Repeated administration of mazindol reduces spontaneous pain-related behaviors without modifying bone density and microarchitecture in a mouse model of complete Freund's adjuvant-induced knee arthritis.

PubMed

Robledo-González, L E; Martínez-Martínez, A; Vargas-Muñoz, V M; Acosta-González, R I; Plancarte-Sánchez, R; Anaya-Reyes, M; Fernández Del Valle-Laisequilla, C; Reyes-García, J G; Jiménez-Andrade, J M

2017-01-01

The role of dopaminergic system in the development of rheumatoid arthritis-related pain, a major symptom in this disease, has not been explored. Therefore, the anti-nociceptive effect of mazindol, a dopamine uptake inhibitor, was evaluated in a model of complete Freund's adjuvant (CFA)-induced arthritis. Furthermore, as studies have shown that the dopaminergic system regulates bone metabolism, the effect of mazindol on bone mass and microarchitecture was determined. Adult ICR male mice received intra-articular injections of either CFA or saline into the right knee joint every week. Spontaneous pain-like behaviors (flinching and guarding) and locomotor activity were assessed at day 26 post-first CFA, following which, a single intraperitoneally (i.p.) administered dose of mazindol was given (1, 3 and 10 mg/kg). Then, the antinociceptive effect of a repeated administration of 3 mg/kg mazindol (daily, i.p.; day 15-day 26) was evaluated. Additionally, at day 26, the participation of D1-like, D2-like or opioid receptors in the antinociceptive effect of mazindol was evaluated. The effect of mazindol on bone density and microarchitecture was evaluated by micro-computed tomography. Acute administration of mazindol decreased the spontaneous pain-like behaviors in a dose-dependent manner without reducing the knee edema. However, mazindol at 10 mg/kg significantly increased the locomotor activity; therefore, 3 mg/kg mazindol was used for further studies. Repeated administration of 3 mg/kg mazindol significantly decreased the pain-like behaviors without modifying locomotor activity. The antinociceptive effect of mazindol was blocked by administration of a D2-like receptor antagonist (haloperidol), but not by administration of D1-like receptor antagonist (SCH 23390) or an opioid receptor antagonist (naloxone). Repeated administration of mazindol did not significantly modify the density and microarchitecture of periarticular bone of the arthritic and nonarthritic knee joints

Transgenerational attenuation of opioid self-administration as a consequence of adolescent morphine exposure.

PubMed

Vassoler, Fair M; Oliver, David J; Wyse, Cristina; Blau, Ashley; Shtutman, Michael; Turner, Jill R; Byrnes, Elizabeth M

2017-02-01

The United States is in the midst of an opiate epidemic, with abuse of prescription and illegal opioids increasing steadily over the past decade. While it is clear that there is a genetic component to opioid addiction, there is a significant portion of heritability that cannot be explained by genetics alone. The current study was designed to test the hypothesis that maternal exposure to opioids prior to pregnancy alters abuse liability in subsequent generations. Female adolescent Sprague Dawley rats were administered morphine at increasing doses (5-25 mg/kg, s.c.) or saline for 10 days (P30-39). During adulthood, animals were bred with drug-naïve colony males. Male and female adult offspring (F1 animals) were tested for morphine self-administration acquisition, progressive ratio, extinction, and reinstatement at three doses of morphine (0.25, 0.75, 1.25 mg/kg/infusion). Grandoffspring (F2 animals, from the maternal line) were also examined. Additionally, gene expression changes within the nucleus accumbens were examined with RNA deep sequencing (PacBio) and qPCR. There were dose- and sex-dependent effects on all phases of the self-administration paradigm that indicate decreased morphine reinforcement and attenuated relapse-like behavior. Additionally, genes related to synaptic plasticity, as well as myelin basic protein (MBP), were dysregulated. Some, but not all, effects persisted into the subsequent (F2) generation. The results demonstrate that even limited opioid exposure during adolescence can have lasting effects across multiple generations, which has implications for mechanisms of the transmission of drug abuse liability in humans. Copyright © 2016 Elsevier Ltd. All rights reserved.

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.

Repeated administration of mazindol reduces spontaneous pain-related behaviors without modifying bone density and microarchitecture in a mouse model of complete Freund’s adjuvant-induced knee arthritis

PubMed Central

Robledo-González, LE; Martínez-Martínez, A; Vargas-Muñoz, VM; Acosta-González, RI; Plancarte-Sánchez, R; Anaya-Reyes, M; Fernández del Valle-Laisequilla, C; Reyes-García, JG; Jiménez-Andrade, JM

2017-01-01

Background The role of dopaminergic system in the development of rheumatoid arthritis-related pain, a major symptom in this disease, has not been explored. Therefore, the anti-nociceptive effect of mazindol, a dopamine uptake inhibitor, was evaluated in a model of complete Freund’s adjuvant (CFA)-induced arthritis. Furthermore, as studies have shown that the dopaminergic system regulates bone metabolism, the effect of mazindol on bone mass and microarchitecture was determined. Methods Adult ICR male mice received intra-articular injections of either CFA or saline into the right knee joint every week. Spontaneous pain-like behaviors (flinching and guarding) and locomotor activity were assessed at day 26 post-first CFA, following which, a single intraperitoneally (i.p.) administered dose of mazindol was given (1, 3 and 10 mg/kg). Then, the antinociceptive effect of a repeated administration of 3 mg/kg mazindol (daily, i.p.; day 15–day 26) was evaluated. Additionally, at day 26, the participation of D1-like, D2-like or opioid receptors in the antinociceptive effect of mazindol was evaluated. The effect of mazindol on bone density and microarchitecture was evaluated by micro-computed tomography. Results Acute administration of mazindol decreased the spontaneous pain-like behaviors in a dose-dependent manner without reducing the knee edema. However, mazindol at 10 mg/kg significantly increased the locomotor activity; therefore, 3 mg/kg mazindol was used for further studies. Repeated administration of 3 mg/kg mazindol significantly decreased the pain-like behaviors without modifying locomotor activity. The antinociceptive effect of mazindol was blocked by administration of a D2-like receptor antagonist (haloperidol), but not by administration of D1-like receptor antagonist (SCH 23390) or an opioid receptor antagonist (naloxone). Repeated administration of mazindol did not significantly modify the density and microarchitecture of periarticular bone of the arthritic

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

A randomized double-blind crossover comparison of continuous and intermittent subcutaneous administration of opioid for cancer pain.

PubMed

Watanabe, Sharon; Pereira, Jose; Tarumi, Yoko; Hanson, John; Bruera, Eduardo

2008-05-01

ABSTRACT Although the preferred route of opioid administration is oral, patients with cancer often require an alternative route. Options include continuous subcutaneous infusion (CSCI) or regularly scheduled intermittent subcutaneous injections (ISCI). CSCI maintains steady drug levels, theoretically avoiding the "bolus effect" of nausea and sedation immediately post-dose, and breakthrough pain prior to the next dose. However, portable infusion pumps can be costly to use. The Edmonton Injector is an inexpensive portable device for ISCI. CSCI and ISCI have not been directly compared. The objective of this trial was to compare CSCI and ISCI of opioid for treatment of cancer pain. Patients were recruited from two tertiary palliative care units. Eligibility criteria included stable cancer pain requiring opioid therapy, need for parenteral route, and normal cognition. Patients were randomly assigned to receive opioid by CSCI by portable pump or ISCI by Edmonton Injector for 48 hours, followed by crossover to the alternative modality for 48 hours. During each phase, placebo was administered by the alternative modality. The study was closed after 12 patients were entered, due to slow accrual. Eleven patients completed the study. There were no differences between CSCI and ISCI in mean visual analogue score (VAS) for pain, nausea or drowsiness; categorical rating score of pain; number of breakthrough opioid doses per day; global rating of treatment effectiveness; or adverse effects. In all cases, patients and investigators expressed no preference for one modality over another. Further research is required to confirm that opioid administration by CSCI and ISCI provide similar analgesic and adverse effects.

Attentional Bias For Prescription Opioid Cues Among Opioid Dependent Chronic Pain Patients

PubMed Central

Garland, Eric L.; Froeliger, Brett; Passik, Steven D.; Howard, Matthew O.

2012-01-01

Recurrent use of prescription opioid analgesics by chronic pain patients may result in opioid dependence, which involves implicit neurocognitive operations that organize and impel craving states and compulsive drug taking behavior. Prior studies have identified an attentional bias (AB) towards heroin among heroin dependent individuals. The aim of this study was to determine whether opioid-dependent chronic pain patients exhibit an AB towards prescription opioidrelated cues. Opioid-dependent chronic pain patients (n = 32) and a comparison group of non-dependent opioid users with chronic pain (n = 33) completed a dot probe task designed to measure opioid AB. Participants also rated their opioid craving and self-reported arousal associated with opioid-related and neutral images, pain severity, and relief from pain treatments. Repeated-measures ANOVA revealed a significant group (opioid-dependent vs. non-dependent opioid user) × presentation duration (200 ms. vs. 2000 ms.) interaction, such that opioid-dependent individuals evidenced a significant AB towards opioid cues presented for 200 ms but not for cues presented for 2000 ms, whereas non-dependent opioid users did not exhibit a significant mean AB at either stimulus duration. Among opioid-dependent individuals, 200 ms opioid AB was significantly associated with opioid craving, while among non-dependent opioid users, 200 ms opioid AB was significantly associated with relief from pain treatments. Furthermore, dependent and non-dependent opioid users experienced opioid cues as significantly more arousing than neutral cues. Opioid dependence among chronic pain patients appears to involve an automatic AB towards opioid-related cues. When coupled with chronic pain, attentional fixation on opioid cues may promote compulsive drug use and addictive behavior. PMID:22968666

Sex-dependent effects of periadolescent exposure to the cannabinoid agonist CP-55,940 on morphine self-administration behaviour and the endogenous opioid system.

PubMed

Biscaia, Miguel; Fernández, Beatriz; Higuera-Matas, Alejandro; Miguéns, Miguel; Viveros, Maria-Paz; García-Lecumberri, Carmen; Ambrosio, Emilio

2008-04-01

Early cannabinoid consumption may predispose individuals to the misuse of addictive drugs later in life. However, there is a lack of experimental evidence as to whether cannabinoid exposure during adolescence might differently affect opiate reinforcing efficacy and the opioid system in adults of both sexes. Our aim was to examine whether periadolescent chronic exposure to the cannabinoid agonist CP-55,940 could exert sex-dependent effects on morphine reinforcing and the opioid system in adulthood. Morphine reinforcing was studied under a progressive ratio (PR) reinforcement schedule in adult male and female rats that previously acquired morphine self-administration under a fixed ratio 1 (FR1) schedule. Binding levels and functionality of mu-opioid receptors were also evaluated. Periadolescent cannabinoid exposure altered morphine self-administration and the opioid system in adult rats in a sex-dependent manner. CP-55,940-exposed males exhibited higher self-administration rates under a FR1, but not under a PR schedule. In females, CP-55,940 did not modify morphine self-administration under either schedule. Moreover, CP-55,940 also increased mu-opioid receptor levels in the subcallosal streak of pre-treated animals and decreased mu-opioid receptor functionality in the nucleus accumbens shell but again, only in males. Our data indicate that adult male rats exposed to the cannabinoid in adolescence self-administer more morphine than females, but only when the demands required by the schedule of reinforcement are low, which might be related to the decrease in mu-opioid receptor functionality in the NAcc-shell observed in these animals.

Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

PubMed Central

Largent-Milnes, Tally M.; Guo, Wenhong; Wang, Hoau-Yan; Burns, Lindsay H.; Vanderah, Todd W.

2017-01-01

Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in μ-opioid receptor (MOR)–G protein coupling from Gi/o to Gs that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L5/L6 spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to Gs in the damaged (ipsilateral) spinal dorsal horn. This MOR-Gs coupling occurred without changing Gi/o coupling levels and without changing the expression of MOR or Gα proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-Gs coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-Gs coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this Gs coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-Gs coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain. PMID:18468954

Attentional bias for prescription opioid cues among opioid dependent chronic pain patients.

PubMed

Garland, Eric L; Froeliger, Brett E; Passik, Steven D; Howard, Matthew O

2013-12-01

Recurrent use of prescription opioid analgesics by chronic pain patients may result in opioid dependence, which involves implicit neurocognitive operations that organize and impel craving states and compulsive drug taking behavior. Prior studies have identified an attentional bias (AB) towards heroin among heroin dependent individuals. The aim of this study was to determine whether opioid-dependent chronic pain patients exhibit an AB towards prescription opioid-related cues. Opioid-dependent chronic pain patients (n = 32) and a comparison group of non-dependent opioid users with chronic pain (n = 33) completed a dot probe task designed to measure opioid AB. Participants also rated their opioid craving and self-reported arousal associated with opioid-related and neutral images, pain severity, and relief from pain treatments. Repeated-measures ANOVA revealed a significant group (opioid-dependent vs. non-dependent opioid user) × presentation duration (200. vs. 2,000 ms.) interaction, such that opioid-dependent individuals evidenced a significant AB towards opioid cues presented for 200 ms but not for cues presented for 2,000 ms, whereas non-dependent opioid users did not exhibit a significant mean AB at either stimulus duration. Among opioid-dependent individuals, 200 ms opioid AB was significantly associated with opioid craving, while among non-dependent opioid users, 200 ms opioid AB was significantly associated with relief from pain treatments. Furthermore, dependent and non-dependent opioid users experienced opioid cues as significantly more arousing than neutral cues. Opioid dependence among chronic pain patients appears to involve an automatic AB towards opioid-related cues. When coupled with chronic pain, attentional fixation on opioid cues may promote compulsive drug use and addictive behavior.

Receipt of Prescription Opioids in a National Sample of Pregnant Veterans Receiving Veterans Health Administration Care.

PubMed

Kroll-Desrosiers, Aimee R; Skanderson, Melissa; Bastian, Lori A; Brandt, Cynthia A; Haskell, Sally; Kerns, Robert D; Mattocks, Kristin M

2016-01-01

A growing number of reproductive-age women veterans are returning from Operations Enduring Freedom, Iraqi Freedom, and New Dawn (OEF/OIF/OND). In 2010, 42% of women veterans receiving Veterans Health Administration (VHA) services were aged 18 to 45. Prescription opioid use has increased among all veterans over the past decade; however, exposure among pregnant veterans has not been examined. We identified 2,331 women who delivered babies within the VHA system between 2001 and 2010. Delivery, opioid prescribing history, and demographic and health-related variables were obtained from a national database of veterans receiving VHA services. Receipt of an opioid prescription was defined as any filled VHA prescription for opioids in the 280-day pregnancy window before delivery. We developed a multivariable logistic regression model adjusted for sociodemographic, service-related, psychiatric diagnosis, and physical health variables to examine the odds of filling an opioid prescription during the pregnancy window. Ten percent of pregnant veterans received VHA prescription opioids during their pregnancy window. Significant factors associated with opioid prescriptions included presence of any psychiatric diagnosis (adjusted odds ratio [aOR], 1.67; 95% CI, 1.24-2.26), diagnosis of back problems (aOR, 2.94; 95% CI, 1.92-4.49), or other nontraumatic joint disorders (aOR, 2.20; 95% CI, 1.36-3.58). This study suggests that a substantial proportion of women veterans received VHA prescriptions for opioids during pregnancy. Providers should be aware of the potential risks of prescription opioid use during pregnancy, assess for potential undertreatment of psychiatric diagnoses, and consider alternate pain management strategies when possible. Published by Elsevier Inc.

Oxycodone plus ultra-low-dose naltrexone attenuates neuropathic pain and associated mu-opioid receptor-Gs coupling.

PubMed

Largent-Milnes, Tally M; Guo, Wenhong; Wang, Hoau-Yan; Burns, Lindsay H; Vanderah, Todd W

2008-08-01

Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in mu-opioid receptor (MOR)-G protein coupling from G(i/o) to G(s) that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L(5)/L(6) spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to G(s) in the damaged (ipsilateral) spinal dorsal horn. This MOR-G(s) coupling occurred without changing G(i/o) coupling levels and without changing the expression of MOR or Galpha proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-G(s) coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-G(s) coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this G(s) coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-G(s) coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain. The current study investigates whether Oxytrex (oxycodone with an ultra-low dose of naltrexone) alleviates mechanical and thermal hypersensitivities in an animal model of neuropathic pain over a period of 7 days, given locally or systemically. In this report, we first describe an injury-induced shift in mu-opioid receptor coupling from G(i/o) to G(s), suggesting

Safety of Oral Dronabinol During Opioid Withdrawal in Humans

PubMed Central

Jicha, Crystal J.; Lofwall, Michelle R.; Nuzzo, Paul A.; Babalonis, Shanna; Elayi, Samy Claude; Walsh, Sharon L.

2015-01-01

Background Opioid dependence remains a significant public health problem worldwide with only three FDA-approved treatments, all targeting the mu-opioid receptor. Dronabinol, a cannabinoid (CB) 1 receptor agonist, is currently under investigation as a novel opioid withdrawal treatment. This study reports on safety outcomes of dronabinol among adults in opioid withdrawal. Methods Twelve adults physically dependent on short-acting opioids participated in this 5-week within-subject, randomized, double blind, placebo-controlled inpatient study. Volunteers were maintained on oral oxycodone 30mg qid. Double-blind placebo substitutions occurred for 21 hours before each of 7 experimental sessions in order to produce opioid withdrawal. A single oral test dose was administered each session (placebo, oxycodone 30 and 60mg, dronabinol 5, 10, 20, and 30mg [decreased from 40mg]). Heart rate, blood pressure, respiratory outcomes and pupil diameter were assessed repeatedly. Results Dronabinol 40mg produced sustained sinus tachycardia accompanied by anxiety and panic necessitating dose reduction to 30mg. Sinus tachycardia and anxiety also occurred in one volunteer after dronabinol 20mg. Compared to placebo, dronabinol 20 and 30mg produced significant increases in heart rate beginning 1 hour after drug administration that lasted approximately two hours (p<0.05). Dronabinol 5 and 10mg produced placebo-like effects. Oxycodone produced prototypic mu-opioid agonist effects (e.g., miosis). Conclusion Dronabinol 20mg and higher increased heart rate among healthy adults at rest who were in a state of opioid withdrawal, raising concern about its safety. These results have important implications for future dosing strategies and may limit the utility of dronabinol as a treatment for opioid withdrawal. PMID:26483357

Association of an Opioid Standard of Practice Intervention With Intravenous Opioid Exposure in Hospitalized Patients.

PubMed

Ackerman, Adam L; O'Connor, Patrick G; Doyle, Deirdre L; Marranca, Sheyla M; Haight, Carolyn L; Day, Christine E; Fogerty, Robert L

2018-06-01

Opioids are commonly used to treat pain in hospitalized patients; however, intravenous administration carries an increased risk of adverse effects compared with oral administration. The subcutaneous route is an effective method of opioid delivery with favorable pharmacokinetics. To assess an intervention to reduce intravenous opioid use, total parenteral opioid exposure, and the rate of patients administered parenteral opioids. A pilot study was conducted in an adult general medical unit in an urban academic medical center. Attending physicians, nurse practitioners, and physician assistants who prescribed drugs were the participants. Use of opioids was compared between a 6-month control period and 3 months following education for the prescribers on opioid routes of administration. Adoption of a local opioid standard of practice, preferring the oral and subcutaneous routes over intravenous administration, and education for prescribers and nursing staff on awareness of the subcutaneous route was implemented. The primary outcome was a reduction in intravenous doses administered per patient-day. Secondary measures included total parenteral and overall opioid doses per patient-day, parenteral and overall opioid exposure per patient-day, and daily rate of patients receiving parenteral opioids. Pain scores were measured on a standard 0- to 10-point Likert scale over the first 5 days of hospitalization. The control period included 4500 patient-days, and the intervention period included 2459 patient-days. Of 127 patients in the intervention group, 59 (46.5%) were men; mean (SD) age was 57.6 (18.5) years. Intravenous opioid doses were reduced by 84% (0.06 vs 0.39 doses per patient-day, P < .001), and doses of all parenteral opioids were reduced by 55% (0.18 vs 0.39 doses per patient-day, P < .001). In addition, mean (SD) daily parenteral opioid exposure decreased by 49% (2.88 [0.72] vs 5.67 [1.14] morphine-milligram equivalents [MMEs] per patient-day). The daily rate

Prescription opioids for occupational injury: results from workers' compensation claims records.

PubMed

Berecki-Gisolf, Janneke; Collie, Alex; McClure, Roderick J

2014-09-01

The objective of this study is to identify the prevalence of opioid prescription use in an Australian workers' compensation population and assess predictors of long-term use. Retrospective administrative data analysis. WorkSafe Victoria (Australia) workers' compensation. Workers with a workers' compensation claim were included if the injury/illness started in 2008 or 2009 (N = 54,931). Claim payments records dating up to 2 years postinjury were analyzed to determine receipt of prescription opioids. Long-term use was defined as use of any opioid beyond 1 year postinjury. Within the follow-up period, 8,933 (16.3%) workers claimed prescription opioids: 10.0% claimed opioids in the first year only, and 6.3% claimed opioids beyond the first year. The most commonly received opioids were codeine (10.4%), oxycodone (7.5%), and tramadol (5.0%). Dextropropoxyphene, which is considered unsafe in many countries because of potentially fatal side effects, was used by 1.9% of injured workers. Progression to long-term use of opioids was common (N = 3,446; 39%): age (35-64 years; the association with age followed an inverse U-shaped curve), women, laborers, lower socioeconomic status, greater work disability, and greater hospital expense were associated with opioid use beyond the first year postinjury. Prescription opioid use for workplace injury in Australia is common but not as common as reports from U.S. workers' compensation schemes. The type of opioid and number of repeat prescriptions are factors that should be carefully considered by practitioners prescribing opioids to injured workers: progression to long-term use is common and not fully explained by injury severity. Wiley Periodicals, Inc.

Mindfulness-Meditation-Based Pain Relief Is Not Mediated by Endogenous Opioids

PubMed Central

Adler-Neal, Adrienne L.; Wells, Rebecca E.; Stagnaro, Emily; May, Lisa M.; Eisenach, James C.; McHaffie, John G.; Coghill, Robert C.

2016-01-01

Mindfulness meditation, a cognitive practice premised on sustaining nonjudgmental awareness of arising sensory events, reliably attenuates pain. Mindfulness meditation activates multiple brain regions that contain a high expression of opioid receptors. However, it is unknown whether mindfulness-meditation-based analgesia is mediated by endogenous opioids. The present double-blind, randomized study examined behavioral pain responses in healthy human volunteers during mindfulness meditation and a nonmanipulation control condition in response to noxious heat and intravenous administration of the opioid antagonist naloxone (0.15 mg/kg bolus + 0.1 mg/kg/h infusion) or saline placebo. Meditation during saline infusion significantly reduced pain intensity and unpleasantness ratings when compared to the control + saline group. However, naloxone infusion failed to reverse meditation-induced analgesia. There were no significant differences in pain intensity or pain unpleasantness reductions between the meditation + naloxone and the meditation + saline groups. Furthermore, mindfulness meditation during naloxone produced significantly greater reductions in pain intensity and unpleasantness than the control groups. These findings demonstrate that mindfulness meditation does not rely on endogenous opioidergic mechanisms to reduce pain. SIGNIFICANCE STATEMENT Endogenous opioids have been repeatedly shown to be involved in the cognitive inhibition of pain. Mindfulness meditation, a practice premised on directing nonjudgmental attention to arising sensory events, reduces pain by engaging mechanisms supporting the cognitive control of pain. However, it remains unknown if mindfulness-meditation-based analgesia is mediated by opioids, an important consideration for using meditation to treat chronic pain. To address this question, the present study examined pain reports during meditation in response to noxious heat and administration of the opioid antagonist naloxone and placebo saline

Development of an opioid self-administration assay to study drug seeking in zebrafish.

PubMed

Bossé, Gabriel D; Peterson, Randall T

2017-09-29

The zebrafish (Danio rerio) has become an excellent tool to study mental health disorders, due to its physiological and genetic similarity to humans, ease of genetic manipulation, and feasibility of small molecule screening. Zebrafish have been shown to exhibit characteristics of addiction to drugs of abuse in non-contingent assays, including conditioned place preference, but contingent assays have been limited to a single assay for alcohol consumption. Using inexpensive electronic, mechanical, and optical components, we developed an automated opioid self-administration assay for zebrafish, enabling us to measure drug seeking and gain insight into the underlying biological pathways. Zebrafish trained in the assay for five days exhibited robust self-administration, which was dependent on the function of the μ-opioid receptor. In addition, a progressive ratio protocol was used to test conditioned animals for motivation. Furthermore, conditioned fish continued to seek the drug despite an adverse consequence and showed signs of stress and anxiety upon withdrawal of the drug. Finally, we validated our assay by confirming that self-administration in zebrafish is dependent on several of the same molecular pathways as in other animal models. Given the ease and throughput of this assay, it will enable identification of important biological pathways regulating drug seeking and could lead to the development of new therapeutic molecules to treat addiction. Copyright © 2017 Elsevier B.V. All rights reserved.

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

Cue-Induced Craving to Paraphernalia and Drug Images in Opioid Dependence

PubMed Central

McHugh, R. Kathryn; Fulciniti, Francesca; Mashhoon, Yasmin; Weiss, Roger D.

