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.

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.

Rats that binge eat fat-rich food do not show somatic signs or anxiety associated with opiate-like withdrawal: implications for nutrient-specific food addiction behaviors.

PubMed

Bocarsly, Miriam E; Berner, Laura A; Hoebel, Bartley G; Avena, Nicole M

2011-10-24

Previous studies suggest that binge eating sugar leads to behavioral and neurochemical changes similar to those seen with drug addiction, including signs of opiate-like withdrawal. Studies are emerging that show multiple neurochemical and behavioral indices of addiction when animals overeat a fat-rich diet. The goal of the present study was to utilize liquid and solid diets high in sugar and fat content to determine whether opiate-like withdrawal is seen after binge consumption of these diets in Sprague-Dawley rats. Control groups were given ad libitum access to the sweet-fat food or standard chow. All rats were then given a battery of tests to measure signs of opiate-like withdrawal, which included somatic signs of distress, elevated plus-maze anxiety, and locomotor hypoactivity. Neither naloxone-precipitated (3 mg/kg) nor deprivation-induced withdrawal was observed in rats that were maintained on a nutritionally complete pelleted sweet-fat diet or a sweet, high-fat diet supplemented with standard rodent chow. Naloxone-precipitated withdrawal was also not seen in rats fed a liquid sweet-fat food. Further, body weight reduction to 85%, which is known to potentiate the reinforcing effects of substances of abuse, did not affect naloxone-precipitated signs of opiate-like withdrawal. Thus, unlike previous findings reported regarding rats with binge access to a sucrose solution, rats that binge eat sweet-fat combinations do not show signs of opiate-like withdrawal under the conditions tested. These data support the idea that excessive consumption of different nutrients can induce behaviors associated with addiction in different ways, and that the behaviors that could characterize "food addiction" may be subtyped based on the nutritional composition of the food consumed. Copyright © 2011 Elsevier Inc. All rights reserved.

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.

Depression of home cage wheel running is an objective measure of spontaneous morphine withdrawal in rats with and without persistent pain

PubMed Central

Kandasamy, Ram; Lee, Andrea T.; Morgan, Michael M.

2017-01-01

Opioid withdrawal in humans is often subtle and almost always spontaneous. In contrast, most preclinical studies precipitate withdrawal by administration of an opioid receptor antagonist such as naloxone. These animal studies rely on measurement of physiological symptoms (e.g., wet dog shakes) in the period immediately following naloxone administration. To more closely model the human condition, we tested the hypothesis that depression of home cage wheel running will provide an objective method to measure the magnitude and duration of spontaneous morphine withdrawal. Rats were allowed access to a running wheel in their home cage for 8 days prior to implantation of two 75 mg morphine or placebo pellets. The pellets were removed 3 or 5 days later to induce spontaneous withdrawal. In normal pain-free rats, removal of the morphine pellets depressed wheel running for 48 hours compared to rats that had placebo pellets removed. Morphine withdrawal-induced depression of wheel running was greatly enhanced in rats with persistent inflammatory pain induced by injection of Complete Freund’s Adjuvant (CFA) into the hindpaw. Removal of the morphine pellets following 3 days of treatment depressed wheel running in these rats for over 6 days. These data demonstrate that home cage wheel running provides an objective and more clinically relevant method to assess spontaneous morphine withdrawal compared to precipitated withdrawal in laboratory rats. Moreover, the enhanced withdrawal in rats with persistent inflammatory pain suggests that pain patients may be especially susceptible to opioid withdrawal. PMID:28366799

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

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.

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

Oral noribogaine shows high brain uptake and anti-withdrawal effects not associated with place preference in rodents.

PubMed

Mash, Deborah C; Ameer, Barbara; Prou, Delphine; Howes, John F; Maillet, Emeline L

2016-07-01

This study investigated the effects of noribogaine, the principal metabolite of the drug ibogaine, on substance-related disorders. In the first experiment, mice chronically treated with morphine were subjected to naloxone-precipitated withdrawal two hours after oral administration of noribogaine. Oral noribogaine dose dependently decreased the global opiate withdrawal score by up to 88% of vehicle control with an ED50 of 13 mg/kg. In the second experiment, blood and brain levels of noribogaine showed a high brain penetration and a brain/blood ratio of 7±1 across all doses tested. In a third experiment, rats given oral noribogaine up to 100 mg/kg were tested for abuse liability using a standard biased conditioned place paradigm. Noribogaine-treated rats did not display place preference, suggesting that noribogaine is not perceived as a hedonic stimulus in rodents. Retrospective review of published studies assessing the efficacy of ibogaine on morphine withdrawal shows that the most likely cause of the discrepancies in the literature is the different routes of administration and time of testing following ibogaine administration. These results suggest that the metabolite noribogaine rather than the parent compound mediates the effects of ibogaine on blocking naloxone-precipitated withdrawal. Noribogaine may hold promise as a non-addicting alternative to standard opiate replacement therapies to transition patients to opiate abstinence. © The Author(s) 2016.

Acute opioid withdrawal is associated with increased neural activity in reward-processing centers in healthy men: A functional magnetic resonance imaging study.

PubMed

Chu, Larry F; Lin, Joanne C; Clemenson, Anna; Encisco, Ellen; Sun, John; Hoang, Dan; Alva, Heather; Erlendson, Matthew; Clark, J David; Younger, Jarred W

2015-08-01

Opioid analgesics are frequently prescribed for chronic pain. One expected consequence of long-term opioid use is the development of physical dependence. Although previous resting state functional magnetic resonance imaging (fMRI) studies have demonstrated signal changes in reward-associated areas following morphine administration, the effects of acute withdrawal on the human brain have been less well-investigated. In an earlier study by our laboratory, ondansetron was shown to be effective in preventing symptoms associated with opioid withdrawal. The purpose of this current study was to characterize neural activity associated with acute opioid withdrawal and examine whether these changes are modified by ondansetron. Ten participants were enrolled in this placebo-controlled, randomized, double-blind, crossover study and attended three acute opioid withdrawal sessions. Participants received either placebo or ondansetron (8Ymg IV) before morphine administration (10Ymg/70Ykg IV). Participants then underwent acute naloxone-precipitated withdrawal during a resting state fMRI scan. Objective and subjective opioid withdrawal symptoms were assessed. Imaging results showed that naloxone-precipitated opioid withdrawal was associated with increased neural activity in several reward processing regions, including the right pregenual cingulate, putamen, and bilateral caudate, and decreased neural activity in networks involved in sensorimotor integration. Ondansetron pretreatment did not have a significant effect on the imaging correlates of opioid withdrawal. This study presents a preliminary investigation of the regional changes in neural activity during acute opioid withdrawal. The fMRI acute opioid withdrawal model may serve as a tool for studying opioid dependence and withdrawal in human participants. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

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

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.

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

Disruption of the CRF(2) receptor pathway decreases the somatic expression of opiate withdrawal.

PubMed

Papaleo, Francesco; Ghozland, Sandy; Ingallinesi, Manuela; Roberts, Amanda J; Koob, George F; Contarino, Angelo

2008-11-01

Escape from the extremely aversive opiate withdrawal symptoms powerfully motivates compulsive drug-seeking and drug-taking behaviors. The corticotropin-releasing factor (CRF) system is hypothesized to mediate the motivational properties of drug dependence. CRF signaling is transmitted by two receptor pathways, termed CRF(1) and CRF(2). To investigate the role for the CRF(2) receptor pathway in somatic opiate withdrawal, in the present study we used genetically engineered mice deficient in the CRF(2) receptor (CRF(2)-/-). We employed a novel, clinically relevant mouse model of 'spontaneous' opiate withdrawal as well as a classical opioid receptor antagonist (naloxone)-precipitated opiate withdrawal paradigm. To induce opiate dependence, mice were treated with intermittent escalating morphine doses (20-100 mg/kg, i.p.). We found that 8-128 h after the last opiate injection, CRF(2)-/- mice showed decreased levels of major somatic signs of spontaneous opiate withdrawal, such as paw tremor and wet dog shake, as compared to wild-type mice. Similarly, challenge with naloxone 2 h after the last morphine injection induced lower levels of paw tremor and wet dog shake in CRF(2)-/- mice as compared to wild-type mice. Despite the differences in somatic signs, wild-type and CRF(2)-/- mice displayed similar plasma corticosterone responses to opiate dosing and withdrawal, indicating a marginal role for the hypothalamus-pituitary-adrenal axis in the CRF(2) receptor mediation of opiate withdrawal. Our results unravel a novel role for the CRF(2) receptor pathway in opiate withdrawal. The CRF(2) receptor pathway might be a critical target of therapies aimed at alleviating opiate withdrawal symptoms and reducing relapse to drug intake.

Disruption of the CRF2 Receptor Pathway Decreases the Somatic Expression of Opiate Withdrawal

PubMed Central

Papaleo, Francesco; Ghozland, Sandy; Ingallinesi, Manuela; Roberts, Amanda J; Koob, George F; Contarino, Angelo

2009-01-01

Escape from the extremely aversive opiate withdrawal symptoms powerfully motivates compulsive drug-seeking and drug-taking behaviors. The corticotropin-releasing factor (CRF) system is hypothesized to mediate the motivational properties of drug dependence. CRF signaling is transmitted by two receptor pathways, termed CRF1 and CRF2. To investigate the role for the CRF2 receptor pathway in somatic opiate withdrawal, in the present study we used genetically engineered mice deficient in the CRF2 receptor (CRF2−/−). We employed a novel, clinically relevant mouse model of ‘spontaneous’ opiate withdrawal as well as a classical opioid receptor antagonist (naloxone)-precipitated opiate withdrawal paradigm. To induce opiate dependence, mice were treated with intermittent escalating morphine doses (20–100 mg/kg, i.p.). We found that 8–128 h after the last opiate injection, CRF2−/− mice showed decreased levels of major somatic signs of spontaneous opiate withdrawal, such as paw tremor and wet dog shake, as compared to wild-type mice. Similarly, challenge with naloxone 2 h after the last morphine injection induced lower levels of paw tremor and wet dog shake in CRF2−/− mice as compared to wild-type mice. Despite the differences in somatic signs, wild-type and CRF2−/− mice displayed similar plasma corticosterone responses to opiate dosing and withdrawal, indicating a marginal role for the hypothalamus–pituitary–adrenal axis in the CRF2 receptor mediation of opiate withdrawal. Our results unravel a novel role for the CRF2 receptor pathway in opiate withdrawal. The CRF2 receptor pathway might be a critical target of therapies aimed at alleviating opiate withdrawal symptoms and reducing relapse to drug intake. PMID:18288089

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.

Extinction of conditioned opiate withdrawal in rats is blocked by intracerebroventricular infusion of an NMDA receptor antagonist

PubMed Central

Coleman, Brian R.; Carlezon, William A.; Myers, Karyn M.

2015-01-01

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. PMID:23416323

Prenatal opiate withdrawal activates the chick embryo hypothalamic pituitary-adrenal axis and dilates vitelline blood vessels via serotonin(2) receptors.

PubMed

Schrott, Lisa M; Baumgart, Mary Irene; Zhang, Xuewei; Sparber, Sheldon B

2002-10-01

Opiate withdrawal during pregnancy may occur because of voluntary or forced detoxification, or from rapid cycling associated with exposure to short-acting "street" opiates. Thus, animal modeling of prenatal withdrawal and development of potential therapeutic interventions is important. Direct developmental effects of opiates and/or withdrawal can be studied using a chick model. In ovo administration of the long-acting opiate N-desmethyl-l-alpha-noracetylmethadol (NLAAM) induces opiate dependence in the chick embryo. We examined activation of the hypothalamic-pituitary-adrenal (HPA) axis (assessed via serum corticosterone) and hemodynamic changes (assessed as changes in apparent diameter of vitelline (extraembryonic) blood vessels) after chronic NLAAM exposure and naloxone (Nx)-precipitated withdrawal during late stages of embryogenesis. Nx-precipitated withdrawal increased corticosterone 2- to 4.5-fold and diameters of vitelline blood vessels by 15 to 45%. NLAAM exposure itself did not effect these measures. In a second set of experiments, isobutylmethylxanthine (IBMX), a phosphodiesterase inhibitor, was injected into eggs with embryos. IBMX similarly increased corticosterone and vitelline vessel diameter, with a similar time course and response magnitude. Previous studies found that serotonin(2) (5-HT(2)) receptors were involved in other withdrawal manifestations, so we determined whether they were likewise involved. Pretreatment with the 5-HT(2) antagonist ritanserin completely blocked HPA axis activation and vasodilation associated with both Nx-precipitated withdrawal and IBMX administration. This indicates that 5-HT(2) receptors, directly or indirectly, mediate these withdrawal manifestations in the chick embryo.

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.

Effects of the NMDA receptor antagonist memantine on the expression and development of acute opiate dependence as assessed by withdrawal-potentiated startle and hyperalgesia.

PubMed

Harris, Andrew C; Rothwell, Patrick E; Gewirtz, Jonathan C

2008-03-01

While the N-methyl-D: -aspartate (NMDA) glutamate receptor has been strongly implicated in chronic opiate dependence, relatively few studies have examined the effects of NMDA receptor antagonists on withdrawal from acute opiate exposure. The current study examined the effects of memantine, a well-tolerated NMDA receptor antagonist, on acute opiate dependence as assessed by elevations in rodent startle responding (i.e., "withdrawal-potentiated startle") and increased pain sensitivity (i.e., hyperalgesia). Administration of memantine either attenuated (5 mg/kg) or blocked (10 mg/kg) the expression of withdrawal-potentiated startle during naloxone (2.5 mg/kg)-precipitated withdrawal from a single dose of morphine sulfate (10 mg/kg). Pre-treatment with the NMDA receptor antagonist also inhibited the exacerbation of withdrawal-potentiated startle across repeated acute opiate exposures. Memantine blocked the expression of acute dependence, but was less effective in inhibiting its escalation, when hyperalgesia was used as a measure of withdrawal. These doses of memantine did not affect startle responding or nociception in otherwise drug-free animals. Data from additional control groups indicated that the effects of memantine on the expression of withdrawal were not influenced by nonspecific interactions between the NMDA antagonist and either morphine or naloxone. These findings suggest that the NMDA receptor may play a key role in the earliest stages of opiate dependence and provide further evidence that memantine may be useful for the treatment of opiate withdrawal.

Rats that binge eat fat-rich food do not show somatic signs or anxiety associated with opiate-like withdrawal: implications for nutrient-specific food addiction behaviors

PubMed Central

Bocarsly, Miriam E.; Berner, Laura A.; Hoebel, Bartley G.; Avena, Nicole M.

2012-01-01

Previous studies suggest that binge eating sugar leads to behavioral and neurochemical changes similar to those seen with drug addiction, including signs of opiate-like withdrawal. Studies are emerging that show multiple neurochemical and behavioral indices of addiction when animals overeat a fat-rich diet. The goal of the present study was to utilize liquid and solid diets high in sugar and fat content to determine whether opiate-like withdrawal is seen after binge consumption of these diets in Sprague Dawley rats. Control groups were given ad libitum access to the sweet-fat food or standard chow. All rats were then given a battery of tests to measure signs of opiate-like withdrawal, which included somatic signs of distress, elevated plus-maze anxiety, and locomotor hypoactivity. Neither naloxone-precipitated (3 mg/kg) nor deprivation-induced withdrawal was observed in rats that were maintained on a nutritionally complete pelleted sweet-fat diet, a sweet, high-fat diet supplemented with standard rodent chow, or a liquid sweet-fat food. Further, body weight reduction to 85%, which is known to potentiate the reinforcing effects of substance of abuse, did not affect naloxone-precipitated signs of opiate-like withdrawal. Thus, unlike previous findings reported regarding rats with binge access to a sucrose solution, rats that binge eat sweet-fat combinations do not show signs of opiate-like withdrawal under the conditions tested. These data support the idea that excessive consumption of different nutrients can induce behaviors associated with addiction in different ways, and that the behaviors that could characterize “food addiction” may be subtyped based on the nutritional composition of the food consumed. PMID:21635910

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

Double dissociation in the neural substrates of acute opiate dependence as measured by withdrawal-potentiated startle.

PubMed

Harris, A C; Atkinson, D M; Aase, D M; Gewirtz, J C

2006-01-01

The basolateral amygdala and portions of the "extended" amygdala (i.e. central nucleus of the amygdala, bed nucleus of the stria terminalis and shell of the nucleus accumbens) have been implicated in the aversive aspects of withdrawal from chronic opiate administration. Given that similar withdrawal signs are observed following a single opiate exposure, these structures may also play a role in "acute opiate dependence." In the current study, drug-naïve rats underwent naloxone-precipitated withdrawal from acute morphine (10 mg/kg) exposure on two successive days. On either the first or second day of testing, the basolateral amygdala, central nucleus of the amygdala, bed nucleus of the stria terminalis, or nucleus accumbens was temporarily inactivated immediately prior to naloxone injection by microinfusion of the glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo(f)quinoxaline-7-sulfonamide (3 microg/0.5 microl). On the first day, inactivation of the basolateral amygdala, central nucleus of the amygdala, or bed nucleus of the stria terminalis, but not the nucleus accumbens blocked withdrawal-potentiated startle, a behavioral measure of the anxiogenic effects of withdrawal. On the second day, inactivation of the nucleus accumbens, but not the basolateral amygdala, central nucleus of the amygdala, or bed nucleus of the stria terminalis disrupted the withdrawal effect. Effects of structural inactivations on withdrawal-potentiated startle were not influenced by differences in withdrawal severity on the two days of testing. A fear-potentiated startle procedure provided functional confirmation of correct cannulae placement in basolateral amygdale- and central nucleus of the amygdala-implanted animals. Our findings indicate a double dissociation in the neural substrates of withdrawal-potentiated startle following a first versus second morphine exposure, and may reflect a reorganization of

Precipitated withdrawal counters the adverse effects of subchronic cannabinoid administration on male rat sexual behavior.

PubMed

Riebe, Caitlin J; Lee, Tiffany T; Hill, Matthew N; Gorzalka, Boris B

2010-03-26

In the present study, sexual behavior of male rats was assessed following prolonged treatment with the CB(1) receptor agonist, HU-210 (0.1mg/mg/day for 10 days) under conditions of drug maintenance, spontaneous withdrawal and precipitated withdrawal (induced via administration of the CB(1) receptor antagonist AM251; 1mg/kg). Following subchronic cannabinoid treatment, sexual activity in male rats was impaired under both the drug maintenance and spontaneous withdrawal conditions, as revealed by a reduction in frequency of both intromissions and ejaculations. Notably, the induction of precipitated drug withdrawal reversed the negative effects of subchronic HU-210 treatment on sexual activity as seen by a reversal of the suppression of ejaculations. These data illustrate that, contrary to expectations, the impairments in male sexual activity following protracted cannabinoid administration are not due to drug withdrawal, per se, but are likely mediated by neuroadaptive changes provoked by repeated drug exposure. 2010 Elsevier Ireland Ltd. All rights reserved.

Relations between precipitation, groundwater withdrawals, and changes in hydrologic conditions at selected monitoring sites in Volusia County, Florida, 1995--2010

USGS Publications Warehouse

Murray, Louis C.

2012-01-01

A study to examine the influences of climatic and anthropogenic stressors on groundwater levels, lake stages, and surface-water discharge at selected sites in northern Volusia County, Florida, was conducted in 2009 by the U.S. Geological Survey. Water-level data collected at 20 monitoring sites (17 groundwater and 3 lake sites) in the vicinity of a wetland area were analyzed with multiple linear regression to examine the relative influences of precipitation and groundwater withdrawals on changes in groundwater levels and lake stage. Analyses were conducted across varying periods of record between 1995 and 2010 and included the effects of groundwater withdrawals aggregated from municipal water-supply wells located within 12 miles of the project sites. Surface-water discharge data at the U.S. Geological Survey Tiger Bay canal site were analyzed for changes in flow between 1978 and 2001. As expected, water-level changes in monitoring wells located closer to areas of concentrated groundwater withdrawals were more highly correlated with withdrawals than were water-level changes measured in wells further removed from municipal well fields. Similarly, water-level changes in wells tapping the Upper Floridan aquifer, the source of municipal supply, were more highly correlated with groundwater withdrawals than were water-level changes in wells tapping the shallower surficial aquifer system. Water-level changes predicted by the regression models over precipitation-averaged periods of record were underestimated for observations having large positive monthly changes (generally greater than 1.0 foot). Such observations are associated with high precipitation and were identified as points in the regression analyses that produced large standardized residuals and/or observations of high influence. Thus, regression models produced by multiple linear regression analyses may have better predictive capability in wetland environments when applied to periods of average or below average

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

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.

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

Precipitated withdrawal from nicotine reduces reinforcing effects of a visual stimulus for rats.

PubMed

Weaver, Matthew T; Sweitzer, Maggie; Coddington, Sarah; Sheppard, Jaimee; Verdecchia, Nicole; Caggiula, Anthony R; Sved, Alan F; Donny, Eric C

2012-07-01

Research has identified at least two positive reinforcement-related effects of nicotine: (a) primary reinforcement and (b) enhancement of reinforcement from concurrently available stimuli. Prior examples of the reinforcement-enhancing effects with rats showed that repeated, intermittent nicotine exposure increased responding for non-nicotine reinforcers, and this effect remained robust over several weeks. However, the effects of continuous nicotine exposure on responding for a non-nicotine reinforcer are unknown, as are the effects of abruptly withdrawing continuous nicotine on behavior maintained by the same reinforcer. Lever pressing for a visual reinforcer under a fixed ratio schedule was assessed while rats were maintained on a chronic, continuous infusion of nicotine (3.16 mg/kg/day; osmotic minipump). The effects of precipitated withdrawal on responding, following 16 days of continuous nicotine exposure, were assessed by pre-session subcutaneous injections of mecamylamine (1.0 mg/kg). Continuous nicotine initially increased active responding for the visual reinforcer; however, continued exposure resulted in an attenuation of this effect. Precipitated withdrawal from nicotine resulted in a significant decline in active responding. The initial increase in responding for the visual reinforcer with chronic nicotine exposure is consistent with prior research showing that intermittent exposure to nicotine acts as a reinforcement enhancer. However, the attenuation of this enhancement following prolonged nicotine exposure is in contrast with the persistent effects previously reported. Finally, the decrease in visual reinforcers below control levels (nicotine-naive animals) following nicotine withdrawal highlights a potential for affective withdrawal, which may serve as a motive for continued nicotine use.

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

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.

Pioglitazone attenuates the opioid withdrawal and vulnerability to relapse to heroin seeking in rodents.

PubMed

de Guglielmo, Giordano; Kallupi, Marsida; Scuppa, Giulia; Demopulos, Gregory; Gaitanaris, George; Ciccocioppo, Roberto

2017-01-01

Relapse to opioids is often driven by the avoidance of the aversive states of opioid withdrawal. We recently demonstrated that activation of peroxisome proliferator-activated receptor gamma (PPARγ) by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties. However, the role of PPARγ in withdrawal and other forms of relapse to heroin is unknown. To further address this issue, we investigated the role of PPARγ on the development and expression of morphine withdrawal in mice and the effect of pioglitazone on several forms of heroin relapse in rats. We induced physical dependence to morphine in mice by injecting morphine twice daily for 6 days. Withdrawal syndrome was precipitated on day 6 with an injection of naloxone. In addition, different groups of rats were trained to self-administer heroin and, after the extinction, the relapse was elicited by cues, priming, or stress. The effect of different doses of pioglitazone was tested on these different paradigms. Data show that chronic and acute administration of pioglitazone attenuates morphine withdrawal symptoms, and these effects are mediated by activation of PPARγ receptors. Activation of PPARγ by pioglitazone also abolishes yohimbine-induced reinstatement of heroin seeking and reduces heroin-induced reinstatement, while it does not affect cue-induced relapse. These findings provide new insights on the role of PPARγ on opioid dependence and suggest that pioglitazone may be useful for the treatment of opioid withdrawal in opioid-addicted individuals.

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.

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

included non-heroin opioid overdoses, there were 5443 patients treated without transport and four deaths from rebound opioid toxicity. The number needed to transport to save one life (NNT) is 1361. Adverse effects were mostly related to opioid withdrawal. If a heroin user is treated in the ED, how long must the patient stay under observation before being safe for discharge? Five articles addressing the duration of ED observation required for patients treated with naloxone for opioid overdoses. Although a wide range of observation durations were reported, one study supported observing patients for one hour. If after this period the patient mobilizes as usual, has normal vital signs, and a Glasgow Coma Scale of 15, they can be discharged safely. What are the likely risks in heroin users following naloxone use by lay bystanders or first responders? Of the 15 relevant papers, a systematic review reported a 100% survival rate in eleven studies and a range of 96-99% survival in the remaining four. Two other studies suffered from poor follow-up and had lower success rates of 83% and 89%. Few if any risks were associated with opioid overdose prevention programs in which lay people were trained to administer naloxone. Patients revived with naloxone after heroin overdose may be safely released without transport to the hospital if they have normal mentation and vital signs. In the absence of co-intoxicants and further opioid use there is very low risk of death from rebound opioid toxicity. For those patients treated in the ED for opioid overdose, an observation period of one hour is sufficient if they ambulate as usual, have normal vital signs and a Glasgow Coma Scale of 15. Patients suffering opioid toxicity can be administered naloxone safely by first responders and trained lay people. Programs that train these individuals are likely safe and beneficial, however further research is necessary.

Concurrent Validation of the Clinical Opiate Withdrawal Scale (COWS) and Single-Item Indices against the Clinical Institute Narcotic Assessment (CINA) Opioid Withdrawal Instrument

PubMed Central

Tompkins, D. Andrew; Bigelow, George E.; Harrison, Joseph A.; Johnson, Rolley E.; Fudala, Paul J.; Strain, Eric C.

2009-01-01

Introduction The Clinical Opiate Withdrawal Scale (COWS) is an 11-item clinician-administered scale assessing opioid withdrawal. Though commonly used in clinical practice, it has not been systematically validated. The present study validated the COWS in comparison to the validated Clinical Institute Narcotic Assessment (CINA) scale. Method Opioid-dependent volunteers were enrolled in a residential trial and stabilized on morphine 30 mg given subcutaneously four times daily. Subjects then underwent double-blind, randomized challenges of intramuscularly administered placebo and naloxone (0.4 mg) on separate days, during which the COWS, CINA, and visual analog scale (VAS) assessments were concurrently obtained. Subjects completing both challenges were included (N=46). Correlations between mean peak COWS and CINA scores as well as self-report VAS questions were calculated. Results Mean peak COWS and CINA scores of 7.6 and 24.4, respectively, occurred on average 30 minutes post-injection of naloxone. Mean COWS and CINA scores 30 minutes after placebo injection were 1.3 and 18.9, respectively. The Pearson correlation coefficient for peak COWS and CINA scores during the naloxone challenge session was 0.85 (p<0.001). Peak COWS scores also correlated well with peak VAS self-report scores of bad drug effect (r=0.57, p<0.001) and feeling sick (r=0.57, p<0.001), providing additional evidence of concurrent validity. Placebo was not associated with any significant elevation of COWS, CINA, or VAS scores, indicating discriminant validity. Cronbach’s alpha for the COWS was 0.78, indicating good internal consistency (reliability). Discussion COWS, CINA, and certain VAS items are all valid measurement tools for acute opiate withdrawal. PMID:19647958

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

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.

