.

  19. Blockade of opioid receptors in the medullary reticularis nucleus dorsalis, but not the rostral ventromedial medulla, prevents analgesia produced by diffuse noxious inhibitory control in rats with muscle inflammation.

    PubMed

    de Resende, Marcos A; Silva, Luis Felipe S; Sato, Karina; Arendt-Nielsen, Lars; Sluka, Kathleen A

    2011-06-01

    Diffuse Noxious Inhibitory Controls (DNIC) involves application of a noxious stimulus outside the testing site to produce analgesia. In human subjects with a variety of chronic pain conditions, DNIC is less effective; however, in animal studies, DNIC is more effective after tissue injury. While opioids are involved in DNIC analgesia, the pathways involved in this opioid-induced analgesia are not clear. The aim of the present study was to test the effectiveness of DNIC in inflammatory muscle pain, and to study which brainstem sites mediate DNIC- analgesia. Rats were injected with 3% carrageenan into their gastrocnemius muscle and responses to cutaneous and muscle stimuli were assessed before and after inflammation, and before and after DNIC induced by noxious heat applied to the tail (45 °C and 47 °C). Naloxone was administered systemically, into rostral ventromedial medulla (RVM), or bilaterally into the medullary reticularis nucleus dorsalis (MdD) prior to the DNIC-conditioning stimuli. DNIC produced a similar analgesic effect in both acute and the chronic phases of inflammation reducing both cutaneous and muscle sensitivity in a dose-dependent manner. Naloxone systemically or microinjected into the MdD prevented DNIC-analgesia, while naloxone into the RVM had no effect on DNIC analgesia. Thus, DNIC analgesia involves activation of opioid receptors in the MdD. The current study shows that DNIC activates opioid receptors in the MdD, but not the RVM, to produce analgesia. These data are important for understanding clinical studies on DNIC as well as for potential treatment of chronic pain patients. Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.

  20. Geographic and specialty distribution of US physicians trained to treat opioid use disorder.

    PubMed

    Rosenblatt, Roger A; Andrilla, C Holly A; Catlin, Mary; Larson, Eric H

    2015-01-01

    The United States is experiencing an epidemic of opioid-related deaths driven by excessive prescribing of opioids, misuse of prescription drugs, and increased use of heroin. Buprenorphine-naloxone is an effective treatment for opioid use disorder and can be provided in office-based settings, but this treatment is unavailable to many patients who could benefit. We sought to describe the geographic distribution and specialties of physicians obtaining waivers from the Drug Enforcement Administration (DEA) to prescribe buprenorphine-naloxone to treat opioid use disorder and to identify potential shortages of physicians. We linked physicians authorized to prescribe buprenorphine on the July 2012 DEA Drug Addiction Treatment Act (DATA) Waived Physician List to the American Medical Association Physician Masterfile to determine their age, specialty, rural-urban status, and location. We then mapped the location of these physicians and determined their supply for all US counties. Sixteen percent of psychiatrists had received a DEA DATA waiver (41.6% of all physicians with waivers) but practiced primarily in urban areas. Only 3.0% of primary care physicians, the largest group of physicians in rural America, had received waivers. Most US counties therefore had no physicians who had obtained waivers to prescribe buprenorphine-naloxone, resulting in more than 30 million persons who were living in counties without access to buprenorphine treatment. In the United States opioid use and related unintentional lethal overdoses continue to rise, particularly in rural areas. Increasing access to office-based treatment of opioid use disorder--particularly in rural America--is a promising strategy to address rising rates of opioid use disorder and unintentional lethal overdoses. © 2015 Annals of Family Medicine, Inc.