2016-01-01

Background and Objectives Stimuli that are repeatedly paired with substance use, such as drug paraphernalia, can themselves elicit drug craving. The aim of this study was to examine whether particular cue types elicit greater craving responses than others among individuals with opioid dependence. Methods Participants seeking inpatient treatment for opioid dependence were recruited for a study of cue-induced craving. This sample (N=50), included 25 primary heroin users, 20 primary prescription opioid users, and 5 users of heroin and prescription opioids equally. Participants completed a cue reactivity task, in which images of drug-related stimuli were presented on a computer screen, each followed by a question assessing state drug craving. Results Overall, participants reported higher craving following paraphernalia stimuli relative to drug stimuli. However, this was moderated by opioid type; there was significantly higher craving in response to images of paraphernalia cues in the heroin group, and higher craving in response to drug cues in the prescription opioid group. Discussion and Conclusions These findings highlight potential differences in cue reactivity to opioid paraphernalia and drug cues, which appears to be moderated by drug type. Scientific Significance Cue-induced craving is an important factor in relapse. This study adds further to the literature on cue-induced craving in opioid dependence, suggesting that craving may vary based on both cue type and opioid type. Future studies designed to discriminate the impact of substance of abuse, route of administration, and cue type will help to further understand cue-induced craving in this population. PMID:26848719

Patient-reported opioid analgesic requirements after elective inguinal hernia repair: A call for procedure-specific opioid-administration strategies.

PubMed

Mylonas, Konstantinos S; Reinhorn, Michael; Ott, Lauren R; Westfal, Maggie L; Masiakos, Peter T

2017-11-01

A better understanding of the analgesia needs of patients who undergo common operative procedures is necessary as we address the growing opioid public health crisis in the United States. The aim of this study was to evaluate patient experience with our opioid prescribing practice after elective inguinal hernia repairs. A prospective, observational study was conducted between October 1, 2015, and September 30, 2016, in a single-surgeon, high-volume, practice of inguinal hernia operation. Adult patients undergoing elective inguinal herniorrhaphy under local anesthesia with intravenous sedation were invited to participate. All patients were prescribed 10 opioid analgesic tablets postoperatively and were counseled to reserve opioids for pain not controlled by nonopioid analgesics. Their experience was captured by completing a questionnaire 2 to 3 weeks postoperatively during their postoperative visit. A total of 185 patients were surveyed. The majority of the participants were males (177, 95.7%) and ≥60 years old (96, 51.9%). Of the 185 patients, 159 (85.9%) reported using ≤4 opioid tablets; 110 patients (59.5%) reported that they used no opioid analgesics postoperatively. None of the patients was taking opioids within 7 days of their postoperative appointment. Of the 147 patients who were employed, 111 (75.5%) reported missing ≤3 work days, 57 of whom (51.4%) missed no work at all. Patients who were employed were more likely to take opioid analgesics postoperatively (P = .049). Patients who took no opioid analgesics experienced less maximum (P < .001) and persistent groin pain (P = .037). Pain interfered less with daily activities (P = .012) and leisure activities (P = .018) for patients who did not use opioids. The majority of our patients reported that they did not require any opioid analgesics, and nearly all of those who thought that they did need opioids used <5 tablets. Our data suggest that for elective inguinal hernia repair under a local

Functional role of peripheral opioid receptors in the regulation of cardiac spinal afferent nerve activity during myocardial ischemia

PubMed Central

Longhurst, John C.

2013-01-01

Thinly myelinated Aδ-fiber and unmyelinated C-fiber cardiac sympathetic (spinal) sensory nerve fibers are activated during myocardial ischemia to transmit the sensation of angina pectoris. Although recent observations showed that myocardial ischemia increases the concentrations of opioid peptides and that the stimulation of peripheral opioid receptors inhibits chemically induced visceral and somatic nociception, the role of opioids in cardiac spinal afferent signaling during myocardial ischemia has not been studied. The present study tested the hypothesis that peripheral opioid receptors modulate cardiac spinal afferent nerve activity during myocardial ischemia by suppressing the responses of cardiac afferent nerve to ischemic mediators like bradykinin and extracellular ATP. The nerve activity of single unit cardiac afferents was recorded from the left sympathetic chain (T2–T5) in anesthetized cats. Forty-three ischemically sensitive afferent nerves (conduction velocity: 0.32–3.90 m/s) with receptive fields in the left and right ventricles were identified. The responses of these afferent nerves to repeat ischemia or ischemic mediators were further studied in the following protocols. First, epicardial administration of naloxone (8 μmol), a nonselective opioid receptor antagonist, enhanced the responses of eight cardiac afferent nerves to recurrent myocardial ischemia by 62%, whereas epicardial application of vehicle (PBS) did not alter the responses of seven other cardiac afferent nerves to ischemia. Second, naloxone applied to the epicardial surface facilitated the responses of seven cardiac afferent nerves to epicardial ATP by 76%. Third, administration of naloxone enhanced the responses of seven other afferent nerves to bradykinin by 85%. In contrast, in the absence of naloxone, cardiac afferent nerves consistently responded to repeated application of ATP (n = 7) or bradykinin (n = 7). These data suggest that peripheral opioid peptides suppress the

Rearing environment differentially modulates cocaine self-administration after opioid pretreatment: A behavioral economic analysis.

PubMed

Hofford, Rebecca S; Beckmann, Joshua S; Bardo, Michael T

2016-10-01

Research has shown that previous experiences during development, especially if stressful, can alter an organism's response to opioids later in life. Given the previous literature on opioid modulation of cocaine self-administration, the current study raised rats in either an enriched condition (EC) or isolated condition (IC) and employed behavioral economics to study the effects of naltrexone and morphine on cocaine self-administration. EC and IC rats were trained to lever press for cocaine using a within-session demand procedure. This procedure measured cocaine consumption under changing cocaine price by decreasing the dose of cocaine earned throughout a session. Rats were able to self-administer cocaine on a FR1; every 10min the cocaine dose was systematically decreased (0.75-0.003mg/kg/infusion cocaine). After reaching stability on this procedure, rats were randomly pretreated with 0, 0.3, 1, or 3mg/kg naltrexone once every 3days, followed by random pretreatments of 0, 0.3, 1, or 3mg/kg morphine once every 3days. Economic demand functions were fit to each rat's cocaine consumption from each pretreatment, and appropriate mathematical parameters were extracted and analyzed. Naltrexone decreased the essential value of cocaine in IC rats only. However, morphine decreased the essential value of cocaine and the consumption of cocaine at zero price in both EC and IC rats. These results indicate that environmental experiences during development should be considered when determining the efficacy of opioid drugs, especially for the treatment of substance abuse. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Receipt of Pharmacotherapy for Opioid Use Disorder by Justice-Involved U.S. Veterans Health Administration Patients

PubMed Central

Finlay, Andrea K.; Harris, Alex H.S.; Rosenthal, Joel; Blue-Howells, Jessica; Clark, Sean; McGuire, Jim; Timko, Christine; Frayne, Susan M.; Smelson, David; Oliva, Elizabeth; Binswanger, Ingrid

2016-01-01

Background Pharmacotherapy – methadone, buprenorphine, or naltrexone – is an evidence-based treatment for opioid use disorder, but little is known about receipt of these medications among veterans involved in the justice system. The current study examines receipt of pharmacotherapy for opioid use disorder among veterans with a history of justice involvement at U.S. Veterans Health Administration (VHA) facilities compared to veterans with no justice involvement. Methods Using national VHA clinical and pharmacy records, we conducted a retrospective cohort study of veterans with an opioid use disorder diagnosis in fiscal year 2012. Using a mixed-effects logistic regression model, we examined receipt of pharmacotherapy in the 1-year period following diagnosis as a function of justice involvement, adjusting for patient and facility characteristics. Results The 1-year rate of receipt for pharmacotherapy for opioid use disorder was 27% for prison-involved veterans, 34% for jail/court-involved veterans, and 33% for veterans not justice-involved. Compared to veterans not justice-involved, those prison-involved had 0.75 lower adjusted odds (95% confidence interval [CI]: 0.65–0.87) of receiving pharmacotherapy whereas jail/court-involved veterans did not have significantly different adjusted odds. Conclusions Targeted efforts to increase receipt of pharmacotherapy for opioid use disorder among veterans exiting prison is needed as they have lower odds of receiving these medications. PMID:26832998

Endogenous Opioid Inhibition of Chronic Low Back Pain Influences Degree of Back Pain Relief Following Morphine Administration

PubMed Central

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

2014-01-01

Background and Objectives Factors underlying differential responsiveness to opioid analgesic medications used in chronic pain management are poorly understood. We tested whether individual differences in endogenous opioid inhibition of chronic low back pain were associated with magnitude of acute reductions in back pain ratings following morphine administration. Methods In randomized, counterbalanced order over three sessions, 50 chronic low back pain patients received intravenous naloxone (8mg), morphine (0.08 mg/kg), or placebo. Back pain intensity was rated pre-drug and again after peak drug activity was achieved using the McGill Pain Questionnaire-Short Form (Sensory and Affective subscales, VAS intensity measure). Opioid blockade effect measures to index degree of endogenous opioid inhibition of back pain intensity were derived as the difference between pre-to post-drug changes in pain intensity across placebo and naloxone conditions, with similar morphine responsiveness measures derived across placebo and morphine conditions. Results Morphine significantly reduced back pain compared to placebo (MPQ-Sensory, VAS; P < .01). There were no overall effects of opioid blockade on back pain intensity. However, individual differences in opioid blockade effects were significantly associated with degree of acute morphine-related reductions in back pain on all measures, even after controlling for effects of age, sex, and chronic pain duration (P < .03). Individuals exhibiting greater endogenous opioid inhibition of chronic back pain intensity reported less acute relief of back pain with morphine. Conclusions Morphine appears to provide better acute relief of chronic back pain in individuals with lower natural opioidergic inhibition of chronic pain intensity. Possible implications for personalized medicine are discussed. PMID:24553304

The convulsive and electroencephalographic changes produced by nonpeptidic delta-opioid agonists in rats: comparison with pentylenetetrazol.

PubMed

Jutkiewicz, Emily M; Baladi, Michelle G; Folk, John E; Rice, Kenner C; Woods, James H

2006-06-01

delta-Opioid agonists produce convulsions and antidepressant-like effects in rats. It has been suggested that the antidepressant-like effects are produced through a convulsant mechanism of action either through overt convulsions or nonconvulsive seizures. This study evaluated the convulsive and seizurogenic effects of nonpeptidic delta-opioid agonists at doses that previously were reported to produce antidepressant-like effects. In addition, delta-opioid agonist-induced electroencephalographic (EEG) and behavioral changes were compared with those produced by the chemical convulsant pentylenetetrazol (PTZ). For these studies, EEG changes were recorded using a telemetry system before and after injections of the delta-opioid agonists [(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenz (SNC80) and [(+)-4-[alpha(R)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide [(+)-BW373U86]. Acute administration of nonpeptidic delta-opioid agonists produced bilateral ictal and paroxysmal spike and/or sharp wave discharges. delta-Opioid agonists produced brief changes in EEG recordings, and tolerance rapidly developed to these effects; however, PTZ produced longer-lasting EEG changes that were exacerbated after repeated administration. Studies with antiepileptic drugs demonstrated that compounds used to treat absence epilepsy blocked the convulsive effects of nonpeptidic delta-opioid agonists. Overall, these data suggest that delta-opioid agonist-induced EEG changes are not required for the antidepressant-like effects of these compounds and that neural circuitry involved in absence epilepsy may be related to delta-opioid agonist-induced convulsions. In terms of therapeutic development, these data suggest that it may be possible to develop delta-opioid agonists devoid of convulsive properties.

Effects of daily delta-9-tetrahydrocannabinol treatment on heroin self-administration in rhesus monkeys.

PubMed

Maguire, David R; France, Charles P

2016-04-01

Opioid abuse remains a significant public health problem; together with the greater availability of marijuana in some regions there is an increasing likelihood that opioids and marijuana will be used together. Polydrug abuse is associated with increased toxicity and poorer treatment outcome; thus, a better understanding of the consequences of repeated coadministration of these drugs will facilitate the development of better prevention and treatment strategies. This study examined the effects of daily treatment with the cannabinoid receptor agonist delta-9-tetrahydrocannabinol (Δ-THC) and its discontinuation on self-administration of heroin in rhesus monkeys (n=4) lever-pressing under a fixed-ratio 30 schedule. Heroin self-administration (0.32-32 μg/kg/infusion, intravenously) generated an inverted U-shaped dose-effect curve. Administered acutely, Δ-THC (0.01-0.32 mg/kg, subcutaneously) dose dependently decreased responding for heroin and flattened the self-administration dose-effect curve. Daily treatment with Δ-THC (0.01-0.1 mg/kg/12 h, subcutaneously) either had no effect on or decreased responding for heroin. In addition, daily treatment did not significantly impact extinction of heroin self-administration or resumption of responding for heroin after extinction. Discontinuation of daily Δ-THC treatment did not systematically impact rates of heroin self-administration. These data suggest that repeated administration of a cannabinoid receptor agonist likely does not increase, and possibly decreases, the positive reinforcing effects of a mu opioid receptor agonist.

Mindfulness-Meditation-Based Pain Relief Is Not Mediated by Endogenous Opioids.

PubMed

Zeidan, Fadel; Adler-Neal, Adrienne L; Wells, Rebecca E; Stagnaro, Emily; May, Lisa M; Eisenach, James C; McHaffie, John G; Coghill, Robert C

2016-03-16

Mindfulness meditation, a cognitive practice premised on sustaining nonjudgmental awareness of arising sensory events, reliably attenuates pain. Mindfulness meditation activates multiple brain regions that contain a high expression of opioid receptors. However, it is unknown whether mindfulness-meditation-based analgesia is mediated by endogenous opioids. The present double-blind, randomized study examined behavioral pain responses in healthy human volunteers during mindfulness meditation and a nonmanipulation control condition in response to noxious heat and intravenous administration of the opioid antagonist naloxone (0.15 mg/kg bolus + 0.1 mg/kg/h infusion) or saline placebo. Meditation during saline infusion significantly reduced pain intensity and unpleasantness ratings when compared to the control + saline group. However, naloxone infusion failed to reverse meditation-induced analgesia. There were no significant differences in pain intensity or pain unpleasantness reductions between the meditation + naloxone and the meditation + saline groups. Furthermore, mindfulness meditation during naloxone produced significantly greater reductions in pain intensity and unpleasantness than the control groups. These findings demonstrate that mindfulness meditation does not rely on endogenous opioidergic mechanisms to reduce pain. Endogenous opioids have been repeatedly shown to be involved in the cognitive inhibition of pain. Mindfulness meditation, a practice premised on directing nonjudgmental attention to arising sensory events, reduces pain by engaging mechanisms supporting the cognitive control of pain. However, it remains unknown if mindfulness-meditation-based analgesia is mediated by opioids, an important consideration for using meditation to treat chronic pain. To address this question, the present study examined pain reports during meditation in response to noxious heat and administration of the opioid antagonist naloxone and placebo saline. The results

Nurses and opioids: results of a bi-national survey on mental models regarding opioid administration in hospitals

PubMed Central

Guest, Charlotte; Sobotka, Fabian; Karavasopoulou, Athina; Ward, Stephen; Bantel, Carsten

2017-01-01

Objective Pain remains insufficiently treated in hospitals. Increasing evidence suggests human factors contribute to this, due to nurses failing to administer opioids. This behavior might be the consequence of nurses’ mental models about opioids. As personal experience and conceptions shape these models, the aim of this prospective survey was to identify model-influencing factors. Material and methods A questionnaire was developed comprising of 14 statements concerning ideations about opioids and seven questions concerning demographics, indicators of adult learning, and strength of religious beliefs. Latent variables that may underlie nurses’ mental models were identified using undirected graphical dependence models. Representative items of latent variables were employed for ordinal regression analysis. Questionnaires were distributed to 1,379 nurses in two London, UK, hospitals (n=580) and one German (n=799) hospital between September 2014 and February 2015. Results A total of 511 (37.1%) questionnaires were returned. Mean (standard deviation) age of participants were 37 (11) years; 83.5% participants were female; 45.2% worked in critical care; and 51.5% had more than 10 years experience. Of the nurses, 84% were not scared of opioids, 87% did not regard opioids as drugs to help patients die, and 72% did not view them as drugs of abuse. More English (41%) than German (28%) nurses were afraid of criminal investigations and were constantly aware of side effects (UK, 94%; Germany, 38%) when using opioids. Four latent variables were identified which likely influence nurses’ mental models: “conscious decision-making”; “medication-related fears”; “practice-based observations”; and “risk assessment”. They were predicted by strength of religious beliefs and indicators of informal learning such as experience but not by indicators of formal learning such as conference attendance. Conclusion Nurses in both countries employ analytical and affective mental

Nurses and opioids: results of a bi-national survey on mental models regarding opioid administration in hospitals.

PubMed

Guest, Charlotte; Sobotka, Fabian; Karavasopoulou, Athina; Ward, Stephen; Bantel, Carsten

2017-01-01

Pain remains insufficiently treated in hospitals. Increasing evidence suggests human factors contribute to this, due to nurses failing to administer opioids. This behavior might be the consequence of nurses' mental models about opioids. As personal experience and conceptions shape these models, the aim of this prospective survey was to identify model-influencing factors. A questionnaire was developed comprising of 14 statements concerning ideations about opioids and seven questions concerning demographics, indicators of adult learning, and strength of religious beliefs. Latent variables that may underlie nurses' mental models were identified using undirected graphical dependence models. Representative items of latent variables were employed for ordinal regression analysis. Questionnaires were distributed to 1,379 nurses in two London, UK, hospitals (n=580) and one German (n=799) hospital between September 2014 and February 2015. A total of 511 (37.1%) questionnaires were returned. Mean (standard deviation) age of participants were 37 (11) years; 83.5% participants were female; 45.2% worked in critical care; and 51.5% had more than 10 years experience. Of the nurses, 84% were not scared of opioids, 87% did not regard opioids as drugs to help patients die, and 72% did not view them as drugs of abuse. More English (41%) than German (28%) nurses were afraid of criminal investigations and were constantly aware of side effects (UK, 94%; Germany, 38%) when using opioids. Four latent variables were identified which likely influence nurses' mental models: "conscious decision-making"; "medication-related fears"; "practice-based observations"; and "risk assessment". They were predicted by strength of religious beliefs and indicators of informal learning such as experience but not by indicators of formal learning such as conference attendance. Nurses in both countries employ analytical and affective mental models when administering the opioids and seem to learn from experience

Development and applications of the Veterans Health Administration's Stratification Tool for Opioid Risk Mitigation (STORM) to improve opioid safety and prevent overdose and suicide.

PubMed

Oliva, Elizabeth M; Bowe, Thomas; Tavakoli, Sara; Martins, Susana; Lewis, Eleanor T; Paik, Meenah; Wiechers, Ilse; Henderson, Patricia; Harvey, Michael; Avoundjian, Tigran; Medhanie, Amanuel; Trafton, Jodie A

2017-02-01

Concerns about opioid-related adverse events, including overdose, prompted the Veterans Health Administration (VHA) to launch an Opioid Safety Initiative and Overdose Education and Naloxone Distribution program. To mitigate risks associated with opioid prescribing, a holistic approach that takes into consideration both risk factors (e.g., dose, substance use disorders) and risk mitigation interventions (e.g., urine drug screening, psychosocial treatment) is needed. This article describes the Stratification Tool for Opioid Risk Mitigation (STORM), a tool developed in VHA that reflects this holistic approach and facilitates patient identification and monitoring. STORM prioritizes patients for review and intervention according to their modeled risk for overdose/suicide-related events and displays risk factors and risk mitigation interventions obtained from VHA electronic medical record (EMR)-data extracts. Patients' estimated risk is based on a predictive risk model developed using fiscal year 2010 (FY2010: 10/1/2009-9/30/2010) EMR-data extracts and mortality data among 1,135,601 VHA patients prescribed opioid analgesics to predict risk for an overdose/suicide-related event in FY2011 (2.1% experienced an event). Cross-validation was used to validate the model, with receiver operating characteristic curves for the training and test data sets performing well (>.80 area under the curve). The predictive risk model distinguished patients based on risk for overdose/suicide-related adverse events, allowing for identification of high-risk patients and enrichment of target populations of patients with greater safety concerns for proactive monitoring and application of risk mitigation interventions. Results suggest that clinical informatics can leverage EMR-extracted data to identify patients at-risk for overdose/suicide-related events and provide clinicians with actionable information to mitigate risk. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Effects of daily delta-9-tetrahydrocannabinol treatment on heroin self-administration in rhesus monkeys

PubMed Central

Maguire, David R.; France, Charles P.

2015-01-01

Opioid abuse remains a significant public health problem; together with the greater availability of marijuana in some regions there is an increasing likelihood that opioids and marijuana will be used together. Poly-drug abuse is associated with increased toxicity and poorer treatment outcome; thus, a better understanding of the consequences of repeated co-administration of these drugs will facilitate the development of better prevention and treatment strategies. This study examined the effects of daily treatment with the cannabinoid receptor agonist delta-9-tetrahydrocannabinol (Δ9-THC) and its discontinuation on self-administration of heroin in rhesus monkeys (n=4) lever-pressing under a fixed-ratio 30 schedule. Heroin self-administration (0.32–32 μg/kg/infusion, i.v.) generated an inverted U-shaped dose–effect curve. Administered acutely, Δ9-THC (0.01–0.32 mg/kg, s.c.) dose dependently decreased responding for heroin and flattened the self-administration dose-effect curve. Daily treatment with Δ9-THC (0.01–0.1 mg/kg/12hr, s.c.) either had no effect on or decreased responding for heroin. In addition, daily treatment did not significantly impact extinction of heroin self-administration or resumption of responding for heroin after extinction. Discontinuation of daily Δ9-THC treatment did not systematically impact rates of heroin self-administration. These data suggest that repeated administration of a cannabinoid receptor agonist likely does not increase, and possibly decreases, the positive reinforcing effects of a mu opioid receptor agonist. PMID:26397756

Intraoperative use of remifentanil and opioid induced hyperalgesia/acute opioid tolerance: systematic review.

PubMed

Kim, Sang Hun; Stoicea, Nicoleta; Soghomonyan, Suren; Bergese, Sergio D

2014-01-01

The use of opioids has been increasing in operating room and intensive care unit to provide perioperative analgesia as well as stable hemodynamics. However, many authors have suggested that the use of opioids is associated with the expression of acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH) in experimental studies and clinical observations in dose and/or time dependent exposure even when used within the clinically accepted doses. Recently, remifentanil has been used for pain management during anesthesia as well as in the intensive care units because of its rapid onset and offset. Search of the available literature to assess remifentanil AOT and OIH based on available published data. We reviewed articles analyzing remifentanil AOT and OIH, and focused our literature search on evidence based information. Experimental and clinical studies were identified using electronic searches of Medline (PubMed, Ovid, Springer, and Elsevier, ClinicalKey). Our results showed that the development of remifentanil AOT and OIH is a clinically significant phenomenon requiring further research. AOT - defined as an increase in the required opioid dose to maintain adequate analgesia, and OIH - defined as decreased pain threshold after chronic opioid treatment, should be suspected with any unexplained pain report unassociated with the disease progression. The clinical significance of these findings was evaluated taking into account multiple methodological issues including the dose and duration of opioids administration, the different infusion mode, the co-administrated anesthetic drug's effect, method assessing pain sensitivity, and the repetitive and potentially tissue damaging nature of the stimuli used to determine the threshold during opioid infusion. Future studies need to investigate the contribution of remifentanil induced hyperalgesia to chronic pain and the role of pharmacological modulation to reverse this process.

Proinflammatory cytokines oppose opioid induced acute and chronic analgesia

PubMed Central

Hutchinson, Mark R.; Coats, Benjamen D.; Lewis, Susannah S.; Zhang, Yingning; Sprunger, David B.; Rezvani, Niloofar; Baker, Eric M.; Jekich, Brian M.; Wieseler, Julie L.; Somogyi, Andrew A.; Martin, David; Poole, Stephen; Judd, Charles M.; Maier, Steven F.; Watkins, Linda R.

2008-01-01

Spinal proinflammatory cytokines are powerful pain-enhancing signals that contribute to pain following peripheral nerve injury (neuropathic pain). Recently, one proinflammatory cytokine, interleukin-1, was also implicated in the loss of analgesia upon repeated morphine exposure (tolerance). In contrast to prior literature, we demonstrate that the action of several spinal proinflammatory cytokines oppose systemic and intrathecal opioid analgesia, causing reduced pain suppression. In vitro morphine exposure of lumbar dorsal spinal cord caused significant increases in proinflammatory cytokine and chemokine release. Opposition of analgesia by proinflammatory cytokines is rapid, occurring ≤5 minutes after intrathecal (perispinal) opioid administration. We document that opposition of analgesia by proinflammatory cytokines cannot be accounted for by an alteration in spinal morphine concentrations. The acute anti-analgesic effects of proinflammatory cytokines occur in a p38 mitogen-activated protein kinase and nitric oxide dependent fashion. Chronic intrathecal morphine or methadone significantly increased spinal glial activation (toll-like receptor 4 mRNA and protein) and the expression of multiple chemokines and cytokines, combined with development of analgesic tolerance and pain enhancement (hyperalgesia, allodynia). Statistical analysis demonstrated that a cluster of cytokines and chemokines was linked with pain-related behavioral changes. Moreover, blockade of spinal proinflammatory cytokines during a stringent morphine regimen previously associated with altered neuronal function also attenuated enhanced pain, supportive that proinflammatory cytokines are importantly involved in tolerance induced by such regimens. These data implicate multiple opioid-induced spinal proinflammatory cytokines in opposing both acute and chronic opioid analgesia, and provide a novel mechanism for the opposition of acute opioid analgesia. PMID:18599265

Repeated Administration of Cigarette Smoke Condensate Increases Glutamate Levels and Behavioral Sensitization

PubMed Central

Ryu, In Soo; Kim, Jieun; Seo, Su Yeon; Yang, Ju Hwan; Oh, Jeong Hwan; Lee, Dong Kun; Cho, Hyun-Wook; Lee, Kyuhong; Yoon, Seong Shoon; Seo, Joung-Wook; Shim, Insop; Choe, Eun Sang

2018-01-01

Nicotine, a nicotinic acetylcholine receptor agonist, produces the reinforcing effects of tobacco dependence by potentiating dopaminergic and glutamatergic neurotransmission. Non-nicotine alkaloids in tobacco also contribute to dependence by activating the cholinergic system. However, glutamatergic neurotransmission in the dorsal striatum associated with behavioral changes in response to cigarette smoking has not been investigated. In this study, the authors investigated alterations in glutamate levels in the rat dorsal striatum related to behavioral alterations after repeated administration of cigarette smoke condensate (CSC) using the real-time glutamate biosensing and an open-field behavioral assessment. Repeated administration of CSC including 0.4 mg nicotine (1.0 mL/kg/day, subcutaneous) for 14 days significantly increased extracellular glutamate concentrations more than repeated nicotine administration. In parallel with the hyperactivation of glutamate levels, repeated administration of CSC-evoked prolonged hypersensitization of psychomotor activity, including locomotor and rearing activities. These findings suggest that the CSC-induced psychomotor activities are closely associated with the elevation of glutamate concentrations in the rat dorsal striatum. PMID:29615877

EFFECT OF SINGLE AND REPEATED TETRACYCLINE ADMINISTRATION ON THE PHAGOCYTIC FUNCTION OF RETICULENDOTHELIAL SYSTEMS

DTIC Science & Technology

It was previously established that single administration of chlortetracycline and oxytetracycline to white mice stimulates the absorptive function of...upon repeated administration. The effect of single and repeated administration of chlortetracycline, tetracycline, and oxytetracycline on the absorptive function of mouse RES were studied.