Management of precipitated opiate withdrawal syndrome induced by nalmefene mistakenly prescribed in opiate-dependent patients: a review for clinicians.

PubMed

Franchitto, Nicolas; Jullian, Benedicte; Salles, Juliette; Pelissier, Fanny; Rolland, Benjamin

2017-06-01

Nalmefene, a long-acting µ-opioid antagonist approved to treat alcohol use disorder, is occasionally mistakenly prescribed to opiate-dependent or opioid-treated patients. We review recent literature on drug-drug interactions between nalmefene and opioids that lead to precipitated opioid withdrawal, and focus on its management and planning for care at discharge. Areas covered: This article provides a brief and comprehensive review of management of precipitated opioid withdrawal syndrome when nalmefene is associated with an opioid, whether misused or legally prescribed. Expert opinion: When treating an opiate-dependent patient with co-occurring alcohol use disorder, both conditions need to be a focus of clinical attention. New drugs for alcohol use disorder have been approved, but must be given cautiously and with a full understanding of their potential drug-drug interactions with opioid medications. Opiate-dependent patients should be intensively monitored for risk factors of alcohol use disorder and should be continuously motivated for treatment maintenance. When nalmefene is administered to opiate-dependent patients, acute opioid withdrawal syndrome may occur. Management of precipitated acute opioid withdrawal may include short or long-acting µ-opioid agonists during hospitalization, in addition to supportive treatment. The best management of polydrug abusers is based on a multidisciplinary approach, which should be pursued and improved through continuing medical education.

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

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

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

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

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.

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.

Nucleus Accumbens AMPA Receptors Are Necessary for Morphine-Withdrawal-Induced Negative-Affective States in Rats

PubMed Central

Russell, Shayla E.; Puttick, Daniel J.; Sawyer, Allison M.; Potter, David N.; Mague, Stephen; Carlezon, William A.

2016-01-01

Dependence is a hallmark feature of opiate addiction and is defined by the emergence of somatic and affective withdrawal signs. The nucleus accumbens (NAc) integrates dopaminergic and glutamatergic inputs to mediate rewarding and aversive properties of opiates. Evidence suggests that AMPA glutamate-receptor-dependent synaptic plasticity within the NAc underlies aspects of addiction. However, the degree to which NAc AMPA receptors (AMPARs) contribute to somatic and affective signs of opiate withdrawal is not fully understood. Here, we show that microinjection of the AMPAR antagonist NBQX into the NAc shell of morphine-dependent rats prevented naloxone-induced conditioned place aversions and decreases in sensitivity to brain stimulation reward, but had no effect on somatic withdrawal signs. Using a protein cross-linking approach, we found that the surface/intracellular ratio of NAc GluA1, but not GluA2, increased with morphine treatment, suggesting postsynaptic insertion of GluA2-lacking AMPARs. Consistent with this, 1-naphthylacetyl spermine trihydrochloride (NASPM), an antagonist of GluA2-lacking AMPARs, attenuated naloxone-induced decreases in sensitivity to brain stimulation reward. Naloxone decreased the surface/intracellular ratio and synaptosomal membrane levels of NAc GluA1 in morphine-dependent rats, suggesting a compensatory removal of AMPARs from synaptic zones. Together, these findings indicate that chronic morphine increases synaptic availability of GluA1-containing AMPARs in the NAc, which is necessary for triggering negative-affective states in response to naloxone. This is broadly consistent with the hypothesis that activation of NAc neurons produces acute aversive states and raises the possibility that inhibiting AMPA transmission selectively in the NAc may have therapeutic value in the treatment of addiction. SIGNIFICANCE STATEMENT Morphine dependence and withdrawal result in profound negative-affective states that play a major role in the

Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast)

PubMed Central

Hutchinson, Mark R.; Lewis, Susannah S.; Coats, Benjamen D.; Skyba, David A.; Crysdale, Nicole Y.; Berkelhammer, Debra L.; Brzeski, Anita; Northcutt, Alexis; Vietz, Christine M.; Judd, Charles M.; Maier, Steven F.; Watkins, Linda R.; Johnson, Kirk W.

2009-01-01

Morphine-induced glial proinflammatory responses have been documented to contribute to tolerance to opioid analgesia. Here, we examined whether drugs previously shown to suppress glial proinflammatory responses can alter other clinically relevant opioid effects; namely, withdrawal or acute analgesia. AV411 (ibudilast) and minocycline, drugs with distinct mechanisms of action that result in attenuation of glial proinflammatory responses, each reduced naloxone-precipitated withdrawal. Analysis of brain nuclei associated with opioid withdrawal revealed that morphine altered expression of glial activation markers, cytokines, chemokines, and a neurotrophic factor. AV411 attenuated many of these morphine-induced effects. AV411 also protected against spontaneous withdrawal-induced hyperactivity and weight loss recorded across a 12-day timecourse. Notably, in the spontaneous withdrawal study, AV411 treatment was delayed relative to the start of the morphine regimen so to also test whether AV411 could still be effective in the face of established morphine dependence, which it was. AV411 did not simply attenuate all opioid effects, as co-administering AV411 with morphine or oxycodone caused 3-to-5-fold increases in acute analgesic potency, as revealed by leftward shifts in the analgesic dose response curves. Timecourse analyses revealed that plasma morphine levels were not altered by AV411, suggestive that potentiated analgesia was not simply due to prolongation of morphine exposure or increased plasma concentrations. These data support and extend similar potentiation of acute opioid analgesia by minocycline, again providing converging lines of evidence of glial involvement. Hence, suppression of glial proinflammatory responses can significantly reduce opioid withdrawal, whilst improving analgesia. PMID:18938237

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

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.

A precipitation-runoff model for analysis of the effects of water withdrawals on streamflow, Ipswich River basin, Massachusetts

USGS Publications Warehouse

Zarriello, Phillip J.; Ries, Kernell G.

2000-01-01

Water withdrawals from the 155-square-mile Ipswich River Basin in northeastern Massachusetts affect aquatic habitat, water quality, and recreational use of the river. To better understand the effects of these withdrawals on streamflow, particularly low flow, the Hydrological Simulation Program-FORTRAN (HSPF) was used to develop a watershed-scale precipitation-runoff model of the Ipswich River to simulate its hydrology and complex water-use patterns.An analytical solution was used to compute time series of streamflow depletions resulting from ground-water withdrawals at wells. The flow depletions caused by pumping from the wells were summed along with any surface-water withdrawals to calculate the total withdrawal along a stream reach. The water withdrawals, records of precipitation, and streamflow records on the Ipswich River at South Middleton and at Ipswich for the period 1989?93 were used to calibrate the model. Model-fit analysis indicates that the simulated flows matched observed flows over a wide range of conditions; at a minimum, the coefficient of model-fit efficiency indicates that the model explained 79 percent of the variance in the observed daily flow.Six alternative water-withdrawal and land-use scenarios were simulated with the model. Three scenarios were examined for the 1989?93 calibration period, and three scenarios were examined for the 1961?95 period to test alternative withdrawals and land use over a wider range of climatic conditions, and to compute 1-, 7-, and 30-day low-flow frequencies using a log-Pearson Type III analysis. Flow-duration curves computed from results of the 1989?93 simulations indicate that, at the South Middleton and Ipswich gaging stations, streamflows when no water withdrawals are being made are nearly identical to streamflows when no ground-water withdrawals are made. Streamflow under no water withdrawals at both stations are about an order of magnitude larger at the 99.8 percent exceedence probability than simulations

Expression of brain-derived neurotrophic factors, neurotrophin-3, and neurotrophin-4 in the nucleus accumbens during heroin dependency and withdrawal.

PubMed

Li, Yixin; Xia, Baijuan; Li, Rongrong; Yin, Dan; Wang, Yanlin; Liang, Wenmei

2017-08-02

Neurotrophins, brain-derived neurotrophic factors (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), have been implicated in the modulation of heroin dependency. This study was designed to explore the expression alterations of BDNF, NT-3, and NT-4 in the context of heroin dependence and withdrawal in the rat nucleus accumbens (NAc). Heroin dependence was induced by a progressive intraperitoneal treatment of heroin. The results showed that the expression levels of BDNF and NT-4 were significantly decreased in the NAc of rats with heroin addiction in comparison with the control group, whereas there was a significant increase in BDNF and NT-4 expressions in the groups of rats with both naloxone-induced and spontaneous withdrawal. Moreover, NT-3 expression was markedly increased in the NAc of rats with heroin addiction and spontaneous withdrawal in comparison with the control group, but decreased in the NAc of rats with naloxone-induced withdrawal. These results indicated that chronic administration of heroin results in the alterations of BDNF, NT-3, and NT-4 expressions in the rat NAc. BDNF, NT-3, and NT-4 may play a critical role in the development of heroin dependency and withdrawal.

Expression of brain-derived neurotrophic factors, neurotrophin-3, and neurotrophin-4 in the nucleus accumbens during heroin dependency and withdrawal

PubMed Central

Li, Yixin; Xia, Baijuan; Li, Rongrong; Yin, Dan; Wang, Yanlin

2017-01-01

Neurotrophins, brain-derived neurotrophic factors (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), have been implicated in the modulation of heroin dependency. This study was designed to explore the expression alterations of BDNF, NT-3, and NT-4 in the context of heroin dependence and withdrawal in the rat nucleus accumbens (NAc). Heroin dependence was induced by a progressive intraperitoneal treatment of heroin. The results showed that the expression levels of BDNF and NT-4 were significantly decreased in the NAc of rats with heroin addiction in comparison with the control group, whereas there was a significant increase in BDNF and NT-4 expressions in the groups of rats with both naloxone-induced and spontaneous withdrawal. Moreover, NT-3 expression was markedly increased in the NAc of rats with heroin addiction and spontaneous withdrawal in comparison with the control group, but decreased in the NAc of rats with naloxone-induced withdrawal. These results indicated that chronic administration of heroin results in the alterations of BDNF, NT-3, and NT-4 expressions in the rat NAc. BDNF, NT-3, and NT-4 may play a critical role in the development of heroin dependency and withdrawal. PMID:28538519

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

Simulating the effects of ground-water withdrawals on streamflow in a precipitation-runoff model

USGS Publications Warehouse

Zarriello, Philip J.; Barlow, P.M.; Duda, P.B.

2004-01-01

Precipitation-runoff models are used to assess the effects of water use and management alternatives on streamflow. Often, ground-water withdrawals are a major water-use component that affect streamflow, but the ability of surface-water models to simulate ground-water withdrawals is limited. As part of a Hydrologic Simulation Program-FORTRAN (HSPF) precipitation-runoff model developed to analyze the effect of ground-water and surface-water withdrawals on streamflow in the Ipswich River in northeastern Massachusetts, an analytical technique (STRMDEPL) was developed for calculating the effects of pumped wells on streamflow. STRMDEPL is a FORTRAN program based on two analytical solutions that solve equations for ground-water flow to a well completed in a semi-infinite, homogeneous, and isotropic aquifer in direct hydraulic connection to a fully penetrating stream. One analytical method calculates unimpeded flow at the stream-aquifer boundary and the other method calculates the resistance to flow caused by semipervious streambed and streambank material. The principle of superposition is used with these analytical equations to calculate time-varying streamflow depletions due to daily pumping. The HSPF model can readily incorporate streamflow depletions caused by a well or surface-water withdrawal, or by multiple wells or surface-water withdrawals, or both, as a combined time-varying outflow demand from affected channel reaches. These demands are stored as a time series in the Watershed Data Management (WDM) file. This time-series data is read into the model as an external source used to specify flow from the first outflow gate in the reach where these withdrawals are located. Although the STRMDEPL program can be run independently of the HSPF model, an extension was developed to run this program within GenScn, a scenario generator and graphical user interface developed for use with the HSPF model. This extension requires that actual pumping rates for each well be stored

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

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.

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.

Mu-opioid receptor redistribution in the locus coeruleus upon precipitation of withdrawal in opiate-dependent rats.

PubMed

Scavone, Jillian L; Van Bockstaele, Elisabeth J

2009-03-01

Administration of mu-opioid receptor (MOR) agonists is known to produce adaptive changes within noradrenergic neurons of the rat locus coeruleus (LC). Alterations in the subcellular distribution of MOR have been shown to occur in the LC in response to full agonists and endogenous peptides; however, there is considerable debate in the literature whether trafficking of MOR occurs after chronic exposure to the partial-agonist morphine. In the present study, we examined adaptations in MOR after chronic opioid exposure using immunofluorescence and electron microscopy (EM), using receptor internalization as a functional endpoint. MOR trafficking in LC neurons was characterized in morphine-dependent rats that were given naltrexone at a dose known to precipitate withdrawal. After chronic morphine exposure, a subtle redistribution of MOR immunoreactivity from the membrane to the cytosol was detected within dendrites of LC neurons. Interestingly, an acute injection of naltrexone in rats exposed to chronic morphine produced a robust internalization of MOR, whereas administration of naltrexone failed to do so in naïve animals. These findings provide anatomical evidence for modified regulation of MOR trafficking after chronic morphine treatment in brain noradrenergic neurons. Adaptations in the MOR signaling pathways that regulate internalization may occur as a consequence of chronic treatment and precipitation of withdrawal. Mechanisms underlying this effect might include differential MOR regulation in the LC, or downstream effects of withdrawal-induced enkephalin (ENK) release from afferents to the LC. (c) 2009 Wiley-Liss, Inc.

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 ...

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.

Ibogaine attenuation of morphine withdrawal in mice: role of glutamate N-methyl-D-aspartate receptors.

PubMed

Leal, Mirna Bainy; Michelin, Kátia; Souza, Diogo Onofre; Elisabetsky, Elaine

2003-08-01

Ibogaine (IBO) is an alkaloid with putative antiaddictive properties, alleviating opiates dependence and withdrawal. The glutamate N-methyl-D-aspartate (NMDA) receptors have been implicated in the physiological basis of drug addiction; accordingly, IBO acts as a noncompetitive NMDA antagonist. The purpose of this study was to evaluate the effects of IBO on naloxone-induced withdrawal syndrome in morphine-dependent mice, focusing on the role of NMDA receptors. Jumping, a major behavioral expression of such withdrawal, was significantly (P<.01) inhibited by IBO (40 and 80 mg/kg, 64.2% and 96.9% inhibition, respectively) and MK-801 (0.15 and 0.30 mg/kg, 67.3% and 97.7%, respectively) given prior to naloxone. Coadministration of the lower doses of IBO (40 mg/kg) and MK-801 (0.15 mg/kg) results in 94.7% inhibition of jumping, comparable to the effects of higher doses of either IBO or MK-801. IBO and MK-801 also significantly inhibited NMDA-induced (99.0% and 71.0%, respectively) jumping when given 30 min (but not 24 h) prior to NMDA in nonaddictive mice. There were no significant differences in [3H]MK-801 binding to cortical membranes from naive animals, morphine-dependent animals, or morphine-dependent animals treated with IBO or MK-801. This study provides further evidence that IBO does have an inhibitory effect on opiate withdrawal symptoms and suggests that the complex process resulting in morphine withdrawal includes an IBO-sensitive functional and transitory alteration of NMDA receptor.

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.

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

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.

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.

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

Imaging Sex Differences in Regional Brain Metabolism during Acute Opioid Withdrawal

PubMed Central

Santoro, Giovanni C; Carrion, Joseph; Dewey, Stephen L

2017-01-01

The rate of opioid overdose continues to rise, necessitating improved treatment options. Current therapeutic approaches rely on administration of either a blocking agent, such as naloxone, or chronic treatment with replacement drugs, including methadone and/or buprenorphine. Recent findings suggest that males and females respond to these treatments uniquely. In an effort to better understand this sex-specific variation in treatment efficacy, we investigated the effects of acute opioid withdrawal in male and female rats using 18FDG and microPET. These data demonstrate that acute opioid withdrawal produces metabolic alterations in brain regions associated with reward and drug dependence, namely corpus striatum, thalamic nuclei, septum, and frontal cortex. Furthermore, certain changes are unique to males. Specifically, males demonstrated increased metabolism in the anterior cingulate cortex and the ventral hippocampus (CA3) following acute opioid withdrawal. If males and females exhibit sex-specific changes in regional brain metabolism following acute opioid withdrawal, then perhaps it is not surprising that they respond to treatment differently. PMID:29046888

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.

A Novel Strategy for Attenuating Opioid Withdrawal in Neonates

PubMed Central

Santoro, Giovanni C; Shukla, Samarth; Patel, Krishna; Kaczmarzyk, Jakub; Agorastos, Stergiani; Scherrer, Sandra; Choi, Yoon Young; Veith, Christina; Carrion, Joseph; Silverman, Rebecca; Mullin, Danielle; Ahmed, Mohamed; Schiffer, Wynne K; Brodie, Jonathan D; Dewey, Stephen L

2016-01-01

The rate of Neonatal Abstinence Syndrome (NAS) has drastically increased over the past decade. The average hospital expense per NAS patient has tripled, while the number of babies born to opioid-dependent mothers has increased to 5 in 1000 births. Current treatment options are limited to opioid replacement and tapering. Consequently, we examined the efficacy of prenatal, low-dose and short-term vigabatrin (γ-vinyl GABA, GVG) exposure for attenuating these symptoms as well as the metabolic changes observed in the brains of these animals upon reaching adolescence. Pregnant Sprague-Dawley rats were treated in one of four ways: 1) saline; 2) morphine alone; 3) morphine+GVG at 25 mg/kg; 4) morphine+GVG at 50 mg/kg. Morphine was administered throughout gestation, while GVG administration occurred only during the last 5 days of gestation. On post-natal day 1, naloxone-induced withdrawal behaviours were recorded in order to obtain a gross behaviour score. Approximately 28 days following birth, 18FDG microPET scans were obtained on these same animals (Groups 1, 2, and 4). Morphine-treated neonates demonstrated significantly higher withdrawal scores than saline controls. However, GVG at 50 but not 25 mg/kg/day significantly attenuated them. Upon reaching adolescence, morphine treated animals showed regionally specific changes in 18FDG uptake. Again, prenatal GVG exposure blocked them. These data demonstrate that low-dose, short-term prenatal GVG administration blocks naloxone-induced withdrawal in neonates. Taken together, these preliminary findings suggest that GVG may provide an alternative and long-lasting pharmacologic approach for the management of neonatal and adolescent symptoms associated with NAS. PMID:28078167

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

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.

Physical dependence on nitrous oxide in mice: resemblance to alcohol but not to opiate withdrawal.

PubMed

Milne, B; Cervenko, F W; Jhamandas, K H

1981-01-01

Mice of two strains, Crl:CD-1(1CR)Br and C57BL6, were exposed to nitrous oxide at concentrations of 50, 65 and 80 per cent for 34 or 68 hours. Cessation of nitrous oxide resulted in characteristic convulsions similar to those seen in alcohol withdrawal in all mice. These peaked in severity within 2-3 minutes after removal from nitrous oxide and declined over 6 hours. The severity and duration of these convulsions were related to the nitrous oxide concentration and duration of exposure. Naloxone or naltrexone produced no significant increase in severity of convulsions. The narcotic antagonists did not precipitate acute weight loss or characteristic jumping behaviour seen in animals dependent on opiates. These results demonstrate that chronic exposure to nitrous oxide results in development of physical dependence which resembles alcohol and not opiate dependence. Analgesia and physical dependence produced by nitrous oxide appear to be mediated through separate mechanisms.

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.

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.

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.

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.

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.

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.

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

Pleiotrophin modulates morphine withdrawal but has no effects on morphine-conditioned place preference.

PubMed

Gramage, Esther; Vicente-Rodríguez, Marta; Herradón, Gonzalo

2015-09-14

Pleiotrophin (PTN) is a neurotrophic factor with important functions in addiction and neurodegenerative disorders. Morphine administration induces an increase in the expression of PTN and Midkine (MK), the only other member of this family of cytokines, in brain areas related with the addictive effects of drug of abuse, like the Ventral Tegmental Area or the hippocampus. In spite of previous studies showing that PTN modulates amphetamine and ethanol rewarding effects, and that PTN is involved in morphine-induced analgesia, it was still unknown if the rewarding effects of morphine may be regulated by endogenous PTN. Thus, we aim to study the role of PTN in the reward and physical dependence induced by morphine. We used the Conditioned Place Preference (CPP) paradigm in PTN genetically deficient (PTN-/-) and wild type (WT) mice to assess the rewarding effects of morphine in absence of endogenous PTN. Second, to study if PTN may be involved in morphine physical dependence, naloxone-precipitated withdrawal syndrome was induced in PTN-/- and WT morphine dependent mice. Although the increase in the time spent in the morphine-paired compartment after conditioning tended to be more pronounced in PTN-/- mice, statistical significance was not achieved. The data suggest that PTN does not exert an important role in morphine reward. However, our results clearly indicate that PTN-/- mice develop a more severe withdrawal syndrome than WT mice, characterized as a significant increase in the time standing and in the total incidences of forepaw licking, forepaw tremors, wet dog shake and writhing. The data presented here suggest that PTN is a novel genetic factor that plays a role in morphine withdrawal syndrome. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

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.

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.

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).

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

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.

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

delta(9)-Tetrahydrocannabinol-dependent mice undergoing withdrawal display impaired spatial memory.

PubMed

Wise, Laura E; Varvel, Stephen A; Selley, Dana E; Wiebelhaus, Jason M; Long, Kelly A; Middleton, Lisa S; Sim-Selley, Laura J; Lichtman, Aron H

2011-10-01

Cannabis users display a constellation of withdrawal symptoms upon drug discontinuation, including sleep disturbances, irritability, and possibly memory deficits. In cannabinoid-dependent rodents, the CB(1) antagonist rimonabant precipitates somatic withdrawal and enhances forskolin-stimulated adenylyl cyclase activity in cerebellum, an effect opposite that of acutely administered ∆(9)-tetrahydrocannabinol (THC), the primary constituent in cannabis. Here, we tested whether THC-dependent mice undergoing rimonabant-precipitated withdrawal display short-term spatial memory deficits, as assessed in the Morris water maze. We also evaluated whether rimonabant would precipitate adenylyl cyclase superactivation in hippocampal and cerebellar tissue from THC-dependent mice. Rimonabant significantly impaired spatial memory of THC-dependent mice at lower doses than those necessary to precipitate somatic withdrawal behavior. In contrast, maze performance was near perfect in the cued task, suggesting sensorimotor function and motivational factors were unperturbed by the withdrawal state. Finally, rimonabant increased adenylyl cyclase activity in cerebellar, but not in hippocampal, membranes. The memory disruptive effects of THC undergo tolerance following repeated dosing, while the withdrawal state leads to a rebound deficit in memory. These results establish spatial memory impairment as a particularly sensitive component of cannabinoid withdrawal, an effect that may be mediated through compensatory changes in the cerebellum.

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

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

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

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.

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

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.

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

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.

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

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.

Similar precipitated withdrawal effects on intracranial self-stimulation during chronic infusion of an e-cigarette liquid or nicotine alone.

PubMed

Harris, A C; Muelken, P; Smethells, J R; Krueger, M; LeSage, M G

2017-10-01

The FDA recently extended their regulatory authority to electronic cigarettes (ECs). Because the abuse liability of ECs is a leading concern of the FDA, animal models are urgently needed to identify factors that influence the relative abuse liability of these products. The ability of tobacco products to induce nicotine dependence, defined by the emergence of anhedonia and other symptoms of nicotine withdrawal following cessation of their use, contributes to tobacco abuse liability. The present study compared the severity of precipitated withdrawal during chronic infusion of nicotine alone or nicotine-dose equivalent concentrations of three different EC refill liquids in rats, as indicated by elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior). Because these EC liquids contain constituents that may enhance their abuse liability (e.g., minor alkaloids), we hypothesized that they would be associated with greater withdrawal effects than nicotine alone. Results indicated that the nicotinic acetylcholine receptor antagonist mecamylamine precipitated elevations in ICSS thresholds in rats receiving a chronic infusion of nicotine alone or EC liquids (3.2mg/kg/day, via osmotic pump). Magnitude of this effect did not differ between formulations. Our findings indicate that nicotine alone is the primary CNS determinant of the ability of ECs to engender dependence. Combined with our previous findings that nicotine alone and these EC liquids do not differ in other preclinical addiction models, these data suggest that product standards set by the FDA to reduce EC abuse liability should primarily target nicotine, other constituents with peripheral sensory effects (e.g. flavorants), and factors that influence product appeal (e.g., marketing). Copyright © 2017 Elsevier Inc. All rights reserved.

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.

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.

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

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.

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.

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.

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

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.

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.

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

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.

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.

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.

Modulation of ethanol withdrawal-induced anxiety-like behavior during later withdrawals by treatment of early withdrawals with benzodiazepine/gamma-aminobutyric acid ligands.

PubMed

Knapp, Darin J; Overstreet, David H; Breese, George R

2005-04-01

Anxiety states, including those arising during acute or protracted withdrawal periods, may be precipitating factors in alcoholic relapse. Given the cyclical nature of ethanol withdrawal associated with repeated cycles of ethanol intake and abstinence in a pattern that often spans years, meaningful attempts to model ethanol withdrawal-associated anxiety should incorporate cycled ethanol treatments. The studies reported herein examined the effects of gamma-aminobutyric acid-modulating drugs on social interaction behavior-an established model of anxiety-in rats exposed to repeated cycles of ethanol treatment and withdrawal. Rats were exposed to 8 to 12 g/kg/day ethanol during three 7-day dietary cycles (5 days on ethanol diet followed by 2 days on control diet). Ethanol was administered either at hour 4 of withdrawal after cessation of each of the first 2 ethanol cycles or during the final withdrawal only. In other groups, the early withdrawals were treated with alphaxalone, diazepam, PK11159, or flumazenil to block anxiety-like behavior during an untreated later (third) withdrawal. The benzodiazepine inverse agonist DMCM (methyl-6, 7-dymerhoxy-4-ethyl-beta-carboline-3-carboxylate) was also given repeatedly to determine whether it would sensitize anxiety-like behavior during a future withdrawal. Finally, the effects of all drugs on deficits in locomotor behavior were assessed. Pretreatment of earlier withdrawals with alphaxalone, diazepam, ethanol, or flumazenil reduced social interaction deficits during a later withdrawal, but pretreatment with PK11195 did not. In contrast, DMCM administered in lieu of early withdrawals increased social interaction deficits during an untreated later withdrawal. Locomotor deficits were significantly reversed only by the acute ethanol and diazepam treatment during the final withdrawal. Single-dose administration of drugs that enhance or diminish activity at benzodiazepine-gamma-aminobutyric acid- receptors during earlier withdrawals

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.

Protective role of Delphinium denudatum (Jadwar) against morphine induced tolerance and dependence in mice.

PubMed

Zafar, S; Ahmad, M A; Siddiqui, T A

2001-11-01

Chronic treatment with Delphinium denudatum (Dd) (Jadwar) (family: Ranunculaceae, 200-1600 mg/kg) suppressed morphine withdrawal jumps in a dose-dependent manner, a sign of the development of dependence to opiate as assessed by naloxone (2 mg/kg) precipitation withdrawal on day 10 of testing in mice. Repeated administration of Dd (200-1600 mg/kg) for 9 days attenuated the development of tolerance to the analgesic effect of morphine (10 mg/kg), also produces significant change in tail-flick latency from the saline pretreated group in a dose-dependent manner.

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

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

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.

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.

[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

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

A Global-Scale Examination of Monsoon-Related Precipitation.

NASA Astrophysics Data System (ADS)

Janowiak, John E.; Xie, Pingping

2003-12-01

A pentad version of the Global Precipitation Climatology Project global precipitation dataset is used to document the annual and interannual variations in precipitation over monsoon regions around the globe. An algorithm is described that determines objectively wet season onset and withdrawal for individual years, and this tool is used to examine the behavior of various characteristics of the major monsoon systems. The definition of onset and withdrawal are determined by examining the ramp-up and diminution of rainfall within the context of the climatological rainfall at each location. Also examined are interannual variations in onset and withdrawal and their relationship to rainy season precipitation accumulations. Changes in the distribution of “heavy” and “light” precipitation events are examined for years in which “abundant” and “poor” wet seasons are observed, and associations with variations in large-scale atmospheric general circulation features are also examined. In particular, some regions of the world have strong associations between wet season rainfall and global-scale patterns of 200-hPa streamfunction anomalies.

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.

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

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.

[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

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

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

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

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�

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.

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.

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.

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.

Emergence of dormant conditioned incentive approach by conditioned withdrawal in nicotine addiction.

PubMed

Scott, Daniel; Hiroi, Noboru

2010-10-15

Nicotine is one of the determinants for the development of persistent smoking, and this maladaptive behavior is characterized by many symptoms, including withdrawal and nicotine seeking. The process by which withdrawal affects nicotine seeking is poorly understood. The impact of a withdrawal-associated cue on nicotine (.2 mg/kg)-conditioned place preference was assessed in male C57BL/6J mice (n = 8-17/group). To establish a cue selectively associated with withdrawal distinct from those associated with nicotine, a tone was paired with withdrawal in their home cages; mice were chronically exposed to nicotine (200 μg/mL for 15 days) from drinking water in their home cages and received the nicotinic acetylcholine receptor antagonist mecamylamine (2.5 mg/kg) to precipitate withdrawal in the presence of a tone. The effect of the withdrawal-associated tone on nicotine-conditioned place preference was then evaluated in the place-conditioning apparatus after a delay, when nicotine-conditioned place preference spontaneously disappeared. A cue associated with precipitated withdrawal reactivated the dormant effect of nicotine-associated cues on conditioned place preference. This effect occurred during continuous exposure to nicotine but not during abstinence. A conditioned withdrawal cue could directly amplify the incentive properties of cues associated with nicotine. This observation extends the contemporary incentive account of the role of withdrawal in addiction to cue-cue interaction. Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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.

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.

A lack of association between severity of nicotine withdrawal and individual differences in compensatory nicotine self-administration in rats

PubMed Central

Harris, Andrew C.; Pentel, Paul R.; Burroughs, Danielle; Staley, Mylissa D.; LeSage, Mark G.

2013-01-01

Rationale Compensatory smoking may represent an adverse consequence of smoking reduction or the use of reduced nicotine tobacco products. Factors contributing to individual variability in compensation are poorly understood. Objective To examine whether severity of nicotine withdrawal as measured by elevated intracranial self-stimulation (ICSS) thresholds is related to individual differences in compensatory nicotine self-administration (NSA) following unit dose reduction. Methods Rats were trained for ICSS and NSA (0.06 mg/kg/inf). After stabilization, effects of reducing the nicotine unit dose to 0.03 mg/kg/inf were examined. Following reacquisition of NSA (0.06 mg/kg/inf), effects of antagonist-precipitated withdrawal and saline extinction (spontaneous withdrawal) were examined. Results Reducing the NSA unit dose produced partial compensation as indicated by increased infusion rates but a 35% mean decrease in daily nicotine intake. Magnitude of compensation varied considerably among rats. Dose reduction did not elicit withdrawal in rats as a group, although there were substantial increases in ICSS thresholds in some animals. Intracranial self-stimulation thresholds were consistently elevated during precipitated and spontaneous withdrawal, confirming that rats were nicotine-dependent. Individual differences in compensation were not correlated with changes in ICSS thresholds during dose reduction, precipitated withdrawal, or spontaneous withdrawal. In a secondary analysis, greater precipitated withdrawal severity predicted greater initial nicotine-seeking during extinction. Conclusions Severity of nicotine withdrawal was not related to the degree of compensation in this protocol. These data do not support a role for nicotine withdrawal in individual differences in compensation during reduced nicotine exposure, but do suggest that withdrawal may contribute to nicotine-seeking during early abstinence. PMID:21494791

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.

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/ ...

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

Opioid withdrawal, craving, and use during and after outpatient buprenorphine stabilization and taper: A discrete survival and growth mixture model

PubMed Central

Stotts, Angela L.; Green, Charles; Potter, Jennifer S.; Marino, Elise N.; Walker, Robrina; Weiss, Roger D.; Trivedi, Madhukar

2014-01-01

Most patients relapse to opioids within one month of opioid agonist detoxification, making the antecedents and parallel processes of first use critical for investigation. Craving and withdrawal are often studied in relationship to opioid outcomes, and a novel analytic strategy applied to these two phenomena may indicate targeted intervention strategies. Specifically, this secondary data analysis of the Prescription Opioid Addiction Treatment Study used a discrete-time mixture analysis with time-to-first opioid use (survival) simultaneously predicted by craving and withdrawal growth trajectories. This analysis characterized heterogeneity among prescription opioid-dependent individuals (N=653) into latent classes (i.e., latent class analysis [LCA]) during and after buprenorphine/naloxone stabilization and taper. A 4-latent class solution was selected for overall model fit and clinical parsimony. In order of shortest to longest time-to-first use, the 4 classes were characterized as 1) high craving and withdrawal 2) intermediate craving and withdrawal 3) high initial craving with low craving and withdrawal trajectories and 4) a low initial craving with low craving and withdrawal trajectories. Odds ratio calculations showed statistically significant differences in time-to-first use across classes. Generally, participants with lower baseline levels and greater decreases in craving and withdrawal during stabilization combined with slower craving and withdrawal rebound during buprenorphine taper remained opioid-free longer. This exploratory work expanded on the importance of monitoring craving and withdrawal during buprenorphine induction, stabilization, and taper. Future research may allow individually tailored and timely interventions to be developed to extend time-to-first opioid use. PMID:25282598

Opioid withdrawal, craving, and use during and after outpatient buprenorphine stabilization and taper: a discrete survival and growth mixture model.

PubMed

Northrup, Thomas F; Stotts, Angela L; Green, Charles; Potter, Jennifer S; Marino, Elise N; Walker, Robrina; Weiss, Roger D; Trivedi, Madhukar

2015-02-01

Most patients relapse to opioids within one month of opioid agonist detoxification, making the antecedents and parallel processes of first use critical for investigation. Craving and withdrawal are often studied in relationship to opioid outcomes, and a novel analytic strategy applied to these two phenomena may indicate targeted intervention strategies. Specifically, this secondary data analysis of the Prescription Opioid Addiction Treatment Study used a discrete-time mixture analysis with time-to-first opioid use (survival) simultaneously predicted by craving and withdrawal growth trajectories. This analysis characterized heterogeneity among prescription opioid-dependent individuals (N=653) into latent classes (i.e., latent class analysis [LCA]) during and after buprenorphine/naloxone stabilization and taper. A 4-latent class solution was selected for overall model fit and clinical parsimony. In order of shortest to longest time-to-first use, the 4 classes were characterized as 1) high craving and withdrawal, 2) intermediate craving and withdrawal, 3) high initial craving with low craving and withdrawal trajectories and 4) a low initial craving with low craving and withdrawal trajectories. Odds ratio calculations showed statistically significant differences in time-to-first use across classes. Generally, participants with lower baseline levels and greater decreases in craving and withdrawal during stabilization combined with slower craving and withdrawal rebound during buprenorphine taper remained opioid-free longer. This exploratory work expanded on the importance of monitoring craving and withdrawal during buprenorphine induction, stabilization, and taper. Future research may allow individually tailored and timely interventions to be developed to extend time-to-first opioid use. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

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

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

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

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

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.

Onset, advance and withdrawal of southwest monsoon over Indian subcontinent: A study from precipitable water measurement using ground based GPS receivers

NASA Astrophysics Data System (ADS)

Puviarasan, N.; Sharma, A. K.; Ranalkar, Manish; Giri, R. K.

2015-01-01

Southwest monsoon (SWM) normally sets over Kerala by 1st June. It subsequently advances northwards and covers the entire country by 15th July. Prior knowledge of determination of date of onset of monsoon (DOM) is vital for many applications. However, accurate determination of DOM avoiding false or 'bogus' onset still remains a challenge to meteorological community. An incorrect identification of onset may lead to declaration of early onset. India Meteorological Department (IMD) has traditionally adopted an objective method to declare onset and withdrawal of monsoon based on rainfall over some specific stations in addition to wind field and Outgoing Longwave Radiation (OLR) from a bounded region. An augmentation of existing criteria of monsoon onset using high temporal resolution tropospheric precipitable water (PW) content over a station obtained through ground based GPS receiver is proposed. It has been shown that variation of PW content is an indicator of the state of monsoon and can potentially be included in operational criteria for declaring onset and withdrawal of monsoon. In the paper, we present daily variation of PW during SWM at five stations viz. Chennai, Kolkata, Guwahati, Mumbai and Delhi. The superposed epoch analysis of PW variation for 13 days with respect to arrival and withdrawal date of SWM reveals that over Kolkata at the time of arrival of monsoon the PW (mm)/SD (Standard Deviation) increases from 48.62/2.5 (day -6) to 61.4/1.9 (day 0) and on withdrawal it decreases from 48.62/4.56 (day -6) to 22.55 mm/4.0 (day 0). Similarly in Guwahati, Mumbai and Delhi the value of PW/SD increase from 53.81/4.2, 43.10/7.2 and 44.6/5.0 mm to 62.74/1.5, 62.09/1.6 and 61.88/2.3 mm and on withdrawal it reduces to 27.12/4.2, 25.94/2.6 and 20.46/4.6 mm respectively. It is also noticed that there is a sharp variation of PW from day -2 to day 0, which indicates GPS PW can be considered as a precursor for monsoon arrival and withdrawal.

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

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.

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.

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.

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

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

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

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

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

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

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.

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.

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...

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...

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.

Comparative effects of pulmonary and parenteral Δ⁹-tetrahydrocannabinol exposure on extinction of opiate-induced conditioned aversion in rats.

PubMed

Manwell, Laurie A; Mallet, Paul E

2015-05-01

Evidence suggesting that the endogenous cannabinoid (eCB) system can be manipulated to facilitate or impair extinction of learned behaviours has important consequences for opiate withdrawal and abstinence. We demonstrated that the fatty acid amide hydrolase (FAAH) inhibitor URB597, which increases eCB levels, facilitates extinction of a naloxone-precipitated morphine withdrawal-induced conditioned place aversion (CPA). The potential of the exogenous CB1 ligand, Δ(9)-tetrahydrocannabinol (Δ(9)-THC), to facilitate extinction of this CPA was tested. Effects of both pulmonary and parenteral Δ(9)-THC exposure were evaluated using comparable doses previously determined. Rats trained to associate a naloxone-precipitated morphine withdrawal with a floor cue were administered Δ(9)-THC-pulmonary (1, 5, 10 mg vapour inhalation) or parenteral (0.5, 1.0, 1.5 mg/kg intraperitoneal injection)-prior to each of 20 to 28 extinction/testing trials. Vapourized Δ(9)-THC facilitated extinction of the CPA in a dose- and time-dependent manner: 5 and 10 mg facilitated extinction compared to vehicle and 1 mg Δ(9)-THC. Injected Δ(9)-THC significantly impaired extinction only for the 1.0-mg/kg dose: it prolonged the CPA fourfold longer than the vehicle and 0.5- and 1.5-mg/kg doses. These data suggest that both dose and route of Δ(9)-THC administration have important consequences for its pharmacokinetic and behavioural effects; specifically, pulmonary exposure at higher doses facilitates, whereas pulmonary and parenteral exposure at lower doses impairs, rates of extinction learning for CPA. Pulmonary-administered Δ(9)-THC may prove beneficial for potentiation of extinction learning for aversive memories, such as those supporting drug-craving/seeking in opiate withdrawal syndrome, and other causes of conditioned aversions, such as illness and stress.

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

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.

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

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.

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…

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

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

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.

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

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.

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

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.

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

Modulation of Ethanol Withdrawal–Induced Anxiety-Like Behavior During Later Withdrawals by Treatment of Early Withdrawals With Benzodiazepine/γ-Aminobutyric Acid Ligands

PubMed Central

Knapp, Darin J.; Overstreet, David H.; Breese, George R.

2010-01-01

Background Anxiety states, including those arising during acute or protracted withdrawal periods, may be precipitating factors in alcoholic relapse. Given the cyclical nature of ethanol withdrawal associated with repeated cycles of ethanol intake and abstinence in a pattern that often spans years, meaningful attempts to model ethanol withdrawal–associated anxiety should incorporate cycled ethanol treatments. The studies reported herein examined the effects of γ-aminobutyric acid–modulating drugs on social interaction behavior—an established model of anxiety—in rats exposed to repeated cycles of ethanol treatment and withdrawal. Methods Rats were exposed to 8 to 12 g/kg/day ethanol during three 7-day dietary cycles (5 days on ethanol diet followed by 2 days on control diet). Ethanol was administered either at hour 4 of withdrawal after cessation of each of the first 2 ethanol cycles or during the final withdrawal only. In other groups, the early withdrawals were treated with alphaxalone, diazepam, PK11159, or flumazenil to block anxiety-like behavior during an untreated later (third) withdrawal. The benzodiazepine inverse agonist DMCM (methyl–6, 7–dymerhoxy–4–ethyl–beta–carboline–3–carboxylate) was also given repeatedly to determine whether it would sensitize anxiety-like behavior during a future withdrawal. Finally, the effects of all drugs on deficits in locomotor behavior were assessed. Results Pretreatment of earlier withdrawals with alphaxalone, diazepam, ethanol, or flumazenil reduced social interaction deficits during a later withdrawal, but pretreatment with PK11195 did not. In contrast, DMCM administered in lieu of early withdrawals increased social interaction deficits during an untreated later withdrawal. Locomotor deficits were significantly reversed only by the acute ethanol and diazepam treatment during the final withdrawal. Conclusions Single-dose administration of drugs that enhance or diminish activity at benzodiazepine�

Wheel running during chronic nicotine exposure is protective against mecamylamine-precipitated withdrawal and up-regulates hippocampal α7 nACh receptors in mice.

PubMed

Keyworth, Helen; Georgiou, Polymnia; Zanos, Panos; Rueda, André Veloso; Chen, Ying; Kitchen, Ian; Camarini, Rosana; Cropley, Mark; Bailey, Alexis

2018-06-01

Evidence suggests that exercise decreases nicotine withdrawal symptoms in humans; however, the mechanisms mediating this effect are unclear. We investigated, in a mouse model, the effect of exercise intensity during chronic nicotine exposure on nicotine withdrawal severity, binding of α4β2*, α7 nicotinic acetylcholine (nAChR), μ-opioid (μ receptors) and D 2 dopamine receptors and on brain-derived neurotrophic factor (BDNF) and plasma corticosterone levels. Male C57Bl/6J mice treated with nicotine (minipump, 24 mg·kg -1 ·day -1 ) or saline for 14 days underwent one of three concurrent exercise regimes: 24, 2 or 0 h·day -1 voluntary wheel running. Mecamylamine-precipitated withdrawal symptoms were assessed on day 14. Quantitative autoradiography of α4β2*, α7 nAChRs, μ receptors and D 2 receptor binding was performed in brain sections of these mice. Plasma corticosterone and brain BDNF levels were also measured. Nicotine-treated mice undertaking 2 or 24 h·day -1 wheel running displayed a significant reduction in withdrawal symptom severity compared with the sedentary group. Wheel running induced a significant up-regulation of α7 nAChR binding in the CA2/3 area of the hippocampus of nicotine-treated mice. Neither exercise nor nicotine treatment affected μ or D 2 receptor binding or BDNF levels. Nicotine withdrawal increased plasma corticosterone levels and α4β2* nAChR binding, irrespective of exercise regimen. We demonstrated for the first time a profound effect of exercise on α7 nAChRs in nicotine-dependent animals, irrespective of exercise intensity. These findings shed light onto the mechanism underlining the protective effect of exercise on the development of nicotine dependence. This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc. © 2017 The British Pharmacological Society.

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.

Low dose naltrexone administration in morphine dependent rats attenuates withdrawal-induced norepinephrine efflux in forebrain.

PubMed

Van Bockstaele, Elisabeth J; Qian, Yaping; Sterling, Robert C; Page, Michelle E

2008-05-15

The administration of low dose opioid antagonists has been explored as a potential means of detoxification in opiate dependence. Previous results from our laboratory have shown that concurrent administration of low dose naltrexone in the drinking water of rats implanted with subcutaneous morphine pellets attenuates behavioral and biochemical signs of withdrawal in brainstem noradrenergic nuclei. Noradrenergic projections originating from the nucleus tractus solitarius (NTS) and the locus coeruleus (LC) have previously been shown to be important neural substrates involved in the somatic expression of opiate withdrawal. The hypothesis that low dose naltrexone treatment attenuates noradrenergic hyperactivity typically associated with opiate withdrawal was examined in the present study by assessing norepinephrine tissue content and norepinephrine efflux using in vivo microdialysis coupled to high performance liquid chromatography (HPLC) with electrochemical detection (ED). The frontal cortex (FC), amygdala, bed nucleus of the stria terminalis (BNST) and cerebellum were analyzed for tissue content of norepinephrine following withdrawal in morphine dependent rats. Naltrexone-precipitated withdrawal elicited a significant decrease in tissue content of norepinephrine in the BNST and amygdala. This decrease was significantly attenuated in the BNST of rats that received low dose naltrexone pre-treatment compared to controls. No significant difference was observed in the other brain regions examined. In a separate group of rats, norepinephrine efflux was assessed with in vivo microdialysis in the BNST or the FC of morphine dependent rats or placebo treated rats subjected to naltrexone-precipitated withdrawal that received either naltrexone in their drinking water (5 mg/L) or unadulterated water. Following baseline dialysate collection, withdrawal was precipitated by injection of naltrexone and sample collection continued for an additional 4 h. At the end of the experiment

Affective and Neuroendocrine Effects of Withdrawal from Chronic, Long-Acting Opiate Administration

PubMed Central

Hamilton, Kathryn L.; Harris, Andrew C.; Gewirtz, Jonathan C.

2013-01-01

Although the long-acting opiate methadone is commonly used to treat drug addiction, relatively little is known about effects of withdrawal from this drug in preclinical models. The current study examined affective, neuroendocrine, and somatic signs of withdrawal from the longer-acting methadone derivative l-alpha-acetylmethydol (LAAM) in rats. Anxiety-like behavior during both spontaneous and antagonist-precipitated withdrawal was measured by potentiation of the startle reflex. Withdrawal elevated corticosterone and somatic signs and blunted circadian variations in baseline startle responding. In addition, fear to an explicit, Pavlovian conditioned stimulus (fear-potentiated startle) was enhanced. These data suggest that anxiety-like behavior as measured using potentiated startle responding does not emerge spontaneously during withdrawal from chronic opiate exposure – in contrast to withdrawal from acute drug exposure – but rather is manifested as exaggerated fear in response to explicit threat cues. PMID:24076207

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.

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

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.

N-acetylcysteine decreased nicotine reward-like properties and withdrawal in mice.

PubMed

Bowers, M S; Jackson, A; Maldoon, P P; Damaj, M I

2016-03-01

N-acetylcysteine can increase extrasynaptic glutamate and reduce nicotine self-administration in rats and smoking rates in humans. The aim of this study was to determine if N-acetylcysteine modulates the development of nicotine place conditioning and withdrawal in mice. N-acetylcysteine was given to nicotine-treated male ICR mice. Experiment 1: reward-like behavior. N-acetylcysteine (0, 5, 15, 30, or 60 mg/kg, i.p.) was given 15 min before nicotine (0.5 mg/kg, s.c.) or saline (10 ml/kg, s.c.) in an unbiased conditioned place preference (CPP) paradigm. Conditioning for highly palatable food served as control. Experiment 2: spontaneous withdrawal. The effect of N-acetylcysteine (0, 15, 30, 120 mg/kg, i.p.) on anxiety-like behavior, somatic signs, and hyperalgesia was measured 18-24 h after continuous nicotine (24 mg/kg/day, 14 days). Experiment 3: mecamylamine-precipitated, withdrawal-induced aversion. The effect of N-acetylcysteine (0, 15, 30, 120 mg/kg, i.p.) on mecamylamine (3.5 mg/kg, i.p.)-precipitated withdrawal was determined after continuous nicotine (24 mg/kg, i.p., 28 days) using the conditioned place aversion (CPA) paradigm. Dose-related reductions in the development of nicotine CPP, somatic withdrawal signs, hyperalgesia, and CPA were observed after N-acetylcysteine pretreatment. No effect of N-acetylcysteine was found on palatable food CPP, anxiety-like behavior, or motoric capacity (crosses between plus maze arms). Finally, N-acetylcysteine did not affect any measure in saline-treated mice at doses effective in nicotine-treated mice. These are the first data suggesting that N-acetylcysteine blocks specific mouse behaviors associated with nicotine reward and withdrawal, which adds to the growing appreciation that N-acetylcysteine may have high clinical utility in combating nicotine dependence.

N-acetylcysteine decreased nicotine reward-like properties and withdrawal in mice

PubMed Central

Bowers, M.S.; Jackson, A.; Maldoon, P.P.; Damaj, M. I.

2016-01-01

Rationale N-acetylcysteine can increase extrasynaptic glutamate and reduce nicotine self-administration in rats and smoking rates in humans. Objectives The aim of this study was to determine if N-acetylcysteine modulates the development of nicotine place conditioning and withdrawal in mice. Methods N-acetylcysteine was given to nicotine-treated male ICR mice. Experiment 1: reward-like behavior. N-acetylcysteine (0, 5, 15, 30, or 60 mg/kg, i.p.) was given 15 min before nicotine (0.5 mg/kg, s.c.) or saline (10 ml/kg, s.c.) in an unbiased conditioned place preference (CPP) paradigm. Conditioning for highly palatable food served as control. Experiment 2: spontaneous withdrawal. The effect of N-acetylcysteine (0, 15, 30, 120 mg/kg, i.p.) on anxiety-like behavior, somatic signs, and hyperalgesia were measured 18 - 24 hrs after continuous nicotine (24 mg/kg/day, 14 days). Experiment 3: Mecamylamine-precipitated, withdrawal-induced aversion. The effect of N-acetylcysteine (0, 15, 30, 120 mg/kg, i.p.) on mecamylamine (3.5 mg/kg, i.p.) precipitated withdrawal was determined after continuous nicotine (24 mg/kg, i.p., 28 days) using the conditioned place aversion (CPA) paradigm. Results Dose-related reductions in the development of nicotine CPP, somatic withdrawal signs, hyperalgesia, and CPA were observed after N-acetylcysteine pretreatment. No effect of N-acetylcysteine were found on palatable food CPP, anxiety-like behavior, or motoric capacity (crosses between plus maze arms). Finally, N-acetylcysteine did not affect any measure in saline-treated mice at doses effective in nicotine-treated mice. Conclusions These are the first data suggesting that N-acetylcysteine blocks specific mouse behaviors associated with nicotine reward and withdrawal, which adds to the growing appreciation that N-acetylcysteine may have high clinical utility in combating nicotine dependence. PMID:26676982

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.

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.

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.

29 CFR 4219.11 - Withdrawal liability upon mass withdrawal.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 9 2010-07-01 2010-07-01 false Withdrawal liability upon mass withdrawal. 4219.11 Section... Redetermination of Withdrawal Liability Upon Mass Withdrawal § 4219.11 Withdrawal liability upon mass withdrawal. (a) Initial withdrawal liability. The plan sponsor of a multiemployer plan that experiences a mass...

29 CFR 4219.11 - Withdrawal liability upon mass withdrawal.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 29 Labor 9 2011-07-01 2011-07-01 false Withdrawal liability upon mass withdrawal. 4219.11 Section... Redetermination of Withdrawal Liability Upon Mass Withdrawal § 4219.11 Withdrawal liability upon mass withdrawal. (a) Initial withdrawal liability. The plan sponsor of a multiemployer plan that experiences a mass...

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.

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…

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

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.

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.

The Small GTPase Rac1 Contributes to Extinction of Aversive Memories of Drug Withdrawal by Facilitating GABAA Receptor Endocytosis in the vmPFC.

PubMed

Wang, Weisheng; Ju, Yun-Yue; Zhou, Qi-Xin; Tang, Jian-Xin; Li, Meng; Zhang, Lei; Kang, Shuo; Chen, Zhong-Guo; Wang, Yu-Jun; Ji, Hui; Ding, Yu-Qiang; Xu, Lin; Liu, Jing-Gen

2017-07-26

Extinction of aversive memories has been a major concern in neuropsychiatric disorders, such as anxiety disorders and drug addiction. However, the mechanisms underlying extinction of aversive memories are not fully understood. Here, we report that extinction of conditioned place aversion (CPA) to naloxone-precipitated opiate withdrawal in male rats activates Rho GTPase Rac1 in the ventromedial prefrontal cortex (vmPFC) in a BDNF-dependent manner, which determines GABA A receptor (GABA A R) endocytosis via triggering synaptic translocation of activity-regulated cytoskeleton-associated protein (Arc) through facilitating actin polymerization. Active Rac1 is essential and sufficient for GABA A R endocytosis and CPA extinction. Knockdown of Rac1 expression within the vmPFC of rats using Rac1-shRNA suppressed GABA A R endocytosis and CPA extinction, whereas expression of a constitutively active form of Rac1 accelerated GABA A R endocytosis and CPA extinction. The crucial role of GABA A R endocytosis in the LTP induction and CPA extinction is evinced by the findings that blockade of GABA A R endocytosis by a dynamin function-blocking peptide (Myr-P4) abolishes LTP induction and CPA extinction. Thus, the present study provides first evidence that Rac1-dependent GABA A R endocytosis plays a crucial role in extinction of aversive memories and reveals the sequence of molecular events that contribute to learning experience modulation of synaptic GABA A R endocytosis. SIGNIFICANCE STATEMENT This study reveals that Rac1-dependent GABA A R endocytosis plays a crucial role in extinction of aversive memories associated with drug withdrawal and identifies Arc as a downstream effector of Rac1 regulations of synaptic plasticity as well as learning and memory, thereby suggesting therapeutic targets to promote extinction of the unwanted memories. Copyright © 2017 the authors 0270-6474/17/377096-15$15.00/0.

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.

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.

"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.

A precipitation-runoff model for the analysis of the effects of water withdrawals and land-use change on streamflow in the Usquepaug-Queen River Basin, Rhode Island

USGS Publications Warehouse

Zarriello, Phillip J.; Bent, Gardner C.