Acute and repeated activation of male sexual behavior by tail pinch: opioid and dopaminergic mechanisms.

PubMed

Leyton, M; Stewart, J

1996-07-01

We studied the effect of tail pinch on male sexual behavior and its neurochemical basis. Male rats were gonadectomized and maintained on low doses of testosterone propionate (20.0 micrograms/day). Tail pinch significantly increased the percentage of males that mounted, intromitted, and ejaculated within a 30-min test, and these increases were attenuated by both pimozide (1.0 mg/kg, i.p.) and by naloxone (0.5, 1.0, and 2.0 mg/kg, s.c.). Moreover, tail pinch in the presence of an estrous female led to significantly increased female-directed behavior 48 h later during a test without tail pinch. Repeated tail pinch tests led to progressively more sexual activity, and the development of this behavioral sensitization was prevented by naloxone. These findings suggest that tail pinch increases the salience of the incentive characteristics of the female. Furthermore, during subsequent tests, with or without tail pinch, the increased salience of the female remains, as measured by the continued increases in sexual activity. These acute and sensitized behavioral increases might result from tail pinch-induced activation of the midbrain dopamine system via an opioid mechanism; either preventing tail pinch-induced dopamine activation (by an opioid antagonist) or blocking the effects of dopamine activation (by a dopamine antagonist) attenuated the long-term facilitation of sexual behavior seen after pairing the female with tail pinch.

Tolerance develops to the antiallodynic effects of the peripherally acting opioid loperamide hydrochloride in nerve-injured rats

PubMed Central

He, Shao-Qiu; Yang, Fei; Perez, Federico M.; Xu, Qian; Shechter, Ronen; Cheong, Yong-Kwan; Carteret, Alene F.; Dong, Xinzhong; Sweitzer, Sarah M.; Raja, Srinivasa N.; Guan, Yun

2013-01-01

Peripherally acting opioids are potentially attractive drugs for the clinical management of certain chronic pain states due to the lack of centrally mediated adverse effects. However, it remains unclear whether tolerance develops to peripheral opioid analgesic effects under neuropathic pain conditions. We subjected rats to L5 spinal nerve ligation (SNL) and examined the analgesic effects of repetitive systemic and local administration of loperamide hydrochloride, a peripherally acting opioid agonist. We found that the inhibition of mechanical hypersensitivity, an important manifestation of neuropathic pain, by systemic loperamide (1.5 mg/kg subcutaneously) decreased after repetitive drug treatment (tolerance-inducing dose: 0.75 to 6.0 mg/kg subcutaneously). Similarly, repeated intraplantar injection of loperamide (150 µg/50 µL intraplantarly) and D-Ala2-MePhe4-Glyol5 enkephalin (300 µg/50 µL), a highly selective mu-opioid receptor (MOR) agonist, also resulted in decreased inhibition of mechanical hypersensitivity. Pretreatment with naltrexone hydrochloride (5 mg/kg intraperitoneally) and MK-801 (0.2 mg/kg intraperitoneally) attenuated systemic loperamide tolerance. Western blot analysis showed that repetitive systemic administration of morphine (3 mg/kg subcutaneously), but not loperamide (3 mg/kg subcutaneously) or saline, significantly increased MOR phosphorylation in the spinal cord of SNL rats. In cultured rat dorsal root ganglion neurons, loperamide dose-dependently inhibited KCl-induced increases in [Ca2+]i. However, this drug effect significantly decreased in cells pretreated with loperamide (3 µM, 72 hours). Intriguingly, in loperamide-tolerant cells, the delta-opioid receptor antagonist naltrindole restored loperamide’s inhibition of KCl-elicited [Ca2+]i increase. Our findings indicate that animals with neuropathic pain may develop acute tolerance to the antiallodynic effects of peripherally acting opioids after repetitive systemic and local drug

Assessing the impact of the extended-release/long-acting opioid an-algesics risk evaluation and mitigation strategies on opioid prescrip-tion volume.

PubMed

Divino, Victoria; Cepeda, M Soledad; Coplan, Paul; Maziere, Jean-Yves; Yuan, Yingli; Wade, Rolin L

The Food and Drug Administration approved the extended-release/long-acting (ER/LA) opioid analgesics risk evaluation and mitigation strategies (REMS) in July 2012 to educate healthcare providers and patients about safe and appropriate opioid analgesic use. The authors evaluated the impact of the REMS on ER/LA opioid analgesic utilization, overall and stratified by patient characteristics and prescriber type associated with greater expected need for analgesia. Retrospective repeated cross-sectional study. QuintilesIMS's National Prescription Audit™ and LifeLink™ patient-level longitudinal prescription databases measured prescription volumes, projected to national estimates. Changes were assessed in ER/LA opioid analgesic prescriptions dispensed from the 2-year pre-REMS implementation (July 2010 to June 2012) to the 18-month post-REMS implementation (July 2013 to December 2014) periods (with 12-month transitional implementation period in between). Average quarterly ER/LA opioid prescription volume significantly decreased by 4.3 percent from Preimple-mentation to the Active Period (5.58 vs 5.34 million, p < 0.001). Differences in prescription volume change were observed between age, gender, and payer types. Prescription volume either significantly decreased or remained stable from Preimplementation to the Active Period among most provider specialties evaluated. The largest volume decreases were observed for dentists (-48.5 percent) and emergency medicine specialists (-25.5 percent) (both p < 0.001). The largest increases were observed for nurse practitioners (+33.7 percent) and physician assistants (+31.2 percent; both p < 0.001), whose overall prescribing of nonopioid medications also increased. A significant decrease in dispensed ER/LA opioid prescriptions was observed following REMS implementation compared to Preimplementation. The impact on volume varied by patient characteristics and prescriber specialty. The REMS program, in conjunction with other healthcare

Timing of opioid administration as a quality indicator for pain crises in sickle cell disease.

PubMed

Mathias, Melissa D; McCavit, Timothy L

2015-03-01

Time to opioid administration (TTO) has been suggested as a quality of care measure for sickle cell disease patients with vaso-occlusive crisis (VOC). We sought to determine whether TTO was associated with outcomes of emergency department (ED) visits for VOC. We conducted a single-center retrospective cohort study of ED visits for VOC. The primary outcome was hospital admission, with secondary outcomes of change between the first 2 pain scores, area under the curve (AUC) for pain scores at 4 hours (pain score AUC), total ED length of stay, and total intravenous opioids. In both univariate and multivariate analyses, mixed regression (logistic for admission, linear for secondary outcome variables) was used to evaluate association of TTO with outcome. In 177 subjects, 414 ED visits for VOC were identified. Inpatient admission occurred in 53% of visits. The median TTO for admitted patients was 86 minutes vs 87 minutes for those not admitted. TTO was not associated with inpatient admission in either univariate or multivariate analyses. In multivariate analyses with secondary outcomes, decreased TTO was associated with greater improvement between the first 2 pain scores, decreased pain score AUC, decreased total ED length of stay, and increased total opioids. Although TTO was not associated with admission, it was independently associated with 4 important secondary outcomes: change in initial pain scores, pain score AUC, total ED length of stay, and total intravenous opioids. The association of a process measure, TTO, with these outcomes encourages the institution of TTO reduction efforts in the ED. Copyright © 2015 by the American Academy of Pediatrics.

Opioid Peptidomimetics: Leads for the Design of Bioavailable Mixed Efficacy Mu Opioid Receptor (MOR) Agonist/Delta Opioid Receptor (DOR) Antagonist Ligands

PubMed Central

Mosberg, Henry I.; Yeomans, Larisa; Harland, Aubrie A.; Bender, Aaron M.; Sobczyk-Kojiro, Katarzyna; Anand, Jessica P.; Clark, Mary J.; Jutkiewicz, Emily M.; Traynor, John R.

2013-01-01

We have previously described opioid peptidomimetic, 1, employing a tetrahydroquinoline scaffold and modeled on a series of cyclic tetrapeptide opioid agonists. We have recently described modifications to these peptides that confer a mu opioid receptor (MOR) agonist, delta opioid receptor (DOR) antagonist profile, which has been shown to reduce the development of tolerance to the analgesic actions of MOR agonists. Several such bifunctional ligands have been reported, but none has been demonstrated to cross the blood brain barrier. Here we describe the transfer of structural features that evoked MOR agonist/DOR antagonist behavior in the cyclic peptides to the tetrahydroquinoline scaffold and show that the resulting peptidomimetics maintain the desired pharmacological profile. Further, the 4R diastereomer of 1 was fully efficacious and approximately equipotent to morphine in the mouse warm water tail withdrawal assay following intraperitoneal administration and thus a promising lead for the development of opioid analgesics with reduced tolerance. PMID:23419026

US Food and Drug Administration's Risk Evaluation and Mitigation Strategy for extended-release and long-acting opioids: pros and cons, and a European perspective.

PubMed

Mercadante, Sebastiano; Craig, David; Giarratano, Antonello

2012-12-24

Prescriptions for opioid analgesics to manage moderate-to-severe chronic non-cancer pain have increased markedly over the last decade. An unintentional consequence of greater prescription opioid utilization has been the parallel increase in misuse, abuse and overdose, which are serious risks associated with all opioid analgesics. In response to disturbing rises in prescription opioid abuse, the US Food and Drug Administration (FDA) has proposed the implementation of aggressive Risk Evaluation and Mitigation Strategies (REMS). While REMS could dramatically change the development, release, marketing and prescription of extended-release opioids, questions remain on how these programmes may influence prescribing practices, patient safety and ultimately patient access to these agents. The extent of the availability and misuse of prescription opioids in Europe is difficult to assess from the data currently available, due in large part to the considerable differences in prescribing patterns and regulations between countries. Balancing the availability of prescription opioids for those patients who have pain, while discouraging illicit use, is a complex challenge and requires effective efforts on many levels, particularly in Europe where policies are quite different between countries.

Dependence and addiction during chronic opioid therapy.

PubMed

Juurlink, David N; Dhalla, Irfan A

2012-12-01

The use of opioids for chronic noncancer pain has increased dramatically over the past 25 years in North America and has been accompanied by a major increase in opioid addiction and overdose deaths. The increase in opioid prescribing is multifactorial and partly reflects concerns about the effectiveness and safety of alternative medications, particularly the nonsteroidal anti-inflammatory drugs. However, much of the rise in opioid prescribing reflects the assertion, widely communicated to physicians in the 1990s, that the risks of dependence and addiction during chronic opioid therapy were low, predictable, and could be minimized by the use of controlled-release opioid formulations. In this narrative review, we offer a critical appraisal of the publications most frequently cited as evidence that the risk of addiction during chronic opioid therapy is low. We conclude that very few well-designed studies support the notion that opioid addiction is rare during chronic opioid therapy and that none can be readily generalized to present-day practice. Despite serious methodological limitations, these studies have been repeatedly mischaracterized as showing that the risk of addiction during chronic opioid therapy is rare. These studies are countered by a larger, more rigorous and contemporary body of evidence demonstrating that dependence and addiction are relatively common consequences of chronic opioid therapy, occurring in up to one-third of patients in some series.

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.

Opioid dependence

PubMed Central

2011-01-01

Introduction Dependence on opioids is a multifactorial condition involving genetic and psychosocial factors. There are three stages to treating opioid dependence. Stabilisation is usually by opioid substitution treatments, and aims to ensure that the drug use becomes independent of mental state (such as craving and mood) and independent of circumstances (such as finance and physical location). The next stage is to withdraw (detox) from opioids. The final stage is relapse prevention. This treatment process contributes to recovery of the individual, which also includes improved overall health and wellbeing, as well as engagement in society. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for stabilisation (maintenance) in people with opioid dependence? What are the effects of drug treatments for withdrawal in people with opioid dependence? What are the effects of drug treatments for relapse prevention in people with opioid dependence? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 26 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review, we present information relating to the effectiveness and safety of the following interventions: buprenorphine; clonidine; lofexidine; methadone; naltrexone; and ultra-rapid withdrawal regimens. PMID:21929827

Opioid dependence.

PubMed

Praveen, K Thyarappa; Law, Fergus; O'Shea, Jacinta; Melichar, Jan

2011-09-20

Dependence on opioids is a multifactorial condition involving genetic and psychosocial factors. There are three stages to treating opioid dependence. Stabilisation is usually by opioid substitution treatments, and aims to ensure that the drug use becomes independent of mental state (such as craving and mood) and independent of circumstances (such as finance and physical location). The next stage is to withdraw (detox) from opioids. The final stage is relapse prevention. This treatment process contributes to recovery of the individual, which also includes improved overall health and wellbeing, as well as engagement in society. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for stabilisation (maintenance) in people with opioid dependence? What are the effects of drug treatments for withdrawal in people with opioid dependence? What are the effects of drug treatments for relapse prevention in people with opioid dependence? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 26 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review, we present information relating to the effectiveness and safety of the following interventions: buprenorphine; clonidine; lofexidine; methadone; naltrexone; and ultra-rapid withdrawal regimens.

Medication-Assisted Treatment For Opioid Addiction in Opioid Treatment Programs. Treatment Improvement Protocol (TIP) Series 43

ERIC Educational Resources Information Center

Tinkler, Emily; Vallejos Bartlett, Catalina; Brooks, Margaret; Gilbert, Johnatnan Max; Henderson, Randi; Shuman, Deborah, J.

2005-01-01

TIP 43 provides best-practice guidelines for medication-assisted treatment of opioid addiction in opioid treatment programs (OTPs). The primary intended audience for this volume is substance abuse treatment providers and administrators who work in OTPs. Recommendations in the TIP are based on both an analysis of current research and determinations…

Sensitivity and specificity of administrative mortality data for identifying prescription opioid-related deaths.

PubMed

Gladstone, Emilie; Smolina, Kate; Morgan, Steven G; Fernandes, Kimberly A; Martins, Diana; Gomes, Tara

2016-03-01

Comprehensive systems for surveilling prescription opioid-related harms provide clear evidence that deaths from prescription opioids have increased dramatically in the United States. However, these harms are not systematically monitored in Canada. In light of a growing public health crisis, accessible, nationwide data sources to examine prescription opioid-related harms in Canada are needed. We sought to examine the performance of 5 algorithms to identify prescription opioid-related deaths from vital statistics data against data abstracted from the Office of the Chief Coroner of Ontario as a gold standard. We identified all prescription opioid-related deaths from Ontario coroners' data that occurred between Jan. 31, 2003, and Dec. 31, 2010. We then used 5 different algorithms to identify prescription opioid-related deaths from vital statistics death data in 2010. We selected the algorithm with the highest sensitivity and a positive predictive value of more than 80% as the optimal algorithm for identifying prescription opioid-related deaths. Four of the 5 algorithms had positive predictive values of more than 80%. The algorithm with the highest sensitivity (75%) in 2010 improved slightly in its predictive performance from 2003 to 2010. In the absence of specific systems for monitoring prescription opioid-related deaths in Canada, readily available national vital statistics data can be used to study prescription opioid-related mortality with considerable accuracy. Despite some limitations, these data may facilitate the implementation of national surveillance and monitoring strategies. © 2016 Canadian Medical Association or its licensors.

Emerging therapies for patients with symptoms of opioid-induced bowel dysfunction

PubMed Central

Leppert, Wojciech

2015-01-01

Opioid-induced bowel dysfunction (OIBD) comprises gastrointestinal (GI) symptoms, including dry mouth, nausea, vomiting, gastric stasis, bloating, abdominal pain, and opioid-induced constipation, which significantly impair patients’ quality of life and may lead to undertreatment of pain. Traditional laxatives are often prescribed for OIBD symptoms, although they display limited efficacy and exert adverse effects. Other strategies include prokinetics and change of opioids or their administration route. However, these approaches do not address underlying causes of OIBD associated with opioid effects on mostly peripheral opioid receptors located in the GI tract. Targeted management of OIBD comprises purely peripherally acting opioid receptor antagonists and a combination of opioid receptor agonist and antagonist. Methylnaltrexone induces laxation in 50%–60% of patients with advanced diseases and OIBD who do not respond to traditional oral laxatives without inducing opioid withdrawal symptoms with similar response (45%–50%) after an oral administration of naloxegol. A combination of prolonged-release oxycodone with prolonged-release naloxone (OXN) in one tablet (a ratio of 2:1) provides analgesia with limited negative effect on the bowel function, as oxycodone displays high oral bioavailability and naloxone demonstrates local antagonist effect on opioid receptors in the GI tract and is totally inactivated in the liver. OXN in daily doses of up to 80 mg/40 mg provides equally effective analgesia with improved bowel function compared to oxycodone administered alone in patients with chronic non-malignant and cancer-related pain. OIBD is a common complication of long-term opioid therapy and may lead to quality of life deterioration and undertreatment of pain. Thus, a complex assessment and management that addresses underlying causes and patomechanisms of OIBD is recommended. Newer strategies comprise methylnaltrexone or OXN administration in the management of OIBD

Changes in Withdrawal and Craving Scores in Participants Undergoing Opioid Detoxification Utilizing Ibogaine.

PubMed

Malcolm, Benjamin J; Polanco, Martin; Barsuglia, Joseph P

2018-04-02

Opioid use disorder (OUD) is currently an epidemic in the United States (US) and ibogaine is reported to have the ability to interrupt opioid addiction by simultaneously mitigating withdrawal and craving symptoms. This study examined opioid withdrawal and drug craving scores in 50 participants with OUD undergoing a week-long detoxification treatment protocol with ibogaine. The Addiction Severity Index (ASI) was used for baseline characterization of participants' OUD. Clinical Opioid Withdrawal Scale (COWS), Subjective Opioid Withdrawal Scale (SOWS), and Brief Substance Craving Scale (BSCS) scores were collected at 48 and 24 hours prior to ibogaine administration, as well as 24 and 48 hours after ibogaine administration. At 48 hours following ibogaine administration, withdrawal and craving scores were significantly lowered in comparison to baseline: 78% of patients did not exhibit objective clinical signs of opioid withdrawal, 79% reported minimal cravings for opioids, and 68% reported subjective withdrawal symptoms in the mild range. Ibogaine appears to facilitate opioid detoxification by reducing opioid withdrawal and craving in participants with OUD. These results warrant further research using rigorous controlled trials.

[Treatment of pain in cancer with systemically administered opioids].

PubMed

Enting, R H; van der Rijt, C C; Wilms, E B; Lieverse, P J; de Wit, R; Smitt, P A

2001-05-19

The World Health Organization guidelines for cancer pain relief have been proven efficacious in 90% of the patients with cancer pain. The patient's self-report of pain is the focus of treatment. When initiating treatment, controlled-release preparations of opioids are generally favoured, and are combined with immediate release morphine to prevent or treat 'breakthrough' pain and to enable the optimum opioid dosage to be calculated. (Breakthrough pain is a transient increase in pain in a patient who has stable, persistent pain treated with opioids.) In patients with an unfavourable balance between analgesia and side effects, the following strategies may be useful, together with appropriate treatment of the side effects: Sequential opioid trials (so-called opioid rotation) is an approach which is effective in 50-70% of the patients. Changing the route of opioid administration is successful in 70-95% of the patients. When selecting an invasive technique, continuous subcutaneous infusion is medically preferred. Spinal analgesia is an alternative. Knowledge of the relative potency of opioid drugs and of their biologic availability is needed to guide changes in drugs or routes of administration.

Social Stress Engages Opioid Regulation of Locus Coeruleus Norepinephrine Neurons and Induces a State of Cellular and Physical Opiate Dependence

PubMed Central

Chaijale, Nayla N; Curtis, Andre L; Wood, Susan K; Zhang, Xiao-Yan; Bhatnagar, Seema; Reyes, Beverly AS; Van Bockstaele, Elisabeth J; Valentino, Rita J

2013-01-01

Stress is implicated in diverse psychiatric disorders including substance abuse. The locus coeruleus–norepinephrine (LC–NE) system is a major stress response system that is also a point of intersection between stress neuromediators and endogenous opioids and so may be a site at which stress can influence drug-taking behaviors. As social stress is a common stressor for humans, this study characterized the enduring impact of repeated social stress on LC neuronal activity. Rats were exposed to five daily consecutive sessions of social stress using the resident-intruder model or control manipulation. LC discharge rate recorded 2 days after the last manipulation was decreased in stressed rats compared with controls. By 10 days after the last manipulation, LC rates were comparable between groups. Systemic administration of the opiate antagonist, naloxone, robustly increased LC discharge rate in a manner suggestive of opiate withdrawal, selectively in stressed rats when administered 2 or 10 days after the last manipulation. This was accompanied by behavioral signs of mild opiate withdrawal. Western blot and electron microscopic studies indicated that repeated social stress decreased corticotropin-releasing factor type 1 receptor and increased μ-opioid receptor levels in the LC. Together, the results suggest that repeated social stress engages endogenous opioid modulation of LC activity and induces signs of cellular and physical opiate dependence that endure after the stress. These cellular effects may predispose individuals with a history of repeated social stress to substance abuse behaviors. PMID:23660707

Social stress engages opioid regulation of locus coeruleus norepinephrine neurons and induces a state of cellular and physical opiate dependence.

PubMed

Chaijale, Nayla N; Curtis, Andre L; Wood, Susan K; Zhang, Xiao-Yan; Bhatnagar, Seema; Reyes, Beverly As; Van Bockstaele, Elisabeth J; Valentino, Rita J

2013-09-01

Stress is implicated in diverse psychiatric disorders including substance abuse. The locus coeruleus-norepinephrine (LC-NE) system is a major stress response system that is also a point of intersection between stress neuromediators and endogenous opioids and so may be a site at which stress can influence drug-taking behaviors. As social stress is a common stressor for humans, this study characterized the enduring impact of repeated social stress on LC neuronal activity. Rats were exposed to five daily consecutive sessions of social stress using the resident-intruder model or control manipulation. LC discharge rate recorded 2 days after the last manipulation was decreased in stressed rats compared with controls. By 10 days after the last manipulation, LC rates were comparable between groups. Systemic administration of the opiate antagonist, naloxone, robustly increased LC discharge rate in a manner suggestive of opiate withdrawal, selectively in stressed rats when administered 2 or 10 days after the last manipulation. This was accompanied by behavioral signs of mild opiate withdrawal. Western blot and electron microscopic studies indicated that repeated social stress decreased corticotropin-releasing factor type 1 receptor and increased μ-opioid receptor levels in the LC. Together, the results suggest that repeated social stress engages endogenous opioid modulation of LC activity and induces signs of cellular and physical opiate dependence that endure after the stress. These cellular effects may predispose individuals with a history of repeated social stress to substance abuse behaviors.

Opioids, pain, the brain, and hyperkatifeia: a framework for the rational use of opioids for pain.

PubMed

Shurman, Joseph; Koob, George F; Gutstein, Howard B

2010-07-01

Opioids have relieved more human suffering than any other medication, but their use is still fraught with significant concerns of misuse, abuse, and addiction. This theoretical article explores the hypothesis that opioid misuse in the context of pain management produces a hypersensitivity to emotional distress, termed hyperkatifeia. In the misuse of opioids, neural substrates that mediate positive emotional states (brain reward systems) are compromised, and substrates mediating negative emotional states (brain stress systems) are enhanced. A reflection and early marker of such a nonhomeostatic state may be the development of opioid-induced hyperkatifeia, defined as the increased intensity of the constellation of negative emotional/motivational symptoms and signs observed during withdrawal from drugs of abuse (derived from the Greek "katifeia" for dejection or negative emotional state) and is most likely to occur in subjects in whom the opioid produces a break with homeostasis and less likely to occur when the opioid is restoring homeostasis, such as in effective pain treatment. When the opioid appropriately relieves pain, opponent processes are not engaged. However, if the opioid is administered in excess of need because of overdose, pharmacokinetic variables, or treating an individual without pain, then the body will react to that perturbation by engaging opponent processes in the domains of both pain (hyperalgesia) and negative emotional states (hyperkatifeia). Repeated engagement of opponent processes without time for the brain's emotional systems to reestablish homeostasis will further drive changes in emotional processes that may produce opioid abuse or addiction, particularly in individuals with genetic or environmental vulnerability.

The human mu opioid receptor: modulation of functional desensitization by calcium/calmodulin-dependent protein kinase and protein kinase C.