2004-01-01

The 36.1-square-mile UsquepaugQueen River Basin in south-central Rhode Island is an important water resource. Streamflow records indicate that withdrawals may have diminished flows enough to affect aquatic habitat. Concern over the effect of withdrawals on streamflow and aquatic habitat prompted the development of a Hydrologic Simulation ProgramFORTRAN (HSPF) model to evaluate the water-management alternatives and land-use change in the basin. Climate, streamflow, and water-use data were collected to support the model development. A logistic-regression equation was developed for long-term simulations to predict the likelihood of irrigation, the primary water use in the basin, from antecedent potential evapotranspiration and precipitation for generating irrigation demands. The HSPF model represented the basin by 13 pervious-area and 2 impervious-area land-use segments and 20 stream reaches. The model was calibrated to the period January 1, 2000 to September 30, 2001, at three continuous streamflow-gaging stations that monitor flow from 10, 54, and 100 percent of the basin drainage area. Hydrographs and flow-duration curves of observed and simulated discharges, along with statistics compiled for various model-fit metrics, indicate a satisfactory model performance. The calibrated HSPF model was modified to evaluate streamflow (1) under no withdrawals to streamflow under current (200001) withdrawal conditions under long-term (19602001) climatic conditions, (2) under withdrawals by the former Ladd School water-supply wells, and (3) under fully developed land use. The effects of converting from direct-stream withdrawals to ground-water withdrawals were evaluated outside of the HSPF model by use of the STRMDEPL program, which calculates the time delayed response of ground-water withdrawals on streamflow depletion. Simulated effects of current withdrawals relative to no withdrawals indicate about a 20-percent decrease in the lowest mean daily streamflows at the basin

CB1 Cannabinoid Receptors Mediate Cognitive Deficits and Structural Plasticity Changes During Nicotine Withdrawal.

PubMed

Saravia, Rocio; Flores, África; Plaza-Zabala, Ainhoa; Busquets-Garcia, Arnau; Pastor, Antoni; de la Torre, Rafael; Di Marzo, Vincenzo; Marsicano, Giovanni; Ozaita, Andrés; Maldonado, Rafael; Berrendero, Fernando

2017-04-01

Tobacco withdrawal is associated with deficits in cognitive function, including attention, working memory, and episodic memory. Understanding the neurobiological mechanisms involved in these effects is crucial because cognitive deficits during nicotine withdrawal may predict relapse in humans. We investigated in mice the role of CB 1 cannabinoid receptors (CB 1 Rs) in memory impairment and spine density changes induced by nicotine withdrawal precipitated by the nicotinic antagonist mecamylamine. Drugs acting on the endocannabinoid system and genetically modified mice were used. Memory impairment during nicotine withdrawal was blocked by the CB 1 R antagonist rimonabant or the genetic deletion of CB 1 R in forebrain gamma-aminobutyric acidergic (GABAergic) neurons (GABA-CB 1 R). An increase of 2-arachidonoylglycerol (2-AG), but not anandamide, was observed during nicotine withdrawal. The selective inhibitor of 2-AG biosynthesis O7460 abolished cognitive deficits of nicotine abstinence, whereas the inhibitor of 2-AG enzymatic degradation JZL184 did not produce any effect in cognitive impairment. Moreover, memory impairment was prevented by the selective mammalian target of rapamycin inhibitor temsirolimus and the protein synthesis inhibitor anisomycin. Mature dendritic spines on CA1 pyramidal hippocampal neurons decreased 4 days after the precipitation of nicotine withdrawal, when the cognitive deficits were still present. Indeed, a correlation between memory performance and mature spine density was found. Interestingly, these structural plasticity alterations were normalized in GABA-CB 1 R conditional knockout mice and after subchronic treatment with rimonabant. These findings underline the interest of CB 1 R as a target to improve cognitive performance during early nicotine withdrawal. Cognitive deficits in early abstinence are associated with increased relapse risk. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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.

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…

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

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.

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.

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.

Inhibition of Morphine Tolerance and Dependence by the NMDA Receptor Antagonist MK-801

NASA Astrophysics Data System (ADS)

Trujillo, Keith A.; Akil, Huda

1991-01-01

The N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor is an important mediator of several forms of neural and behavioral plasticity. The present studies examined whether NMDA receptors might be involved in the development of opiate tolerance and dependence, two examples of behavioral plasticity. The noncompetitive NMDA receptor antagonist MK-801 attenuated the development of tolerance to the analgesic effect of morphine without affecting acute morphine analgesia. In addition, MK-801 attenuated the development of morphine dependence as assessed by naloxone-precipitated withdrawal. These results suggest that NMDA receptors may be important in the development of opiate tolerance and dependence.

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.

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.

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

[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

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.

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.

MDMA attenuates THC withdrawal syndrome in mice.

PubMed

Touriño, Clara; Maldonado, Rafael; Valverde, Olga

2007-07-01

3, 4-Methylenedioxymethamphetamine (MDMA) and cannabis are widely abused illicit drugs that are frequently consumed in combination. Interactions between these two drugs have been reported in several pharmacological responses observed in animals, such as body temperature, anxiety, cognition, and reward. However, the interaction between MDMA and cannabis in addictive processes such as physical dependence has not been elucidated yet. In this study, the effects of acute and chronic MDMA were evaluated on the behavioral manifestations of Delta(9)-tetrahydrocannabinol (THC) abstinence in mice. THC withdrawal syndrome was precipitated by injecting the cannabinoid antagonist rimonabant (10 mg/kg, i.p.) in mice chronically treated with THC and receiving MDMA (2.5, 5 and 10 mg/kg i.p.) or saline just before the withdrawal induction or chronically after the THC administration. Both chronic and acute MDMA decreased in a dose-dependent manner the severity of THC withdrawal. In vivo microdialysis experiments showed that acute MDMA (5 mg/kg, i.p.) administration increased extracellular serotonin levels in the prefrontal cortex, but not dopamine levels in the nucleus accumbens. Our results also indicate that the attenuation of THC abstinence symptoms was not due to a direct interaction between rimonabant and MDMA nor to the result of the locomotor stimulating effects of MDMA. The modulation of the cannabinoid withdrawal syndrome by acute or chronic MDMA suggests a possible mechanism to explain the associated consumption of these two drugs in humans.

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

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.

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

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

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.

Cocaine withdrawal

MedlinePlus

... Substance use - cocaine withdrawal; Substance abuse - cocaine withdrawal; Drug abuse - cocaine withdrawal; Detox - cocaine ... Elsevier Saunders; 2016:chap 50. National Institute on Drug Abuse. What is cocaine? Updated May 2016. www.drugabuse. ...

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.

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.

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.

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.

Withdrawal

MedlinePlus

... However, withdrawal is considered a better method of contraception than none at all. Protection Against STDs Withdrawal ... 2013 More on this topic for: Teens Emergency Contraception Talking to Your Partner About Condoms Birth Control ...

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.

Effects of chronic mild stress on the development of drug dependence in rats.

PubMed

Papp, Mariusz; Gruca, Piotr; Lason-Tyburkiewicz, Magdalena; Litwa, Ewa; Willner, Paul

2014-09-01

There is high comorbidity between depression and addiction. Features of addiction relevant to depression have been studied extensively, but less is known about features of depression relevant to addiction. Here, we have studied the effects of chronic mild stress (CMS), a valid animal model of depression, on measures of physical and psychological dependence resulting from subchronic treatment of rats with three drugs of abuse that act through disparate neurobiological mechanisms: morphine, nicotine and diazepam. In animals not treated subchronically with drugs of abuse, CMS increased the withdrawal-like effects of the opiate antagonist naloxone, but not those of the nicotinic antagonist mecamylamine or the benzodiazepine antagonist flumazenil. In animals treated subchronically with drugs of abuse, CMS exacerbated, precipitated and conditioned withdrawal effects associated with all three antagonists. CMS also potentiated withdrawal-induced and cue-induced place aversions associated with all three antagonists. All of the effects of CMS were reversed by chronic treatment with the specific serotonin reuptake inhibitor citalopram. These results suggest that treatment of comorbid depression, although not a primary treatment for addiction, may facilitate other treatments for addiction, by decreasing the severity of withdrawal symptoms and the likelihood of relapse.

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

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

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.

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.

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

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.

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

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...

A Two-Day Continuous Nicotine Infusion Is Sufficient to Demonstrate Nicotine Withdrawal in Rats as Measured Using Intracranial Self-Stimulation.

PubMed

Muelken, Peter; Schmidt, Clare E; Shelley, David; Tally, Laura; Harris, Andrew C

2015-01-01

Avoidance of the negative affective (emotional) symptoms of nicotine withdrawal (e.g., anhedonia, anxiety) contributes to tobacco addiction. Establishing the minimal nicotine exposure conditions required to demonstrate negative affective withdrawal signs in animals, as well as understanding moderators of these conditions, could inform tobacco addiction-related research, treatment, and policy. The goal of this study was to determine the minimal duration of continuous nicotine infusion required to demonstrate nicotine withdrawal in rats as measured by elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior). Administration of the nicotinic acetylcholine receptor antagonist mecamylamine (3.0 mg/kg, s.c.) on alternate test days throughout the course of a 2-week continuous nicotine infusion (3.2 mg/kg/day via osmotic minipump) elicited elevations in ICSS thresholds beginning on the second day of infusion. Magnitude of antagonist-precipitated withdrawal did not change with further nicotine exposure and mecamylamine injections, and was similar to that observed in a positive control group receiving mecamylamine following a 14-day nicotine infusion. Expression of a significant withdrawal effect was delayed in nicotine-infused rats receiving mecamylamine on all test days rather than on alternate test days. In a separate study, rats exhibited a transient increase in ICSS thresholds following cessation of a 2-day continuous nicotine infusion (3.2 mg/kg/day). Magnitude of this spontaneous withdrawal effect was similar to that observed in rats receiving a 9-day nicotine infusion. Our findings demonstrate that rats exhibit antagonist-precipitated and spontaneous nicotine withdrawal following a 2-day continuous nicotine infusion, at least under the experimental conditions studied here. Magnitude of these effects were similar to those observed in traditional models involving more prolonged nicotine exposure. Further development of these models

A Two-Day Continuous Nicotine Infusion Is Sufficient to Demonstrate Nicotine Withdrawal in Rats as Measured Using Intracranial Self-Stimulation

PubMed Central

Muelken, Peter; Schmidt, Clare E.; Shelley, David; Tally, Laura; Harris, Andrew C.

2015-01-01

Avoidance of the negative affective (emotional) symptoms of nicotine withdrawal (e.g., anhedonia, anxiety) contributes to tobacco addiction. Establishing the minimal nicotine exposure conditions required to demonstrate negative affective withdrawal signs in animals, as well as understanding moderators of these conditions, could inform tobacco addiction-related research, treatment, and policy. The goal of this study was to determine the minimal duration of continuous nicotine infusion required to demonstrate nicotine withdrawal in rats as measured by elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior). Administration of the nicotinic acetylcholine receptor antagonist mecamylamine (3.0 mg/kg, s.c.) on alternate test days throughout the course of a 2-week continuous nicotine infusion (3.2 mg/kg/day via osmotic minipump) elicited elevations in ICSS thresholds beginning on the second day of infusion. Magnitude of antagonist-precipitated withdrawal did not change with further nicotine exposure and mecamylamine injections, and was similar to that observed in a positive control group receiving mecamylamine following a 14-day nicotine infusion. Expression of a significant withdrawal effect was delayed in nicotine-infused rats receiving mecamylamine on all test days rather than on alternate test days. In a separate study, rats exhibited a transient increase in ICSS thresholds following cessation of a 2-day continuous nicotine infusion (3.2 mg/kg/day). Magnitude of this spontaneous withdrawal effect was similar to that observed in rats receiving a 9-day nicotine infusion. Our findings demonstrate that rats exhibit antagonist-precipitated and spontaneous nicotine withdrawal following a 2-day continuous nicotine infusion, at least under the experimental conditions studied here. Magnitude of these effects were similar to those observed in traditional models involving more prolonged nicotine exposure. Further development of these models

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.

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

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…

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.

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

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.

[An examination of the determinants of social withdrawal and affinity for social withdrawal].

PubMed

Watanabe, Asami; Matsui, Yutaka; Takatsuka, Yusuke

2010-12-01

This study examined the determinants of social withdrawal using data from a survey by the Tokyo Metropolitan Government Office for Youth Affairs and Public Safety (2008). In addition, this study identified young people who showed an affinity for social withdrawal although they were not in a state of withdrawal, and examined the determinants of an affinity for social withdrawal. The results of stepwise discriminant analysis showed that factors such as social phobia, depression, violence, and emotional bonds with family differentiated between the general youth group and the social withdrawal group and the "affinity group". Social phobia, violence, and refusal to be interfered in self-decision making differentiated between the social withdrawal group and the "affinity group". This study shows that an "affinity group" should be cared as well as an actual withdrawal group.

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.

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.

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

Treatment for amphetamine withdrawal.

PubMed

Shoptaw, Steven J; Kao, Uyen; Heinzerling, Keith; Ling, Walter

2009-04-15

Few studies examined treatments for amphetamine withdrawal, although it is a common problem among amphetamine users. Its symptoms, in particular intense craving, may be a critical factor leading to relapse to amphetamine use. In clinical practice, medications for cocaine withdrawal are commonly used to manage amphetamine withdrawal although the pharmacodynamic and pharmacokinetic properties of these two illicit substances are different. To assess the effectiveness of pharmacological alone or in combination with psychosocial treatment for amphetamine withdrawals on discontinuation rates, global state, withdrawal symptoms, craving, and other outcomes. MEDLINE (1966 - 2008), CINAHL (1982 - 2008), PsycINFO (1806 - 2008), CENTRAL (Cochrane Library 2008 issue 2), references of obtained articles. All randomised controlled and clinical trials evaluating pharmacological and or psychosocial treatments (alone or combined) for people with amphetamine withdrawal symptoms. Two authors evaluated and extracted data independently. The data were extracted from intention-to-treat analyses. The Relative Risk (RR) with the 95% confidence interval (95% CI) was used to assess dichotomous outcomes. The Weighted Mean Difference (WMD) with 95% CI was used to assess continuous outcomes. Four randomised controlled trials (involving 125 participants) met the inclusion criteria for the review. Two studies found that amineptine significantly reduced discontinuation rates and improved overall clinical presentation, but did not reduce withdrawal symptoms or craving compared to placebo. The benefits of mirtazapine over placebo for reducing amphetamine withdrawal symptoms were not as clear. One study suggested that mirtazapine may reduce hyperarousal and anxiety symptoms associated with amphetamine withdrawal. A more recent study failed to find any benefit of mirtazapine over placebo on retention or on amphetamine withdrawal symptoms. No medication is effective for treatment of amphetamine

CRF1 receptor activation mediates nicotine withdrawal-induced deficit in brain reward function and stress-induced relapse

PubMed Central

Bruijnzeel, Adrie W.; Prado, Melissa; Isaac, Shani

2010-01-01

Background Tobacco addiction is a chronic brain disorder that is characterized by a negative affective state upon smoking cessation and relapse after periods of abstinence. Previous research has shown that blockade of CRF receptors with a non-specific CRF1/CRF2 receptor antagonist prevents the deficit in brain reward function associated with nicotine withdrawal and stress-induced reinstatement of extinguished nicotine seeking in rats. The aim of these studies was to investigate the role of CRF1 and CRF2 receptors in the deficit in brain reward function associated with precipitated nicotine withdrawal and stress-induced reinstatement of nicotine seeking. Methods The intracranial self-stimulation (ICSS) procedure was used to assess the negative affective state of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. Stress-induced reinstatement of nicotine seeking was investigated in animals in which responding for intravenously infused nicotine was extinguished by substituting saline for nicotine. Results In the ICSS experiments, the nicotinic receptor antagonist mecamylamine elevated the brain reward thresholds of the nicotine dependent rats but not those of the control rats. The CRF1 receptor antagonist R278995/CRA0450, but not the CRF2 receptor antagonist astressin-2B, prevented the elevations in brain reward thresholds associated with precipitated nicotine withdrawal. Furthermore, R278995/CRA0450, but not astressin-2B, prevented stress-induced reinstatement of extinguished nicotine seeking. Neither R278995/CRA0450 nor astressin-2B affected operant responding for chocolate-flavored food pellets. Conclusions These studies indicate that CRF1 receptors, but not CRF2 receptors, play an important role in the anhedonic-state associated with acute nicotine withdrawal and stress-induced reinstatement of nicotine seeking. PMID:19217073

Opiate and opioid withdrawal

MedlinePlus

... opiate withdrawal; Oxycontin - opiate withdrawal; Hydrocodone - opiate withdrawal; Detox - opiates; Detoxification - opiates ... facilities set up to help people with detoxification (detox). In a regular hospital, if symptoms are severe. ...

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.

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

Withdrawal Method (Coitus Interruptus)

MedlinePlus

Withdrawal method (coitus interruptus) Overview The withdrawal method of contraception, also known as coitus interruptus, is the practice of withdrawing the penis from the vagina and away from a woman's external ...

Topiramate in opiate withdrawal.

PubMed

Zullino, Daniele F; Cottier, Anne-Claude; Besson, Jacques

2002-10-01

The alpha2-adrenergic agonist clonidine is the mainly used drug for the opiate withdrawal. Its efficacy and tolerance in treating withdrawal symptoms is, however, suboptimal. The pharmacological profile of topiramate suggests it could be rather valuable for opiate withdrawal, as there is some evidence that topiramate acts, among others, through inhibition of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, which play an important role in the withdrawal-induced activation of the locus coeruleus (LC) by glutamate. Three patients undergoing an inpatient opiate detoxification program were treated with topiramate, which achieved a nearly complete control of withdrawal symptoms.

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

The Cannabis Withdrawal Scale development: patterns and predictors of cannabis withdrawal and distress.

PubMed

Allsop, David J; Norberg, Melissa M; Copeland, Jan; Fu, Shanlin; Budney, Alan J

2011-12-01

Rates of treatment seeking for cannabis are increasing, and relapse is common. Management of cannabis withdrawal is an important intervention point. No psychometrically sound measure for cannabis withdrawal exists, and as a result treatment developments cannot be optimally targeted. The aim is to develop and test the psychometrics of the Cannabis Withdrawal Scale and use it to explore predictors of cannabis withdrawal. A volunteer sample of 49 dependent cannabis users provided daily scores on the Cannabis Withdrawal Scale during a baseline week and 2 weeks of abstinence. Internal reliability (Cronbach's alpha=0.91), test-retest stability (average intra-class correlation=0.95) and content validity analysis show that the Cannabis Withdrawal Scale has excellent psychometric properties. Nightmares and/or strange dreams was the most valid item (Wald χ²=105.6, P<0.0001), but caused relatively little associated distress (Wald χ²=25.11, P=0.03). Angry outbursts were considered intense (Wald χ²=73.69, P<0.0001) and caused much associated distress (Wald χ²=45.54, P<0.0001). Trouble getting to sleep was also an intense withdrawal symptom (Wald χ²=42.31, P<0.0001) and caused significant associated distress (Wald χ²=47.76, P<0.0001). Scores on the Severity of Dependence Scale predicted cannabis withdrawal. The Cannabis Withdrawal Scale can be used as a diagnostic instrument in clinical and research settings where regular monitoring of withdrawal symptoms is required. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

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.

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

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.

Evaluation of the effects of precipitation on ground-water levels from wells in selected alluvial aquifers in Utah and Arizona, 1936-2005

USGS Publications Warehouse

Gardner, Philip M.; Heilweil, Victor M.

2009-01-01

Increased withdrawals from alluvial aquifers of the southwestern United States during the last half-century have intensified the effects of drought on ground-water levels in valleys where withdrawal for irrigation is greatest. Furthermore, during wet periods, reduced withdrawals coupled with increased natural recharge cause rising ground-water levels. In order to manage water resources more effectively, analysis of ground-water levels under the influence of natural and anthropogenic stresses is useful. This report evaluates the effects of precipitation patterns on ground-water levels in areas of Utah and Arizona that have experienced different amounts of ground-water withdrawal. This includes a comparison of water-level records from basins that are hydrogeologically and climatologically similar but have contrasting levels of ground-water development. Hydrologic data, including records of ground-water levels, basin-wide annual ground-water withdrawals, and precipitation were examined from two basins in Utah (Milford and central Sevier) and three in Arizona (Aravaipa Canyon, Willcox, and Douglas). Most water-level records examined in this study from basins experiencing substantial ground-water development (Milford, Douglas, and Willcox) showed strong trends of declining water levels. Other water-level records, generally from the less-developed basins (central Sevier and Aravaipa Canyon) exhibited trends of increasing water levels. These trends are likely the result of accumulating infiltration of unconsumed irrigation water. Water-level records that had significant trends were detrended by subtraction of a low-order polynomial in an attempt to eliminate the variation in the water-level records that resulted from ground-water withdrawal or the application of water for irrigation. After detrending, water-level residuals were correlated with 2- to 10-year moving averages of annual precipitation from representative stations for the individual basins. The water

Effects of acute alcohol withdrawal on nest building in mice selectively bred for alcohol withdrawal severity

PubMed Central

Greenberg, Gian D.; Phillips, Tamara J.; Crabbe, John C.

2017-01-01

Nest building has been used to assess thermoregulatory behavior and positive motivational states in mice. There are known genetic influences on ethanol withdrawal severity as well as individual/thermoregulatory nest building. Withdrawal Seizure-Prone (WSP-1, WSP-2) and Withdrawal Seizure-Resistant (WSR-1, WSR-2) mice were selectively bred for high vs low handling-induced convulsion (HIC) severity, respectively, during withdrawal from chronic ethanol vapor inhalation. They also differ in HIC severity during withdrawal from an acute, 4 g/kg ethanol injection. In our initial study, withdrawal from an acute dose of ethanol dose-dependently impaired nest building over the initial 24 h of withdrawal in genetically segregating Withdrawal Seizure Control (WSC) mice. In two further studies, acute ethanol withdrawal suppressed nest building for up to two days in WSP-1 females. Deficits in nest building from ethanol were limited to the initial 10 h of withdrawal in WSR-1 females and to the initial 24 h of withdrawal in WSP-1 and WSR-1 males. Effects of ethanol on nest building for up to two days were found in WSP-2 and WSR-2 mice of both sexes. Nest building deficits in female mice from the first replicate could not be explained by a general decrease in locomotor behavior. These results suggest that nest building is a novel behavioral phenotype for indexing the severity of acute ethanol withdrawal, and that genes contributing to this trait differ from those affecting acute withdrawal HIC severity. PMID:27503811

40 CFR 74.18 - Withdrawal.

Code of Federal Regulations, 2014 CFR

2014-07-01

... opt-in source may request to withdraw from the Acid Rain Program by submitting an administrative... paragraph (f)(1) of this section. (b) Requesting withdrawal. To withdraw from the Acid Rain Program, the...-in source's prior violations. An opt-in source that withdraws from the Acid Rain Program shall comply...

40 CFR 74.18 - Withdrawal.

Code of Federal Regulations, 2013 CFR

2013-07-01

... opt-in source may request to withdraw from the Acid Rain Program by submitting an administrative... paragraph (f)(1) of this section. (b) Requesting withdrawal. To withdraw from the Acid Rain Program, the...-in source's prior violations. An opt-in source that withdraws from the Acid Rain Program shall comply...

40 CFR 74.18 - Withdrawal.

Code of Federal Regulations, 2012 CFR

2012-07-01

... opt-in source may request to withdraw from the Acid Rain Program by submitting an administrative... paragraph (f)(1) of this section. (b) Requesting withdrawal. To withdraw from the Acid Rain Program, the...-in source's prior violations. An opt-in source that withdraws from the Acid Rain Program shall comply...

40 CFR 74.18 - Withdrawal.

Code of Federal Regulations, 2011 CFR

2011-07-01

... opt-in source may request to withdraw from the Acid Rain Program by submitting an administrative... paragraph (f)(1) of this section. (b) Requesting withdrawal. To withdraw from the Acid Rain Program, the...-in source's prior violations. An opt-in source that withdraws from the Acid Rain Program shall comply...

40 CFR 74.18 - Withdrawal.

Code of Federal Regulations, 2010 CFR

2010-07-01

... opt-in source may request to withdraw from the Acid Rain Program by submitting an administrative... paragraph (f)(1) of this section. (b) Requesting withdrawal. To withdraw from the Acid Rain Program, the...-in source's prior violations. An opt-in source that withdraws from the Acid Rain Program shall comply...

Assessment of freshwater withdrawals and availability for Marcellus shale natural gas development: a case study in Pennsylvania

Treesearch

Patrick C. Eisenhauer; Nicolas P. Zegre; Samuel J. Lamont

2013-01-01

To evaluate surface water withdrawals used for Marcellus shale natural gas development and to assess potential impacts on water yield, a regional water balance model was developed for the Pine Creek watershed, located primarily in Lycoming County, Pennsylvania. Marcellus shale development has increased rapidly in Lycoming County since 2007. We used precipitation,...

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

Treatment for amphetamine withdrawal.

PubMed

Srisurapanont, M; Jarusuraisin, N; Kittirattanapaiboon, P

2001-01-01

Amphetamine withdrawal has been less studied although it is a common problem with a prevalent rate of 87% among amphetamine users. Its symptoms, in particular intense craving, may be a critical factor leading to relapse of amphetamine use. In clinical practice, treatment for cocaine withdrawal has been recommended for the management of amphetamine withdrawal although the pharmacodynamic and pharmacokinetic properties of these two substances are not the same. To search and determine risks, benefits, and costs of a variety of treatments for the management of amphetamine withdrawal. Electronic searches of MEDLINE (1966 - December 2000), EMBASE (1980 - February 2001), CINAHL (1982 - January 2001) and Cochrane Controlled Trials Register (Cochrane Library 2000 issue 4) were undertaken. References to the articles obtained by any means were searched. All relevant randomised controlled trials (RCTs) and controlled clinical trials (CCTs) were included. Participants were people with amphetamine withdrawal, diagnosed by any set of criteria. Any kinds of biological and psychological treatments both alone and combined were examined. A variety of outcomes, for example, number of treatment responders, score changes, were considered. Two reviewers evaluated and extracted the data independently. The dichotomous data were extracted on an intention-to-treat basis in which the dropouts were assigned as participants with the worst outcomes. The Relative Risk (RR) with the 95% confidence interval (95% CI) was used to assess the dichotomous data. The Weighted Mean Difference (WMD) with 95% CI was used to assessed the continuous data. The results of two studies have shown some benefits of amineptine in the treatment of amphetamine withdrawal. Those benefits can be seen in the respects of discontinuation rate and global state, as measured by Clinical Global Impression Scale. However, no direct benefit of amineptine on amphetamine withdrawal symptoms or craving was shown. The evidence about

Withdrawal: Expanding a Key Addiction Construct

PubMed Central

2015-01-01

Withdrawal is an essential component of classical addiction theory; it is a vital manifestation of dependence and motivates relapse. However, the traditional conceptualization of withdrawal as a cohesive collection of symptoms that emerge during drug deprivation and decline with either the passage of time or reinstatement of drug use, may be inadequate to explain scientific findings or fit with modern theories of addiction. This article expands the current understanding of tobacco withdrawal by examining: (1) withdrawal variability; (2) underlying causes of withdrawal variability, including biological and person factors, environmental influences, and the influence of highly routinized behavioral patterns; (3) new withdrawal symptoms that allow for enhanced characterization of the withdrawal experience; and (4) withdrawal-related cognitive processes. These topics provide guidance regarding the optimal assessment of withdrawal and illustrate the potential impact modern withdrawal conceptualization and assessment could have on identifying treatment targets. PMID:25744958

Corticotropin-releasing factor-1 receptor activation mediates nicotine withdrawal-induced deficit in brain reward function and stress-induced relapse.

PubMed

Bruijnzeel, Adrie W; Prado, Melissa; Isaac, Shani

2009-07-15

Tobacco addiction is a chronic brain disorder that is characterized by a negative affective state upon smoking cessation and relapse after periods of abstinence. Previous research has shown that blockade of corticotropin-releasing factor (CRF) receptors with a nonspecific CRF1/CRF2 receptor antagonist prevents the deficit in brain reward function associated with nicotine withdrawal and stress-induced reinstatement of extinguished nicotine-seeking in rats. The aim of these studies was to investigate the role of CRF1 and CRF2 receptors in the deficit in brain reward function associated with precipitated nicotine withdrawal and stress-induced reinstatement of nicotine-seeking. The intracranial self-stimulation (ICSS) procedure was used to assess the negative affective state of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. Stress-induced reinstatement of nicotine-seeking was investigated in animals in which responding for intravenously infused nicotine was extinguished by substituting saline for nicotine. In the ICSS experiments, the nicotinic receptor antagonist mecamylamine elevated the brain reward thresholds of the nicotine-dependent rats but not those of the control rats. The CRF1 receptor antagonist R278995/CRA0450 but not the CRF2 receptor antagonist astressin-2B prevented the elevations in brain reward thresholds associated with precipitated nicotine withdrawal. Furthermore, R278995/CRA0450 but not astressin-2B prevented stress-induced reinstatement of extinguished nicotine-seeking. Neither R278995/CRA0450 nor astressin-2B affected operant responding for chocolate-flavored food pellets. These studies indicate that CRF(1) receptors but not CRF(2) receptors play an important role in the anhedonic-state associated with acute nicotine withdrawal and stress-induced reinstatement of nicotine-seeking.

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

Effects of acute alcohol withdrawal on nest building in mice selectively bred for alcohol withdrawal severity.

PubMed

Greenberg, Gian D; Phillips, Tamara J; Crabbe, John C

2016-10-15

Nest building has been used to assess thermoregulatory behavior and positive motivational states in mice. There are known genetic influences on ethanol withdrawal severity as well as individual/thermoregulatory nest building. Withdrawal Seizure-Prone (WSP-1, WSP-2) and Withdrawal Seizure-Resistant (WSR-1, WSR-2) mice were selectively bred for high vs low handling-induced convulsion (HIC) severity, respectively, during withdrawal from chronic ethanol vapor inhalation. They also differ in HIC severity during withdrawal from an acute, 4g/kg ethanol injection. In our initial study, withdrawal from an acute dose of ethanol dose-dependently impaired nest building over the initial 24h of withdrawal in genetically segregating Withdrawal Seizure Control (WSC) mice. In two further studies, acute ethanol withdrawal suppressed nest building for up to two days in WSP-1 females. Deficits in nest building from ethanol were limited to the initial 10h of withdrawal in WSR-1 females and to the initial 24h of withdrawal in WSP-1 and WSR-1 males. Effects of ethanol on nest building for up to two days were found in WSP-2 and WSR-2 mice of both sexes. Nest building deficits in female mice from the first replicate could not be explained by a general decrease in locomotor behavior. These results suggest that nest building is a novel behavioral phenotype for indexing the severity of acute ethanol withdrawal, and that genes contributing to this trait differ from those affecting acute withdrawal HIC severity. Published by Elsevier Inc.

Withdrawal: Expanding a Key Addiction Construct.

PubMed

Piper, Megan E

2015-12-01

Withdrawal is an essential component of classical addiction theory; it is a vital manifestation of dependence and motivates relapse. However, the traditional conceptualization of withdrawal as a cohesive collection of symptoms that emerge during drug deprivation and decline with either the passage of time or reinstatement of drug use, may be inadequate to explain scientific findings or fit with modern theories of addiction. This article expands the current understanding of tobacco withdrawal by examining: (1) withdrawal variability; (2) underlying causes of withdrawal variability, including biological and person factors, environmental influences, and the influence of highly routinized behavioral patterns; (3) new withdrawal symptoms that allow for enhanced characterization of the withdrawal experience; and (4) withdrawal-related cognitive processes. These topics provide guidance regarding the optimal assessment of withdrawal and illustrate the potential impact modern withdrawal conceptualization and assessment could have on identifying treatment targets. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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.

Low Doses of Allyphenyline and Cyclomethyline, Effective against Morphine Dependence, Elicit an Antidepressant-like Effect

PubMed Central

2012-01-01

This study demonstrated that cyclomethyline (2) and the corresponding enantiomers (R)-(−)-2 and (S)-(+)-2, displaying α2C-adrenoreceptor (AR) agonism/α2A-AR antagonism, similarly to allyphenyline (1) and its enantiomers, significantly decreased the naloxone-precipitated withdrawal symptoms in mice at very low doses. It also highlighted that such positive effects on morphine dependence can even be improved by additional serotoninergic 5-HT1A receptor (5-HT1A-R) activation. Indeed, 1 or the single (S)-(+)-1, 2, or both its enantiomers, all behaving as α2C-AR agonists/α2A-AR antagonists/5-HT1A-R agonists, alone and at the same low dose, improved morphine withdrawal syndrome and exerted a potent antidepressant-like effect. Therefore, considering the elevated comorbidity between opiate abuse and depressed mood and the benefit of these multifunctional compounds to both disorders, it is possible that they prove more efficacious and less toxic than a cocktail of drugs in managing opioid addiction. PMID:24900506

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.

Role of different brain structures in the behavioural expression of WIN 55,212-2 withdrawal in mice

PubMed Central

Castañé, Anna; Maldonado, Rafael; Valverde, Olga

2004-01-01

We have evaluated several responses induced by the cannabinoid agonist WIN 55,212-2 related to its addictive properties, including rewarding effects and the development of physical dependence in mice. Moreover, we have studied the specific involvement of several brain regions with high density of CB1 cannabinoid receptors, such as striatum, hippocampus, amygdala and cerebellum, in the behavioural expression of SR 141716A-precipitated WIN 55,212-2 withdrawal. The systemic administration of the CB1 receptor antagonist SR 141716A (10 mg kg−1, s.c.) precipitated behavioural signs of withdrawal in mice chronically treated with WIN 55,212-2 (1 and 2 mg kg−1, intraperitoneal (i.p.)), revealing the development of physical dependence. The microinjection of SR 141716A (1.5 and 3 μg) into the cerebellum induced severe manifestations of abstinence in mice dependent on WIN 55,212-2 (1 mg kg−1, i.p.). Out of 10 signs evaluated, seven were statistically significant: wet dog shakes, body tremor, paw tremor, piloerection, mastication, genital licks and sniffing. When the cannabinoid antagonist was administered into the hippocampus and the amygdala, a moderate but significant withdrawal syndrome was also observed. However, no signs of abstinence were induced when SR 141716A was microinjected into the striatum. WIN 55,212-2 produced rewarding effects in the place-conditioning paradigm in mice pre-exposed to a priming injection of the drug. These results show a reliable behavioural model to reveal rewarding effects and physical dependence induced by the repeated administration of WIN 55,212-2 in mice. The cerebellum and to a lesser extent the hippocampus and the amygdala participate in the behavioural expression of cannabinoid withdrawal. PMID:15265804

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...

Development of the caffeine withdrawal symptom questionnaire: caffeine withdrawal symptoms cluster into 7 factors.

PubMed

Juliano, Laura M; Huntley, Edward D; Harrell, Paul T; Westerman, Ashley T

2012-08-01

Habitual caffeine consumers who abstain from caffeine experience withdrawal symptoms such as headache, fatigue, difficulty concentrating, mood disturbances, and flu-like symptoms (Juliano and Griffiths, 2004). The caffeine withdrawal syndrome has been documented across many experimental studies; however, little is known about how withdrawal symptoms co-vary during a discrete episode. Furthermore, a validated measure of caffeine withdrawal is lacking. To develop, evaluate, and reduce a 23-item measure of caffeine withdrawal symptoms; the Caffeine Withdrawal Symptom Questionnaire (CWSQ), to a set of composite variables. Caffeine consumers (N=213) completed the CWSQ after 16h of caffeine abstinence. A subset of participants also completed the CWSQ during a preceding baseline period and/or after double-blind consumption of caffeinated coffee. Principal components analysis resulted in a solution comprised of 7-factors: (1) Fatigue/drowsiness; (2) Low alertness/difficulty concentrating; (3) Mood disturbances; (4) Low sociability/motivation to work; (5) Nausea/upset stomach; (6) Flu-like feelings; and (7) Headache. With the exception of nausea/upset stomach, the CWSQ total score and individual composite scores were significantly greater during caffeine abstinence relative to both baseline and double-blind consumption of caffeinated coffee, thereby demonstrating sensitivity of the measure. Compared to non-daily coffee consumers, daily consumers had greater increases in total withdrawal, fatigue/drowsiness, low alertness/difficulty concentrating, mood disturbances, and headache. Future directions include replication, assessment on a clinical population, and further examination of psychometric properties of the CWSQ. The CWSQ should facilitate the assessment and diagnosis of caffeine withdrawal and increase our knowledge of the caffeine withdrawal syndrome. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

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

Exploring the long-term balance between net precipitation and net groundwater exchange in Florida seepage lakes

USGS Publications Warehouse

Lee, Terrie M.; Sacks, Laura A.; Swancar, Amy

2014-01-01

The long-term balance between net precipitation and net groundwater exchange that maintains thousands of seepage lakes in Florida’s karst terrain is explored at a representative lake basin and then regionally for the State’s peninsular lake district. The 15-year water budget of Lake Starr includes El Niño Southern Oscillation (ENSO)-related extremes in rainfall, and provides the longest record of Bowen ratio energy-budget (BREB) lake evaporation and lake-groundwater exchanges in the southeastern United States. Negative net precipitation averaging -25 cm/yr at Lake Starr overturns the previously-held conclusion that lakes in this region receive surplus net precipitation. Net groundwater exchange with the lake was positive on average but too small to balance the net precipitation deficit. Groundwater pumping effects and surface-water withdrawals from the lake widened the imbalance. Satellite-based regional estimates of potential evapotranspiration at five large lakes in peninsular Florida compared well with basin-scale evaporation measurements from seven open-water sites that used BREB methods. The regional average lake evaporation estimated for Lake Starr during 1996-2011 was within 5 percent of its measured average, and regional net precipitation agreed within 10 percent. Regional net precipitation to lakes was negative throughout central peninsular Florida and the net precipitation deficit increased by about 20 cm from north to south. Results indicate that seepage lakes farther south on the peninsula receive greater net groundwater inflow than northern lakes and imply that northern lakes are in comparatively leakier hydrogeologic settings. Findings reveal the peninsular lake district to be more vulnerable than was previously realized to drier climate, surface-water withdrawals from lakes, and groundwater pumping effects.

Lithium carbonate in the management of cannabis withdrawal: a randomized placebo-controlled trial in an inpatient setting.

PubMed

Johnston, Jennifer; Lintzeris, Nicholas; Allsop, David J; Suraev, Anastasia; Booth, Jessica; Carson, Dean S; Helliwell, David; Winstock, Adam; McGregor, Iain S

2014-12-01

Preclinical studies suggest that lithium carbonate (lithium) can reduce precipitated cannabinoid withdrawal in rats by stimulating release of the neuropeptide oxytocin, while two open-label studies indicate lithium may ameliorate cannabis withdrawal symptoms in humans. This study was conducted to examine the efficacy and safety of lithium in the inpatient management of cannabis withdrawal and to determine whether lithium affects plasma oxytocin and the rate of elimination of plasma cannabinoids during abstinence. Treatment-seeking cannabis-dependent adults (n = 38) were admitted for 8 days to an inpatient withdrawal unit and randomized to either oral lithium (500 mg) or placebo given twice a day under double-blind randomized controlled trial (RCT) conditions. Primary outcomes included withdrawal severity [cannabis withdrawal scale (CWS)], rates of detoxification completion, and adverse events. Plasma cannabinoids, plasma oxytocin and serum lithium levels were measured repeatedly over admission. Follow-up research interviews were conducted at 14, 30, and 90 days postdischarge. Lithium did not significantly affect total CWS scores relative to placebo, although it significantly reduced individual symptoms of "loss of appetite," "stomach aches," and "nightmares/strange dreams." No significant group differences were found in treatment retention or adverse events. Lithium did not increase plasma oxytocin levels nor influence the rate of elimination of cannabinoids. Both placebo- and lithium-treated participants showed reduced levels of cannabis use (verified by urinalysis) and improved health and psychosocial outcomes at 30- and 90-day follow-up relative to pretreatment baselines. Despite the strong rationale for the present study, the efficacy of lithium over placebo in the management of cannabis withdrawal was not demonstrated.

Preadolescent tobacco smoke exposure leads to acute nicotine dependence but does not affect the rewarding effects of nicotine or nicotine withdrawal in adulthood in rats.

PubMed

Yamada, Hidetaka; Bishnoi, Mahendra; Keijzers, Kim F M; van Tuijl, Irma A; Small, Elysia; Shah, Hina P; Bauzo, Rayna M; Kobeissy, Firas H; Sabarinath, Sreedharan N; Derendorf, Hartmut; Bruijnzeel, Adrie W

2010-06-01

Epidemiological studies indicate that parental smoking increases the risk for smoking in children. However, the underlying mechanisms by which parental smoking increases the risk for smoking are not known. The aim of these studies was to investigate if preadolescent tobacco smoke exposure, postnatal days 21-35, affects the rewarding effects of nicotine and nicotine withdrawal in adult rats. The rewarding effects of nicotine were investigated with the conditioned place preference procedure. Nicotine withdrawal was investigated with the conditioned place aversion procedure and intracranial self-stimulation (ICSS). Elevations in brain reward thresholds in the ICSS paradigm reflect a dysphoric state. Plasma nicotine and cotinine levels in the preadolescent rats immediately after smoke exposure were 188 ng/ml and 716 ng/ml, respectively. Preadolescent tobacco smoke exposure led to the development of nicotine dependence as indicated by an increased number of mecamylamine-precipitated somatic withdrawal signs in the preadolescent tobacco smoke exposed rats compared to the control rats. Nicotine induced a similar place preference in adult rats that had been exposed to tobacco smoke or air during preadolescence. Furthermore, mecamylamine induced place aversion in nicotine dependent rats but there was no effect of preadolescent tobacco smoke exposure. Finally, preadolescent tobacco smoke exposure did not affect the elevations in brain reward thresholds associated with precipitated or spontaneous nicotine withdrawal. These studies indicate that passive exposure to tobacco smoke during preadolescence leads to the development of nicotine dependence but preadolescent tobacco smoke exposure does not seem to affect the rewarding effects of nicotine or nicotine withdrawal in adulthood. Published by Elsevier Inc.

Visualization of groundwater withdrawals

USGS Publications Warehouse

Winston, Richard B.; Goode, Daniel J.

2017-12-21

Generating an informative display of groundwater withdrawals can sometimes be difficult because the symbols for closely spaced wells can overlap. An alternative method for displaying groundwater withdrawals is to generate a “footprint” of the withdrawals. WellFootprint version 1.0 implements the Footprint algorithm with two optional variations that can speed up the footprint calculation. ModelMuse has been modified in order to generate the input for WellFootprint and to read and graphically display the output from WellFootprint.

Withdrawal When You’re Pregnant

Cancer.gov

The nicotine in cigarettes is addictive. That’s why many smokers who decide to quit go through some degree of withdrawal. Quitting smoking while you’re pregnant won’t change withdrawal symptoms. You may still be uncomfortable or feel not quite like yourself. But withdrawal from cigarettes will not harm your baby.

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

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...

Activators of potassium M currents have anticonvulsant actions in two rat models of encephalitis

PubMed Central

Solbrig, Marylou V.; Adrian, Russell; Wechsler, Steven L.; Koob, George F.

2010-01-01

Opioid systems in hippocampus regulate excitability and kappa opioids have a role in anticonvulsant protection, but their mechanisms of action are incompletely understood. We examined the ability of opioid and nonopioid agents with overlapping ionic mechanisms and actions similar to kappa opioid agonists, to block seizures in rat models of encephalitis due to Borna Disease virus and Herpes Simplex Virus Type-1. Naltrindole, a delta antagonist and thus a kappa opioid sparing agent, (10 mg/kg s.c.) blocked spontaneous and naloxone (opioid antagonist)-induced seizures in the models, but produced somatic signs similar to opioid withdrawal. Given that delta antagonists as well as kappa opioid agonists in hippocampus enhance potassium M currents (IM), we tested the effect of the IM augmenter flupirtine. Flupirtine (20 mg/kg i.p.) prevented seizures in Borna and herpes infected rats, without signs of withdrawal, hypotonia or sedation. The results support the efficacy of opioid and nonopioid drugs in modulating naloxone-induced seizures in critical illness due to viral encephalitis and by analogy, opioid withdrawal seizures. PMID:17126318

Antinociceptive action of DBO 17 and DBO 11 in mice: two 3,8 diazabicyclo (3.2.1.) octane derivates with selective mu opioid receptor affinity.

PubMed

Fadda, P; Barlocco, D; Tronci, S; Cignarella, G; Fratta, W

1997-11-01

Two 3,8 diazabicyclo (3.2.1.) octane derivates, namely DBO 17 and DBO 11, were studied for the opioid-like activity. In the rat brain membrane preparation binding studies, DBO 17 and DBO 11 showed a high affinity and selectivity for the mu opioid receptor (Ki's: 5.1 and 25 nM, respectively). DBO 17 and DBO 11 inhibited the nociceptive response in the hot-plate test of mice with ED50 values of 0.16 mg/kg and 0.44 mg/kg, respectively. The antinociceptive action of both DBO 17 and DBO 11 was blocked by naloxone. Tolerance to the antinociceptive action of DBO 17 and DBO 11 was present after 13 and 7 days of repeated treatment, respectively. Both DBO 17 and DBO 11 were ineffective in morphine-tolerant mice and vice versa. Chronic treatments (three times daily for seven consecutive days) of DBO 17 and DBO 11 induced a naloxone-precipitated withdrawal syndrome in DBO 17 treated mice similar to that in morphine treated mice, whereas in DBO 11 treated mice abstinence signs were virtually absent. These results indicate an interesting pharmacological profile that suggests these compounds as possible new candidates for the clinical treatment of pain.

Pregabalin role in inhibition of morphine analgesic tolerance and physical dependency in rats.

PubMed

Hasanein, Parisa; Shakeri, Saeed

2014-11-05

Pregabalin is recently proposed as analgesic or adjuvant in pain management. While previous preclinical investigations have evaluated pregabalin-opioid interactions, the effect of pregabalin on opioid tolerance and dependency has not yet been studied. Here we evaluated the effects of different doses of pregabalin (50, 100 and 200mg/kg, s.c.) on morphine-induced tolerance and dependency in rats. Adult male Wistar rats were rendered tolerant to analgesic effect of morphine by injection of morphine (10mg/kg, s.c.) twice daily for 7 days. To develop morphine dependence, rats were given escalating doses of morphine. To determine the effect of pregabalin on the development of morphine tolerance and dependence, different doses of pregabalin were administrated before morphine. The tail-flick and naloxone precipitation withdrawal tests were used to evaluate the degree of tolerance and dependence, respectively. Chronic morphine-injected rats showed significant decrements in the percentage maximum possible effect (%MPE) of morphine on the days 5 and 7 (32.5%±3.5, 21.5%±4, respectively) compared to the first day (100%) which showed morphine tolerance. Pregabalin 200mg/kg completely prevented the development of morphine tolerance. In addition, concomitant treatment of morphine with pregabalin attenuated almost all of the naloxone-induced withdrawal signs which include weight loss, jumping, penis licking, teeth chattering, wet dog shakes, rearing, standing, sniffing, face grooming and paw tremor. These data show that pregabaline has a potential anti-tolerant/anti-dependence property against chronic usage of morphine. Therefore, pregabalin appears to be a promising candidate for the treatment of opioid addiction after confirming by future clinical studies. Copyright © 2014 Elsevier B.V. All rights reserved.

Nicotine Withdrawal; Measure Your Symptoms (Quiz)

MedlinePlus

... Free Resources Medications Can Help You Quit Using Nicotine Replacement Therapy Busting NRT Myths Smokefree Phone Apps ... Withdrawal Understanding Withdrawal Quiz: How Strong is Your Nicotine Addiction? Quiz: What Are Your Withdrawal Symptoms? Dealing ...

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.

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.

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.

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

Evaluating Distal and Proximal Explanations for Withdrawal: A Rejoinder to Varnum and Kwon's "The Ecology of Withdrawal".

PubMed

Norasakkunkit, Vinai; Uchida, Yukiko; Takemura, Kosuke

2017-01-01

In their 2016 commentary on our theorizing about how youth withdrawal from economic and social participation in Japanese society (i.e., NEET and Hikikomori phenomena) stems from generational inequality of economic opportunities, Varnum and Kwon correctly point out that our explanation for withdrawal is yet untested. They then offered an alternative, evolutionary psychological explanation for withdrawal in which they claim that in resource-rich ecologies like Japan, the option to withdraw from participating in society is a possible life strategy, a strategy that would be much more costly in resource-poor ecologies. While we agree with this premise, we argue that this distal explanatory framework, at least in its current form, has limits in reconciling some of the more recent cross-cultural observations, as well as well-established sociological claims about the causes of withdrawal. Thus we argue that much work remains in refining and expanding the explanatory power of more distal explanations on the issue of withdrawal. Until then, the more proximal and culture-specific explanations are probably the useful and meaningful explanations for the withdrawal phenomenon.

Estimated freshwater withdrawals in Texas, 1990

USGS Publications Warehouse

Lurry, Dee L.

1994-01-01

This report presents 1990 freshwater withdrawal estimates for Texas by source and category. Withdrawal source is either ground water or surface water. Withdrawal categories include: self-supplied irrigation, thermoelectric-power generation, water supply, industrial and mining, and other (domestic, commercial, livestock). Withdrawal data are aggregated by county, major aquifer, and principal river basin. Only the four major categories of irrigation, thermoelectric-power generation, water supply, and industrial and mining are illustrated in this report, although all data are tabulated.

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…

A Detection Model of College Withdrawal

ERIC Educational Resources Information Center

Pleskac, Timothy J.; Keeney, Jessica; Merritt, Stephanie M.; Schmitt, Neal; Oswald, Frederick L.

2011-01-01

Many students during their college careers consider withdrawing from their respective college or university. Understanding why some students decide to withdraw yet others persist has implications for both the well being of students as well as for institutes of higher education. The present study develops a model of the decision to withdraw drawing…

Water withdrawals in Florida, 2012

USGS Publications Warehouse

Marella, Richard L.

2015-09-01

The largest percentage of freshwater withdrawals was from the South Florida Water Management District (46 percent), followed by the St. Johns River Water Management District (20 percent), Southwest Florida Water Management District (19 percent), Northwest Florida Water Management District (9 percent), and Suwannee River Water Management District (6 percent). The South Florida Water Management District accounted for the largest percentage of freshwater withdrawals for public-supply use (46 percent), commercial-industrial-mining self-supplied use (24 percent), agricultural self-supplied use (59 percent), and recreational-landscape irrigation use (63 percent). The Northwest Florida Water Management District accounted for the largest percentage of freshwater withdrawals for power-generation use (44 percent), and the Southwest Florida Water Management District accounted for the largest percentage of saline-water withdrawals for power-generation use (58 percent).

Nitrendipine decreases benzodiazepine withdrawal seizures but not the development of benzodiazepine tolerance or withdrawal signs.

PubMed Central

Dolin, S. J.; Patch, T. L.; Rabbani, M.; Siarey, R. J.; Bowhay, A. R.; Little, H. J.

1990-01-01

1. The effects of the calcium channel blocking agent, nitrendipine, were studied on seizures in mice produced during withdrawal from chronic benzodiazepine treatment and on the development of tolerance to benzodiazepines. 2. Nitrendipine produced a dose-dependent decrease in seizure incidence, when seizures were produced by the partial inverse agonist FG7142 during withdrawal from seven days treatment with flurazepam. 3. Nitrendipine did not raise the seizure thresholds in naïve mice to the full inverse agonist methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), or to the gamma-aminobutyric acid (GABA) antagonist, bicuculline. 4. When given concurrently with flurazepam for seven days, nitrendipine did not affect the incidence of seizures during flurazepam withdrawal. 5. When given concurrently with the benzodiazepines, nitrendipine did not prevent the development of tolerance to midazolam general anaesthesia or tolerance to the ataxic actions of flurazepam or midazolam. 6. Chronic treatment with flurazepam for seven days did not affect the Kd or Bmax of [3H]-nimodipine binding in mouse whole brain or cerebral cortex. 7. These results with benzodiazepines are partially in contrast with those for ethanol, where nitrendipine not only decreased ethanol withdrawal seizures when given acutely, but also prevented the development of tolerance and withdrawal signs when given concurrently with ethanol. However, they do confirm the selectivity of nitrendipine for withdrawal-induced seizures. PMID:1963805

Total water withdrawals in Mississippi, 1990

USGS Publications Warehouse

Johnson, P.M.

1994-01-01

During 1990, the amount of water withdrawn from ground- and surface-water sources in Mississippi was about 3,600 Mgal/d (million gallons per day). Of this amount, 91 percent, or 3,300 Mgal/d, was withdrawn from freshwater sources. Of the total freshwater withdrawals, about 82 percent, or 2,700 Mgal/d, was withdrawn from ground-water sources. Total water withdrawals in Mississippi in 1990 for eight categories of use were as follows: irrigation, 1,900 Mgal/d; thermoelectric power, 700 Mgal/d; aquaculture, 400 Mgal/d; public supply, 320 Mgal/d; industrial and mining, 270 Mgal/d; domestic, 33 Mgal/d; commercial, 16 Mgal/d; and livestock, 16 Mgal/d. Overall, total withdrawals increased by 20 percent from 1985 to 1990, although the total population decreased about 2 percent. During the same period, total freshwater withdrawals increased by about 17 percent. Total saline with- drawals increased by about 60 percent from 1985 due to an increase in salin withdrawals for thermo- electric power generation. Total fresh and saline surface-water withdrawals decreased by about 6 percent from 1985, due to decrease in surface-water withdrawals for irrigation. Fresh ground-water withdrawals in Mississippi increased by about 33 percent, primarily due to an increase in irrigation. Since 1960, total ground- and surface-water with- drawals increased 70 percent for the same period. Irrigation had the greatest increase in with- drawals since 1960, with a 269 percent increase. Public supply had the second greatest, with a 178 percent increase.

Anticonvulsants for alcohol withdrawal.