PubMed

Mestek, A; Hurley, J H; Bye, L S; Campbell, A D; Chen, Y; Tian, M; Liu, J; Schulman, H; Yu, L

1995-03-01

Opioids are some of the most efficacious analgesics used in humans. Prolonged administration of opioids, however, often causes the development of drug tolerance, thus limiting their effectiveness. To explore the molecular basis of those mechanisms that may contribute to opioid tolerance, we have isolated a cDNA for the human mu opioid receptor, the target of such opioid narcotics as morphine, codeine, methadone, and fentanyl. The receptor encoded by this cDNA is 400 amino acids long with 94% sequence similarity to the rat mu opioid receptor. Transient expression of this cDNA in COS-7 cells produced high-affinity binding sites to mu-selective agonists and antagonists. This receptor displays functional coupling to a recently cloned G-protein-activated K+ channel. When both proteins were expressed in Xenopus oocytes, functional desensitization developed upon repeated stimulation of the mu opioid receptor, as observed by a reduction in K+ current induced by the second mu receptor activation relative to that induced by the first. The extent of desensitization was potentiated by both the multifunctional calcium/calmodulin-dependent protein kinase and protein kinase C. These results demonstrate that kinase modulation is a molecular mechanism by which the desensitization of mu receptor signaling may be regulated at the cellular level, suggesting that this cellular mechanism may contribute to opioid tolerance in humans.

Dual-opioid therapy: changing the paradigm. Introduction.

PubMed

Nicholson, Bruce D

2012-03-01

Morphine sulfate and oxycodone hydrochloride are commonly used for pain management because of their pharmacologic profile, pharmacokinetics, and analgesic potency. However, opioids are associated with a significant adverse event (AE) burden that limits their use in both the acute and the chronic pain settings. Co-administration of opioids demonstrated synergistic analgesia and reduced side effects. Thus, dual-opioid therapy has the potential to enhance the positive analgesic benefits of opioids, while limiting the burden of opioid-related AEs. This symposium proceedings was based on presentations at the 13th World Congress on Pain in August 2010. This program will review the rationale for dual-opioid therapy based on preclinical findings and data from clinical studies showing the efficacy and tolerability profile of a dual-opioid formulation when used to treat acute postoperative pain. Wiley Periodicals, Inc.

Daily morphine administration increases impulsivity in rats responding under a 5‐choice serial reaction time task

PubMed Central

Maguire, DR; Henson, C

2016-01-01

Background and Purpose Repeated administration of a μ opioid receptor agonist can enhance some forms of impulsivity, such as delay discounting. However, it is unclear whether repeated administration alters motor impulsivity. Experimental Approach We examined the effects of acute administration of morphine and amphetamine prior to and during daily morphine administration in rats responding under a five‐choice serial reaction time task. Rats (n = 5) were trained to detect a brief flash of light presented randomly in one of five response holes; responding in the target hole delivered food, whereas responding in the wrong hole or responding prior to illumination of the target stimulus (premature response) initiated a timeout. Premature responding served as an index of motor impulsivity. Key Results Administered acutely, morphine (0.1–10 mg·kg−1, i.p.) increased omissions and modestly, although not significantly, premature responding without affecting response accuracy; amphetamine (0.1–1.78 mg·kg−1, i.p.) increased premature responding without changing omissions or response accuracy. After 3 weeks of 10 mg·kg−1·day−1 morphine, tolerance developed to its effects on omissions whereas premature responding increased approximately fourfold, compared with baseline. Effects of amphetamine were not significantly affected by daily morphine administration. Conclusions and Implications These data suggest that repeated administration of morphine increased effects of morphine on motor impulsivity, although tolerance developed to other effects, such as omissions. To the extent that impulsivity is a risk factor for drug abuse, repeated administration of μ opioid receptor agonists, for recreational or therapeutic purposes, might increase impulsivity and thus the risk for drug abuse. PMID:26776751

Understanding opioid overdose characteristics involving prescription and illicit opioids: A mixed methods analysis.

PubMed

Yarborough, Bobbi Jo H; Stumbo, Scott P; Janoff, Shannon L; Yarborough, Micah T; McCarty, Dennis; Chilcoat, Howard D; Coplan, Paul M; Green, Carla A

2016-10-01

Opioid abuse and misuse are significant public health issues. The CDC estimated 72% of pharmaceutical-related overdose deaths in the US in 2012 involved opioids. While studies of opioid overdoses have identified sociodemographic characteristics, agents used, administration routes, and medication sources associated with overdoses, we know less about the context and life circumstances of the people who experience these events. We analyzed interviews (n=87) with survivors of opioid overdoses or family members of decedents. Individuals experiencing overdoses were members of a large integrated health system. Using ICD codes for opioid overdoses and poisonings, we identified participants from five purposefully derived pools of health-plan members who had: 1) prescriptions for OxyContin(®) or single-ingredient sustained-release oxycodone, 2) oxycodone single-ingredient immediate release, 3) other long-acting opioids, 4) other short-acting opioids, or 5) no active opioid prescriptions. Individuals who experienced opioid overdoses abused and misused multiple medications/drugs; experienced dose-related miscommunications or medication-taking errors; had mental health and/or substance use conditions; reported chronic pain; or had unstable resources or family/social support. Many had combinations of these risks. Most events involved polysubstance use, often including benzodiazepines. Accidental overdoses were commonly the result of abuse or misuse, some in response to inadequately treated chronic pain or, less commonly, medication-related mistakes. Suicide attempts were frequently triggered by consecutive negative life events. To identify people at greater risk of opioid overdose, efforts should focus on screening for prescribed and illicit polysubstance use, impaired cognition, and changes in life circumstances, psychosocial risks/supports, and pain control. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Endogenous opioid systems: physiological role in the self-limitation of seizures.

PubMed

Tortella, F C; Long, J B; Holaday, J W

1985-04-15

Immediately following a seizure, the severity of subsequent seizures is significantly reduced. The involvement of endogenous opioid systems as a physiological regulator of this postseizure inhibition was studied in rats using repeated maximal electroshock (MES) seizures. Both the opiate antagonist (-)-naloxone and morphine tolerance abolished the progressive seizure protection associated with repeated MES. We propose that endogenous opioids, activated by a prior seizure, provide a central homeostatic inhibitory mechanism which may be responsible for the initiation of a postictal refractory state in the epileptic.

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.

Neuraxial Opioid-Induced Itch and Its Pharmacological Antagonism

PubMed Central

2015-01-01

Given its profound analgesic nature, neuraxial opioids are frequently used for pain management. Unfortunately, the high incident rate of itch/pruritus after spinal administration of opioid analgesics reported in postoperative and obstetric patients greatly diminishes patient satisfaction and thus the value of the analgesics. Many endeavors to solve the mystery behind neuraxial opioid-induced itch had not been successful, as the pharmacological antagonism other than the blockade of mu opioid receptors remains elusive. Nevertheless, as the characteristics of all opioid receptor subtypes have become more understood, more studies have shed light on the potential effective treatments. This review discusses the mechanisms underlying neuraxial opioid-induced itch and compares pharmacological evidence in nonhuman primates with clinical findings across diverse drugs. Both nonhuman primate and human studies corroborate that mixed mu/kappa opioid partial agonists seem to be the most effective drugs in ameliorating neuraxial opioid-induced itch while retaining neuraxial opioid-induced analgesia. PMID:25861787

Intrathecal opioids versus epidural local anesthetics for labor analgesia: a meta-analysis.

PubMed

Bucklin, Brenda A; Chestnut, David H; Hawkins, Joy L

2002-01-01

Some anesthesiologists contend that intrathecal opioid administration has advantages over conventional epidural techniques during labor. Randomized clinical trials comparing analgesia and obstetric outcome using single-injection intrathecal opioids versus epidural local anesthetics suggest that intrathecal opioids provide comparable analgesia with few serious side effects. This meta-analysis compared the analgesic efficacy, side effects, and obstetric outcome of single-injection intrathecal opioid techniques versus epidural local anesthetics in laboring women. Relevant clinical studies were identified using electronic and manual searches of the literature covering the period from 1989 to 2000. Searches used the following descriptors: intrathecal analgesia, spinal opioids, epidural analgesia, epidural local anesthetics, and analgesia for labor. Data were extracted from 7 randomized clinical trials comparing analgesic measures, incidence of motor block, pruritus, nausea, hypotension, mode of delivery, and/or Apgar scores. Combined test results indicated comparable analgesic efficacy 15 to 20 minutes after injection with single-injection intrathecal opioid administration. Intrathecal opioid injections were associated with a greater incidence of pruritus (odds ratio, 14.01; 99% confidence interval, 6.9 to 28.3), but there was no difference in the incidence of nausea or in the method of delivery. Published studies suggest that intrathecal opioids provide comparable early labor analgesia when compared with epidural local anesthetics. Intrathecal opioid administration results in a greater incidence of pruritus. The choice of technique does not appear to affect the method of delivery.

Opioid doses required for pain management in lung cancer patients with different cholesterol levels: negative correlation between opioid doses and cholesterol levels.

PubMed

Huang, Zhenhua; Liang, Lining; Li, Lingyu; Xu, Miao; Li, Xiang; Sun, Hao; He, Songwei; Lin, Lilong; Zhang, Yixin; Song, Yancheng; Yang, Man; Luo, Yuling; Loh, Horace H; Law, Ping-Yee; Zheng, Dayong; Zheng, Hui

2016-03-08

Pain management has been considered as significant contributor to broad quality-of-life improvement for cancer patients. Modulating serum cholesterol levels affects analgesia abilities of opioids, important pain killer for cancer patients, in mice system. Thus the correlation between opioids usages and cholesterol levels were investigated in human patients with lung cancer. Medical records of 282 patients were selected with following criteria, 1) signed inform consent, 2) full medical records on total serum cholesterol levels and opioid administration, 3) opioid-naïve, 4) not received/receiving cancer-related or cholesterol lowering treatment, 5) pain level at level 5-8. The patients were divided into different groups basing on their gender and cholesterol levels. Since different opioids, morphine, oxycodone, and fentanyl, were all administrated at fixed low dose initially and increased gradually only if pain was not controlled, the percentages of patients in each group who did not respond to the initial doses of opioids and required higher doses for pain management were determined and compared. Patients with relative low cholesterol levels have larger percentage (11 out of 28 in female and 31 out of 71 in male) to not respond to the initial dose of opioids than those with high cholesterol levels (0 out of 258 in female and 8 out of 74 in male). Similar differences were obtained when patients with different opioids were analyzed separately. After converting the doses of different opioids to equivalent doses of oxycodone, significant correlation between opioid usages and cholesterol levels was also observed. Therefore, more attention should be taken to those cancer patients with low cholesterol levels because they may require higher doses of opioids as pain killer.

Role of mu, but not delta or kappa, opioid receptors in context-induced reinstatement of oxycodone seeking.

PubMed

Bossert, Jennifer M; Hoots, Jennifer K; Fredriksson, Ida; Adhikary, Sweta; Zhang, Michelle; Venniro, Marco; Shaham, Yavin

2018-05-19

Relapse to nonmedical use of prescription opioids often occurs after exposure to places previously associated with drug use. Here, we describe a rat model of context-induced reinstatement of oxycodone seeking after repeated cycles of drug self-administration and extinction-induced abstinence. We also determined the role of mu, delta, and kappa opioid receptors (MOR, DOR, KOR) in this reinstatement. We trained rats to self-administer oxycodone for 6 h/d in Context A; lever pressing was paired with a discrete cue. Next, we extinguished the lever pressing in the presence of the discrete cue in Context B and then tested the rats for reinstatement of oxycodone seeking in both contexts. We retrained rats to self-administer oxycodone in Context A, re-extinguished their lever pressing in Context B, and retested them for reinstatement in both contexts. Prior to testing, we injected the rats with vehicle or antagonists of MOR (naltrexone; 0.5 or 1.0 mg/kg), DOR (naltrindole; 7.5 or 15 mg/kg), or KOR (LY2456302; 5 or 10 mg/kg). We also tested the effect of naltrexone, naltrindole, and LY2456302 on oxycodone self-administration under fixed-ratio-1 (FR1) and progressive-ratio (PR) reinforcement schedules. We observed context-induced reinstatement of oxycodone seeking after repeated cycles of drug self-administration and extinction. Naltrexone, but not naltrindole or LY2456302, injections decreased this reinstatement. Additionally, naltrexone increased oxycodone self-administration under the FR1 schedule and decreased oxycodone self-administration under the PR schedule; naltrindole and LY2456302 were ineffective. Results demonstrate a critical role of MOR, but not DOR or KOR, in context-induced reinstatement of oxycodone seeking and oxycodone self-administration. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Effectiveness of ketamine as an adjuvant to opioid-based therapy in decreasing pain associated with opioid tolerance in adults undergoing orthopedic surgery: a systematic review protocol.

PubMed

Bennett, Marsha; Bonanno, Laura; Kuhn, William

2016-10-01

The objective of this systematic review is to examine the best available evidence on the clinical effectiveness of ketamine as an adjuvant to opioid-based therapy versus opioid-based therapy alone in decreasing perioperative pain associated with opioid tolerance in adult patients, aged 18-70 years, undergoing orthopedic surgical procedures.The following question guides the systematic review: does the administration of ketamine as an adjuvant to opioid-based therapy, compared to opioid-based therapy alone, improve perioperative pain relief in opioid-tolerant adult patients undergoing orthopedic surgical procedures?

Effects of Repeated Morphine on Intracranial Self-Stimulation in Male Rats In the Absence or Presence of a Noxious Pain Stimulus

PubMed Central

Miller, Laurence L.; Altarifi, Ahmad A.; Negus, S. Stevens

2015-01-01

Research on opioid analgesics such as morphine suggests that expression of abuse-related effects increases with repeated exposure. Repeated exposure to opioids often occurs clinically in the context of pain management, and a major concern for clinicians is the risk of iatrogenic addiction and dependence in patients receiving opioids for treatment of pain. This study compared abuse-related morphine effects in male rats in an intracranial self-stimulation (ICSS) procedure after repeated treatment either with morphine alone or with morphine in combination with a repeated noxious stimulus (intraperitoneal administration of dilute acid). The study also permitted comparison of morphine potency and effectiveness to block acid-induced depression of ICSS (antinociception) and to produce enhanced facilitation of ICSS (abuse-related effect). There were three main findings. First, initial morphine exposure to drug naïve rats did not produce abuse-related ICSS facilitation. Second, repeated daily treatment with 3.2 mg/kg/day morphine for six days increased expression of ICSS facilitation. This occurred whether morphine was administered in the absence or presence of the noxious stimulus. Finally, a lower dose of 1.0 mg/kg/day morphine was sufficient to produce antinociception during repeated acid treatment, but this lower dose did not reliably increase abuse-related morphine effects. Taken together, these results suggest that prior morphine exposure can increase abuse liability of subsequent morphine treatments even when that morphine exposure occurs in the context of a pain state. However, it may be possible to relieve pain with relatively low morphine doses that do not produce increases in abuse-related morphine effects. PMID:26375515

Opioid Analgesics Administered for Pain in the Inpatient Pediatric Setting.

PubMed

Walco, Gary A; Gove, Nancy; Phillips, Jennifer; Weisman, Steven J

2017-10-01

This study aimed to describe utilization of opioid medications among infants, children, and adolescents on the inpatient setting. These data are needed to guide clinical trials and improve research methodologies, as well as to inform more about possible sources of opioid misuse in the United States. A retrospective chart review was conducted covering a span of 1 year, with a special focus on the prescription of opioids for long-term treatment of chronic pain. Opioid medications were prescribed for <5 days in most (75%) patients. Among those who were prescribed opioids for >14 days, the focus was often for reasons other than pain. These data indicate that models of chronic pain that may be utilized in clinical trials of longer-term opioid usage in pediatrics are exceedingly limited. In addition, the patterns of utilization indicate that opioid administration among pediatric inpatients is not a likely contributory factor to concerns about opioid misuse in the United States. This article presents data on the administration of opioids in a major children's hospital, with a special eye toward usage beyond treatment for short-term acute pain. These data are important to better inform discussions of research strategies for chronic pain, as well as concerns for misuse in the pediatric population. Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.

Remifentanil-acute opioid tolerance and opioid-induced hyperalgesia: a systematic review.

PubMed

Kim, Sang Hun; Stoicea, Nicoleta; Soghomonyan, Suren; Bergese, Sergio D

2015-01-01

The use of opioids may seem to be a double-edged sword; they provide straight analgesic and antihyperalgesic effects initially, but subsequently are associated with the expression of acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH) that have been reported in experimental studies and clinical observations. It has been suggested that opioids can induce an acute tolerance and hyperalgesia in dose- and/or time-dependent manners even when used within the clinically accepted doses. Recently, remifentanil has been used for pain management in clinical anesthesia and in the intensive care units because of its rapid onset and offset. We reviewed articles analyzing AOT and/or OIH by remifentanil and focused on the following issues: (1) evidence of remifentanil inducing AOT and/or OIH and (2) importance of AOT and/or OIH in considering the reduction of remifentanil dosage or adopting preventive modulations. Twenty-four experimental and clinical studies were identified using electronic searches of MEDLINE (PubMed, Ovid, Springer, and Elsevier). However, the development of AOT and OIH by remifentanil administration remains controversial. There is no sufficient evidence to support or refute the existence of OIH in humans.

Parenteral opioids for maternal pain management in labour

PubMed Central

Ullman, Roz; Smith, Lesley A; Burns, Ethel; Mori, Rintaro; Dowswell, Therese

2014-01-01

Background Parenteral opioids are used for pain relief in labour in many countries throughout the world. Objectives To assess the acceptability, effectiveness and safety of different types, doses and modes of administration of parenteral opioids given to women in labour. Search methods We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (30 April 2011) and reference lists of retrieved studies. Selection criteria We included randomised controlled trials examining the use of intramuscular or intravenous opioids (including patient controlled analgesia) for women in labour. We looked at studies comparing an opioid with another opioid, placebo, other non-pharmacological interventions (TENS) or inhaled analgesia. Data collection and analysis At least two review authors independently assessed study eligibility, collected data and assessed risk of bias. Main results We included 57 studies involving more than 7000 women that compared an opioid with placebo, another opioid administered intramuscularly or intravenously or compared with TENS to the back. The 57 studies reported on 29 different comparisons, and for many outcomes only one study contributed data. Overall, the evidence was of poor quality regarding the analgesic effect of opioids, satisfaction with analgesia, adverse effects and harm to women and babies. There were few statistically significant results. Many of the studies had small sample sizes, and low statistical power. Overall findings indicated that parenteral opioids provided some pain relief and moderate satisfaction with analgesia in labour, although up to two-thirds of women who received opioids reported moderate or severe pain and/or poor or moderate pain relief one or two hours after administration. Opioid drugs were associated with maternal nausea, vomiting and drowsiness, although different opioid drugs were associated with different adverse effects. There was no clear evidence of adverse effects of opioids on the newborn. We

Lorcaserin Suppresses Oxycodone Self-Administration and Relapse Vulnerability in Rats.

PubMed

Neelakantan, Harshini; Holliday, Erica D; Fox, Robert G; Stutz, Sonja J; Comer, Sandra D; Haney, Margaret; Anastasio, Noelle C; Moeller, F Gerard; Cunningham, Kathryn A

2017-05-17

Opioid use disorder (OUD) is a major public health problem. High relapse rates and poor treatment retention continue to pose major challenges in OUD treatment. Of the abused opioids, oxycodone is well described to maintain self-administration and evoke the durable conditioned responses ("cue reactivity") that result from pairing of opioid-related stimuli (e.g., paraphernalia) with repeated abuse. Serotonin (5-HT) neurotransmission, particularly through the 5-HT 2C receptor (5-HT 2C R), regulates psychostimulant reward and cue reactivity, and in the present experiments, we investigated the hypothesis that the selective 5-HT 2C R agonist lorcaserin, which is approved by the United States Food and Drug Administration (FDA) for the treatment of obesity, will suppress oxycodone self-administration and oxycodone-associated cue reactivity in rats. We found that lorcaserin inhibited oxycodone intake, an effect blocked by the selective 5-HT 2C R antagonist SB242084. Lorcaserin also decreased responding for the discrete cue complex ("cue reactivity") previously associated with delivery of oxycodone (i.e., stimulus lights, infusion pump sounds) in both abstinence and extinction-reinstatement models. The selected dose range of lorcaserin (0.25-1 mg/kg) does not overtly alter spontaneous behaviors nor operant responding on inactive levers in the present study. Taken together, the ability of lorcaserin to reduce the oxycodone self-administration and decrease cue reactivity associated with relapse highlights the therapeutic potential for lorcaserin in the treatment of OUD.

The macrocyclic tetrapeptide [D-Trp]CJ-15,208 produces short-acting κ opioid receptor antagonism in the CNS after oral administration

PubMed Central

Eans, Shainnel O; Ganno, Michelle L; Reilley, Kate J; Patkar, Kshitij A; Senadheera, Sanjeewa N; Aldrich, Jane V; McLaughlin, Jay P

2013-01-01

Background and Purpose Cyclic peptides are resistant to proteolytic cleavage, therefore potentially exhibiting activity after systemic administration. We hypothesized that the macrocyclic κ opioid receptor (KOR)-selective antagonist [D-Trp]CJ-15,208 would demonstrate antagonist activity after systemic, that is, s.c. and oral (per os, p. o.), administration. Experimental Approach C57BL/6J mice were pretreated with [D-Trp]CJ-15,208 s.c. or p.o. before administration of the KOR-selective agonist U50,488 and the determination of antinociception in the warm-water tail-withdrawal assay. The locomotor activity of mice treated with [D-Trp]CJ-15,208 was determined by rotorod testing. Additional mice demonstrating cocaine conditioned place preference and subsequent extinction were pretreated daily with vehicle or [D-Trp]CJ-15,208 and then exposed to repeated forced swim stress or a single additional session of cocaine place conditioning before redetermining place preference. Key Results Pretreatment with [D-Trp]CJ-15,208 administered s.c. or p.o. dose-dependently antagonized the antinociception induced by i.p. administration of U50,488 in mice tested in the warm-water tail-withdrawal assay for less than 12 and 6 h respectively. [D-Trp]CJ-15,208 also produced limited (<25%), short-duration antinociception mediated through KOR agonism. Orally administered [D-Trp]CJ-15,208 dose-dependently antagonized centrally administered U50,488-induced antinociception, and prevented stress-, but not cocaine-induced, reinstatement of extinguished cocaine-seeking behaviour, consistent with its KOR antagonist activity, without affecting locomotor activity. Conclusions and Implications The macrocyclic tetrapeptide [D-Trp]CJ-15,208 is a short-duration KOR antagonist with weak KOR agonist activity that is active after oral administration and demonstrates blood–brain barrier permeability. These data validate the use of systemically active peptides such as [D-Trp]CJ-15,208 as potentially useful

Women who abuse prescription opioids: findings from the Addiction Severity Index-Multimedia Version Connect prescription opioid database.

PubMed

Green, Traci C; Grimes Serrano, Jill M; Licari, Andrea; Budman, Simon H; Butler, Stephen F

2009-07-01

Evidence suggests gender differences in abuse of prescription opioids. This study aimed to describe characteristics of women who abuse prescription opioids in a treatment-seeking sample and to contrast gender differences among prescription opioid abusers. Data collected November 2005 to April 2008 derived from the Addiction Severity Index Multimedia Version Connect (ASI-MV Connect) database. Bivariate and multivariable logistic regression examined correlates of prescription opioid abuse stratified by gender. 29,906 assessments from 220 treatment centers were included, of which 12.8% (N=3821) reported past month prescription opioid abuse. Women were more likely than men to report use of any prescription opioid (29.8% females vs. 21.1% males, p<0.001) and abuse of any prescription opioid (15.4% females vs. 11.1% males, p<0.001) in the past month. Route of administration and source of prescription opioids displayed gender-specific tendencies. Women-specific correlates of recent prescription opioid abuse were problem drinking, age <54, inhalant use, residence outside of West US Census region, and history of drug overdose. Men-specific correlates were age <34, currently living with their children, residence in the South and Midwest, hallucinogen use, and recent depression. Women prescription opioid abusers were less likely to report a pain problem although they were more likely to report medical problems than women who abused other drugs. Gender-specific factors should be taken into account in efforts to screen and identify those at highest risk of prescription opioid abuse. Prevention and intervention efforts with a gender-specific approach are warranted.

Respiratory depression in the intoxicated trauma patient: are opioids to blame?

PubMed

Shenk, Eleni; Barton, Cassie A; Mah, Nathan D; Ran, Ran; Hendrickson, Robert G; Watters, Jennifer

2016-02-01

Providing effective pain management to acutely intoxicated trauma patients represents a challenge of balancing appropriate pain management with the risk of potential respiratory depression from opioid administration. The objective of this study was to quantify the incidence of respiratory depression in trauma patients acutely intoxicated with ethanol who received opioids as compared with those who did not and identify potential risk factors for respiratory depression in this population. Retrospective medical record review was conducted for subjects identified via the trauma registry who were admitted as a trauma activation and had a detectable serum ethanol level upon admission. Risk factors and characteristics compared included demographics, Injury Severity Score, Glasgow Coma Score, serum ethanol level upon arrival, urine drug screen results, incidence of respiratory depression, and opioid and other sedative medication use. A total of 233 patients were included (78.5% male). Patients who received opioids were more likely to have a higher Injury Severity Score and initial pain score on admission as compared with those who did not receive opioids. Blood ethanol content was higher in patients who did not receive opioids (0.205 vs 0.237 mg/dL, P = .015). Patients who did not receive opioids were more likely to be intubated within 4 hours of admission (1.7% vs 12.1%, P = .02). Opioid administration was not associated with increased risk of respiratory depression (19.7% vs 22.4%, P = .606). Increased cumulative fentanyl dose was associated with increased risk of respiratory depression. Increased cumulative fentanyl dose, but not opioid administration alone, was found to be a risk factor for respiratory depression. Copyright © 2015 Elsevier Inc. All rights reserved.

Continuous delivery of naltrexone and nalmefene leads to tolerance in reducing alcohol drinking and to supersensitivity of brain opioid receptors.