PubMed

Minozzi, Silvia; Amato, Laura; Vecchi, Simona; Davoli, Marina

2010-03-17

Alcohol abuse and dependence represents a most serious health problem worldwide with major social, interpersonal and legal interpolations. Besides benzodiazepines, anticonvulsants are often used for the treatment of alcohol withdrawal symptoms. Anticonvulsants drugs are indicated for the treatment of alcohol withdrawal syndrome, alone or in combination with benzodiazepine treatments. In spite of the wide use, the exact role of the anticonvulsants for the treatment of alcohol withdrawal has not yet bee adequately assessed. To evaluate the effectiveness and safety of anticonvulsants in the treatment of alcohol withdrawal. We searched Cochrane Drugs and Alcohol Group' Register of Trials (December 2009), PubMed, EMBASE, CINAHL (1966 to December 2009), EconLIT (1969 to December 2009). Parallel searches on web sites of health technology assessment and related agencies, and their databases. Randomized controlled trials (RCTs) examining the effectiveness, safety and overall risk-benefit of anticonvulsants in comparison with a placebo or other pharmacological treatment. All patients were included regardless of age, gender, nationality, and outpatient or inpatient therapy. Two authors independently screened and extracted data from studies. Fifty-six studies, with a total of 4076 participants, met the inclusion criteria. Comparing anticonvulsants with placebo, no statistically significant differences for the six outcomes considered.Comparing anticonvulsant versus other drug, 19 outcomes considered, results favour anticonvulsants only in the comparison carbamazepine versus benzodiazepine (oxazepam and lorazepam) for alcohol withdrawal symptoms (CIWA-Ar score): 3 studies, 262 participants, MD -1.04 (-1.89 to -0.20), none of the other comparisons reached statistical significance.Comparing different anticonvulsants no statistically significant differences in the two outcomes considered.Comparing anticonvulsants plus other drugs versus other drugs (3 outcomes considered), results

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

Perinatal risk factors and social withdrawal behaviour.

PubMed

Guedeney, Antoine; Marchand-Martin, Laetitia; Cote, Sylvana J; Larroque, Béatrice

2012-04-01

The objectives of the study were (1) to assess prevalence of social withdrawal behaviour in infants aged 12 months included in the French Perinatal Risk Factor Study Eden; (2) To study the correlation between relational withdrawal and several perinatal and parental factors assessed in the EDEN study. A longitudinal study using the ADBB scale was conducted within the Eden Cohort in the year 2008. 1,586 infants were included in the study. Fourteen percent of the children who had an ADBB assessment had a score at 5 and over on the ADBB, a scale designed to assess social withdrawal behaviour at age 0-24 months. Social withdrawal at 12 months was associated with low birth weight, low gestational age and with intra uterine growth retardation. Social withdrawal was independently associated with several maternal and paternal risk factors. The level of social withdrawal behaviour increased with a score of maternal difficulties. This study on a large longitudinally followed volunteer sample demonstrate a clear association of social withdrawal behaviour at age one with low birth weight and preterm birth, possibly mediated by parental vulnerabilities. Social withdrawal behaviour seems to be an important alarm signal to detect early on particularly in premature and small for date babies. © Springer-Verlag 2012

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.

Motor impairment: a new ethanol withdrawal phenotype in mice

PubMed Central

Philibin, Scott D.; Cameron, Andy J.; Metten, Pamela; Crabbe, John C.

2015-01-01

Alcoholism is a complex disorder with genetic and environmental risk factors. The presence of withdrawal symptoms is one criterion for alcohol dependence. Genetic animal models have followed a reductionist approach by quantifying various effects of ethanol withdrawal separately. Different ethanol withdrawal symptoms may have distinct genetic etiologies, and therefore differentiating distinct neurobiological mechanisms related to separate signs of withdrawal would increase our understanding of various aspects of the complex phenotype. This study establishes motor incoordination as a new phenotype of alcohol withdrawal in mice. Mice were made physically dependent on ethanol by exposure to ethanol vapor for 72 h. The effects of ethanol withdrawal in mice from different genetic backgrounds were measured on the accelerating rotarod, a simple motor task. Ethanol withdrawal disrupted accelerating rotarod behavior in mice. The disruptive effects of withdrawal suggest a performance rather than a learning deficit. Inbred strain comparisons suggest genetic differences in magnitude of this withdrawal phenotype. The withdrawal-induced deficits were not correlated with the selection response difference in handling convulsion severity in selectively bred Withdrawal Seizure-Prone and Withdrawal Seizure-Resistant lines. The accelerating rotarod seems to be a simple behavioral measure of ethanol withdrawal that is suitable for comparing genotypes. PMID:18690115

Tobacco withdrawal among opioid-dependent smokers.

PubMed

Streck, Joanna M; Heil, Sarah H; Higgins, Stephen T; Bunn, Janice Y; Sigmon, Stacey C

2018-04-01

Prevalence of cigarette smoking among opioid-dependent individuals is 6-fold that of the general U.S. adult population and their quit rates are notoriously poor. One possible reason for the modest cessation outcomes in opioid-dependent smokers may be that they experience more severe tobacco withdrawal upon quitting. In this secondary analysis, we evaluated tobacco withdrawal in opioid-dependent (OD) smokers versus smokers without co-occurring substance use disorders (SUDs). Participants were 47 methadone- or buprenorphine-maintained smokers and 25 non-SUD smokers who completed 1 of several 2-week studies involving daily visits for biochemical monitoring, delivery of financial incentives contingent on smoking abstinence, and assessment of withdrawal via the Minnesota Nicotine Withdrawal Scale (MNWS). Prior to quitting smoking, OD smokers presented with higher baseline withdrawal scores than non-SUD smokers (1.7 ± 0.2 vs. 0.7 ± 0.2, respectively; F [1, 63] = 7.31, p < .001). Withdrawal scores in both groups decreased over the subsequent 2-week period with no group differences, F (1, 910) = 0.50, p = .48. A similar pattern was observed on craving (i.e., Desire to Smoke item of MNWS), although the trajectory of decrease over time on this item was also moderated by gender. Overall, there was no difference in withdrawal during biochemically verified smoking abstinence between OD and non-SUD smokers, suggesting that elevated withdrawal severity following quitting may not be a major factor contributing to the poor cessation outcomes consistently observed among OD smokers. Further scientific efforts are needed to improve our understanding of the high smoking rates and modest cessation outcomes in this challenging population. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Effects of ground-water withdrawals on the Rock River and associated valley aquifer, eastern Rock County, Minnesota

USGS Publications Warehouse

Lindgren, Richard J.; Landon, M.K.

2000-01-01

Model results indicate that the additional water withdrawn by wells due to anticipated increased ground-water withdrawals was derived from a decrease in net leakage of ground water from the aquifer to the streams. The simulations indicated that the increased ground-water withdrawals and normal precipitation resulted in an increase in induced infiltration from the Rock River of 0.1 cubic feet per second for the Luverne Municipal well field and 0.3 cubic feet per second for the Rock County Rural Water well field. Maximum drawdowns ranged from 0.5 to 1.4 feet near the three well fields. For drought conditions, the simulated streamflow losses constituted approximately 30 percent and nearly 65 percent of the flows in the Rock River for the Luverne Municipal and Rock County Rural Water well fields, respectively. Maximum drawdowns ranged from 3.8 to 7.0 feet near the three well fields. Transient simulations with anticipated increased ground-water withdrawals and drought conditions indicated declines in hydraulic heads ranging from 0.2 to 0.4 feet per year in the vicinity of the three well fields, except for near the Rock River. 

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

Alcohol withdrawal

MedlinePlus

... Seeing or feeling things that aren't there (hallucinations) Seizures Severe confusion ... alcohol withdrawal. You will be watched closely for hallucinations and other signs of delirium tremens. Treatment may ...

Oxycodone physical dependence and its oral self-administration in C57BL/6J mice.

PubMed

Enga, Rachel M; Jackson, Asti; Damaj, M Imad; Beardsley, Patrick M

2016-10-15

Abuse of prescription opioids, such as oxycodone, has markedly increased in recent decades. While oxycodone's antinociceptive effects have been detailed in several preclinical reports, surprisingly few preclinical reports have elaborated its abuse-related effects. This is particularly surprising given that oxycodone has been in clinical use since 1917. In a novel oral operant self-administration procedure, C57BL/6J mice were trained to self-administer water before introducing increasing concentrations of oxycodone (0.056-1.0mg/ml) under post-prandial conditions during daily, 3-h test sessions. As the concentration of oxycodone increased, the numbers of deliveries first increased, then decreased in an inverted U-shape fashion characteristic of the patterns of other drugs self-administered during limited access conditions. After post-prandial conditions were removed, self-administration at the highest concentration was maintained suggesting oral oxycodone served as a positive reinforcer. In other mice, using a novel regimen of physical dependence, mice were administered increasing doses of oxycodone (9.0-33.0mg/kg, s.c.) over 9 days, challenged with naloxone (0.1-10.0mg/kg, s.c.), and then observed for 30min. Naloxone dose-dependently increased the observed number of somatic signs of withdrawal, suggesting physical dependence of oxycodone was induced under this regimen. This is the first report demonstrating induction of oral operant self-administration of oxycodone and dose-dependent precipitations of oxycodone withdrawal in C57BL/6J mice. The use of oral operant self-administration as well as the novel physical dependence regimen provides useful approaches to further examine the abuse- and dependence-related effects of this highly abused prescription opioid. Copyright © 2016 Elsevier B.V. All rights reserved.

5 CFR 362.407 - Withdrawal and readmission.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 1 2014-01-01 2014-01-01 false Withdrawal and readmission. 362.407 Section 362.407 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS PATHWAYS PROGRAMS Presidential Management Fellows Program § 362.407 Withdrawal and readmission. (a) Withdrawal. (1...

5 CFR 362.407 - Withdrawal and readmission.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 1 2013-01-01 2013-01-01 false Withdrawal and readmission. 362.407 Section 362.407 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS PATHWAYS PROGRAMS Presidential Management Fellows Program § 362.407 Withdrawal and readmission. (a) Withdrawal. (1...

19 CFR 144.27 - Withdrawal from warehouse by transferee.

Code of Federal Regulations, 2012 CFR

2012-04-01

...; DEPARTMENT OF THE TREASURY (CONTINUED) WAREHOUSE AND REWAREHOUSE ENTRIES AND WITHDRAWALS Transfer of Right To Withdraw Merchandise from Warehouse § 144.27 Withdrawal from warehouse by transferee. At any time within... withdraw all or part of the merchandise covered by the transfer by filing any authorized kind of withdrawal...

19 CFR 144.27 - Withdrawal from warehouse by transferee.

Code of Federal Regulations, 2010 CFR

2010-04-01

...; DEPARTMENT OF THE TREASURY (CONTINUED) WAREHOUSE AND REWAREHOUSE ENTRIES AND WITHDRAWALS Transfer of Right To Withdraw Merchandise from Warehouse § 144.27 Withdrawal from warehouse by transferee. At any time within... withdraw all or part of the merchandise covered by the transfer by filing any authorized kind of withdrawal...

New mechanisms and perspectives in nicotine withdrawal

PubMed Central

Jackson, K.J.; Muldoon, P.P.; De Biasi, M.; Damaj, M.I.

2014-01-01

Diseases associated with tobacco use constitute a major health problem worldwide. Upon cessation of tobacco use, an unpleasant withdrawal syndrome occurs in dependent individuals. Avoidance of the negative state produced by nicotine withdrawal represents a motivational component that promotes continued tobacco use and relapse after smoking cessation. With the modest success rate of currently available smoking cessation therapies, understanding mechanisms involved in the nicotine withdrawal syndrome are crucial for developing successful treatments. Animal models provide a useful tool for examining neuroadaptative mechanisms and factors influencing nicotine withdrawal, including sex, age, and genetic factors. Such research has also identified an important role for nicotinic receptor subtypes in different aspects of the nicotine withdrawal syndrome (e.g., physical vs. affective signs). In addition to nicotinic receptors, the opioid and endocannabinoid systems, various signal transduction pathways, neurotransmitters, and neuropeptides have been implicated in the nicotine withdrawal syndrome. Animal studies have informed human studies of genetic variants and potential targets for smoking cessation therapies. Overall, the available literature indicates that the nicotine withdrawal syndrome is complex, and involves a range of neurobiological mechanisms. As research in nicotine withdrawal progresses, new pharmacological options for smokers attempting to quit can be identified, and treatments with fewer side effects that are better tailored to the unique characteristics of patients may become available. PMID:25433149

29 CFR 4219.12 - Employers liable upon mass withdrawal.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 9 2010-07-01 2010-07-01 false Employers liable upon mass withdrawal. 4219.12 Section 4219... Redetermination of Withdrawal Liability Upon Mass Withdrawal § 4219.12 Employers liable upon mass withdrawal. (a... experiences successive mass withdrawals, an employer that has been determined to be liable under this subpart...

29 CFR 4219.12 - Employers liable upon mass withdrawal.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 29 Labor 9 2011-07-01 2011-07-01 false Employers liable upon mass withdrawal. 4219.12 Section 4219... Redetermination of Withdrawal Liability Upon Mass Withdrawal § 4219.12 Employers liable upon mass withdrawal. (a... experiences successive mass withdrawals, an employer that has been determined to be liable under this subpart...

29 CFR 1626.13 - Withdrawal of charge.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 29 Labor 4 2012-07-01 2012-07-01 false Withdrawal of charge. 1626.13 Section 1626.13 Labor Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION PROCEDURES-AGE DISCRIMINATION IN EMPLOYMENT ACT § 1626.13 Withdrawal of charge. Charging parties may request withdrawal of a...

29 CFR 1626.13 - Withdrawal of charge.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 4 2010-07-01 2010-07-01 false Withdrawal of charge. 1626.13 Section 1626.13 Labor Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION PROCEDURES-AGE DISCRIMINATION IN EMPLOYMENT ACT § 1626.13 Withdrawal of charge. Charging parties may request withdrawal of a...

29 CFR 1626.13 - Withdrawal of charge.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 29 Labor 4 2013-07-01 2013-07-01 false Withdrawal of charge. 1626.13 Section 1626.13 Labor Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION PROCEDURES-AGE DISCRIMINATION IN EMPLOYMENT ACT § 1626.13 Withdrawal of charge. Charging parties may request withdrawal of a...

29 CFR 1626.13 - Withdrawal of charge.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 29 Labor 4 2014-07-01 2014-07-01 false Withdrawal of charge. 1626.13 Section 1626.13 Labor Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION PROCEDURES-AGE DISCRIMINATION IN EMPLOYMENT ACT § 1626.13 Withdrawal of charge. Charging parties may request withdrawal of a...

29 CFR 1626.13 - Withdrawal of charge.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 29 Labor 4 2011-07-01 2011-07-01 false Withdrawal of charge. 1626.13 Section 1626.13 Labor Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION PROCEDURES-AGE DISCRIMINATION IN EMPLOYMENT ACT § 1626.13 Withdrawal of charge. Charging parties may request withdrawal of a...

21 CFR 870.1800 - Withdrawal-infusion pump.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Withdrawal-infusion pump. 870.1800 Section 870...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Diagnostic Devices § 870.1800 Withdrawal-infusion pump. (a) Identification. A withdrawal-infusion pump is a device designed to inject accurately drugs...

Alcohol Withdrawal Syndrome: Benzodiazepines and Beyond

PubMed Central

Sachdeva, Ankur; Chandra, Mina

2015-01-01

Alcohol dependence is an increasing and pervasive problem. Alcohol withdrawal symptoms are a part of alcohol dependence syndrome and are commonly encountered in general hospital settings, in most of the departments. Alcohol withdrawal syndrome ranges from mild to severe. The severe complicated alcohol withdrawal may present with hallucinations, seizures or delirium tremens. Benzodiazepines have the largest and the best evidence base in the treatment of alcohol withdrawal, and are considered the gold standard. Others, such as anticonvulsants, barbiturates, adrenergic drugs, and GABA agonists have been tried and have evidence. Supportive care and use of vitamins is essential in the management. Symptom triggered regime is favoured over fixed tapering dose regime, although monitoring through scales is cumbersome. This article aims to review the evidence base for appropriate clinical management of the alcohol withdrawal syndrome. We searched Pubmed for articles published in English on ‘Alcohol withdrawal syndrome’ in humans during the last 10 years. A total of 1182 articles came up. Articles not relevant to clinical utility and management were excluded based on the titles and abstract available. Full text articles, meta-analyses, systematic reviews and randomized controlled trials were obtained from this list and were considered for review. PMID:26500991

Nicotinic Mechanisms Modulate Ethanol Withdrawal and Modify Time Course and Symptoms Severity of Simultaneous Withdrawal from Alcohol and Nicotine.

PubMed

Perez, Erika; Quijano-Cardé, Natalia; De Biasi, Mariella

2015-09-01

Alcohol and nicotine are among the top causes of preventable death in the United States. Unfortunately, people who are dependent on alcohol are more likely to smoke than individuals in the general population. Similarly, smokers are more likely to abuse alcohol. Alcohol and nicotine codependence affects health in many ways and leads to poorer treatment outcomes in subjects who want to quit. This study examined the interaction of alcohol and nicotine during withdrawal and compared abstinence symptoms during withdrawal from one of the two drugs only vs both. Our results indicate that simultaneous withdrawal from alcohol and nicotine produces physical symptoms that are more severe and last longer than those experienced during withdrawal from one of the two drugs alone. In animals experiencing withdrawal after chronic ethanol treatment, acute nicotine exposure was sufficient to prevent abstinence symptoms. Similarly, symptoms were prevented when alcohol was injected acutely in mice undergoing nicotine withdrawal. These experiments provide evidence for the involvement of the nicotinic cholinergic system in alcohol withdrawal. Furthermore, the outcomes of intracranial microinfusions of mecamylamine, a nonselective nicotinic receptor antagonist, highlight a major role for the nicotinic receptors expressed in medial habenula and interpeduncular nucleus during withdrawal. Overall, the data support the notion that modulating the nicotinic cholinergic system might help to maintain long-term abstinence from alcohol.

47 CFR 1.8 - Withdrawal of papers.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 47 Telecommunication 1 2011-10-01 2011-10-01 false Withdrawal of papers. 1.8 Section 1.8 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL PRACTICE AND PROCEDURE General Rules of Practice and Procedure General § 1.8 Withdrawal of papers. The granting of a request to dismiss or withdraw an...

47 CFR 1.8 - Withdrawal of papers.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 1 2010-10-01 2010-10-01 false Withdrawal of papers. 1.8 Section 1.8 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL PRACTICE AND PROCEDURE General Rules of Practice and Procedure General § 1.8 Withdrawal of papers. The granting of a request to dismiss or withdraw an...

Quantifying the Clinical Significance of Cannabis Withdrawal

PubMed Central

Allsop, David J.; Copeland, Jan; Norberg, Melissa M.; Fu, Shanlin; Molnar, Anna; Lewis, John; Budney, Alan J.

2012-01-01

Background and Aims Questions over the clinical significance of cannabis withdrawal have hindered its inclusion as a discrete cannabis induced psychiatric condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). This study aims to quantify functional impairment to normal daily activities from cannabis withdrawal, and looks at the factors predicting functional impairment. In addition the study tests the influence of functional impairment from cannabis withdrawal on cannabis use during and after an abstinence attempt. Methods and Results A volunteer sample of 49 non-treatment seeking cannabis users who met DSM-IV criteria for dependence provided daily withdrawal-related functional impairment scores during a one-week baseline phase and two weeks of monitored abstinence from cannabis with a one month follow up. Functional impairment from withdrawal symptoms was strongly associated with symptom severity (p = 0.0001). Participants with more severe cannabis dependence before the abstinence attempt reported greater functional impairment from cannabis withdrawal (p = 0.03). Relapse to cannabis use during the abstinence period was associated with greater functional impairment from a subset of withdrawal symptoms in high dependence users. Higher levels of functional impairment during the abstinence attempt predicted higher levels of cannabis use at one month follow up (p = 0.001). Conclusions Cannabis withdrawal is clinically significant because it is associated with functional impairment to normal daily activities, as well as relapse to cannabis use. Sample size in the relapse group was small and the use of a non-treatment seeking population requires findings to be replicated in clinical samples. Tailoring treatments to target withdrawal symptoms contributing to functional impairment during a quit attempt may improve treatment outcomes. PMID:23049760

19 CFR 144.36 - Withdrawal for transportation.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 19 Customs Duties 2 2010-04-01 2010-04-01 false Withdrawal for transportation. 144.36 Section 144... § 144.36 Withdrawal for transportation. (a) Time limit. Merchandise may be withdrawn from warehouse for transportation to another port of entry if withdrawal for consumption or exportation can be accomplished at the...

19 CFR 144.36 - Withdrawal for transportation.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 19 Customs Duties 2 2013-04-01 2013-04-01 false Withdrawal for transportation. 144.36 Section 144... § 144.36 Withdrawal for transportation. (a) Time limit. Merchandise may be withdrawn from warehouse for transportation to another port of entry if withdrawal for consumption or exportation can be accomplished at the...

19 CFR 144.36 - Withdrawal for transportation.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 19 Customs Duties 2 2011-04-01 2011-04-01 false Withdrawal for transportation. 144.36 Section 144... § 144.36 Withdrawal for transportation. (a) Time limit. Merchandise may be withdrawn from warehouse for transportation to another port of entry if withdrawal for consumption or exportation can be accomplished at the...

19 CFR 144.36 - Withdrawal for transportation.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 19 Customs Duties 2 2012-04-01 2012-04-01 false Withdrawal for transportation. 144.36 Section 144... § 144.36 Withdrawal for transportation. (a) Time limit. Merchandise may be withdrawn from warehouse for transportation to another port of entry if withdrawal for consumption or exportation can be accomplished at the...

Estimated freshwater withdrawals in Washington, 2010

USGS Publications Warehouse

Lane, Ron C.; Welch, Wendy B.

2015-03-18

The amount of public- and self-supplied water used for domestic, irrigation, livestock, aquaculture, industrial, mining, and thermoelectric power was estimated for state, county, and eastern and western regions of Washington during calendar year 2010. Withdrawals of freshwater for offstream uses were estimated to be about 4,885 million gallons per day. The total estimated freshwater withdrawals for 2010 was approximately 15 percent less than the 2005 estimate because of decreases in irrigation and thermoelectric power withdrawals.

19 CFR 144.38 - Withdrawal for consumption.

Code of Federal Regulations, 2014 CFR

2014-04-01

... provided in § 141.61(e) of this chapter. (b) Withdrawal for exportation to Canada or Mexico. A withdrawal... withdrawal of cigars, cigarettes, or cigarette papers or tubes subject to internal revenue tax, the statement... will be finally due upon liquidation. (e) Permit for release of merchandise. When the duties and other...

19 CFR 144.38 - Withdrawal for consumption.

Code of Federal Regulations, 2011 CFR

2011-04-01

... provided in § 141.61(e) of this chapter. (b) Withdrawal for exportation to Canada or Mexico. A withdrawal... withdrawal of cigars, cigarettes, or cigarette papers or tubes subject to internal revenue tax, the statement... will be finally due upon liquidation. (e) Permit for release of merchandise. When the duties and other...

19 CFR 144.38 - Withdrawal for consumption.

Code of Federal Regulations, 2013 CFR

2013-04-01

... provided in § 141.61(e) of this chapter. (b) Withdrawal for exportation to Canada or Mexico. A withdrawal... withdrawal of cigars, cigarettes, or cigarette papers or tubes subject to internal revenue tax, the statement... will be finally due upon liquidation. (e) Permit for release of merchandise. When the duties and other...

19 CFR 144.38 - Withdrawal for consumption.

Code of Federal Regulations, 2012 CFR

2012-04-01

... provided in § 141.61(e) of this chapter. (b) Withdrawal for exportation to Canada or Mexico. A withdrawal... withdrawal of cigars, cigarettes, or cigarette papers or tubes subject to internal revenue tax, the statement... will be finally due upon liquidation. (e) Permit for release of merchandise. When the duties and other...

19 CFR 144.38 - Withdrawal for consumption.

Code of Federal Regulations, 2010 CFR

2010-04-01

... provided in § 141.61(e) of this chapter. (b) Withdrawal for exportation to Canada or Mexico. A withdrawal... withdrawal of cigars, cigarettes, or cigarette papers or tubes subject to internal revenue tax, the statement... will be finally due upon liquidation. (e) Permit for release of merchandise. When the duties and other...

5 CFR 1650.31 - Age-based withdrawals.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 3 2012-01-01 2012-01-01 false Age-based withdrawals. 1650.31 Section... FUNDS FROM THE THRIFT SAVINGS PLAN In-Service Withdrawals § 1650.31 Age-based withdrawals. (a) A participant who has reached age 591/2 and who has not separated from Government employment is eligible to...

5 CFR 1650.31 - Age-based withdrawals.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Age-based withdrawals. 1650.31 Section... FUNDS FROM THE THRIFT SAVINGS PLAN In-Service Withdrawals § 1650.31 Age-based withdrawals. (a) A participant who has reached age 591/2 and who has not separated from Government employment is eligible to...

5 CFR 1650.31 - Age-based withdrawals.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 3 2013-01-01 2013-01-01 false Age-based withdrawals. 1650.31 Section... FUNDS FROM THE THRIFT SAVINGS PLAN In-Service Withdrawals § 1650.31 Age-based withdrawals. (a) A participant who has reached age 591/2 and who has not separated from Government service is eligible to...

5 CFR 1650.31 - Age-based withdrawals.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 3 2014-01-01 2014-01-01 false Age-based withdrawals. 1650.31 Section... FUNDS FROM THE THRIFT SAVINGS PLAN In-Service Withdrawals § 1650.31 Age-based withdrawals. (a) A participant who has reached age 591/2 and who has not separated from Government service is eligible to...

5 CFR 1650.31 - Age-based withdrawals.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 3 2011-01-01 2011-01-01 false Age-based withdrawals. 1650.31 Section... FUNDS FROM THE THRIFT SAVINGS PLAN In-Service Withdrawals § 1650.31 Age-based withdrawals. (a) A participant who has reached age 591/2 and who has not separated from Government employment is eligible to...

N-Oleoyl-glycine reduces nicotine reward and withdrawal in mice.

PubMed

Donvito, Giulia; Piscitelli, Fabiana; Muldoon, Pretal; Jackson, Asti; Vitale, Rosa Maria; D'Aniello, Enrico; Giordano, Catia; Ignatowska-Jankowska, Bogna M; Mustafa, Mohammed A; Guida, Francesca; Petrie, Gavin N; Parker, Linda; Smoum, Reem; Sim-Selley, Laura; Maione, Sabatino; Lichtman, Aron H; Damaj, M Imad; Di Marzo, Vincenzo; Mechoulam, Raphael

2018-03-19

Cigarette smokers with brain damage involving the insular cortex display cessation of tobacco smoking, suggesting that this region may contribute to nicotine addiction. In the present study, we speculated that molecules in the insular cortex that are sensitive to experimental traumatic brain injury (TBI) in mice might provide leads to ameliorate nicotine addiction. Using targeted lipidomics, we found that TBI elicited substantial increases of a largely uncharacterized lipid, N-acyl-glycine, N-oleoyl-glycine (OlGly), in the insular cortex of mice. We then evaluated whether intraperitoneal administration of OlGly would alter withdrawal responses in nicotine-dependent mice as well as the rewarding effects of nicotine, as assessed in the conditioned place preference paradigm (CPP). Systemic administration of OlGly reduced mecamylamine-precipitated withdrawal responses in nicotine-dependent mice and prevented nicotine CPP. However, OlGly did not affect morphine CPP, demonstrating a degree of selectivity. Our respective in vitro and in vivo observations that OlGly activated peroxisome proliferator-activated receptor alpha (PPAR-α) and the PPAR-α antagonist GW6471 prevented the OlGly-induced reduction of nicotine CPP in mice suggests that this lipid acts as a functional PPAR-α agonist to attenuate nicotine reward. These findings raise the possibility that the long chain fatty acid amide OlGly may possess efficacy in treating nicotine addiction. Copyright © 2018. Published by Elsevier Ltd.

Nicotine Withdrawal Induces Neural Deficits in Reward Processing.