PubMed

Korpi, Esa R; Linden, Anni-Maija; Hytönen, Heidi R; Paasikoski, Nelli; Vashchinkina, Elena; Dudek, Mateusz; Herr, Deron R; Hyytiä, Petri

2017-07-01

Opioid antagonist treatments reduce alcohol drinking in rodent models and in alcohol-dependent patients, with variable efficacy across different studies. These treatments may suffer from the development of tolerance and opioid receptor supersensitivity, as suggested by preclinical models showing activation of these processes during and after subchronic high-dose administration of the short-acting opioid antagonist naloxone. In the present study, we compared equipotent low and moderate daily doses of naltrexone and nalmefene, two opioid antagonists in the clinical practice for treatment of alcoholism. The antagonists were given here subcutaneously for 7 days either as daily injections or continuous osmotic minipump-driven infusions to alcohol-preferring AA rats having trained to drink 10% alcohol in a limited access protocol. One day after stopping the antagonist treatment, [ 35 S]GTPγS autoradiography on brain cryostat sections was carried out to examine the coupling of receptors to G protein activation. The results prove the efficacy of repeated injections over infused opioid antagonists in reducing alcohol drinking. Tolerance to the reducing effect on alcohol drinking and to the enhancement of G protein coupling to μ-opioid receptors in various brain regions were consistently detected only after infused antagonists. Supersensitivity of κ-opioid receptors was seen in the ventral and dorsal striatal regions especially by infused nalmefene. Nalmefene showed no clear agonistic activity in rat brain sections or at human recombinant κ-opioid receptors. The findings support the as-needed dosing practice, rather than the standard continual dosing, in the treatment of alcoholism with opioid receptor antagonists. © 2016 Society for the Study of Addiction.

Peptide and non-peptide opioid-induced hyperthermia in rabbits

NASA Technical Reports Server (NTRS)

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

1983-01-01

The intracerebroventricular administration of prototype nonpeptide opioid receptor (mu, kappa, and sigma) agonists, morphine, ketocyclazocine, and N-allyl-normetazocine was found to induce hyperthermia in rabbits. The similar administration of peptide opioids like beta-endorphin (BE), methionine-enkephalin (ME), and its synthetic analogue D-ala2-methionine-enkephalinamide (DAME) was also found to cause hyperthermia. Results indicate that only the liver-like transport system is important to the ventricular inactivation of BE and DAME. Prostaglandins and norepinephrine were determined not to be involved in peptide and nonpeptide opioid-induced hyperthermia. In addition, cAMP was not required since a phosphodiesterase inhibitor, theophylline, did not accentuate the hyperthermia due to peptide and nonpeptide opioids. Naloxone-sensitive receptors were found to be involved in the induction of hyperthermia by morphine, BE, ME, and DAME since naloxone attenuated them. However, the hyperthermic response to ketocyclazocine and N-allyl-normetazocine was not antagonized by naloxone.

Theory of Planned Behavior Constructs Associated with Nurses' Pain Assessment and Pro Re Nata (PRN) Opioid Analgesic Administration: A Cross-sectional Study.

PubMed

Youngcharoen, Phichpraorn; Vincent, Catherine; Park, Chang G

2017-06-01

Little theory-based research has been performed to better understand nurses' perceptions of pain management. Framed by the theory of planned behavior, the aims of the study were to describe nurses' beliefs (behavioral, normative, and control) about pain management for hospitalized elderly patients with postoperative pain; to present an item analysis for beliefs, attitudes, perceived norms, perceived behavioral control, intentions, and behaviors (measured in case study vignettes) for nurses (a) with different durations of nursing experience, (b) working in university, public health, and military hospitals, and (c) who either had or had not received pain management training in the past six months; and to compare differences in the constructs across these three groups. A comparative descriptive cross-sectional design was used with a convenience sample of 140 Thai nurses working in three Bangkok hospitals. Participants responded to pain assessment and management questionnaires. Most nurses expressed fairly strong beliefs about pain assessment and pro re nata (PRN) opioid analgesic administration. Nurses with more than 10 years of experience had the highest scores for attitudes toward pain assessment and perceptions of others' expectations about PRN opioid analgesic administration. Responses of nurses working in different types of hospitals indicated significantly different pain assessment and PRN opioid analgesic administration behaviors. No significant differences were found for nurses who did and did not receive pain management training. The study highlighted the need for improved pain management education for nurses to enhance the quality of patient care. Copyright © 2017 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

Effects of repeated morphine on intracranial self-stimulation in male rats in the absence or presence of a noxious pain stimulus.

PubMed

Miller, Laurence L; Altarifi, Ahmad A; Negus, S Stevens

2015-10-01

Research on opioid analgesics such as morphine suggests that expression of abuse-related effects increases with repeated exposure. Repeated exposure to opioids often occurs clinically in the context of pain management, and a major concern for clinicians is the risk of iatrogenic addiction and dependence in patients receiving opioids for treatment of pain. This study compared abuse-related morphine effects in male rats in an intracranial self-stimulation (ICSS) procedure after repeated treatment either with morphine alone or with morphine in combination with a repeated noxious stimulus (intraperitoneal administration of dilute acid). The study also permitted comparison of morphine potency and effectiveness to block acid-induced depression of ICSS (antinociception) and to produce enhanced facilitation of ICSS (abuse-related effect). There were 3 main findings. First, initial morphine exposure to drug naïve rats did not produce abuse-related ICSS facilitation. Second, repeated daily treatment with 3.2 mg/kg/day morphine for 6 days increased expression of ICSS facilitation. This occurred whether morphine was administered in the absence or presence of the noxious stimulus. Finally, a lower dose of 1.0 mg/kg/day morphine was sufficient to produce antinociception during repeated acid treatment, but this lower dose did not reliably increase abuse-related morphine effects. Taken together, these results suggest that prior morphine exposure can increase abuse liability of subsequent morphine treatments even when that morphine exposure occurs in the context of a pain state. However, it may be possible to relieve pain with relatively low morphine doses that do not produce increases in abuse-related morphine effects. (c) 2015 APA, all rights reserved).

Opioid activation of Toll-Like receptor 4 contributes to drug reinforcement

PubMed Central

Hutchinson, M.R.; Northcutt, A.L.; Hiranita, T.; Wang, X.; Lewis, S.; Thomas, J.; van Steeg, K.; Kopajtic, T.A.; Loram, L.; Sfregola, C.; Galer, E.; Miles, N.E.; Bland, S.T.; Amat, J.; Rozeske, R.R.; Maslanik, T.; Chapman, T.; Strand, K.; Fleshner, M.; Bachtell, R.K.; Somogyi, A.A.; Yin, H.; Katz, J.L.; Rice, K.C.; Maier, S.F.; Watkins, L.R.

2012-01-01

Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, Toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the non-opioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knockouts of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4 −/− mice had reduced oxycodone-induced p38 and JNK phosphorylation, whilst displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system which amplifies opioid-induced elevations in extracellular dopamine levels and therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward. PMID:22895704

Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in India: a report from the Global Opioid Policy Initiative (GOPI).

PubMed

Cleary, J; Simha, N; Panieri, A; Scholten, W; Radbruch, L; Torode, J; Cherny, N I

2013-12-01

India is the world's largest democracy with control of opioids divided between the national and state governments. While the global consumption of opioids has increased, the consumption has not increased at the same rate. This is the first comprehensive study of opioid availability and accessibility for cancer patients in India. Data are reported on the availability and accessibility of opioids for the management of cancer pain in 24 of the states that make up India and the Administrative area around Delhi. About 1061 million of the nation's 1189 million people (89%) are covered by this survey. Without exception, opioid availability continues to be low throughout all of India. Even when opioids are on formulary, they are often unavailable. Access is significantly impaired by widespread over-regulation that continues to be pervasive across the nation.

Delta Opioid Receptor Signaling Promotes Resilience to Stress Under the Repeated Social Defeat Paradigm in Mice

PubMed Central

Henry, Mathilde S.; Bisht, Kanchan; Vernoux, Nathalie; Gendron, Louis; Torres-Berrio, Angélica; Drolet, Guy; Tremblay, Marie-Ève

2018-01-01

The adaptation to chronic stress is highly variable across individuals. Resilience to stress is a complex process recruiting various brain regions and neurotransmitter systems. The aim of this study was to investigate the involvement of endogenous opioid enkephalin (ENK) signaling in the development of stress resilience in mice. The translational model of repeated social defeat (RSD) stress was selected to mimic the unpredictable disruptions of daily life and induce resilience or vulnerability to stress. As in humans, adult C57BL/6J mice demonstrated a great variability in their response to stress under this paradigm. A social interaction (SI) test was used to discriminate between the phenotypes of resilience or vulnerability to stress. After social defeat, the expression levels of ENK mRNA and their delta opioid receptors (DOPr) were quantified in the basolateral amygdala (BLA) and BLA-target areas by in situ hybridization. In this manner, ENK mRNA levels were found to decrease in the BLA and those of DOPr in the ventral hippocampus (HPC) CA1 of vulnerable mice only. Stimulating the DOPr pathway during social defeat by pharmacological treatment with the nonpeptide, selective DOPr agonist SNC80 further induced a resilient phenotype in a majority of stressed animals, with the proportion of resilient ones increasing from 33% to 58% of the total population. Ultrastructural analyses additionally revealed a reduction of oxidative stress markers in the pyramidal cells and interneurons of the ventral HPC CA1 upon SNC80 treatment, thus proposing a mechanism by which ENK-DOPr signaling may prevent the deleterious effects of chronic social stress. PMID:29681795

Association of Opioids and Sedatives with Increased Risk of In-Hospital Cardiopulmonary Arrest from an Administrative Database

PubMed Central

Overdyk, Frank J.; Dowling, Oonagh; Marino, Joseph; Qiu, Jiejing; Chien, Hung-Lun; Erslon, Mary; Morrison, Neil; Harrison, Brooke; Dahan, Albert; Gan, Tong J.

2016-01-01

Background While opioid use confers a known risk for respiratory depression, the incremental risk of in-hospital cardiopulmonary arrest, respiratory arrest, or cardiopulmonary resuscitation (CPRA) has not been studied. Our aim was to investigate the prevalence, outcomes, and risk profile of in-hospital CPRA for patients receiving opioids and medications with central nervous system sedating side effects (sedatives). Methods A retrospective analysis of adult inpatient discharges from 2008–2012 reported in the Premier Database. Patients were grouped into four mutually exclusive categories: (1) opioids and sedatives, (2) opioids only, (3) sedatives only, and (4) neither opioids nor sedatives. Results Among 21,276,691 inpatient discharges, 53% received opioids with or without sedatives. A total of 96,554 patients suffered CPRA (0.92 per 1000 hospital bed-days). Patients who received opioids and sedatives had an adjusted odds ratio for CPRA of 3.47 (95% CI: 3.40–3.54; p<0.0001) compared with patients not receiving opioids or sedatives. Opioids alone and sedatives alone were associated with a 1.81-fold and a 1.82-fold (p<0.0001 for both) increase in the odds of CPRA, respectively. In opioid patients, locations of CPRA were intensive care (54%), general care floor (25%), and stepdown units (15%). Only 42% of patients survived CPRA and only 22% were discharged home. Opioid patients with CPRA had mean increased hospital lengths of stay of 7.57 days and mean increased total hospital costs of $27,569. Conclusions Opioids and sedatives are independent and additive risk factors for in-hospital CPRA. The impact of opioid sparing analgesia, reduced sedative use, and better monitoring on CPRA incidence deserves further study. PMID:26913753

Opioid Analgesics and Nicotine: More Than Blowing Smoke.

PubMed

Yoon, Jin H; Lane, Scott D; Weaver, Michael F

2015-09-01

Practitioners are highly likely to encounter patients with concurrent use of nicotine products and opioid analgesics. Smokers present with more severe and extended chronic pain outcomes and have a higher frequency of prescription opioid use. Current tobacco smoking is a strong predictor of risk for nonmedical use of prescription opioids. Opioid and nicotinic-cholinergic neurotransmitter systems interact in important ways to modulate opioid and nicotine effects: dopamine release induced by nicotine is dependent on facilitation by the opioid system, and the nicotinic-acetylcholine system modulates self-administration of several classes of abused drugs-including opioids. Nicotine can serve as a prime for the use of other drugs, which in the case of the opioid system may be bidirectional. Opioids and compounds in tobacco, including nicotine, are metabolized by the cytochrome P450 enzyme system, but the metabolism of opioids and tobacco products can be complicated. Accordingly, drug interactions are possible but not always clear. Because of these issues, asking about nicotine use in patients taking opioids for pain is recommended. When assessing patient tobacco use, practitioners should also obtain information on products other than cigarettes, such as cigars, pipes, smokeless tobacco, and electronic nicotine delivery systems (ENDS, or e-cigarettes). There are multiple forms of behavioral therapy and pharmacotherapy available to assist patients with smoking cessation, and opioid agonist maintenance and pain clinics represent underutilized opportunities for nicotine intervention programs.

Lorcaserin suppresses oxycodone self-administration and relapse vulnerability in rats

PubMed Central

Neelakantan, Harshini; Holliday, Erica D.; Fox, Robert G.; Stutz, Sonja J.; Comer, Sandra D.; Haney, Margaret; Anastasio, Noelle C.; Moeller, F. Gerard; Cunningham, Kathryn A.

2017-01-01

Opioid use disorder (OUD) is a major public health problem. High relapse rates and poor treatment retention continue to pose major challenges in OUD treatment. Of the abused opioids, oxycodone is well described to maintain self-administration and evoke the durable conditioned responses (“cue reactivity”) that result from pairing of opioid-related stimuli (e.g., paraphernalia) with repeated abuse. Serotonin (5-HT) neurotransmission, particularly through the 5-HT2C receptor (5-HT2CR), regulates psychostimulant reward and cue reactivity, and in the present experiments, we investigated the hypothesis that the selective 5-HT2CR agonist lorcaserin, which is FDA-approved for the treatment of obesity, will suppress oxycodone self-administration and oxycodone-associated cue reactivity in rats. We found that lorcaserin inhibited oxycodone intake, an effect blocked by the selective 5-HT2CR antagonist SB242084. Lorcaserin also decreased responding for the discrete cue complex (“cue reactivity”) previously associated with delivery of oxycodone (i.e., stimulus lights, infusion pump sounds) in both abstinence and extinction-reinstatement models. The selected dose range of lorcaserin (0.25–1 mg/kg) does not overtly alter spontaneous behaviors nor operant responding on inactive levers in the present study. Taken together, the ability of lorcaserin to reduce the oxycodone self-administration and decrease cue reactivity associated with relapse highlights the therapeutic potential for lorcaserin in the treatment of OUD. PMID:28107783

A Leptin-Mediated Central Mechanism in Analgesia-Enhanced Opioid Reward in Rats

PubMed Central

Lim, Grewo; Kim, Hyangin; McCabe, Michael F.; Chou, Chiu-Wen; Wang, Shuxing; Chen, Lucy L.; Marota, John J.A.; Blood, Anne; Breiter, Hans C.

2014-01-01

Opioid analgesics are commonly used in chronic pain management despite a potential risk of rewarding. However, it remains unclear whether opioid analgesia would enhance the opioid rewarding effect thereby contributing to opioid rewarding. Utilizing a rat paradigm of conditioned place preference (CPP) combined with ankle monoarthritis as a condition of persistent nociception, we showed that analgesia induced by either morphine or the nonsteroid anti-inflammatory drug ibuprofen increased CPP scores in arthritic rats, suggesting that analgesia itself had a rewarding effect. However, arthritic rats exhibited a significantly higher CPP score in response to morphine than ibuprofen. Thus, the rewarding effect of morphine was enhanced in the presence of persistent nociception, producing a phenomenon of analgesia-enhanced opioid reward. At the cellular level, administration of morphine activated a cascade of leptin expression, glial activation, and dopamine receptor upregulation in the nucleus accumbens (NAc), while administration of ibuprofen decreased glial activation with no effect on leptin expression in the NAc. Furthermore, the morphine rewarding effect was blocked in leptin deficient ob/ob mice or by neutralizing leptin or interleukin-1β in the NAc without diminishing morphine analgesia. The data indicate that systemic opioid can activate a leptin-mediated central mechanism in the NAc that led to the enhanced opioid rewarding effect. These findings provide evidence for an interaction between opioid analgesia and opioid rewarding, which may have implications in clinical opioid dose escalation in chronic pain management. PMID:25031415

Opioid adjuvant strategy: improving opioid effectiveness.

PubMed

Bihel, Frédéric

2016-01-01

Opioid analgesics continue to be the mainstay of pharmacologic treatment of moderate to severe pain. Many patients, particularly those suffering from chronic pain, require chronic high-dose analgesic therapy. Achieving clinical efficacy and tolerability of such treatment regimens is hampered by the appearance of opioid-induced side effects such as tolerance, hyperalgesia and withdrawal syndrome. Among the therapeutic options to improve the opioid effectiveness, this current review focuses on strategies combining opioids to other drugs that can modulate opioid-mediated effects. We will discuss about experimental evidences reported for several potential opioid adjuvants, including N-methyl-D-aspartate receptor antagonists, 5-HT7 agonists, sigma-1 antagonists, I2-R ligands, cholecystokinin antagonists, neuropeptide FF-R antagonists and toll-like receptor 4 antagonists.

Treating Opioid-Induced Constipation in Older Adults: New Options.

PubMed

Sani, Halima; Mahan, Rebecca J

2015-10-01

Numerous factors, such as changes in gastrointestinal physiology, reduced mobility, decreased liquid and nutritional intake, and certain comorbidities, predispose older adults to constipation. Use of opioid medications further compounds this problem. Unlike other side effects associated with opioid use, patients do not develop tolerance to constipation and other opioid-induced bowel dysfunctions. Although opioid-induced constipation has a prevalence rate of 80% in this population, it remains highly undertreated. Despite this problem, there have been limited therapeutic options available for older adults suffering from opioid-induced constipation. On September 16, 2014, a new oral agent, naloxegol, a peripherally acting muopioid receptor antagonist (PAMORA), approved by the Food and Drug Administration, provides new hope for patients. This paper explores clinical complications associated with opioid-induced constipation in older adults, analyzes the efficacy and safety of laxatives and PAMORAs, and defines the future role of naloxegol in this vulnerable population.

Relationship of opioid prescription sales and overdoses, North Carolina.

PubMed

Modarai, F; Mack, K; Hicks, P; Benoit, S; Park, S; Jones, C; Proescholdbell, S; Ising, A; Paulozzi, L

2013-09-01

In the United States, fatal drug overdoses have tripled since 1991. This escalation in deaths is believed to be driven primarily by prescription opioid medications. This investigation compared trends and patterns in sales of opioids, opioid drug overdoses treated in emergency departments (EDs), and unintentional overdose deaths in North Carolina (NC). Our ecological study compared rates of opioid sales, opioid related ED overdoses, and unintentional drug overdose deaths in NC. Annual sales data, provided by the Drug Enforcement Administration, for select opioids were converted into morphine equivalents and aggregated by zip code. These opioid drug sales rates were trended from 1997 to 2010. In addition, opioid sales were correlated and compared to opioid related ED visits, which came from a Centers for Disease Control and Prevention syndromic surveillance system, and unintentional overdose deaths, which came from NC Vital Statistics, from 2008 to 2010. Finally, spatial cluster analysis was performed and rates were mapped by zip code in 2010. Opioid sales increased substantially from 1997 to 2010. From 2008 to 2010, the quarterly rates of opioid drug overdoses treated in EDs and opioid sales correlated (r=0.68, p=0.02). Specific regions of the state, particularly in the southern and western corners, had both high rates of prescription opioid sales and overdoses. Temporal trends in sales of prescription opioids correlate with trends in opioid related ED visits. The spatial correlation of opioid sales with ED visit rates shows that opioid sales data may be a timely way to identify high-risk communities in the absence of timely ED data. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Demethylation regulation of BDNF gene expression in dorsal root ganglion neurons is implicated in opioid-induced pain hypersensitivity in rats.

PubMed

Chao, Yu-Chieh; Xie, Fang; Li, Xueyang; Guo, Ruijuan; Yang, Ning; Zhang, Chen; Shi, Rong; Guan, Yun; Yue, Yun; Wang, Yun

2016-07-01

Repeated administration of morphine may result in opioid-induced hypersensitivity (OIH), which involves altered expression of numerous genes, including brain-derived neurotrophic factor (BDNF) in dorsal root ganglion (DRG) neurons. Yet, it remains unclear how BDNF expression is increased in DRG neurons after repeated morphine treatment. DNA methylation is an important mechanism of epigenetic control of gene expression. In the current study, we hypothesized that the demethylation regulation of certain BDNF gene promoters in DRG neurons may contribute to the development of OIH. Real-time RT-PCR was used to assess changes in the mRNA transcription levels of major BDNF exons including exon I, II, IV, VI, as well as total BDNF mRNA in DRGs from rats after repeated morphine administration. The levels of exon IV and total BDNF mRNA were significantly upregulated by repeated morphine administration, as compared to that in saline control group. Further, ELISA array and immunocytochemistry study revealed a robust upregulation of BDNF protein expression in DRG neurons after repeated morphine exposure. Correspondingly, the methylation levels of BDNF exon IV promoter showed a significant downregulation by morphine treatment. Importantly, intrathecal administration of a BDNF antibody, but not control IgG, significantly inhibited mechanical hypersensitivity that developed in rats after repeated morphine treatment. Conversely, intrathecal administration of an inhibitor of DNA methylation, 5-aza-2'-deoxycytidine (5-aza-dC) markedly upregulated the BDNF protein expression in DRG neurons and enhanced the mechanical allodynia after repeated morphine exposure. Together, our findings suggest that demethylation regulation of BDNF gene promoter may be implicated in the development of OIH through epigenetic control of BDNF expression in DRG neurons. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evaluating the abuse potential of opioids and abuse-deterrent -opioid formulations: A review of clinical study methodology.

PubMed

Setnik, Beatrice; Schoedel, Kerri A; Levy-Cooperman, Naama; Shram, Megan; Pixton, Glenn C; Roland, Carl L

With the development of opioid abuse-deterrent formulations (ADFs), there is a need to conduct well-designed human abuse potential studies to evaluate the effectiveness of their deterrent properties. Although these types of studies have been conducted for many years, largely to evaluate inherent abuse potential of a molecule and inform drug scheduling, methodological approaches have varied across studies. The focus of this review is to describe current "best practices" and methodological adaptations required to assess abuse-deterrent opioid formulations for regulatory submissions. A literature search was conducted in PubMed® to review methodological approaches (study conduct and analysis) used in opioid human abuse potential studies. Search terms included a combination of "opioid," "opiate," "abuse potential," "abuse liability," "liking," AND "pharmacodynamic," and only studies that evaluated single doses of opioids in healthy, nondependent individuals with or without prior opioid experience were included. Seventy-one human abuse potential studies meeting the prespecified criteria were identified, of which 21 studies evaluated a purported opioid ADF. Based on these studies, key methodological considerations were reviewed and summarized according to participant demographics, study prequalification, comparator and dose selection, route of administration and drug manipulation, study blinding, outcome measures and training, safety, and statistical analyses. The authors recommend careful consideration of key elements (eg, a standardized definition of a "nondependent recreational user"), as applicable, and offer key principles and "best practices" when conducting human abuse potential studies for opioid ADFs. Careful selection of appropriate study conditions is dependent on the type of ADF technology being evaluated.

Modulation of opioid analgesia by agmatine.

PubMed

Kolesnikov, Y; Jain, S; Pasternak, G W

1996-01-18

Administered alone, agmatine at doses of 0.1 or 10 mg/kg is without effect in the mouse tailflick assay. However, agmatine enhances morphine analgesia in a dose-dependent manner, shifting morphine's ED50 over 5-fold. A far greater effect is observed when morphine is given intrathecally (9-fold shift) than after intracerebroventricular administration (2-fold). In contrast to the potentiation of morphine analgesia, agmatine (10 mg/kg) has no effect on morphine's inhibition of gastrointestinal transit. delta-Opioid receptor-mediated analgesia also is potentiated by agmatine, but kappa1-receptor-mediated (U50,488H; trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetemide) and kappa3-opioid receptor-mediated (naloxone benzoylhydrazone) analgesia is not significantly enhanced by any dose of agmatine tested in this acute model. In chronic studies, agmatine at a low dose (0.1 mg/kg) which does not affect morphine analgesia acutely prevents tolerance following chronic morphine dosing for 10 days. A higher agmatine dose (10 mg/kg) has a similar effect. Agmatine also blocks tolerance to the delta-opioid receptor ligand [D-Pen2,D-Pen5]enkephalin given intrathecally, but not to the kappa3-opioid receptor agonist naloxone benzoylhydrazone. Despite its inactivity on kappa1-opioid analgesia in the acute model, agmatine prevents kappa1-opioid receptor-mediated tolerance. These studies demonstrate the dramatic interactions between agmatine and opioid analgesia and tolerance.

The macrocyclic tetrapeptide [D-Trp]CJ-15,208 produces short-acting κ opioid receptor antagonism in the CNS after oral administration.

PubMed

Eans, Shainnel O; Ganno, Michelle L; Reilley, Kate J; Patkar, Kshitij A; Senadheera, Sanjeewa N; Aldrich, Jane V; McLaughlin, Jay P

2013-05-01

Cyclic peptides are resistant to proteolytic cleavage, therefore potentially exhibiting activity after systemic administration. We hypothesized that the macrocyclic κ opioid receptor (KOR)-selective antagonist [D-Trp]CJ-15,208 would demonstrate antagonist activity after systemic, that is, s.c. and oral (per os, p. o.), administration. C57BL/6J mice were pretreated with [D-Trp]CJ-15,208 s.c. or p.o. before administration of the KOR-selective agonist U50,488 and the determination of antinociception in the warm-water tail-withdrawal assay. The locomotor activity of mice treated with [D-Trp]CJ-15,208 was determined by rotorod testing. Additional mice demonstrating cocaine conditioned place preference and subsequent extinction were pretreated daily with vehicle or [D-Trp]CJ-15,208 and then exposed to repeated forced swim stress or a single additional session of cocaine place conditioning before redetermining place preference. Pretreatment with [D-Trp]CJ-15,208 administered s.c. or p.o. dose-dependently antagonized the antinociception induced by i.p. administration of U50,488 in mice tested in the warm-water tail-withdrawal assay for less than 12 and 6 h respectively. [D-Trp]CJ-15,208 also produced limited (<25%), short-duration antinociception mediated through KOR agonism. Orally administered [D-Trp]CJ-15,208 dose-dependently antagonized centrally administered U50,488-induced antinociception, and prevented stress-, but not cocaine-induced, reinstatement of extinguished cocaine-seeking behaviour, consistent with its KOR antagonist activity, without affecting locomotor activity. The macrocyclic tetrapeptide [D-Trp]CJ-15,208 is a short-duration KOR antagonist with weak KOR agonist activity that is active after oral administration and demonstrates blood-brain barrier permeability. These data validate the use of systemically active peptides such as [D-Trp]CJ-15,208 as potentially useful therapeutics. © 2013 The Authors. British Journal of Pharmacology © 2013 The

Compulsive-like responding for opioid analgesics in rats with extended access.

PubMed

Wade, Carrie L; Vendruscolo, Leandro F; Schlosburg, Joel E; Hernandez, Daniel O; Koob, George F

2015-01-01

The abuse of prescription opioids that are used for the treatment of chronic pain is a major public health concern, costing ∼$53.4 billion annually in lost wages, health-care costs, and criminal costs. Although opioids remain a first-line therapy for the treatment of severe chronic pain, practitioners remain cautious because of the potential for abuse and addiction. Opioids such as heroin are considered very rewarding and reinforcing, but direct and systematic comparisons of compulsive intake between commonly prescribed opioids and heroin in animal models have not yet been performed. In the present study, we evaluated the potential for compulsive-like drug seeking and taking, using intravenous self-administration of oxycodone, fentanyl, and buprenorphine in rats allowed long access sessions (12 h). We measured compulsive-like intake using an established escalation model and responding on a progressive ratio schedule of reinforcement. We compared the potential for compulsive-like self-administration of these prescription opioids and heroin, which has been previously established to induce increasing intake that models the transition to addiction in humans. We found that animals that self-administered oxycodone, fentanyl, or heroin, but not buprenorphine had similar profiles of escalation and increases in breakpoints. The use of extended access models of prescription opioid intake will help better understand the biological factors that underlie opioid dependence.

Low efficacy of non-opioid drugs in opioid withdrawal symptoms.

PubMed

Hermann, Derik; Klages, Eckard; Welzel, Helga; Mann, Karl; Croissant, Bernhard

2005-06-01

Opioid withdrawal, stress or cues associated with opioid consumption can induce opioid craving. If opioids are not available, opioid-dependent patients usually search for alternative drugs. Because several non-opioid drugs stimulate the endogenous opioidergic system, this concept may explain their frequent use by opioid-dependent patients. We hypothesized that non-opioid drugs alleviate opioid withdrawal symptoms and are therefore consumed by opioid addicts. We asked 89 opioid-dependent patients participating in an out-patient opioid maintenance program to estimate the potential of several non-opioid drugs in being able to alleviate opioid withdrawal. We applied a five-point Lickert scale (1 = very good reduction of opioid withdrawal; 5 = no reduction of opioid withdrawal). Patients could also indicate a worsening of opioid withdrawal. Values (mean +/- SD) were: for benzodiazepines, 3.2 +/- 1.1; tricyclic antidepressants, 3.6 +/- 1.1; cannabis, 3.6 +/- 1.0; alcohol, 4.1 +/- 1.1; cocaine, 4.2 +/- 1.1; amphetamine, 4.4 +/- 0.9; nicotine, 4.7 +/- 0.7; and caffeine, 4.9 +/- 0.5. A worsening of opioid withdrawal was reported by 62% of the patients for cocaine, 62% for amphetamine, 50% for caffeine, 37.5% for cannabis, 27% for nicotine, 26% for alcohol, 8% for tricyclic antidepressants and 3% for benzodiazepines. Our study shows a low efficacy of non-opioid drugs in alleviating opioid withdrawal symptoms. The data basis of this study was good and the sample was suitable to be asked for estimations of drug-drug interactions. Of the patients, 26 - 62% even reported a worsening of opioid withdrawal for cannabis, alcohol, cocaine and amphetamine. Only benzodiazepines and tricyclic antidepressants were reported to have a moderate positive effect on opioid withdrawal.

Repeated administration of an acetylcholinesterase inhibitor attenuates nicotine taking in rats and smoking behavior in human smokers

PubMed Central

Ashare, R L; Kimmey, B A; Rupprecht, L E; Bowers, M E; Hayes, M R; Schmidt, H D

2016-01-01

Tobacco smoking remains the leading cause of preventable death worldwide and current smoking cessation medications have limited efficacy. Thus, there is a clear need for translational research focused on identifying novel pharmacotherapies for nicotine addiction. Our previous studies demonstrated that acute administration of an acetylcholinesterase inhibitor (AChEI) attenuates nicotine taking and seeking in rats and suggest that AChEIs could be repurposed for smoking cessation. Here, we expand upon these findings with experiments designed to determine the effects of repeated AChEI administration on voluntary nicotine taking in rats as well as smoking behavior in human smokers. Rats were trained to self-administer intravenous infusions of nicotine (0.03 mg kg−1 per 0.59 ml) on a fixed-ratio-5 schedule of reinforcement. Once rats maintained stable nicotine taking, galantamine or donepezil was administered before 10 consecutive daily nicotine self-administration sessions. Repeated administration of 5.0 mg kg−1 galantamine and 3.0 mg kg−1 donepezil attenuated nicotine self-administration in rats. These effects were reinforcer-specific and not due to adverse malaise-like effects of drug treatment as repeated galantamine and donepezil administration had no effects on sucrose self-administration, ad libitum food intake and pica. The effects of repeated galantamine (versus placebo) on cigarette smoking were also tested in human treatment-seeking smokers. Two weeks of daily galantamine treatment (8.0 mg (week 1) and 16.0 mg (week 2)) significantly reduced smoking rate as well as smoking satisfaction and reward compared with placebo. This translational study indicates that repeated AChEI administration reduces nicotine reinforcement in rats and smoking behavior in humans at doses not associated with tolerance and/or adverse effects. PMID:26784967

Regulated endocytosis of opioid receptors: cellular mechanisms and proposed roles in physiological adaptation to opiate drugs.

PubMed

von Zastrow, Mark; Svingos, Adena; Haberstock-Debic, Helena; Evans, Chris

2003-06-01

Opiate drugs such as morphine and heroin are among the most effective analgesics known. Prolonged or repeated administration of opiates produces adaptive changes in the nervous system that lead to reduced drug potency or efficacy (tolerance), as well as physiological withdrawal symptoms and behavioral manifestations such as craving when drug use is terminated (dependence). These adaptations limit the therapeutic utility of opiate drugs, particularly in the treatment of chronically painful conditions, and are thought to contribute to the highly addictive nature of opiates. For many years it has been proposed that physiological tolerance to opiate drugs is associated with a modification of the number or functional activity of opioid receptors in specific neurons. We now understand certain mechanisms of opioid receptor desensitization and endocytosis in considerable detail. However, the functional roles that these mechanisms play in the complex physiological adaptation of the intact nervous system to opiates are only beginning to be explored.

Review of Factors, Methods, and Outcome Definition in Designing Opioid Abuse Predictive Models.

PubMed

Alzeer, Abdullah H; Jones, Josette; Bair, Matthew J

2018-05-01

Several opioid risk assessment tools are available to prescribers to evaluate opioid analgesic abuse among chronic patients. The objectives of this study are to 1) identify variables available in the literature to predict opioid abuse; 2) explore and compare methods (population, database, and analysis) used to develop statistical models that predict opioid abuse; and 3) understand how outcomes were defined in each statistical model predicting opioid abuse. The OVID database was searched for this study. The search was limited to articles written in English and published from January 1990 to April 2016. This search generated 1,409 articles. Only seven studies and nine models met our inclusion-exclusion criteria. We found nine models and identified 75 distinct variables. Three studies used administrative claims data, and four studies used electronic health record data. The majority, four out of seven articles (six out of nine models), were primarily dependent on the presence or absence of opioid abuse or dependence (ICD-9 diagnosis code) to define opioid abuse. However, two articles used a predefined list of opioid-related aberrant behaviors. We identified variables used to predict opioid abuse from electronic health records and administrative data. Medication variables are the recurrent variables in the articles reviewed (33 variables). Age and gender are the most consistent demographic variables in predicting opioid abuse. Overall, there is similarity in the sampling method and inclusion/exclusion criteria (age, number of prescriptions, follow-up period, and data analysis methods). Intuitive research to utilize unstructured data may increase opioid abuse models' accuracy.

Anti-nociceptive interactions between opioids and a cannabinoid receptor 2 agonist in inflammatory pain

PubMed Central

Hale, David E; Guindon, Josée; Morgan, Daniel J

2017-01-01

The cannabinoid 1 receptor and cannabinoid 2 receptor can both be targeted in the treatment of pain; yet, they have some important differences. Cannabinoid 1 receptor is expressed at high levels in the central nervous system, whereas cannabinoid 2 receptor is found predominantly, although not exclusively, outside the central nervous system. The objective of this study was to investigate potential interactions between cannabinoid 2 receptor and the mu-opioid receptor in pathological pain. The low level of adverse side effects and lack of tolerance for cannabinoid 2 receptor agonists are attractive pharmacotherapeutic traits. This study assessed the anti-nociceptive effects of a selective cannabinoid 2 receptor agonist (JWH-133) in pathological pain using mice subjected to inflammatory pain using the formalin test. Furthermore, we examined several ways in which JWH-133 may interact with morphine. JWH-133 produces dose-dependent anti-nociception during both the acute and inflammatory phases of the formalin test. This was observed in both male and female mice. However, a maximally efficacious dose of JWH-133 (1 mg/kg) was not associated with somatic withdrawal symptoms, motor impairment, or hypothermia. After eleven once-daily injections of 1 mg/JWH-133, no tolerance was observed in the formalin test. Cross-tolerance for the anti-nociceptive effects of JWH-133 and morphine were assessed to gain insight into physiologically relevant cannabinoid 2 receptor and mu-opioid receptor interaction. Mice made tolerant to the effects of morphine exhibited a lower JWH-133 response in both phases of the formalin test compared to vehicle-treated morphine-naïve animals. However, repeated daily JWH-133 administration did not cause cross-tolerance for morphine, suggesting opioid and cannabinoid 2 receptor cross-tolerance is unidirectional. However, preliminary data suggest co-administration of JWH-133 with morphine modestly attenuates morphine tolerance. Isobolographic analysis

Repeated hematopoietic stem and progenitor cell mobilization without depletion of the bone marrow stem and progenitor cell pool in mice after repeated administration of recombinant murine G-CSF.

PubMed

de Kruijf, Evert-Jan F M; van Pel, Melissa; Hagoort, Henny; Kruysdijk, Donnée; Molineux, Graham; Willemze, Roel; Fibbe, Willem E

2007-05-01

Administration of recombinant-human G-CSF (rhG-CSF) is highly efficient in mobilizing hematopoietic stem and progenitor cells (HSC/HPC) from the bone marrow (BM) toward the peripheral blood. This study was designed to investigate whether repeated G-CSF-induced HSC/HPC mobilization in mice could lead to a depletion of the bone marrow HSC/HPC pool with subsequent loss of mobilizing capacity. To test this hypothesis Balb/c mice were treated with a maximum of 12 repeated 5-day cycles of either 10 microg rhG-CSF/day or 0.25 microg rmG-CSF/day. Repeated administration of rhG-CSF lead to strong inhibition of HSC/HPC mobilization toward the peripheral blood and spleen after >4 cycles because of the induction of anti-rhG-CSF antibodies. In contrast, after repeated administration of rmG-CSF, HSC/HPC mobilizing capacity remained intact for up to 12 cycles. The number of CFU-GM per femur did not significantly change for up to 12 cycles. We conclude that repeated administration of G-CSF does not lead to depletion of the bone marrow HSC/HPC pool.

Intermittent subcutaneous methadone administration in the management of cancer pain.

PubMed

Centeno, Carlos; Vara, Francisco

2005-01-01

Methadone is a strong opioid analgesic that has been used successfully in cancer pain management. The oral route of administration is generally preferred for opioid analgesics. However that route sometimes cannot be used. Experience with continuous subcutaneous methadone infusions has produced local intolerance. The aim of this study was to analyze the use of intermittent subcutaneous methadone injections. Ten patients whose pain was well-controlled with oral methadone (average dose 30 mg, range 10 to 120 mg) participated in the study. A subcutaneous small vein needle (butterfly) was used exclusively for administration of methadone. Over a period of seven days the local discomfort of each injection was evaluated by means of a Verbal Numerical Rating Scale (NRS) and the site of infusion was observed. When any degree of erythema or inflammation was seen, the infusion site was changed. The initial subcutaneous dose was the same as the previously administered oral dose. A daily record was kept of the dose used, level of pain, and toxicity symptoms. This close vigilance was aimed at avoiding dosage errors due to variations among individuals in acceptance to previous oral medication. Changes in dosage were allowed according to standard medical criteria. Two patients were withdrawn from the study due to non-painful irritation at the infusion point. Another eight patients tolerated repeated administration of subcutaneous methadone over seven days. Any local irritation from subcutaneous methadone that occurred was managed satisfactorily by changing the infusion site and limiting doses to 30 mg. In seven of 182 repeat administration, injection site changes were necessitated by local irritation. The NRS for local discomfort was 2/10. The two patients who were intolerant of the subcutaneous injections were receiving injected doses which were significantly higher than the others (42 mg as compared to 25 mg). Dose adjustments needed when changing from the oral to the

A review of opioid prescription in a teaching hospital in Colombia

PubMed Central

Moyano, Jairo; Figueras, Albert

2012-01-01

Introduction: Review of opioid prescriptions in a hospital provides valuable information to health care professionals which may contribute to proper pain management; opioid utilization studies may help uncover factors that can be improved for better prescribing. To evaluate the use of opioid analgesics in a university hospital, a review of opioids prescribed in hospitalized patients was developed. Methods: Information was obtained from the pharmacy database and medical records. The study period was 1 month. Results: Medical records of 1156 patients admitted in July 2009 were analyzed. The most widely prescribed opioid was tramadol; the preferred administration route was intravenous; the main indication was severe pain; and major prescribers were from surgical departments. Discussion: Underutilization of potent opioids for acute and chronic pain seems to occur. Conclusion: Most prescribers prefer weak opioids, given intravenously to treat acute and chronic pain, while some patients may benefit from the prescription of more potent opioids. PMID:23049273

Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis.

PubMed

Nielsen, Suzanne; Sabioni, Pamela; Trigo, Jose M; Ware, Mark A; Betz-Stablein, Brigid D; Murnion, Bridin; Lintzeris, Nicholas; Khor, Kok Eng; Farrell, Michael; Smith, Andrew; Le Foll, Bernard

2017-08-01

Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of analgesic efficacy (ie, an opioid-sparing effect). The aim of this study was to conduct a systematic review to determine the opioid-sparing potential of cannabinoids. Eligible studies included pre-clinical and clinical studies for which the outcome was either analgesia or opioid dose requirements. Clinical studies included controlled studies and case series. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Nineteen pre-clinical and nine clinical studies met the search criteria. Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration. Our meta-analysis of pre-clinical studies indicated that the median effective dose (ED 50 ) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% confidence interval (CI) 1.95, 6.76; n=6) than the ED 50 of morphine alone. In addition, the ED 50 for codeine administered in combination with delta-9-THC was 9.5 times lower (95% CI 1.6, 57.5, n=2) than the ED 50 of codeine alone. One case series (n=3) provided very-low-quality evidence of a reduction in opioid requirements with cannabinoid co-administration. Larger controlled clinical studies showed some clinical benefits of cannabinoids; however, opioid dose changes were rarely reported and mixed findings were observed for analgesia. In summary, pre-clinical studies provide robust evidence of the opioid-sparing effect of cannabinoids, whereas one of the nine clinical studies identified provided very-low-quality evidence of such an effect. Prospective high-quality-controlled clinical trials are required to determine the opioid-sparing effect of cannabinoids.

Behavioral intervention to reduce opioid overdose among high-risk persons with opioid use disorder: A pilot randomized controlled trial

PubMed Central

Santos, Glenn-Milo; Matheson, Tim; Behar, Emily; Rowe, Chris; Rubin, Talia; Silvis, Janelle; Vittinghoff, Eric

2017-01-01

Objective The United States is amidst an opioid epidemic, including synthetic opioids that may result in rapid death, leaving minimal opportunity for bystander rescue. We pilot tested a behavioral intervention to reduce the occurrence of opioid overdose among opioid dependent persons at high-risk for subsequent overdose. Materials and methods We conducted a single-blinded randomized-controlled trial of a repeated dose motivational interviewing intervention (REBOOT) to reduce overdose versus treatment as usual, defined as information and referrals, over 16 months at the San Francisco Department of Public Health from 2014–2016. Participants were 18–65 years of age, had opioid use disorder by Structured Clinical Interview, active opioid use, opioid overdose within 5 years, and prior receipt of naloxone kits. The intervention was administered at months 0, 4, 8, and 12, preceded by the assessment which was also administered at month 16. Dual primary outcomes were any overdose event and number of events, collected by computer-assisted personal interview, as well as any fatal overdose events per vital records. Results A total of 78 persons were screened and 63 enrolled. Mean age was 43 years, 67% were born male, 65% White, 17% African-American, and 14% Latino. Ninety-two percent of visits and 93% of counseling sessions were completed. At baseline, 33.3% of participants had experienced an overdose in the past four months, with a similar mean number of overdoses in both arms (p = 0.95); 29% overdosed during follow-up. By intention-to-treat, participants assigned to REBOOT were less likely to experience any overdose (incidence rate ratio [IRR] 0.62 [95%CI 0.41–0.92, p = 0.019) and experienced fewer overdose events (IRR 0.46, 95%CI 0.24–0.90, p = 0.023), findings that were robust to sensitivity analyses. There were no differences between arms in days of opioid use, substance use treatment, or naloxone carriage. Conclusions REBOOT reduced the occurrence of any opioid

Opioid Analgesics.

PubMed

Jamison, Robert N; Mao, Jianren

2015-07-01

Chronic pain is an international health issue of immense importance that is influenced by both physical and psychological factors. Opioids are useful in treating chronic pain but have accompanying complications. It is important for clinicians to understand the basics of opioid pharmacology, the benefits and adverse effects of opioids, and related problematic issues of tolerance, dependence, and opioid-induced hyperalgesia. In this article, the role of psychiatric comorbidity and the use of validated assessment tools to identify individuals who are at the greatest risk for opioid misuse are discussed. Additionally, interventional treatment strategies for patients with chronic pain who are at risk for opioid misuse are presented. Specific behavioral interventions designed to improve adherence with prescription opioids among persons treated for chronic pain, such as frequent monitoring, periodic urine screens, opioid therapy agreements, opioid checklists, and motivational counseling, are also reviewed. Use of state-sponsored prescription drug monitoring programs is also encouraged. Areas requiring additional investigation are identified, and the future role of abuse-deterrent opioids and innovative technology in addressing issues of opioid therapy and pain are presented. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Novel opioid cyclic tetrapeptides: Trp isomers of CJ-15,208 exhibit distinct opioid receptor agonism and short-acting κ opioid receptor antagonism.

PubMed

Ross, Nicolette C; Reilley, Kate J; Murray, Thomas F; Aldrich, Jane V; McLaughlin, Jay P

2012-02-01

The κ opioid receptor antagonists demonstrate potential for maintaining abstinence from psychostimulant abuse, but existing non-peptide κ-receptor selective antagonists show exceptionally long activity. We hypothesized that the L- and D-Trp isomers of CJ-15,208, a natural cyclic tetrapeptide reported to be a κ-receptor antagonist in vitro, would demonstrate short-acting, dose-dependent antagonism in vivo, preventing reinstatement of cocaine-seeking behaviour. Affinity, selectivity and efficacy of the L-Trp and D-Trp isomers for opioid receptors were assessed in vitro in radioligand and GTPγS binding assays. Opioid receptor agonist and antagonist activities were characterized in vivo following i.c.v. administration with the 55°C warm water tail-withdrawal assay. The D-Trp isomer, which demonstrated primarily κ-receptor selective antagonist activity, was further evaluated for its prevention of stress- and drug-induced reinstatement of extinguished cocaine conditioned place preference (CPP). The two isomers showed similar affinity and selectivity for κ receptors (K(i)  30-35 nM) as well as κ receptor antagonism in vitro. As expected, the D-Trp cyclic tetrapeptide exhibited minimal agonist activity and induced dose-dependent κ-receptor selective antagonism lasting less than 18 h in vivo. Pretreatment with this peptide prevented stress-, but not cocaine-induced, reinstatement of extinguished cocaine CPP. In contrast, the L-Trp cyclic tetrapeptide unexpectedly demonstrated mixed opioid agonist/antagonist activity. The L-Trp and the D-Trp isomers of CJ-15,208 demonstrate stereospecific opioid activity in vivo. The relatively brief κ opioid receptor antagonism, coupled with the prevention of stress-induced reinstatement of extinguished cocaine-seeking behaviour, suggests the D-Trp isomer could be used therapeutically to maintain abstinence from psychostimulant abuse. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological

Non-analgesic effects of opioids: opioids and the endocrine system.

PubMed

Elliott, Jennifer A; Opper, Susan E; Agarwal, Sonali; Fibuch, Eugene E

2012-01-01

Opioids are among the oldest known and most widely used analgesics. The application of opioids has expanded over the last few decades, especially in the treatment of chronic non-malignant pain. This upsurge in opioid use has been accompanied by the increasingly recognized occurrence of opioid-associated endocrinopathy. This may arise after exposure to enteral, parenteral, or neuraxial opioids. Opioid-associated endocrinopathy consists primarily of hypothalamic-pituitary-gonadal axis or hypothalamic-pituitary-adrenal axis dysfunction and may manifest with symptoms of hypogonadism, adrenal dysfunction, and other hormonal disturbances. Additionally, opioid related endocrine dysfunction may be coupled with such disorders as osteoporosis and mood disturbances including depression. Undesirable changes in pain sensitivity such as opioid-induced hyperalgesia, and reduced potency of opioid analgesia may also be potential consequences of chronic opioid consumption. Few studies to date have been able to establish what degree of opioid exposure, in terms of dose or duration of therapy, may predispose patients to opioid-associated endocrinopathy. This article will review the currently available literature concerning opioid-associated endocrinopathy and will provide recommendations for the evaluation, monitoring, and management of opioid-associated endocrinopathy and its other accompanying undesired effects.

Are We Still Prescribing Opioids for Osteoarthritis?

PubMed

DeMik, David E; Bedard, Nicholas A; Dowdle, S Blake; Burnett, Robert A; McHugh, Michael A; Callaghan, John J

2017-12-01

The United States is in the midst of an opioid epidemic. These medications continue to be used to manage pain associated with osteoarthritis, despite mounting evidence questioning the benefits. The rate at which opioids are prescribed for osteoarthritis is largely unknown. We sought to identify rates of opioid prescriptions for osteoarthritis and identify factors associated with higher rates of prescribing. We queried the Humana, Inc. administrative claims database from 2007 to 2014. Patients with osteoarthritis were identified using International Classification of Diseases 9th Revision codes and classified as having hip, knee, or any joint osteoarthritis. Claims data were reviewed to identify opioid prescriptions associated with a diagnosis of osteoarthritis. Rates of prescribing were trended over time and stratified by sex, age, and geographic region. From 2007 to 2014, 17.0% of patients with any joint osteoarthritis, 13.4% of patients with hip osteoarthritis, and 15.9% with knee osteoarthritis were prescribed an opioid for their condition. Yearly rates of prescription were fairly stable over this period. Patients in the South had the highest odds of opioid prescription, while those in the Northeast had the lowest. Patients ≤49 years old were more likely to receive a prescription than those ≥50 years old. This study provides important epidemiologic data about the use of opioids for osteoarthritis. Despite increasing evidence calling proposed benefits into question and increasing awareness of risks of opioids, prescribing rates remained stable between 2007 and 2014. This provides important baseline data as we work to combat excessive and inappropriate opioid use within the United States. Copyright © 2017 Elsevier Inc. All rights reserved.

Problems of long-term spinal opioid treatment in advanced cancer patients.

PubMed

Mercadante, S

1999-01-01

Epidural and intrathecal techniques are well established techniques in cancer pain. However, several questions remain unresolved. The several problems of long-term spinal opioid treatment in advance cancer patients were reviewed. Indications for the use of spinal opioids include patients treated by systemic opioids with effective pain relief but with unacceptable side effects, or unsuccessful treatment with sequential strong opioid drug trials despite escalating doses. Therefore, the previous aggressive treatment with systemic opioids would leave as failures patients with difficult pain syndromes unresponsive to opioids. The choice of external or totally implanted delivery systems is based on different clinical considerations. The use of externalized tunneled intrathecal catheters has not been associated with higher rates of complications and is easier to place and use at home in debilitated patients late in the course of their disease. The intrathecal administration has a lower incidence of catheter occlusion, lower malfunctioning rate, lower dose requirement, and more effective pain control. Due to the lower daily doses and volumes, intrathecal treatment proved to be more suitable for treatment at home by a continuous infusion than the epidural treatment. Advantages of infusion techniques are more evident when using local anesthetics, since intermittent administration of bupivacaine often results in motor paralysis and hemodynamic instability. Morphine is the opioid of choice. An epidural dose of 10% of the systemic dose is often used. However, intrathecal administration of opioids and bupivacaine may substantially improve pain relief in patients unresponsive to high epidural doses of these drugs, Bupivacaine-induced adverse effects, including sensory deficits, motor complaints, signs of autonomic dysfunction or neurotoxicity have been reported to not occur with bupivacaine doses less than 30-60 mg/day. Adjuvant drugs may further improve analgesia. Different

Opioid errors in inpatient palliative care services: a retrospective review.