PubMed

Oliver, Jason A; Evans, David E; Addicott, Merideth A; Potts, Geoffrey F; Brandon, Thomas H; Drobes, David J

2017-06-01

Nicotine withdrawal reduces neurobiological responses to nonsmoking rewards. Insight into these reward deficits could inform the development of targeted interventions. This study examined the effect of withdrawal on neural and behavioral responses during a reward prediction task. Smokers (N = 48) attended two laboratory sessions following overnight abstinence. Withdrawal was manipulated by having participants smoke three regular nicotine (0.6 mg yield; satiation) or very low nicotine (0.05 mg yield; withdrawal) cigarettes. Electrophysiological recordings of neural activity were obtained while participants completed a reward prediction task that involved viewing four combinations of predictive and reward-determining stimuli: (1) Unexpected Reward; (2) Predicted Reward; (3) Predicted Punishment; (4) Unexpected Punishment. The task evokes a medial frontal negativity that mimics the phasic pattern of dopaminergic firing in ventral tegmental regions associated with reward prediction errors. Nicotine withdrawal decreased the amplitude of the medial frontal negativity equally across all trial types (p < .001). Exploratory analyses indicated withdrawal increased time to initiate the next trial following unexpected punishment trials (p < .001) and response time on reward trials during withdrawal was positively related to nicotine dependence (p < .001). Nicotine withdrawal had equivocal impact across trial types, suggesting reward processing deficits are unlikely to stem from changes in phasic dopaminergic activity during prediction errors. Effects on tonic activity may be more pronounced. Pharmacological interventions directly targeting the dopamine system and behavioral interventions designed to increase reward motivation and responsiveness (eg, behavioral activation) may aid in mitigating withdrawal symptoms and potentially improving smoking cessation outcomes. Findings from this study indicate nicotine withdrawal impacts reward processing signals that are observable in

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

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

20 CFR 408.355 - Can you withdraw your application?

Code of Federal Regulations, 2010 CFR

2010-04-01

... Section 408.355 Employees' Benefits SOCIAL SECURITY ADMINISTRATION SPECIAL BENEFITS FOR CERTAIN WORLD WAR II VETERANS Filing Applications Withdrawal of Application § 408.355 Can you withdraw your application? (a) Request for withdrawal filed before a determination is made. You may withdraw your application...

46 CFR 390.10 - Nonqualified withdrawals.

Code of Federal Regulations, 2011 CFR

2011-10-01

... expenditure is incident to new and advanced ship design, machinery and equipment; (iii) The withdrawal would be a qualified withdrawal except for the fact that there is no tax basis left that can be reduced; or...

46 CFR 390.10 - Nonqualified withdrawals.

Code of Federal Regulations, 2010 CFR

2010-10-01

... expenditure is incident to new and advanced ship design, machinery and equipment; (iii) The withdrawal would be a qualified withdrawal except for the fact that there is no tax basis left that can be reduced; or...

Severity of Withdrawal Symptoms, Plasma Oxytocin Levels, and Treatment Outcome in Heroin Users Undergoing Acute Withdrawal.

PubMed

Nikolaou, Kakia; Kapoukranidou, Dorothea; Ndungu, Samuel; Floros, Georgios; Kovatsi, Leda

2017-01-01

Pre-clinical studies show that, following chronic opioid exposure, oxytocin neurons exhibit over-excitation upon withdrawal, causing an increase in oxytocin brain and plasma levels. Relevant clinical data on humans are scarce. This study investigates the opioid withdrawal stress effect on oxytocin plasma levels in humans. We evaluated 57 male chronic heroin users in a residential detoxification program. We determined plasma oxytocin levels by ELISA and measured the stress effects of withdrawal using the COWS scale for opioid withdrawal, the VAS scale for craving, and the Hamilton scales for anxiety and depression on the second day of admission. Out of the 57 patients enrolled in the study, 27 completed the 21-day program, while the remaining 30 dropped out prior to completion. Plasma oxytocin levels were significantly higher in those individuals who dropped out than in those who completed the program. Participants who dropped out at some stage scored higher in the COWS, VAS-Craving, and Hamilton-anxiety scales, indicating a higher stress and explaining the higher oxytocin levels. In addition, plasma oxytocin levels correlated positively with the scores achieved in the COWS and Hamilton-anxiety scales. Higher withdrawal stress levels are associated with higher plasma oxytocin levels and early treatment discharge.

8 CFR 235.4 - Withdrawal of application for admission.

Code of Federal Regulations, 2010 CFR

2010-01-01

... right to withdraw his or her application for admission. Permission to withdraw an application for... 8 Aliens and Nationality 1 2010-01-01 2010-01-01 false Withdrawal of application for admission... INSPECTION OF PERSONS APPLYING FOR ADMISSION § 235.4 Withdrawal of application for admission. The Attorney...

Estimated Freshwater Withdrawals in Oklahoma, 1990

USGS Publications Warehouse

Lurry, Dee L.; Tortorelli, Robert L.

1996-01-01

This report presents 1990 freshwater withdrawal estimates for Oklahoma by source and category. Withdrawal source is either ground water or surface water. Withdrawal categories include: irrigation, water supply, livestock, thermoelectric-power generation, domestic and commercial, and industrial and mining. Withdrawal data are aggregated by county, major aquifer, and principal river basin. Only the four major categories of irrigation, water supply, livestock, and thermoelectric-power generation are illustrated in this report, although data for all categories are tabulated. The U.S. Geological Survey (USGS) established the National Water-Use Information Program in 1977 to collect uniform, current, and reliable information on water use. The Oklahoma District of the USGS and the Oklahoma Water Resources Board participate in a cooperative program to collect and publish water-use information for Oklahoma. Data contained in this report were made available through the cooperative program.

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

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.

Social Withdrawal in Childhood

PubMed Central

Rubin, Kenneth H.; Coplan, Robert J.; Bowker, Julie C.

2013-01-01

Socially withdrawn children frequently refrain from social activities in the presence of peers. The lack of social interaction in childhood may result from a variety of causes, including social fear and anxiety or a preference for solitude. From early childhood through to adolescence, socially withdrawn children are concurrently and predictively at risk for a wide range of negative adjustment outcomes, including socio-emotional difficulties (e.g., anxiety, low self-esteem, depressive symptoms, and internalizing problems), peer difficulties (e.g., rejection, victimization, poor friendship quality), and school difficulties (e.g., poor-quality teacher-child relationships, academic difficulties, school avoidance). The goals of the current review are to (a) provide some definitional, theoretical, and methodological clarity to the complex array of terms and constructs previously employed in the study of social withdrawal; (b) examine the predictors, correlates, and consequences of child and early-adolescent social withdrawal; and (c) present a developmental framework describing pathways to and from social withdrawal in childhood. PMID:18851686

Inpatient alcohol withdrawal syndrome.

PubMed

Monte-Secades, R; Rabuñal-Rey, R; Guerrero-Sande, H

2015-03-01

A 55-year-old man was admitted for a femur fracture; an alcohol fetor was noted on admission. The following day, the patient began to experience tremors and nervousness. Intravenous haloperidol was administered. Shortly afterwards, the patient experienced two generalized seizures and then began to experience delirium and uncontrollable agitation. The patient was diagnosed with alcohol withdrawal syndrome; high doses of intravenous midazolam were prescribed and infused. A few hours later, the patient presented signs of respiratory depression, requiring a transfer to the intensive care unit. After a review of the medical history, it was determined that the patient had been admitted on 3 previous occasions due to alcohol withdrawal and had progressed to delirium tremens after experiencing seizures. Can the risk of alcohol withdrawal syndrome and the need for prophylactic treatment be assessed on admission? Were appropriate monitoring and treatment measures employed? Would it have been possible to change his outcome? Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Decreased runoff response to precipitation, Little Missouri River Basin, northern Great Plains, USA

USGS Publications Warehouse

Griffin, Eleanor R.; Friedman, Jonathan M.

2017-01-01

High variability in precipitation and streamflow in the semiarid northern Great Plains causes large uncertainty in water availability. This uncertainty is compounded by potential effects of future climate change. We examined historical variability in annual and growing season precipitation, temperature, and streamflow within the Little Missouri River Basin and identified differences in the runoff response to precipitation for the period 1976-2012 compared to 1939-1975 (n = 37 years in both cases). Computed mean values for the second half of the record showed little change (<5%) in annual or growing season precipitation, but average annual runoff at the basin outlet decreased by 22%, with 66% of the reduction in flow occurring during the growing season. Our results show a statistically significant (p < 0.10) 27% decrease in the annual runoff response to precipitation (runoff ratio). Surface-water withdrawals for various uses appear to account for <12% of the reduction in average annual flow volume, and we found no published or reported evidence of substantial flow reduction caused by groundwater pumping in this basin. Results of our analysis suggest that increases in monthly average maximum and minimum temperatures, including >1°C increases in January through March, are the dominant driver of the observed decrease in runoff response to precipitation in the Little Missouri River Basin.

29 CFR 1956.24 - Procedures for withdrawal of approval.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 9 2010-07-01 2010-07-01 false Procedures for withdrawal of approval. 1956.24 Section 1956..., Change, Evaluation and Withdrawal of Approval Procedures § 1956.24 Procedures for withdrawal of approval... withdrawal of approval of plans approved under this part 1956, except that (because these plans, as do public...

Factors Associated with Student Withdrawal from Community College

ERIC Educational Resources Information Center

Scoggin, Donna; Styron, Ronald

2006-01-01

Research was designed to identify commonalities of personal, enrollment, withdrawal, and evaluative factors as they relate to student withdrawal from community college. The study sought to identify interrelationships between identified reasons for student withdrawal and the variables of gender, race, classification status, degree sought, plans for…

20 CFR 416.355 - Withdrawal of an application.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Withdrawal of an application. 416.355 Section 416.355 Employees' Benefits SOCIAL SECURITY ADMINISTRATION SUPPLEMENTAL SECURITY INCOME FOR THE AGED, BLIND, AND DISABLED Filing of Applications Withdrawal of Application § 416.355 Withdrawal of an...

20 CFR 404.640 - Withdrawal of an application.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Withdrawal of an application. 404.640 Section 404.640 Employees' Benefits SOCIAL SECURITY ADMINISTRATION FEDERAL OLD-AGE, SURVIVORS AND DISABILITY INSURANCE (1950- ) Filing of Applications and Other Forms Withdrawal of Application § 404.640 Withdrawal of...

Mean annual, seasonal, and monthly precipitation and runoff in Arkansas, 1951-2011

USGS Publications Warehouse

Pugh, Aaron L.; Westerman, Drew A.

2014-01-01

This report describes long-term annual, seasonal, and monthly means for precipitation and runoff in Arkansas for the period from 1951 through 2011. Precipitation means were estimated using data from the Parameter-elevation Regressions on Independent Slopes Model database; while total runoff, groundwater runoff, and surface runoff means were estimated using data from 123 active and inactive U.S. Geological Survey continuous-record streamflow-gaging stations located in Arkansas and surrounding States. Annual precipitation in Arkansas for the period from 1951 through 2011 had a mean of 49.8 inches. Of the six physiographic sections in Arkansas, the Ouachita Mountains had the largest mean annual precipitation at 53.0 inches, while the Springfield-Salem plateaus had the smallest mean annual precipitation at 45.5 inches. The mean annual total runoff for Arkansas was 17.8 inches. The Ouachita Mountains had the largest mean annual total runoff at 20.4 inches, while the Springfield-Salem plateaus had the smallest mean annual total runoff at 15.0 inches. Runoff is diminished during the dry season, which is attributed to increased losses from evapotranspiration, consumptive uses including irrigation, and increased withdrawals for public and private water supplies. The decline in runoff during the dry season is observed across the State in all physiographic sections. Spatial results for precipitation and runoff are presented in a series of maps that are available for download from the publication Web page in georeferenced raster formats.

Withdrawal symptoms in internet gaming disorder: A systematic review.

PubMed

Kaptsis, Dean; King, Daniel L; Delfabbro, Paul H; Gradisar, Michael

2016-02-01

Internet gaming disorder (IGD) is currently positioned in the appendix of the DSM-5 as a condition requiring further study. The aim of this review was to examine the state of current knowledge of gaming withdrawal symptomatology, given the importance of withdrawal in positioning the disorder as a behavioral addiction. A total of 34 studies, including 10 qualitative studies, 17 research reports on psychometric instruments, and 7 treatment studies, were evaluated. The results indicated that the available evidence on Internet gaming withdrawal is very underdeveloped. Internet gaming withdrawal is most consistently referred to as 'irritability' and 'restlessness' following cessation of the activity. There exists a concerning paucity of qualitative studies that provide detailed clinical descriptions of symptoms arising from cessation of internet gaming. This has arguably compromised efforts to quantify withdrawal symptoms in empirical studies of gaming populations. Treatment studies have not reported on the natural course of withdrawal and/or withdrawal symptom trajectory following intervention. It is concluded that many more qualitative clinical studies are needed, and should be prioritised, to develop our understanding of gaming withdrawal. This should improve clinical descriptions of problematic internet gaming and in turn improve the quantification of IGD withdrawal and thus treatments for harmful internet gaming. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

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…

SSRI and SNRI withdrawal symptoms reported on an internet forum.

PubMed

Stockmann, Tom; Odegbaro, Dolapo; Timimi, Sami; Moncrieff, Joanna

2018-05-09

Antidepressant withdrawal symptoms are well-recognised, but their potential duration remains uncertain. We aimed to describe the characteristics of withdrawal associated with two popular classes of antidepressants, including duration. We analysed the content of a sample of posts on an antidepressant withdrawal website. We compared the characteristics of withdrawal associated with SSRIs and SNRIs, including time of onset, duration and nature of symptoms. 110 posts about SSRI withdrawal, and 63 concerning SNRI withdrawal, were analysed. The mean duration of withdrawal symptoms was significantly longer with SSRIs than SNRIs: 90.5 weeks (standard deviation, SD, 150.0) and 50.8 weeks (SD 76.0) respectively; p = 0.043). Neurological symptoms, such as 'brain zaps,' were more common among SNRI users (p = 0.023). Psychosexual/genitourinary symptoms may be more common among SSRI users (p = 0.054). The website aims to help people with antidepressant withdrawal, and is therefore likely to attract people who have difficulties. Length of prior use of antidepressants was long, with a mean of 252.2 weeks (SD 250.8). People accessing antidepressant withdrawal websites report experiencing protracted withdrawal symptoms. There are some differences in the characteristics of withdrawal associated with different classes of antidepressants.

Drug withdrawal conceptualized as a stressor

PubMed Central

Chartoff, Elena H.; Carlezon, William A.

2015-01-01

Drug withdrawal is often conceptualized as an aversive state that motivates drug-seeking and drug-taking behaviors in humans. Stress is more difficult to define, but is also frequently associated with aversive states. Here we describe evidence for the simple theory that drug withdrawal is a stress-like state, on the basis of common effects on behavioral, neurochemical, and molecular endpoints. We also describe data suggesting a more complex relationship between drug withdrawal and stress. As one example, we will highlight evidence that, depending on drug class, components of withdrawal can produce effects that have characteristics consistent with mood elevation. In addition, some stressors can act as positive reinforcers, defined as having the ability to increase the probability of a behavior that produces it. As such, accumulating evidence supports the general principles of opponent process theory, whereby processes that have an affective valence are followed in time by an opponent process that has the opposite valence. Throughout, we identify gaps in knowledge and propose future directions for research. A better understanding of the similarities, differences, and overlaps between drug withdrawal and stress will lead to the development of improved treatments for addiction, as well as for a vast array of neuropsychiatric conditions that are triggered or exacerbated by stress. PMID:25083570

Treadmill exercise attenuates the severity of physical dependence, anxiety, depressive-like behavior and voluntary morphine consumption in morphine withdrawn rats receiving methadone maintenance treatment.

PubMed

Alizadeh, Maryam; Zahedi-Khorasani, Mahdi; Miladi-Gorji, Hossein

2018-05-30

This study was designed to examine whether treadmill exercise would attenuate the severity of physical dependence, methadone-induced anxiety, depression and voluntary morphine consumption in morphine withdrawn rats receiving methadone maintenance treatment (MMT). The rats were chronically treated with bi-daily doses (10 mg/kg, at 12 h intervals) of morphine for 14 days. The exercising rats receiving MMT were forced to run on a motorized treadmill for 30 days during morphine withdrawal. Then, rats were tested for the severity of morphine dependence, the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that naloxone- precipitated opioid withdrawal signs were decreased in exercising morphine-dependent rats receiving MMT than sedentary rats. Also, the exercising morphine-dependent rats receiving MMT exhibited an increased time on open arms, preference for sucrose and a lower morphine preference ratio than sedentary rats. We conclude that treadmill exercise decreased the severity of physical dependence, anxiety/depressive-like behaviors and also the voluntary morphine consumption in morphine withdrawn rats receiving MMT. Thus, exercise may benefit in the treatment of addicts during MMT. Copyright © 2018. Published by Elsevier B.V.

Transferring Patients From Methadone to Buprenorphine: The Feasibility and Evaluation of Practice Guidelines.

PubMed

Lintzeris, Nicholas; Monds, Lauren A; Rivas, Consuelo; Leung, Stefanie; Dunlop, Adrian; Newcombe, David; Walters, Carina; Galea, Susanna; White, Nancy; Montebello, Mark; Demirkol, Apo; Swanson, Nicola; Ali, Robert

Transfer from methadone to buprenorphine is problematic for many opioid-dependent patients, with limited documented evidence or practical clinical guidance, particularly for the range of methadone doses routinely prescribed for most patients (>50 mg). This study aimed to implement and evaluate recent national Australian guidelines for transferring patients from methadone to buprenorphine. A multisite prospective cohort study. Participants were patients who transferred from methadone to buprenorphine-naloxone at 1 of 4 specialist addiction centers in Australia and New Zealand. Clinicians were trained in the guidelines, and medical records were reviewed to examine process (eg, transfer setting, doses, and guideline adherence) and safety (precipitated withdrawal) measures. Participants completed research interviews before and after transfer-assessing changes in substance use, health outcomes, and side effects. In all, 33 participants underwent transfer, 9 from low methadone doses (<30 mg), 9 from medium doses (30-50 mg), and 15 from high doses (>50 mg). The majority of high-dose transfers occurred in inpatient settings. There was reasonable guideline adherence, and no complications identified in the low and medium-dose transfers. Three high-dose transfers (20%) experienced precipitated withdrawal, and 7/33 participants (21%) returned to methadone within 1 week of attempted transfer. Transfer is feasible in outpatient settings for those transferring from methadone doses below 50 mg; however, inpatient settings and specialist supervision is recommended for higher-dose transfers. The Australian clinical guidelines appear safe and feasible, although further research is required to optimize high-dose transfer procedures.

12 CFR 925.26 - Voluntary withdrawal from membership.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Voluntary withdrawal from membership. 925.26 Section 925.26 Banks and Banking FEDERAL HOUSING FINANCE BOARD FEDERAL HOME LOAN BANK MEMBERS AND HOUSING ASSOCIATES MEMBERS OF THE BANKS Withdrawal and Removal From Membership § 925.26 Voluntary withdrawal from...

Improving alcohol withdrawal outcomes in acute care.

PubMed

Melson, Jo; Kane, Michelle; Mooney, Ruth; Mcwilliams, James; Horton, Terry

2014-01-01

Excessive alcohol consumption is the nation's third leading cause of preventable deaths. If untreated, 6% of alcohol-dependent patients experience alcohol withdrawal, with up to 10% of those experiencing delirium tremens (DT), when they stop drinking. Without routine screening, patients often experience DT without warning. Reduce the incidence of alcohol withdrawal advancing to DT, restraint use, and transfers to the intensive care unit (ICU) in patients with DT. In October 2009, the alcohol withdrawal team instituted a care management guideline used by all disciplines, which included tools for screening, assessment, and symptom management. Data were obtained from existing datasets for three quarters before and four quarters after implementation. Follow-up data were analyzed and showed a great deal of variability in transfers to the ICU and restraint use. Percentage of patients who developed DT showed a downward trend. Incidence of alcohol withdrawal advancing to DT and, in patients with DT, restraint use and transfers to the ICU. Initial data revealed a decrease in percentage of patients with alcohol withdrawal who experienced DT (16.4%-12.9%). In patients with DT, restraint use decreased (60.4%-44.4%) and transfers to the ICU decreased (21.6%-15%). Follow-up data indicated a continued downward trend in patients with DT. Changes were not statistically significant. Restraint use and ICU transfers maintained postimplementation levels initially but returned to preimplementation levels by third quarter 2012. Early identification of patients for potential alcohol withdrawal followed by a standardized treatment protocol using symptom-triggered dosing improved alcohol withdrawal management and outcomes.

Withdrawal-oriented therapy for smokers.

PubMed

Hajek, P

1989-06-01

The treatment approach of the Maudsley Hospital Smokers Clinic is described. It stems from the notion that smokers seeking help are dependent on nicotine, and that withdrawal discomfort is a major block to their success in quitting. Accordingly, therapy focuses on helping clients overcome nicotine deprivation. It uses nicotine replacement and a special format of group treatment. Details are given of preparation of clients, use of nicotine chewing gum, use of group-oriented groupwork, use of information about withdrawal, and training in withdrawal-oriented therapy. Data are presented concerning characteristics of the clientele, treatment adherence, and treatment results. A number of controversial issues are addressed, such as the optimal duration of treatment, timing of the quit date, the value of educational input, and the value of individualization of treatment goals.

42 CFR 457.170 - Withdrawal process.

Code of Federal Regulations, 2010 CFR

2010-10-01

...) STATE CHILDREN'S HEALTH INSURANCE PROGRAMS (SCHIPs) ALLOTMENTS AND GRANTS TO STATES Introduction; State Plans for Child Health Insurance Programs and Outreach Strategies § 457.170 Withdrawal process. (a... 42 Public Health 4 2010-10-01 2010-10-01 false Withdrawal process. 457.170 Section 457.170 Public...

27 CFR 19.729 - Withdrawal of fuel alcohol.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2013-04-01 2013-04-01 false Withdrawal of fuel alcohol..., DEPARTMENT OF THE TREASURY ALCOHOL DISTILLED SPIRITS PLANTS Distilled Spirits for Fuel Use Rules for Use, Withdrawal, and Transfer of Spirits § 19.729 Withdrawal of fuel alcohol. (a) For each shipment or other...

27 CFR 19.729 - Withdrawal of fuel alcohol.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2011-04-01 2011-04-01 false Withdrawal of fuel alcohol. 19.729 Section 19.729 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU..., Withdrawal, and Transfer of Spirits § 19.729 Withdrawal of fuel alcohol. (a) For each shipment or other...

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.

21 CFR 314.620 - Withdrawal procedures.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Approval of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible § 314.620 Withdrawal procedures. (a) Reasons to withdraw...

21 CFR 314.620 - Withdrawal procedures.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Approval of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible § 314.620 Withdrawal procedures. (a) Reasons to withdraw...

21 CFR 314.620 - Withdrawal procedures.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Approval of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible § 314.620 Withdrawal procedures. (a) Reasons to withdraw...

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.

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.

37 CFR 10.40 - Withdrawal from employment,

Code of Federal Regulations, 2010 CFR

2010-07-01

... such request or such withdrawal is because: (1) The petitioner's client: (i) Insists upon presenting a... the Office, that the Office will find the existence of other good cause for withdrawal. ...

Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents.

PubMed

Burma, Nicole E; Bonin, Robert P; Leduc-Pessah, Heather; Baimel, Corey; Cairncross, Zoe F; Mousseau, Michael; Shankara, Jhenkruthi Vijaya; Stemkowski, Patrick L; Baimoukhametova, Dinara; Bains, Jaideep S; Antle, Michael C; Zamponi, Gerald W; Cahill, Catherine M; Borgland, Stephanie L; De Koninck, Yves; Trang, Tuan

2017-03-01

Opiates are essential for treating pain, but termination of opiate therapy can cause a debilitating withdrawal syndrome in chronic users. To alleviate or avoid the aversive symptoms of withdrawal, many of these individuals continue to use opiates. Withdrawal is therefore a key determinant of opiate use in dependent individuals, yet its underlying mechanisms are poorly understood and effective therapies are lacking. Here, we identify the pannexin-1 (Panx1) channel as a therapeutic target in opiate withdrawal. We show that withdrawal from morphine induces long-term synaptic facilitation in lamina I and II neurons within the rodent spinal dorsal horn, a principal site of action for opiate analgesia. Genetic ablation of Panx1 in microglia abolished the spinal synaptic facilitation and ameliorated the sequelae of morphine withdrawal. Panx1 is unique in its permeability to molecules up to 1 kDa in size and its release of ATP. We show that Panx1 activation drives ATP release from microglia during morphine withdrawal and that degrading endogenous spinal ATP by administering apyrase produces a reduction in withdrawal behaviors. Conversely, we found that pharmacological inhibition of ATP breakdown exacerbates withdrawal. Treatment with a Panx1-blocking peptide ( 10 panx) or the clinically used broad-spectrum Panx1 blockers, mefloquine or probenecid, suppressed ATP release and reduced withdrawal severity. Our results demonstrate that Panx1-mediated ATP release from microglia is required for morphine withdrawal in rodents and that blocking Panx1 alleviates the severity of withdrawal without affecting opiate analgesia.

The cannabis withdrawal syndrome: current insights

PubMed Central

Bonnet, Udo; Preuss, Ulrich W

2017-01-01

The cannabis withdrawal syndrome (CWS) is a criterion of cannabis use disorders (CUDs) (Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition) and cannabis dependence (International Classification of Diseases [ICD]-10). Several lines of evidence from animal and human studies indicate that cessation from long-term and regular cannabis use precipitates a specific withdrawal syndrome with mainly mood and behavioral symptoms of light to moderate intensity, which can usually be treated in an outpatient setting. Regular cannabis intake is related to a desensitization and downregulation of human brain cannabinoid 1 (CB1) receptors. This starts to reverse within the first 2 days of abstinence and the receptors return to normal functioning within 4 weeks of abstinence, which could constitute a neurobiological time frame for the duration of CWS, not taking into account cellular and synaptic long-term neuroplasticity elicited by long-term cannabis use before cessation, for example, being possibly responsible for cannabis craving. The CWS severity is dependent on the amount of cannabis used pre-cessation, gender, and heritable and several environmental factors. Therefore, naturalistic severity of CWS highly varies. Women reported a stronger CWS than men including physical symptoms, such as nausea and stomach pain. Comorbidity with mental or somatic disorders, severe CUD, and low social functioning may require an inpatient treatment (preferably qualified detox) and post-acute rehabilitation. There are promising results with gabapentin and delta-9-tetrahydrocannabinol analogs in the treatment of CWS. Mirtazapine can be beneficial to treat CWS insomnia. According to small studies, venlafaxine can worsen the CWS, whereas other antidepressants, atomoxetine, lithium, buspirone, and divalproex had no relevant effect. Certainly, further research is required with respect to the impact of the CWS treatment setting on long-term CUD prognosis and with respect to

31 CFR 103.84 - Withdrawing requests.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Withdrawing requests. 103.84 Section 103.84 Money and Finance: Treasury Regulations Relating to Money and Finance FINANCIAL RECORDKEEPING... requests. A person may withdraw a request for an administrative ruling at any time before the ruling has...

Ajoene restored behavioral patterns and liver glutathione level in morphine treated C57BL6 mice.

PubMed

Yun, Jaesuk; Oliynyk, Sergiy; Lee, Yeonju; Kim, Jieun; Yun, Kyunghwa; Jeon, Raok; Ryu, Jae-Ha; Oh, Seikwan

2017-01-01

Oxidative stress exacerbates drug dependence induced by administration of opiate analgesics such as morphine-induced tolerance and physical dependence associated with the reduction in hepatic glutathione (GSH) level. Ajoene obtained from garlic (Allium sativum L.) has been reported for anti-tumorigenic, anti-oxidative and neuroprotective properties, however, little is known about its effect on morphine-induced dependence. Therefore, this study aimed at the effect of ajoene on physical and/or psychological dependence and liver GSH content in morphine-treated mice. Conditioned place preference (CPP) test and measurement of morphine withdrawal syndrome were performed in C57BL6 mice for behavioral experiments. Thereafter, mice were sacrificed for measurement of serum and liver GSH levels. Ajoene restored CPP and naloxone-precipitated jumping behavior in mice exposed to morphine. Moreover, the reduced level of liver GSH content in morphine treated mice was back to normal after ajoene administration. Taken together, ajoene improved behavioral patterns in mice exposed to morphine suggesting its potential therapeutic benefit against morphine-induced dependence.

Water Withdrawals, Use, and Trends in Florida, 2005

USGS Publications Warehouse

Marella, Richard L.

2009-01-01

In 2005, the total amount of water withdrawals in Florida was estimated at 18,359 million gallons per day (Mgal/d). Saline water accounted for 11,486 Mgal/d (63 percent), and freshwater accounted for 6,873 Mgal/d (37 percent). Groundwater accounted for 4,247 Mgal/d (62 percent) of freshwater withdrawals, and surface water accounted for the remaining 2,626 Mgal/d (38 percent). Surface water accounted for nearly all (99.9 percent) saline-water withdrawals. An additional 660 Mgal/d of reclaimed wastewater was used in Florida during 2005. The largest amount of freshwater was withdrawn from Palm Beach County, and the largest amount of saline water was withdrawn from Pasco County. Fresh groundwater provided drinking water (public supplied and self-supplied) for 16.19 million people (90 percent of Florida's population), and fresh surface water provided drinking water for 1.73 million people (10 percent). The majority of groundwater withdrawals (nearly 60 percent) in 2005 was obtained from the Floridan aquifer system which is present throughout the entire State. The majority of fresh surface-water withdrawals (59 percent) came from the southern Florida hydrologic unit subregion and is associated with Lake Okeechobee and the canals in the Everglades Agricultural Area of Glades, Hendry, and Palm Beach Counties, as well as the Caloosahatchee River and its tributaries in the agricultural areas of Collier, Glades, Hendry, and Lee Counties. Overall, agricultural irrigation accounted for 40 percent of the total freshwater withdrawals (ground and surface), followed by public supply with 37 percent. Public supply accounted for 52 percent of groundwater withdrawals, followed by agricultural self-supplied (31 percent), ommercial-industrial-mining self-supplied (8.5 percent), recreational irrigation and domestic self-supplied (4 percent each), and power generation (0.5 percent). Agricultural self-supplied accounted for 56 percent of fresh surface-water withdrawals, followed by power

Importance of Dry-Season Precipitation to the Water Resources of Monteverde, Costa Rica

NASA Astrophysics Data System (ADS)

Guswa, A. J.; Rhodes, A. L.

2005-12-01

Monteverde, Costa Rica harbors montane forests that exemplify the delicate balances among climate, hydrology, habitat, and development. Most of the annual precipitation to this region arrives during the wet season, but the importance of orographic precipitation during the dry and transitional seasons should not be underestimated. Changes in regional land-cover and global climate may lead to reduced precipitation and cloud cover and a subsequent decline in endemic species, and a boom in ecotourism has put stress on water resources. A recent attempt to withdraw water from a local stream led to a standoff between conservationists and business developers, and there is a clear need for hydrologic data and understanding in support of policy. Through signals observed in the stable isotopic composition of precipitation and streamflow, we seek to understand how precipitation from the drier seasons propagates through the hydrologic cycle. In precipitation, δ18O and δ2H are heaviest during the dry and transitional seasons and light during the rainy season, consistent with the condensation mechanisms and degree of rainout typical of these periods. The signal in d-excess indicates a contribution of recycled water to precipitation in Monteverde from late in the rainy season through the dry season. Attenuated versions of these seasonal signals propagate through to the stream samples and provide a means of determining the importance of dry-season precipitation to water resources for the region. Results from six catchments on the leeward slope indicate that the Brillante Gap in the continental divide exerts strong control on the input of orographic precipitation to the region. Disparities in the temporal signals of precipitation and streamflow isotopes indicate non-linear behavior in the hydrologic processes that move water through these catchments.

Alcohol dependence and opiate dependence: lack of relationship in mice.

PubMed

Goldstein, A; Judson, B A

1971-04-16

According to a recently proposed hypothesis, physical dependence upon alcohol is due to the formation of an endogenous opiate. We tested the hypothesis by determining whether or not ethanol-dependent mice would show typical opiate-dependent behavior (withdrawal jumping syndrome) when challenged with the opiate antagonist naloxone. Our results do not support the hypothesis.

Increased QT interval variability index in acute alcohol withdrawal.

PubMed

Bär, Karl-Jürgen; Boettger, Michael Karl; Koschke, Mandy; Boettger, Silke; Grotelüschen, Marei; Voss, Andreas; Yeragani, Vikram K

2007-07-10

Acute alcohol withdrawal is associated with increased cardiovascular mortality, most likely due to cardiac arrhythmias. As the QT interval reflects the most critical phase for the generation of reentry and thus for arrhythmia, we examined QT variability in patients suffering from acute alcohol withdrawal. High resolution electrocardiographic recordings were performed in 18 male unmedicated patients suffering from acute alcohol withdrawal, 18 matched controls and 15 abstained alcoholics. From these, parameters of beat-to-beat heart rate and QT variability such as approximate entropy and QT variability index (QTvi) were calculated. Measures were correlated with the severity of withdrawal symptoms and with serum electrolyte concentrations. Heart rate and QTvi were significantly increased in acute alcohol withdrawal. Abstained alcoholics did not significantly differ from controls. While QTvi correlated with the severity of alcohol withdrawal symptoms, the mean QT interval duration showed an inverse relationship with serum potassium concentrations. Our data indicate increased QT variability and thus increased repolarization lability in acute alcohol withdrawal. This might add to the elevated risk for serious cardiac arrhythmias. In part, these changes might be related to increased cardiac sympathetic activity or low potassium, thus suggesting the latter as possible targets for adjuvant pharmacological therapy during withdrawal.

Mitragynine Attenuates Withdrawal Syndrome in Morphine-Withdrawn Zebrafish

PubMed Central

Khor, Beng-Siang; Amar Jamil, Mohd Fadzly; Adenan, Mohamad Ilham; Chong Shu-Chien, Alexander

2011-01-01

A major obstacle in treating drug addiction is the severity of opiate withdrawal syndrome, which can lead to unwanted relapse. Mitragynine is the major alkaloid compound found in leaves of Mitragyna speciosa, a plant widely used by opiate addicts to mitigate the harshness of drug withdrawal. A series of experiments was conducted to investigate the effect of mitragynine on anxiety behavior, cortisol level and expression of stress pathway related genes in zebrafish undergoing morphine withdrawal phase. Adult zebrafish were subjected to two weeks chronic morphine exposure at 1.5 mg/L, followed by withdrawal for 24 hours prior to tests. Using the novel tank diving tests, we first showed that morphine-withdrawn zebrafish display anxiety-related swimming behaviors such as decreased exploratory behavior and increased erratic movement. Morphine withdrawal also elevated whole-body cortisol levels, which confirms the phenotypic stress-like behaviors. Exposing morphine-withdrawn fish to mitragynine however attenuates majority of the stress-related swimming behaviors and concomitantly lower whole-body cortisol level. Using real-time PCR gene expression analysis, we also showed that mitragynine reduces the mRNA expression of corticotropin releasing factor receptors and prodynorphin in zebrafish brain during morphine withdrawal phase, revealing for the first time a possible link between mitragynine's ability to attenuate anxiety during opiate withdrawal with the stress-related corticotropin pathway. PMID:22205946

5 CFR 831.1207 - Withdrawal of disability retirement applications.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Withdrawal of disability retirement...) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Disability Retirement § 831.1207 Withdrawal of... any further consideration. (b) Withdrawal of a disability retirement application does not ensure the...

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.

40 CFR 97.86 - Withdrawal from NOX Budget Trading Program.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 22 2013-07-01 2013-07-01 false Withdrawal from NOX Budget Trading... PROGRAMS (CONTINUED) FEDERAL NOX BUDGET TRADING PROGRAM AND CAIR NOX AND SO2 TRADING PROGRAMS Individual Unit Opt-ins § 97.86 Withdrawal from NOX Budget Trading Program. (a) Requesting withdrawal. To withdraw...

40 CFR 97.86 - Withdrawal from NOX Budget Trading Program.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 22 2012-07-01 2012-07-01 false Withdrawal from NOX Budget Trading... PROGRAMS (CONTINUED) FEDERAL NOX BUDGET TRADING PROGRAM AND CAIR NOX AND SO2 TRADING PROGRAMS Individual Unit Opt-ins § 97.86 Withdrawal from NOX Budget Trading Program. (a) Requesting withdrawal. To withdraw...

40 CFR 97.86 - Withdrawal from NOX Budget Trading Program.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 21 2014-07-01 2014-07-01 false Withdrawal from NOX Budget Trading... PROGRAMS (CONTINUED) FEDERAL NOX BUDGET TRADING PROGRAM AND CAIR NOX AND SO2 TRADING PROGRAMS Individual Unit Opt-ins § 97.86 Withdrawal from NOX Budget Trading Program. (a) Requesting withdrawal. To withdraw...

[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

Steroid withdrawal in lung transplant recipients.

PubMed

Borro, J M; Solé, A; De la Torre, M; Pastor, A; Tarazona, V

2005-11-01

Many of the long-term complications in lung transplantations are secondary effects of immunosuppression. Corticosteroids are partially responsible for the development of osteoporosis, raised blood pressure, diabetes, muscular disorders, gastric ulcers, and other conditions. We analyzed the long-term result of steroid withdrawal in our lung transplant recipients. When respiratory function stabilized, to avoid secondary effects, steroid treatment was withdrawn in 34 of the 375 lung transplant patients in our centers We evaluated the characteristics of the donors and recipients, their compatibility, the pre, and post-steroid withdrawal complications, and type of immunosuppressant. The mean age of patients was 42 +/- 7 years and of donors, 25 +/- 9 years. The primary diseases were: 15 emphysema, six pulmonary fibrosis, 10 cystic fibrosis, and three primary pulmonary hypertension. Twenty seven patients had double lung transplants and seven single lung. The mean steroid withdrawal period was 881 +/- 237 days posttransplantation. The most frequent treatment regimen at the time of steroid withdrawal was cyclosporine, azathioprine, and minimal steroid doses. Six recipients had to be restarted on steroids one patient who required a kidney transplant, three cases due to an infectious process with a differential diagnosis of rejection, and two cases due to loss of FEV1 (forced expiratory volume in 1 s), suggestive of chronic rejection. There was an improvement in blood pressure in five patients, in plasma cholesterol and triglyceride levels in eight patients, and insulin withdrawal in two diabetic patients. Steroid treatment may be suspended 2 to 3 years, posttransplant in selected lung transplant recipients. The usual patient profile shows few rejection episodes with cyclosporine and azathioprine immunosuppression. What is notable is the low mean age of donors. Close clinical monitoring and lung function testing are of major importance in the weeks following steroid

Withdrawing to a Virtual World: Associations between Subtypes of Withdrawal, Media Use, and Maladjustment in Emerging Adults

ERIC Educational Resources Information Center

Nelson, Larry J.; Coyne, Sarah M.; Howard, Emily; Clifford, Brandon N.

2016-01-01

An approach-avoidance model of social withdrawal (Asendorpf, 1990) identifies 3 types of social withdrawal including shyness, unsociability, and avoidance. Each appears to be uniquely associated with varying indicators of maladjustment in emerging adulthood (Nelson, 2013) but little, if any, work has been done to see how they might be linked to…

Placebo caffeine reduces withdrawal in abstinent coffee drinkers.

PubMed

Mills, Llewellyn; Boakes, Robert A; Colagiuri, Ben

2016-04-01

Expectancies have been shown to play a role in the withdrawal syndrome of many drugs of addiction; however, no studies have examined the effects of expectancies across a broad range of caffeine withdrawal symptoms, including craving. The purpose of the current study was to use caffeine as a model to test the effect of expectancy on withdrawal symptoms, specifically whether the belief that one has ingested caffeine is sufficient to reduce caffeine withdrawal symptoms and cravings in abstinent coffee drinkers. We had 24-h abstinent regular coffee drinkers complete the Caffeine Withdrawal Symptom Questionnaire (CWSQ) before and after receiving decaffeinated coffee. One-half of the participants were led to believe the coffee was regular caffeinated coffee (the 'Told Caffeine' condition) and one-half were told that it was decaffeinated (the 'Told Decaf' condition). Participants in the Told Caffeine condition reported a significantly greater reduction in the factors of cravings, fatigue, lack of alertness and flu-like feelings of the CWSQ, than those in the Told Decaf condition. Our results indicated that the belief that one has consumed caffeine can affect caffeine withdrawal symptoms, especially cravings, even when no caffeine was consumed. © The Author(s) 2016.

Analysis of Participant Withdrawal in Huntington Disease Clinical Trials.

PubMed

Banno, Haruhiko; Andrzejewski, Kelly L; McDermott, Michael P; Murphy, Alyssa; Majumder, Madhurima; de Blieck, Elisabeth A; Auinger, Peggy; Cudkowicz, Merit E; Atassi, Nazem

2017-01-01

Excellent retention in Huntington disease (HD) clinical trials is essential for testing new therapies. The stage of disease, cognitive status, and availability of a care partner may influence retention in HD clinical trials. We sought to analyze reasons for early withdrawal in three HD clinical trials, and evaluated if either baseline characteristics or follow-up assessments were associated with time to withdrawal. Analyses of participant withdrawal were performed for three randomized, double-blind, placebo-controlled trials including the CARE-HD (coenzyme Q10 and remacemide in HD, n = 347), DOMINO (pilot study of minocycline in HD, n = 114), and 2CARE (coenzyme Q10 in HD, n = 609) trials. Reasons for withdrawal were obtained by review of textual data in the study databases. Participant demographic and clinical characteristics were analyzed as potential predictors of time to withdrawal using Cox-proportional hazards models. Estimated probabilities of withdrawal at 12 months were 2.9% for CARE-HD, 10.5% for DOMINO, and 5.9% for 2CARE. The top reasons for withdrawal (202 in total), expressed as mean percentage across the three trials, were loss to follow-up (23.2%), death (15.9%), and loss of interest/desire to participate (15.2%). Baseline and time-dependent variables associated with time to withdrawal were mainly motor, behavioral, and functional scores. Age, gender, ethnicity, and educational level were not associated with time to withdrawal in any of the three studies. The estimated withdrawal probability at 12 months ranged from 2.9% to 10.5% in the three HD trials considered here. A possible strategy to improve retention of participants in future HD clinical trials is to enroll individuals with higher baseline functional and behavioral status.

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.

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

5 CFR 1650.16 - Required withdrawal date.

Code of Federal Regulations, 2011 CFR

2011-01-01

... FUNDS FROM THE THRIFT SAVINGS PLAN Post-Employment Withdrawals § 1650.16 Required withdrawal date. (a) A... date described in paragraph (a) of this section, but is not required to do so. (c) In the event that a...

Behavioral and biochemical effects of ethanol withdrawal in zebrafish.

PubMed

da Silva Chaves, Suianny Nayara; Felício, Gabriel Rocha; Costa, Bruna Patrícia Dutra; de Oliveira, Witallo Etevaldo Araújo; Lima-Maximino, Monica Gomes; Siqueira Silva, Diógenes Henrique de; Maximino, Caio

2018-06-01

Chronic alcohol use induces adaptations and toxicity that can induce symptoms of anxiety, autonomic hyperarousal, and epileptic seizures when alcohol is removed (withdrawal syndrome). Zebrafish has recently gained wide attention as a behavioral model to study the neurobehavioral effects of acute and chronic alcohol use, including withdrawal. The literature, however, is very contradictory on findings regarding withdrawal effects, with some studies reporting increased anxiety, while others report no effect. A meta-analytic approach was taken to find the sources of this heterogeneity, and ethanol concentration during exposure and exposure duration were found to be the main sources of variation. A conceptual replication was also made using continuous exposure for 16 days in waterborne ethanol (0.5%) and assessing anxiety-like behavior in the light/dark test after 60 min withdrawal. Withdrawal was shown to reduce preference for darkness, consistent with decreased anxiety, but to increase risk assessment, consistent with increased anxiety. Animals were also subjected to the withdrawal protocol and injected with pilocarpine in a sub-convulsive dose to assess susceptibility to epileptic seizure-like behavior. The protocol was sufficient to increase susceptibility to epileptic seizure-like behavior in animals exposed to ethanol. Finally, withdrawal also decreased catalase activity in the brain, but not in the head kidney, suggesting mechanisms associated with the behavioral effects of ethanol withdrawal. Copyright © 2018 Elsevier Inc. All rights reserved.

Estimated Withdrawals and Use of Water in Colorado, 2005

USGS Publications Warehouse

Ivahnenko, Tamara; Flynn, Jennifer L.

2010-01-01

The future health and economic welfare of the people and environment of Colorado depend on a continuous supply of fresh water. Detailed, comprehensive information on the use of water from Colorado's diverse surface-water and groundwater resources is important to water managers and planners by providing information they need to quantify current stresses and estimate and plan for future water needs. As part of the U.S. Geological Survey's (USGS) National Water Use Information Program (NWUIP), Statewide water withdrawal and water-use data have been collected or estimated and summarized in this report by county and by four-digit hydrologic unit code for the following seven water-use categories: irrigation (crop and golf course), public supply, self-supplied domestic, self-supplied industrial, livestock, mining, and thermoelectric power generation. A summary for instream water use for hydroelectric power generation also is included. This report is published in cooperation with the Colorado Water Conservation Board. In 2005, an estimated 13,581.22 million gallons per day (Mgal/d) was withdrawn from groundwater and surface-water sources in Colorado for the seven water-use categories. Withdrawals from surface water represented about 11,035 Mgal/d, or 81.3 percent of the total, whereas withdrawals from groundwater sources represented an estimated 2,546 Mgal/d or 18.7 percent of the total. Irrigation (combined crop and golf course) totaled 12,362.49 Mgal/d or 91 percent of the total water withdrawals in the State of Colorado. Crop irrigation accounted for 99.7 percent (12,321.85 Mgal/d) of the irrigation, whereas the 243 turf golf courses in Colorado accounted for 0.3 percent (40.64 Mgal/d) of the total irrigation water withdrawals. Total withdrawals for the other water-use categories were public supply, 864.17 Mgal/d; self-supplied domestic, 34.43 Mgal/d; self-supplied industrial, 142.44 Mgal/d; livestock, 33.06 Mgal/d; mining, 21.42 Mgal/d (includes both fresh and saline

Prolonged, severe intrathecal baclofen withdrawal syndrome: a case report.

PubMed

Hansen, Colby R; Gooch, Judith L; Such-Neibar, Teresa

2007-11-01

Intrathecal baclofen (ITB) withdrawal is a well-recognized complication when drug delivery is disrupted for any reason. ITB withdrawal varies widely in its severity and poses the very real possibility of death if not promptly managed. Cases of withdrawal lasting greater than 1 or 2 weeks, however, are sparse. We report the case of an 11-year-old girl with spastic quadriplegic cerebral palsy who developed an infected pump and subsequent meningitis, prompting the removal of her pump and catheter. She subsequently developed a severe, prolonged baclofen withdrawal syndrome marked by increased spasticity, agitation, hypertension, and tachycardia that lasted nearly 2 months, requiring intensive care and continuous intravenous sedation with benzodiazepines and opiates. Her pump was eventually replaced on hospital day 56 and within 24 hours her symptoms dramatically improved. She was eventually weaned off sedating medications and returned to baseline functional status. Typical management of baclofen withdrawal is reviewed. To date, the literature has not discussed the potential role for opiates in managing baclofen withdrawal, yet a growing body of literature is examining the interplay between opiates and gamma-aminobutyric acid B pathways. A potential role for opiates in managing severe baclofen withdrawal is proposed.

Ethical analysis of withdrawing ventricular assist device support.

PubMed

Mueller, Paul S; Swetz, Keith M; Freeman, Monica R; Carter, Kari A; Crowley, Mary Eliot; Severson, Cathy J Anderson; Park, Soon J; Sulmasy, Daniel P

2010-09-01

To describe a series of patients with heart failure supported with a ventricular assist device (VAD) who requested (or whose surrogates requested) withdrawal of VAD support and the legal and ethical aspects pertaining to these requests. We retrospectively reviewed the medical records of patients at Mayo Clinic, Rochester, MN, from March 1, 2003, through January 31, 2009, who requested (or whose surrogates requested) withdrawal of VAD support and for whom the requests were fulfilled. We then explored the legal and ethical permissibility of carrying out such requests. The median age of the 14 patients identified (13 men, 1 woman) was 57 years. Requests were made by 2 patients and 12 surrogates. None of the patients' available advance directives mentioned the VAD. For 11 patients, multidisciplinary care conferences were held before withdrawal of VAD support. Only 1 patient had an ethics consultation. All 14 patients died within 1 day of withdrawal of VAD support. Patients have the right to refuse or request the withdrawal of any unwanted treatment, and we argue that this right extends to VAD support. We also argue that the cause of death in these cases is the underlying heart disease, not assisted suicide or euthanasia. Therefore, patients with heart failure supported with VADs or their surrogates may request withdrawal of this treatment. In our view, carrying out such requests is permissible in accordance with the principles that apply to withdrawing other life-sustaining treatments.

20 CFR 408.355 - Can you withdraw your application?

Code of Federal Regulations, 2011 CFR

2011-04-01

... 20 Employees' Benefits 2 2011-04-01 2011-04-01 false Can you withdraw your application? 408.355 Section 408.355 Employees' Benefits SOCIAL SECURITY ADMINISTRATION SPECIAL BENEFITS FOR CERTAIN WORLD WAR II VETERANS Filing Applications Withdrawal of Application § 408.355 Can you withdraw your application...

8 CFR 1244.14 - Withdrawal of Temporary Protected Status.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 8 Aliens and Nationality 1 2013-01-01 2013-01-01 false Withdrawal of Temporary Protected Status... JUSTICE IMMIGRATION REGULATIONS TEMPORARY PROTECTED STATUS FOR NATIONALS OF DESIGNATED STATES § 1244.14 Withdrawal of Temporary Protected Status. (a) Authority of director. The director may withdraw the status of...

8 CFR 1244.14 - Withdrawal of Temporary Protected Status.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 8 Aliens and Nationality 1 2012-01-01 2012-01-01 false Withdrawal of Temporary Protected Status... JUSTICE IMMIGRATION REGULATIONS TEMPORARY PROTECTED STATUS FOR NATIONALS OF DESIGNATED STATES § 1244.14 Withdrawal of Temporary Protected Status. (a) Authority of director. The director may withdraw the status of...

8 CFR 1244.14 - Withdrawal of Temporary Protected Status.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 8 Aliens and Nationality 1 2010-01-01 2010-01-01 false Withdrawal of Temporary Protected Status... JUSTICE IMMIGRATION REGULATIONS TEMPORARY PROTECTED STATUS FOR NATIONALS OF DESIGNATED STATES § 1244.14 Withdrawal of Temporary Protected Status. (a) Authority of director. The director may withdraw the status of...

8 CFR 1244.14 - Withdrawal of Temporary Protected Status.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 8 Aliens and Nationality 1 2014-01-01 2014-01-01 false Withdrawal of Temporary Protected Status... JUSTICE IMMIGRATION REGULATIONS TEMPORARY PROTECTED STATUS FOR NATIONALS OF DESIGNATED STATES § 1244.14 Withdrawal of Temporary Protected Status. (a) Authority of director. The director may withdraw the status of...

8 CFR 1244.14 - Withdrawal of Temporary Protected Status.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 8 Aliens and Nationality 1 2011-01-01 2011-01-01 false Withdrawal of Temporary Protected Status... JUSTICE IMMIGRATION REGULATIONS TEMPORARY PROTECTED STATUS FOR NATIONALS OF DESIGNATED STATES § 1244.14 Withdrawal of Temporary Protected Status. (a) Authority of director. The director may withdraw the status of...

8 CFR 244.14 - Withdrawal of Temporary Protected Status.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 8 Aliens and Nationality 1 2012-01-01 2012-01-01 false Withdrawal of Temporary Protected Status... TEMPORARY PROTECTED STATUS FOR NATIONALS OF DESIGNATED STATES § 244.14 Withdrawal of Temporary Protected Status. (a) Authority of USCIS. USCIS may withdraw the status of an alien granted Temporary Protected...

8 CFR 244.14 - Withdrawal of Temporary Protected Status.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 8 Aliens and Nationality 1 2014-01-01 2014-01-01 false Withdrawal of Temporary Protected Status... TEMPORARY PROTECTED STATUS FOR NATIONALS OF DESIGNATED STATES § 244.14 Withdrawal of Temporary Protected Status. (a) Authority of USCIS. USCIS may withdraw the status of an alien granted Temporary Protected...

8 CFR 244.14 - Withdrawal of Temporary Protected Status.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 8 Aliens and Nationality 1 2013-01-01 2013-01-01 false Withdrawal of Temporary Protected Status... TEMPORARY PROTECTED STATUS FOR NATIONALS OF DESIGNATED STATES § 244.14 Withdrawal of Temporary Protected Status. (a) Authority of USCIS. USCIS may withdraw the status of an alien granted Temporary Protected...

Demand-Withdraw Patterns in Marital Conflict in the Home.

PubMed

Papp, Lauren M; Kouros, Chrystyna D; Cummings, E Mark

2009-06-01

The present study extended laboratory-based findings of demand-withdraw communication into marital conflict in the home and further explored its linkages with spousal depression. U.S. couples (N = 116) provided diary reports of marital conflict and rated depressive symptoms. Hierarchical linear modeling results indicated that husband demand-wife withdraw and wife demand-husband withdraw occurred in the home at equal frequency, and both were more likely to occur when discussing topics that concerned the marital relationship. For both patterns, conflict initiator was positively linked to the demander role. Accounting for marital satisfaction, both demand-withdraw patterns predicted negative emotions and tactics during marital interactions and lower levels of conflict resolution. Spousal depression was linked to increased likelihood of husband demand-wife withdraw.

49 CFR 1103.18 - Withdrawal from employment.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 8 2010-10-01 2010-10-01 false Withdrawal from employment. 1103.18 Section 1103.18 Transportation Other Regulations Relating to Transportation (Continued) SURFACE TRANSPORTATION... Duties and Responsibilities Toward A Client § 1103.18 Withdrawal from employment. The right of a...

46 CFR 287.10 - Withdrawals from fund.

Code of Federal Regulations, 2010 CFR

2010-10-01

... obligations or liquidation. (1) Checks, drafts, or other instruments of withdrawal to meet obligations under a... subsequently incurred purchase-money indebtedness, after having been executed by the taxpayer, shall be... proposed withdrawal, including properly certified invoices or other supporting papers. Such instruments of...

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