PubMed

Heneka, Nicole; Shaw, Tim; Rowett, Debra; Lapkin, Samuel; Phillips, Jane L

2018-06-01

Opioids are a high-risk medicine frequently used to manage palliative patients' cancer-related pain and other symptoms. Despite the high volume of opioid use in inpatient palliative care services, and the potential for patient harm, few studies have focused on opioid errors in this population. To (i) identify the number of opioid errors reported by inpatient palliative care services, (ii) identify reported opioid error characteristics and (iii) determine the impact of opioid errors on palliative patient outcomes. A 24-month retrospective review of opioid errors reported in three inpatient palliative care services in one Australian state. Of the 55 opioid errors identified, 84% reached the patient. Most errors involved morphine (35%) or hydromorphone (29%). Opioid administration errors accounted for 76% of reported opioid errors, largely due to omitted dose (33%) or wrong dose (24%) errors. Patients were more likely to receive a lower dose of opioid than ordered as a direct result of an opioid error (57%), with errors adversely impacting pain and/or symptom management in 42% of patients. Half (53%) of the affected patients required additional treatment and/or care as a direct consequence of the opioid error. This retrospective review has provided valuable insights into the patterns and impact of opioid errors in inpatient palliative care services. Iatrogenic harm related to opioid underdosing errors contributed to palliative patients' unrelieved pain. Better understanding the factors that contribute to opioid errors and the role of safety culture in the palliative care service context warrants further investigation. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Opioid Challenge Evaluation of Blockade by Extended-Release Naltrexone in Opioid-Abusing Adults: Dose-Effects and Time-Course

PubMed Central

Bigelow, George E.; Preston, Kenzie L.; Schmittner, John; Dong, Qunming; Gastfriend, David R.

2013-01-01

Background Oral naltrexone's effectiveness as an opioid antagonist has been limited due to poor patient adherence. A long-acting naltrexone formulation may be beneficial. This study evaluated the effects of extended-release injectable naltrexone (XR-NTX), targeted for a one-month duration of action, in blocking opioid agonist challenge effects in humans. Methods Outpatient non-dependent opioid abusers (N=27) were randomly assigned to a single double-blind IM administration of 75, 150, or 300 mg XR-NTX. To assess the extent of opioid blockade, hydromorphone challenges (0, 3, 4.5, 6 mg IM in ascending order at 1-hr intervals [up to 13.5 mg total]) were given at pretreatment baseline and on days 7, 14, 21, 28, 42, and 56. Opioid blockade was assessed via (1) tolerability of the ascending hydromorphone doses; (2) Visual Analog Scale (VAS) ratings of subjective opioid effects and (3) pupil diameter. Effects on the VAS and pupils were assessed via the slope of the time-action function over ascending hydromorphone doses, with zero slope indicating complete blockade. Results Blockade of the VAS “any drug effect” response to 3 mg hydromorphone was complete for 14, 21, and 28 days, respectively, for the XR-NTX doses of 75, 150 and 300 mg. Subjective effects were more readily blocked than was pupil constriction. Higher hydromorphone doses produced only modest increases in agonist effects. With the 300 mg XR-NTX dose the slope of VAS responses remained at or near zero for one month even with maximal cumulative hydromorphone dosing. Conclusions These data quantify the month-long opioid blockade underlying XR-NTX's efficacy in opioid dependence treatment. PMID:22079773

Neurobiological mechanisms involved in nicotine dependence and reward: participation of the endogenous opioid system

PubMed Central

Berrendero, Fernando; Robledo, Patricia; Trigo, José Manuel; Martín-García, Elena; Maldonado, Rafael

2010-01-01

Nicotine is the primary component of tobacco that maintains the smoking habit and develops addiction. The adaptive changes of nicotinic acetylcholine receptors produced by repeated exposure to nicotine play a crucial role in the establishment of dependence. However, other neurochemical systems also participate in the addictive effects of nicotine including glutamate, cannabinoids, GABA and opioids. This review will cover the involvement of these neurotransmitters in nicotine addictive properties, with a special emphasis on the endogenous opioid system. Thus, endogenous enkephalins and beta-endorphins acting on mu-opioid receptors are involved in nicotine rewarding effects, whereas opioid peptides derived from prodynorphin participate in nicotine aversive responses. An upregulation of mu-opioid receptors has been reported after chronic nicotine treatment that could counteract the development of nicotine tolerance, whereas the downregulation induced on kappa-opioid receptors seems to facilitate nicotine tolerance. Endogenous enkephalins acting on mu-opioid receptors also play a role in the development of physical dependence to nicotine. In agreement with these actions of the endogenous opioid system, the opioid antagonist naltrexone has shown to be effective for smoking cessation in certain subpopulations of smokers. PMID:20170672

Are Prescription Opioids Driving the Opioid Crisis? Assumptions vs Facts.

PubMed

Rose, Mark Edmund

2018-04-01

Sharp increases in opioid prescriptions, and associated increases in overdose deaths in the 2000s, evoked widespread calls to change perceptions of opioid analgesics. Medical literature discussions of opioid analgesics began emphasizing patient and public health hazards. Repetitive exposure to this information may influence physician assumptions. While highly consequential to patients with pain whose function and quality of life may benefit from opioid analgesics, current assumptions about prescription opioid analgesics, including their role in the ongoing opioid overdose epidemic, have not been scrutinized. Information was obtained by searching PubMed, governmental agency websites, and conference proceedings. Opioid analgesic prescribing and associated overdose deaths both peaked around 2011 and are in long-term decline; the sharp overdose increase recorded in 2014 was driven by illicit fentanyl and heroin. Nonmethadone prescription opioid analgesic deaths, in the absence of co-ingested benzodiazepines, alcohol, or other central nervous system/respiratory depressants, are infrequent. Within five years of initial prescription opioid misuse, 3.6% initiate heroin use. The United States consumes 80% of the world opioid supply, but opioid access is nonexistent for 80% and severely restricted for 4.1% of the global population. Many current assumptions about opioid analgesics are ill-founded. Illicit fentanyl and heroin, not opioid prescribing, now fuel the current opioid overdose epidemic. National discussion has often neglected the potentially devastating effects of uncontrolled chronic pain. Opioid analgesic prescribing and related overdoses are in decline, at great cost to patients with pain who have benefited or may benefit from, but cannot access, opioid analgesic therapy.

Exploring Opioid-Sparing Multimodal Analgesia Options in Trauma: A Nursing Perspective.

PubMed

Sullivan, Denise; Lyons, Mary; Montgomery, Robert; Quinlan-Colwell, Ann

Challenges with opioids (e.g., adverse events, misuse and abuse with long-term administration) have led to a renewed emphasis on opioid-sparing multimodal management of trauma pain. To assess the extent to which currently available evidence supports the efficacy and safety of various nonopioid analgesics and techniques to manage trauma pain, a literature search of recently published references was performed. Additional citations were included on the basis of authors' knowledge of the literature. Effective options for opioid-sparing analgesics include oral and intravenous (IV) acetaminophen; nonsteroidal anti-inflammatory drugs available via multiple routes; and anticonvulsants, which are especially effective for neuropathic pain associated with trauma. Intravenous routes (e.g., IV acetaminophen, IV ketorolac) may be associated with a faster onset of action than oral routes. Additional adjuvants for the treatment of trauma pain are muscle relaxants and alpha-2 adrenergic agonists. Ketamine and regional techniques play an important role in multimodal therapy but require medical and nursing support. Nonpharmacologic treatments (e.g., cryotherapy, distraction techniques, breathing and relaxation, acupuncture) supplement pharmacologic analgesics and can be safe and easy to implement. In conclusion, opioid-sparing multimodal analgesia addresses concerns associated with high doses of opioids, and many pharmacologic and nonpharmacologic options are available to implement this strategy. Nurses play key roles in comprehensive patient assessment; administration of patient-focused, opioid-sparing, multimodal analgesia in trauma; and monitoring for safety concerns.

Prescription Opioid Analgesics Commonly Unused After Surgery: A Systematic Review.

PubMed

Bicket, Mark C; Long, Jane J; Pronovost, Peter J; Alexander, G Caleb; Wu, Christopher L

2017-11-01

Prescription opioid analgesics play an important role in the treatment of postoperative pain; however, unused opioids may be diverted for nonmedical use and contribute to opioid-related injuries and deaths. To quantify how commonly postoperative prescription opioids are unused, why they remain unused, and what practices are followed regarding their storage and disposal. MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched from database inception to October 18, 2016, for studies describing opioid oversupply for adults after a surgical procedure. The primary outcome-opioid oversupply-was defined as the number of patients with either filled but unused opioid prescriptions or unfilled opioid prescriptions. Two reviewers independently screened studies for inclusion, extracted data, and assessed the study quality. Six eligible studies reported on a total of 810 unique patients (range, 30-250 patients) who underwent 7 different types of surgical procedures. Across the 6 studies, 67% to 92% of patients reported unused opioids. Of all the opioid tablets obtained by surgical patients, 42% to 71% went unused. Most patients stopped or used no opioids owing to adequate pain control, and 16% to 29% of patients reported opioid-induced adverse effects. In 2 studies examining storage safety, 73% to 77% of patients reported that their prescription opioids were not stored in locked containers. All studies reported low rates of anticipated or actual disposal, but no study reported US Food and Drug Administration-recommended disposal methods in more than 9% of patients. Postoperative prescription opioids often go unused, unlocked, and undisposed, suggesting an important reservoir of opioids contributing to nonmedical use of these products, which could cause injuries or even deaths.

Blockade of NMDA receptors prevents analgesic tolerance to repeated transcutaneous electrical nerve stimulation (TENS) in rats

PubMed Central

Hingne, Priyanka M.; Sluka, Kathleen A.

2008-01-01

Repeated daily application transcutaneous electrical nerve stimulation (TENS) results in tolerance, at spinal opioid receptors, to the anti-hyperalgesia produced by TENS. Since N-Methyl-D-Aspartate (NMDA) receptor antagonists prevent analgesic tolerance to opioid agonists we hypothesized that blockade of NMDA receptors will prevent tolerance to TENS. In rats with knee joint inflammation, TENS was applied for 20 minute daily at high frequency (100 Hz), low frequency (4 Hz), or sham TENS. Rats were treated with the NMDA antagonist MK-801 (0.01 mg/kg-0.1 mg/kg) or vehicle daily before TENS. Paw withdrawal thresholds were tested before and after inflammation, and before and after TENS treatment for 4 days. On day 1 TENS reversed the decreased mechanical withdrawal threshold induced by joint inflammation. On day 4 TENS had no effect on the decreased withdrawal threshold in the group treated with vehicle demonstrating development of tolerance. However, in the group treated with 0.1 mg/kg MK-801, TENS significantly reversed the mechanical withdrawal thresholds on day 4 demonstrating that tolerance did not develop. Vehicle treated animals developed cross-tolerance at spinal opioid receptors. Treatment with MK-801 reversed this cross-tolerance at spinal opioid receptors. In summary, blockade of NMDA receptors prevents analgesic tolerance to daily TENS by preventing tolerance at spinal opioid receptors. Perspective Tolerance observed to the clinical treatment of TENS could be prevented by administration of pharmaceutical agents with NMDA receptors activity such as ketamine or dextromethorphan. PMID:18061543

Short-term repeated corticosterone administration enhances glutamatergic but not GABAergic transmission in the rat motor cortex.

PubMed

Kula, Joanna; Blasiak, Anna; Czerw, Anna; Tylko, Grzegorz; Sowa, Joanna; Hess, Grzegorz

2016-04-01

It has been demonstrated that stress impairs performance of skilled reaching and walking tasks in rats due to the action of glucocorticoids involved in the stress response. Skilled reaching and walking are controlled by the primary motor cortex (M1); however, it is not known whether stress-related impairments in skilled motor tasks are related to functional and/or structural alterations within the M1. We studied the effects of single and repeated injections of corticosterone (twice daily for 7 days) on spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) recorded from layer II/III pyramidal neurons in ex vivo slices of the M1, prepared 2 days after the last administration of the hormone. We also measured the density of dendritic spines on pyramidal cells and the protein levels of selected subunits of AMPA, NMDA, and GABAA receptors after repeated corticosterone administration. Repeatedly administered corticosterone induced an increase in the frequency but not in the amplitude of sEPSCs, while a single administration had no effect on the recorded excitatory currents. The frequency and amplitude of sIPSCs as well as the excitability of pyramidal cells were changed neither after single nor after repeated corticosterone administration. Treatment with corticosterone for 7 days did not modify the density of dendritic spines on pyramidal neurons. Corticosterone influenced neither the protein levels of GluA1, GluA2, GluN1, GluN2A, and GluN2B subunits of glutamate receptors nor those of α1, β2, and γ2 subunits of the GABAA receptor. The increase in sEPSCs frequency induced by repeated corticosterone administration faded out within 7 days. These data indicate that prolonged administration of exogenous corticosterone selectively and reversibly enhances glutamatergic, but not GABAergic transmission in the rat motor cortex. Our results suggest that corticosterone treatment results in an enhancement of spontaneous glutamate release from presynaptic

NKTR-181: A Novel Mu-Opioid Analgesic with Inherently Low Abuse Potential.

PubMed

Miyazaki, Takahiro; Choi, Irene Y; Rubas, Werner; Anand, Neel K; Ali, Cherie; Evans, Juli; Gursahani, Hema; Hennessy, Marlene; Kim, Grace; McWeeney, Daniel; Pfeiffer, Juergen; Quach, Phi; Gauvin, David; Riley, Timothy A; Riggs, Jennifer A; Gogas, Kathleen; Zalevsky, Jonathan; Doberstein, Stephen K

2017-10-01

The increasing availability of prescription opioid analgesics for the treatment of pain has been paralleled by an epidemic of opioid misuse, diversion, and overdose. The development of abuse-deterrent formulations (ADFs) of conventional opioids such as oxycodone and morphine represents an advance in the field and has had a positive but insufficient impact, as most opioids are still prescribed in highly abusable, non-ADF forms, and abusers can tamper with ADF medications to liberate the abusable opioid within. The abuse liability of mu-opioid agonists appears to be dependent on their rapid rate of entry into the central nervous system (CNS), whereas analgesic activity appears to be a function of CNS exposure alone, suggesting that a new opioid agonist with an inherently low rate of influx across the blood-brain barrier could mediate analgesia with low abuse liability, regardless of formulation or route of administration. NKTR-181 is a novel, long-acting, selective mu-opioid agonist with structural properties that reduce its rate of entry across the blood-brain barrier compared with traditional mu-opioid agonists. NKTR-181 demonstrated maximum analgesic activity comparable to that of oxycodone in hot-plate latency and acetic-acid writhing models. NKTR-181 was distinguishable from oxycodone by its reduced abuse potential in self-administration and progressive-ratio break point models, with behavioral effects similar to those of saline, as well as reduced CNS side effects as measured by the modified Irwin test. The in vitro and in vivo studies presented here demonstrate that NKTR-181 is the first selective mu-opioid agonist to combine analgesic efficacy and reduced abuse liability through the alteration of brain-entry kinetics. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Epigenetic regulation of spinal cord gene expression contributes to enhanced postoperative pain and analgesic tolerance subsequent to continuous opioid exposure

PubMed Central

Liang, De-Yong; Shi, Xiao-You; Sun, Yuan; Clark, J David

2016-01-01

Background Opioids have become the mainstay for treatment of moderate to severe pain and are commonly used to treat surgical pain. While opioid administration has been shown to cause opioid-induced hyperalgesia and tolerance, interactions between opioid administration and surgery with respect to these problematic adaptations have scarcely been addressed. Accumulating evidence suggests opioids and nociceptive signaling may converge on epigenetic mechanisms in spinal cord to enhance or prolong neuroplastic changes. Epigenetic regulation of Bdnf (brain-derived neurotrophic factor) and Pdyn (prodynorphin) genes may be involved. Results Four days of ascending doses of morphine treatment caused opioid-induced hyperalgesia and reduced opioid analgesic efficacy in mice. Both opioid-induced hyperalgesia and the reduced opioid analgesic efficacy were enhanced in mice that received hindpaw incisions. The expression of Bdnf and Pdyn (qPCR) was increased after morphine treatment and incision. Chromatin immunoprecipitation assays demonstrated that the Pdyn and Bdnf promoters were more strongly associated with acetylated H3K9 after morphine plus incision than in the morphine or incision alone groups. Selective tropomyosin-related kinase B (ANA-12) and κ-opioid receptor (nor-binaltorphimine) antagonists were administered intrathecally, both reduced hyperalgesia one or three days after surgery. Administration of ANA-12 or nor-binaltorphimine attenuated the decreased morphine analgesic efficacy on day 1, but only nor-binaltorphimine was effective on day 3 after incision in opioid-exposed group. Coadministration of histone acetyltransferase inhibitor anacardic acid daily with morphine blocked the development of opioid-induced hyperalgesia and attenuated incision-enhanced hyperalgesia in morphine-treated mice. Anacardic acid had similar effects on analgesic tolerance, showing the involvement of histone acetylation in the interactions detected. Conclusions Spinal epigenetic changes

Epigenetic regulation of spinal cord gene expression contributes to enhanced postoperative pain and analgesic tolerance subsequent to continuous opioid exposure.

PubMed

Sahbaie, Peyman; Liang, De-Yong; Shi, Xiao-You; Sun, Yuan; Clark, J David

2016-01-01

Opioids have become the mainstay for treatment of moderate to severe pain and are commonly used to treat surgical pain. While opioid administration has been shown to cause opioid-induced hyperalgesia and tolerance, interactions between opioid administration and surgery with respect to these problematic adaptations have scarcely been addressed. Accumulating evidence suggests opioids and nociceptive signaling may converge on epigenetic mechanisms in spinal cord to enhance or prolong neuroplastic changes. Epigenetic regulation of Bdnf (brain-derived neurotrophic factor) and Pdyn (prodynorphin) genes may be involved. Four days of ascending doses of morphine treatment caused opioid-induced hyperalgesia and reduced opioid analgesic efficacy in mice. Both opioid-induced hyperalgesia and the reduced opioid analgesic efficacy were enhanced in mice that received hindpaw incisions. The expression of Bdnf and Pdyn (qPCR) was increased after morphine treatment and incision. Chromatin immunoprecipitation assays demonstrated that the Pdyn and Bdnf promoters were more strongly associated with acetylated H3K9 after morphine plus incision than in the morphine or incision alone groups. Selective tropomyosin-related kinase B (ANA-12) and κ-opioid receptor (nor-binaltorphimine) antagonists were administered intrathecally, both reduced hyperalgesia one or three days after surgery. Administration of ANA-12 or nor-binaltorphimine attenuated the decreased morphine analgesic efficacy on day 1, but only nor-binaltorphimine was effective on day 3 after incision in opioid-exposed group. Coadministration of histone acetyltransferase inhibitor anacardic acid daily with morphine blocked the development of opioid-induced hyperalgesia and attenuated incision-enhanced hyperalgesia in morphine-treated mice. Anacardic acid had similar effects on analgesic tolerance, showing the involvement of histone acetylation in the interactions detected. Spinal epigenetic changes involving Bdnf and Pdyn may

New Opioid Analgesic Approvals and Outpatient Utilization of Opioid Analgesics in the United States, 1997 through 2015.

PubMed

Chai, Grace; Xu, Jing; Osterhout, James; Liberatore, Mark A; Miller, Kathleen L; Wolff, Carolyn; Cruz, Marisa; Lurie, Peter; Dal Pan, Gerald

2018-05-01

The opioid epidemic, driven in part by increased prescribing, is a public health emergency. This study examines dispensed prescription patterns and approvals of new opioid analgesic products to investigate whether the introduction of these new drugs increases prescribing. Prescribing patterns based on dispensed prescription claims from the U.S. retail setting were assessed with new brand and generic opioid analgesic products approved in the United States from 1997 through 2015. From 1997 through 2015, the U.S. Food and Drug Administration (Silver Spring, Maryland) approved 263 opioid analgesic products, including 33 brand products. Dispensed prescriptions initially increased 80% from 145 million prescriptions in 1997 to a peak of 260 million prescriptions in 2012 before decreasing by 12% to 228 million prescriptions in 2015. Morphine milligram equivalents dispensed per prescription increased from 486 in 1997 to a peak of 950 in 2010, before decreasing to 905 in 2015. In 2015, generic products accounted for 96% (218/228 million prescriptions) of all opioid analgesic prescriptions dispensed. The remaining prescriptions were dispensed for brand products, of which nearly half were dispensed for one brand product (OxyContin, Purdue, USA). There has been a dramatic increase in prescriptions dispensed for opioid analgesics since 1997 and an increasing number of opioid analgesic approvals; however, the number of prescriptions dispensed has declined since 2012 despite an increasing number of approvals. Examination of dispensed prescriptions shows a shifting and complex market where multiple factors likely influence prescribing; the approval of new products alone may not be sufficient to be a primary driver of increased prescribing. An online visual overview is available for this article at http://links.lww.com/ALN/B705.

Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy μ-Opioid Receptor (MOR) Agonists/δ-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities.

PubMed

Harland, Aubrie A; Yeomans, Larisa; Griggs, Nicholas W; Anand, Jessica P; Pogozheva, Irina D; Jutkiewicz, Emily M; Traynor, John R; Mosberg, Henry I

2015-11-25

In a previously described peptidomimetic series, we reported the development of bifunctional μ-opioid receptor (MOR) agonist and δ-opioid receptor (DOR) antagonist ligands with a lead compound that produced antinociception for 1 h after intraperitoneal administration in mice. In this paper, we expand on our original series by presenting two modifications, both of which were designed with the following objectives: (1) probing bioavailability and improving metabolic stability, (2) balancing affinities between MOR and DOR while reducing affinity and efficacy at the κ-opioid receptor (KOR), and (3) improving in vivo efficacy. Here, we establish that, through N-acetylation of our original peptidomimetic series, we are able to improve DOR affinity and increase selectivity relative to KOR while maintaining the desired MOR agonist/DOR antagonist profile. From initial in vivo studies, one compound (14a) was found to produce dose-dependent antinociception after peripheral administration with an improved duration of action of longer than 3 h.

ACCUMULATION AND METABOLISM OF ARSENIC IN MICE AFTER REPEATED ADMINISTRATION OF ARSENATE

EPA Science Inventory

Accumulation and metabolism of arsenic in mice after repeated oral administration of arsenate, Hughes, M. F., Kenyon, E. M., Edwards, B. C., Mitchell, C. T., Del Razo, L. M., and Thomas,
D. J.

The human carcinogen inorganic arsenic (iAs) is a pervasive environmental ...

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.

Prospects for Creation of Cardioprotective and Antiarrhythmic Drugs Based on Opioid Receptor Agonists

PubMed Central

Maslov, Leonid N; Oeltgen, Peter R.; Naryzhnaya, Natalia V.; Pei, Jian‐Ming; Brown, Stephen A.; Lishmanov, Yury B.; Downey, James M.

2016-01-01

Abstract It has now been demonstrated that the μ, δ1, δ2, and κ1 opioid receptor (OR) agonists represent the most promising group of opioids for the creation of drugs enhancing cardiac tolerance to the detrimental effects of ischemia/reperfusion (I/R). Opioids are able to prevent necrosis and apoptosis of cardiomyocytes during I/R and improve cardiac contractility in the reperfusion period. The OR agonists exert an infarct‐reducing effect with prophylactic administration and prevent reperfusion‐induced cardiomyocyte death when ischemic injury of heart has already occurred; that is, opioids can mimic preconditioning and postconditioning phenomena. Furthermore, opioids are also effective in preventing ischemia‐induced arrhythmias. PMID:27197922

The endogenous opioid system in cocaine addiction: what lessons have opioid peptide and receptor knockout mice taught us?

PubMed Central

Yoo, Ji Hoon; Kitchen, Ian; Bailey, Alexis

2012-01-01

Cocaine addiction has become a major concern in the UK as Britain tops the European ‘league table’ for cocaine abuse. Despite its devastating health and socio-economic consequences, no effective pharmacotherapy for treating cocaine addiction is available. Identifying neurochemical changes induced by repeated drug exposure is critical not only for understanding the transition from recreational drug use towards compulsive drug abuse but also for the development of novel targets for the treatment of the disease and especially for relapse prevention. This article focuses on the effects of chronic cocaine exposure and withdrawal on each of the endogenous opioid peptides and receptors in rodent models. In addition, we review the studies that utilized opioid peptide or receptor knockout mice in order to identify and/or clarify the role of different components of the opioid system in cocaine-addictive behaviours and in cocaine-induced alterations of brain neurochemistry. The review of these studies indicates a region-specific activation of the µ-opioid receptor system following chronic cocaine exposure, which may contribute towards the rewarding effect of the drug and possibly towards cocaine craving during withdrawal followed by relapse. Cocaine also causes a region-specific activation of the κ-opioid receptor/dynorphin system, which may antagonize the rewarding effect of the drug, and at the same time, contribute to the stress-inducing properties of the drug and the triggering of relapse. These conclusions have important implications for the development of effective pharmacotherapy for the treatment of cocaine addiction and the prevention of relapse. PMID:22428846

Latin-American guidelines for opioid use in chronic nononcologic pain.

PubMed

Lara-Solares, Argelia; Aguayo Zamora, Carlos; Amescua García, César; Garcia, João Batista Santos; Berenguel Cook, María Del Rosario; Bonilla Sierra, Patricia; Campos Kraychete, Durval; Flores Cantisani, José Alberto; Guerrero, Carlos; Guillén Núñez, María Del Rocío; Hernández Castro, John Jairo; Hernández Ortíz, Andrés; Jreige Iskandar, Aziza; Lech, Osvandré; Macías Guerra, Jacqueline; Ramírez Samayoa, Gerardo; Rangel Morillo, Edwin; Rico Pazos, María Antonieta; Sempértegui Gallegos, Manuel

2017-05-01

Latin-American experts in the use of opioids in patients with chronic nononcologic pain (CNOP) have updated existing recommendations to current Latin-American reality. Several key opinion leaders from Latin America participated in a face-to-face meeting in Guatemala (April 2015) to discuss the use of opioids in CNOP. Subgroups of experts worked on specific topics, reviewed the literature and shaped the final manuscript. The expert panel developed guidelines taking into consideration the utility of both opioid and nonopioid analgesics and factors pertaining to their efficacy, safety, adherence, administration and risks for abuse/addiction. Latin-American guidelines for the use of opioids in CNOP should improve pain relief and patients' quality of life by increasing access to these effective agents.

Influence of opioid-related side effects on disability, mood, and opioid misuse risk among patients with chronic pain in primary care.

PubMed

Jamison, Robert N; Dorado, Kathleen; Mei, Anna; Edwards, Robert R; Martel, Marc O

2017-03-01

There is increasing concern among primary care practitioners about the use of opioids for chronic pain, including their adverse effects, but little attention has been given to how reports of side effects from prescription medication can contribute to outcomes among patients with chronic pain. The aim of this study was to investigate the impact of frequently reported side effects on mood, disability, and opioid misuse in patients with chronic pain prescribed opioids within primary care. Two hundred (N = 200) patients with chronic pain taking opioids for pain were recruited into the study. All patients completed baseline measures and a monthly side effects checklist once a month for 6 months. Patients were divided evenly based on a median split of the number of endorsed side effects over 6 months. The subjects repeated the baseline measures at the end of the study period. Over time, reports of medication side effects tended to decrease, but differences in frequency of reported side effects from baseline to follow-up (6-month time) were not significant, and the order of the frequency of the reported side effects remained similar. Patients who reported significant medication-related adverse effects reported significantly greater activity interference, negative affect, and catastrophizing compared with those with fewer side effects ( P < 0.01). In addition, those patients with pain who reported more side effects showed significantly higher scores on opioid misuse risk ( P < 0.001). This study demonstrates the important role of monitoring medication-related side effects among patients with chronic pain who are prescribed opioid medication for pain within primary care.

Clinical interpretation of opioid tolerance versus opioid-induced hyperalgesia.

PubMed

Chen, Lucy; Sein, Michael; Vo, Trang; Amhmed, Shihab; Zhang, Yi; Hilaire, Kristin St; Houghton, Mary; Mao, Jianren

2014-01-01

Opioid analgesics are commonly used to manage moderate to severe pain. However, the long-term use of opioids could lead to opioid tolerance (OT) and opioid-induced hyperalgesia (OIH). Distinguishing OIH from OT would impact the practice of opioid therapy because opioid dose adjustment may differentially influence OT and OIH. Currently, there are no standard criteria of OT versus OIH causing considerable ambiguity in clinical interpretation and management of these conditions. The authors designed a practitioner-based survey consisting of 20 targeted questions. Answering these questions would require responders' actual clinical experiences with opioid therapy. The survey was conducted between 2011 and 2012 through direct mails or e-mails to 1,408 physicians who are currently practicing in the United States. The authors find that certain clinical characteristics (eg, increased pain despite opioid dose escalation) are often used by practitioners to make differential diagnosis of OT and OIH despite some overlap in their clinical presentation. A key difference in clinical outcome is that OT and OIH could be improved and exacerbated by opioid dose escalation, respectively. Our survey results revealed a significant knowledge gap in some responders regarding differential diagnosis and management of OT and OIH. The results also identified several issues, such as opioid dose adjustment and clinical comorbidities related to OT and OIH, which require future patient-based studies.

Exploring Opioid-Sparing Multimodal Analgesia Options in Trauma: A Nursing Perspective

PubMed Central

Lyons, Mary; Montgomery, Robert; Quinlan-Colwell, Ann

2016-01-01

Challenges with opioids (e.g., adverse events, misuse and abuse with long-term administration) have led to a renewed emphasis on opioid-sparing multimodal management of trauma pain. To assess the extent to which currently available evidence supports the efficacy and safety of various nonopioid analgesics and techniques to manage trauma pain, a literature search of recently published references was performed. Additional citations were included on the basis of authors' knowledge of the literature. Effective options for opioid-sparing analgesics include oral and intravenous (IV) acetaminophen; nonsteroidal anti-inflammatory drugs available via multiple routes; and anticonvulsants, which are especially effective for neuropathic pain associated with trauma. Intravenous routes (e.g., IV acetaminophen, IV ketorolac) may be associated with a faster onset of action than oral routes. Additional adjuvants for the treatment of trauma pain are muscle relaxants and alpha-2 adrenergic agonists. Ketamine and regional techniques play an important role in multimodal therapy but require medical and nursing support. Nonpharmacologic treatments (e.g., cryotherapy, distraction techniques, breathing and relaxation, acupuncture) supplement pharmacologic analgesics and can be safe and easy to implement. In conclusion, opioid-sparing multimodal analgesia addresses concerns associated with high doses of opioids, and many pharmacologic and nonpharmacologic options are available to implement this strategy. Nurses play key roles in comprehensive patient assessment; administration of patient-focused, opioid-sparing, multimodal analgesia in trauma; and monitoring for safety concerns. PMID:27828892

Neonatal opioid withdrawal and antenatal opioid prescribing

PubMed Central

Gomes, Tara; Camacho, Ximena; Yao, Zhan; Guttmann, Astrid; Mamdani, Muhammad M.; Juurlink, David N.; Dhalla, Irfan A.

2015-01-01

Background The incidence of neonatal opioid withdrawal is increasing in both Canada and the United States. However, the degree to which the treatment of pain with opioids, rather than the misuse of prescription opioids or heroin, contributes to the prevalence of neonatal opioid withdrawal remains unknown. Methods We conducted a retrospective, population-based, cross-sectional study between 1992 and 2011 in Ontario with 2 objectives. First, we determined the annual incidence of neonatal abstinence syndrome. Second, using data from a subset of women eligible for publicly funded prescription drugs, we determined what proportion of women who deliver an infant with neonatal abstinence syndrome were given a prescription for an opioid before and during pregnancy. Results The incidence of neonatal abstinence syndrome in Ontario increased 15-fold during the study period, from 0.28 per 1000 live births in 1992 to 4.29 per 1000 live births in 2011. During the final 5 years of the study, we identified 927 deliveries of infants with neonatal abstinence syndrome to mothers who were public drug plan beneficiaries. Of these mothers, 67% had received an opioid prescription in the 100 days preceding delivery, including 53.3% who received methadone, an increase from 28.6% in the interval spanning 1 to 2 years before delivery (p < 0.001). Prescription for nonmethadone opioids decreased from 38% to 17% (p < 0.001). Interpretation The incidence of neonatal opioid withdrawal in Ontario has increased substantially over the last 20 years. Most of the women in this cohort who delivered an infant with neonatal abstinence syndrome had received a prescription for an opioid both before and during their pregnancy. PMID:25844370

Magnesium ions and opioid agonists in vincristine-induced neuropathy.

PubMed

Bujalska, Magdalena; Makulska-Nowak, Helena; Gumułka, Stanisław W

2009-01-01

Neuropathic pain is difficult to treat. Classic analgesics (i.e., opioid receptor agonists) usually possess low activity. Therefore other agents such as antidepressants, anticonvulsants, and corticosteroids are used. It is commonly known that NMDA antagonists increase analgesic activity of opioids. Unfortunately, clinical use of NMDA antagonists is limited because of the relatively frequent occurrence of adverse effects e.g., memory impairment, psychomimetic effects, ataxia and motor in-coordination. Magnesium ions (Mg(2+)) are NMDA receptor blockers in physiological conditions. Therefore, in this study the effect of opioid receptor agonists and the influence of Mg(2+) on the action of opioid agonists in vincristine-induced hyperalgesia were examined. Opioid agonists such as morphine (5 mg/kg, ip), and fentanyl (0.0625 mg/kg, ip), as well as the partial agonist buprenorphine (0.075 mg/kg, ip) administered alone on 5 consecutives days did not modify the hyperalgesia in vincristine rats. In contrast, pretreatment with a low dose of magnesium sulfate (30 mg/kg, ip) resulted in a progressive increase of the analgesic action of all three investigated opioids. After discontinuation of drug administration, the effect persisted for several days.

Pavlovian conditioning of multiple opioid-like responses in mice.

PubMed

Bryant, Camron D; Roberts, Kristofer W; Culbertson, Christopher S; Le, Alan; Evans, Christopher J; Fanselow, Michael S

2009-07-01

Conditional responses in rodents such as locomotion have been reported for drugs of abuse and similar to the placebo response in humans, may be associated with the expectation of reward. We examined several conditional opioid-like responses and the influence of drug expectation on conditioned place preference and concomitant conditional locomotion. Male C57BL/6J mice were conditioned with the selective mu opioid receptor agonist fentanyl (0.2mg/kg, i.p.) in a novel context and subsequently given a vehicle injection. In separate experiments, locomotor activity, Straub tail, hot plate sensitivity, and conditioned place preference (CPP) were measured. Mice exhibited multiple conditional opioid-like responses including conditional hyperlocomotion, a conditional pattern of opioid-like locomotion, Straub tail, analgesia, and place preference. Modulating drug expectation via administration of fentanyl to "demonstrator" mice in the home cage did not affect the expression of conditioned place preference or the concomitant locomotor activity in "observer" mice. In summary, Pavlovian conditioning of an opioid in a novel context induced multiple conditional opioid-like behaviors and provides a model for studying the neurobiological mechanisms of the placebo response in mice.

Opioid receptors mediate direct predictive fear learning: evidence from one-trial blocking.

PubMed

Cole, Sindy; McNally, Gavan P

2007-04-01

Pavlovian fear learning depends on predictive error, so that fear learning occurs when the actual outcome of a conditioning trial exceeds the expected outcome. Previous research has shown that opioid receptors, including mu-opioid receptors in the ventrolateral quadrant of the midbrain periaqueductal gray (vlPAG), mediate such predictive fear learning. Four experiments reported here used a within-subject one-trial blocking design to study whether opioid receptors mediate a direct or indirect action of predictive error on Pavlovian association formation. In Stage I, rats were trained to fear conditioned stimulus (CS) A by pairing it with shock. In Stage II, CSA and CSB were co-presented once and co-terminated with shock. Two novel stimuli, CSC and CSD, were also co-presented once and co-terminated with shock in Stage II. The results showed one-trial blocking of fear learning (Experiment 1) as well as one-trial unblocking of fear learning when Stage II training employed a higher intensity footshock than was used in Stage I (Experiment 2). Systemic administrations of the opioid receptor antagonist naloxone (Experiment 3) or intra-vlPAG administrations of the selective mu-opioid receptor antagonist CTAP (Experiment 4) prior to Stage II training prevented one-trial blocking. These results show that opioid receptors mediate the direct actions of predictive error on Pavlovian association formation.

Abuse-deterrent formulations of prescription opioid analgesics in the management of chronic noncancer pain.

PubMed

Hale, Martin E; Moe, Derek; Bond, Mary; Gasior, Maciej; Malamut, Richard

2016-10-01

Misuse, abuse and diversion of prescription opioid analgesics represent a global public health concern. The development of abuse-deterrent formulations (ADFs) of prescription opioid analgesics is an important step toward reducing abuse and diversion of these medications, as well as potentially limiting medical consequences when misused or administered in error. ADFs aim to hinder extraction of the active ingredient, prevent administration through alternative routes and/or make abuse of the manipulated product less attractive, less rewarding or aversive. However, opioid ADFs may still be abused via the intended route of administration by increasing the dose and/or dosing frequency. The science of abuse deterrence and the regulatory landscape are still relatively new and evolving. This paper reviews the current status of opioid ADFs, with particular focus on different approaches that can be used to deter abuse, regulatory considerations and implications for clinical management.

A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates.

PubMed

Ding, Huiping; Czoty, Paul W; Kiguchi, Norikazu; Cami-Kobeci, Gerta; Sukhtankar, Devki D; Nader, Michael A; Husbands, Stephen M; Ko, Mei-Chuan

2016-09-13

Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors. The aim of this preclinical study was to establish the functional profile of BU08028 in monkeys using clinically used MOP receptor agonists for side-by-side comparisons in various well-honed behavioral and physiological assays. Systemic BU08028 (0.001-0.01 mg/kg) produced potent long-lasting (i.e., >24 h) antinociceptive and antiallodynic effects, which were blocked by MOP or NOP receptor antagonists. More importantly, the reinforcing strength of BU08028 was significantly lower than that of cocaine, remifentanil, or buprenorphine in monkeys responding under a progressive-ratio schedule of drug self-administration. Unlike MOP receptor agonists, BU08028 at antinociceptive doses and ∼10- to 30-fold higher doses did not cause respiratory depression or cardiovascular adverse events as measured by telemetry devices. After repeated administration, the monkeys developed acute physical dependence on morphine, as manifested by precipitated withdrawal signs, such as increased respiratory rate, heart rate, and blood pressure. In contrast, monkeys did not show physical dependence on BU08028. These in vivo findings in primates not only document the efficacy and tolerability profile of bifunctional MOP/NOP receptor agonists, but also provide a means of translating such ligands into therapies as safe and potentially abuse-free opioid analgesics.

Chronic Opioid Usage in Surgical Patients in a Large Academic Center

PubMed Central

Jiang, Xueying; Orton, Margaret; Feng, Rui; Hossain, Erik; Malhotra, Neil R.; Zager, Eric L.; Liu, Renyu

2017-01-01

Objective The objective of this study is to investigate the prevalence and disparity of chronic opioid usage in surgical patients and the potential risk factors associated with chronic opioid usage. Background Chronic opioid usage is common in surgical patients; however, the characteristics of opioid usage in surgical patients is unclear. In this study, we hypothesize that the prevalence of chronic opioid usage in surgical patients is high, and that significant disparities may exist among different surgical populations. Methods Data of opioid usage in outpatients among different surgical services were extracted from the electronic medical record database. Patient demographics, clinical characteristics of sex, age, race, body mass index (BMI), specialty visited, duration of opioid use, and opioid type were collected. Chronic opioid users were defined as patients who had been recorded as taking opioids for at least 90 days determined by the first and last visit dates under opioid usage during the investigation. Results There were 79,123 patients included in this study. The average prevalence is 9.2%, ranging from 4.4% to 23.8% among various specialties. The prevalence in orthopedics (23.8%), neurosurgery (18.7%), and gastrointestinal surgery (14.4%) ranked in the top three subspecialties. Major factors influencing chronic opioid use include age, Ethnicitiy, Subspecialtiy, and multiple specialty visits. Approximately 75% of chronic users took opioids that belong to the category II Drug Enforcement Administration classification. Conclusions Overall prevalence of chronic opioid usage in surgical patients is high with widespread disparity among different sex, age, ethnicity, BMI, and subspecialty groups. Information obtained from this study provides clues to reduce chronic opioid usage in surgical patients. PMID:27163960

Buprenorphine implants in medical treatment of opioid addiction.

PubMed

Chavoustie, Steven; Frost, Michael; Snyder, Ole; Owen, Joel; Darwish, Mona; Dammerman, Ryan; Sanjurjo, Victoria

2017-08-01

Opioid use disorder is a chronic, relapsing disease that encompasses use of both prescription opioids and heroin and is associated with a high annual rate of overdose deaths. Medical treatment has proven more successful than placebo treatment or psychosocial intervention, and the partial µ-opioid receptor agonist and κ-opioid receptor antagonist buprenorphine is similar in efficacy to methadone while offering lower risk of respiratory depression. However, frequent dosing requirements and potential for misuse and drug diversion contribute to significant complications with treatment adherence for available formulations. Areas covered: This review describes the development of and preliminary data from clinical trials of an implantable buprenorphine formulation. Efficacy and safety data from comparative studies with other administrations of buprenorphine, including tablets and sublingual film, will be described. Key premises of the Risk Evaluation and Mitigation Strategy program for safely administering buprenorphine implants, which all prescribing physicians must complete, are also discussed. Expert commentary: Long-acting implantable drug formulations that offer consistent drug delivery and lower risk of misuse, diversion, or accidental pediatric exposure over traditional formulations represent a promising development for the effective treatment of opioid use disorder.

Successful Treatment of Opioid-Refractory Cancer Pain with Short-Course, Low-Dose Ketamine.

PubMed

Waldfogel, Julie M; Nesbit, Suzanne; Cohen, Steven P; Dy, Sydney M

2016-12-01

Opioids remain the mainstay of treatment for severe cancer pain, but up to 20% of patients have persistent or refractory pain despite rapid and aggressive opioid titration, or develop refractory pain after long-term opioid use. In these scenarios, alternative agents and mechanisms for analgesia should be considered. This case report describes a 28-year-old man with metastatic pancreatic neuroendocrine cancer with severe, intractable pain despite high-dose opioids including methadone and a hydromorphone patient-controlled analgesia (PCA). After treatment with short-course, low-dose ketamine, his opioid requirements decreased by 99% and pain ratings by 50%, with the majority of this decrease occurring in the first 48 hours. As this patient's pain and opioid regimen escalated, he likely experienced some component of central sensitization and hyperalgesia. Administration of ketamine reduced opioid consumption by 99% and potentially "reset" neuronal hyperexcitability and reduced pain signaling, allowing for improved pain control.

Changes in misuse and abuse of prescription opioids following implementation of Extended-Release and Long-Acting Opioid Analgesic Risk Evaluation and Mitigation Strategy.

PubMed

Bucher Bartelson, Becki; Le Lait, M Claire; Green, Jody L; Cepeda, M Soledad; Coplan, Paul M; Maziere, Jean-Yves; Wedin, Gregory P; Dart, Richard C

2017-09-01

An unintended consequence of extended-release (ER) and long-acting (LA) prescription opioids is that these formulations can be more attractive to abusers than immediate-release (IR) formulations. The US Food and Drug Administration recognized these risks and approved the ER/LA Opioid Analgesic Risk Evaluation and Mitigation Strategy (ER/LA REMS), which has a goal of reducing opioid misuse and abuse and their associated consequences. The primary objective of this analysis is to determine whether ER/LA REMS implementation was associated with decreased reports of misuse and abuse. Data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS(R)) System Poison Center Program were utilized. Poison center cases are assigned a reason for exposure, a medical outcome, and a level of health care received. Rates adjusted for population and drug utilization were analyzed over time. RADARS System Poison Center Program data indicate a notable decrease in ER/LA opioid rates of intentional abuse and misuse as well as major medical outcomes or hospitalizations following implementation of the ER/LA REMS. While similar decreases were observed for the IR prescription opioid group, the decreasing rate for the ER/LA opioids exceeded the decreasing rates for the IR prescription opioids and was distinctly different than that for the prescription stimulants, indicating that the ER/LA REMS program may have had an additional effect on decreases in opioid abuse and intentional misuse beyond secular trends. Copyright © 2017 John Wiley & Sons, Ltd.

Intravenous Acetaminophen as an Adjunct Analgesic in Cardiac Surgery Reduces Opioid Consumption But Not Opioid-Related Adverse Effects: A Randomized Controlled Trial.

PubMed

Jelacic, Srdjan; Bollag, Laurent; Bowdle, Andrew; Rivat, Cyril; Cain, Kevin C; Richebe, Philippe

2016-08-01

The authors hypothesized that intravenous acetaminophen as an adjunct analgesic would significantly decrease 24-hour postoperative opioid consumption. Double-blind, randomized, placebo-controlled trial. A single academic medical center. The study was comprised of 68 adult patients undergoing cardiac surgery. Patients were assigned randomly to receive either 1,000 mg of intravenous acetaminophen or placebo immediately after anesthesia induction, at the end of surgery, and then every 6 hours for the first 24 hours in the intensive care unit, for a total of 6-1,000 mg doses. The primary outcome was 24-hour postoperative opioid consumption. The secondary outcomes included 48-hour postoperative opioid consumption, incisional pain scores, opioid-related adverse effects, length of mechanical ventilation, length of intensive care unit stay, and the extent of wound hyperalgesia assessed at 24 and 48 hours postoperatively. The mean±standard deviation postoperative 24-hour opioid consumption expressed in morphine equivalents was significantly less in the acetaminophen group (45.6±29.5 mg) than in the placebo group (62.3±29.5 mg), representing a 27% reduction in opioid consumption (95% CI, 2.3-31.1 mg; p = 0.024). There were no differences in pain scores and opioid-related adverse effects between the 2 groups. A significantly greater number of patients in the acetaminophen group responded "very much" and "extremely well" when asked how their overall pain experience met their expectation (p = 0.038). The administration of intravenous acetaminophen during cardiac surgery and for the first 24 hours postoperatively reduced opioid consumption and improved patient satisfaction with their overall pain experience but did not reduce opioid side effects. Copyright © 2016 Elsevier Inc. All rights reserved.

Opioid Analgesics for Chronic Non-Cancer Pain: A Guideline on Opioid Prescribing.

PubMed

Van Demark, Robert; Chang, Peter; Heinemann, Daniel

2016-01-01

Over the past decade, the use of opioid analgesics has risen dramatically both in the U.S. and South Dakota. Opioids have been increasingly used to treat chronic non-cancer pain; however, the utilization of opioids for this role has limited and questionable utility. The U.S. has also seen a rise of opioid abuse, addiction, misuse, and overdose. The various pharmacological and non-pharmacological strategies to help physicians manage chronic non-cancer pain and a guideline on appropriate opioid prescribing are presented. Before the decision is made to begin opioid therapy for chronic non-cancer pain, other pharmacological and non-pharmacological therapeutic strategies should be explored. The schema for responsible opioid prescribing can be dived into the following: the initial assessment, initiating opioid therapy, maintenance therapy, and the discontinuation of opioid treatment. These categories are explored, and a general approach to prescribing opioids for chronic non-cancer pain is presented. The Centers for Disease Control and Prevention (CDC) has declared opioid prescription abuse an "epidemic." There are a variety of methods clinicians can utilize to relieve chronic non-cancer pain. If opioid therapy is sought, clinicians should be mindful of the current state of opioid abuse and misuse. This guideline may aid clinicians in appropriate opioid prescribing.

Influence of opioid-related side effects on disability, mood, and opioid misuse risk among patients with chronic pain in primary care

PubMed Central

Jamison, Robert N.; Dorado, Kathleen; Mei, Anna; Edwards, Robert R.; Martel, Marc O.

2017-01-01

Abstract Background: There is increasing concern among primary care practitioners about the use of opioids for chronic pain, including their adverse effects, but little attention has been given to how reports of side effects from prescription medication can contribute to outcomes among patients with chronic pain. The aim of this study was to investigate the impact of frequently reported side effects on mood, disability, and opioid misuse in patients with chronic pain prescribed opioids within primary care. Methods: Two hundred (N = 200) patients with chronic pain taking opioids for pain were recruited into the study. All patients completed baseline measures and a monthly side effects checklist once a month for 6 months. Patients were divided evenly based on a median split of the number of endorsed side effects over 6 months. The subjects repeated the baseline measures at the end of the study period. Results: Over time, reports of medication side effects tended to decrease, but differences in frequency of reported side effects from baseline to follow-up (6-month time) were not significant, and the order of the frequency of the reported side effects remained similar. Patients who reported significant medication-related adverse effects reported significantly greater activity interference, negative affect, and catastrophizing compared with those with fewer side effects (P < 0.01). In addition, those patients with pain who reported more side effects showed significantly higher scores on opioid misuse risk (P < 0.001). Discussion: This study demonstrates the important role of monitoring medication-related side effects among patients with chronic pain who are prescribed opioid medication for pain within primary care. PMID:29392205

The present and future of opioid analgesics in small animal practice.

PubMed

Simon, B T; Steagall, P V

2017-08-01

Opioids are the cornerstone for the treatment of acute pain in small animal patients. This is primarily because of their remarkable safety profile, high efficacy, and benefit of reversibility. There have been some significant advances in our knowledge on opioid pharmacology and clinical usage in companion animal medicine. This review discusses the progression of opioid use in small animal practice providing current misconceptions and controversies in light of routes of administration. Potential targets for research and drug development and novel therapies are discussed in addition to the concepts of glial cell modulators, individual variability, and opioid tolerance and hyperalgesia. The future brings an interesting perspective with the application of pharmacogenetics and individualized pain management in canine and feline practice. © 2016 John Wiley & Sons Ltd.

Opioids with abuse-deterrent properties: A regulatory and technological overview.

PubMed

Haddox, J David

Three concurrent public health problems coexist in the United States: endemic nonmedical use/misuse of opioid analgesics, epidemic overdose fatalities involving opioid analgesics, and endemic chronic pain in adults. These intertwined issues comprise an opioid crisis that has spurred the development of formulations of opioids with abuse-deterrent properties and label claims (OADP). To reduce abuse and misuse of prescription opioids, the federal Food and Drug Administration (FDA) has issued a formal Guidance to drug developers that delineates four categories of testing to generate data sufficient for a description of a product's abuse-deterrent properties, along with associated claims, in its Full Prescribing Information (FPI). This article reviews the epidemiology of the crisis as background for the development of OADP, summarizes the FDA Guidance for Industry regarding abuse-deterrent technologies, and provides an overview of some technologies that are currently employed or are under study for incorporation into OADP. Such technologies include physical and chemical barriers to abuse, combined formulations of opioid agonists and antagonists, inclusion of aversive agents, use of delivery systems that deter abuse, development of new molecular entities and prodrugs, and formulation of products that include some combination of these approaches. Opioids employing these novel technologies are one part of a comprehensive intervention strategy that can deter abuse of prescription opioid analgesics without creating barriers to the safe use of prescription opioids. The maximal public health contribution of OADP will probably occur only when all opioids have FDA-recognized abuse-deterrent properties and label claims.

Current Impact and Application of Abuse-Deterrent Opioid Formulations in Clinical Practice.

PubMed

Lee, Ya-Han; Brown, Daniel L; Chen, Hsiang-Yin

2017-11-01

Abuse-deterrent formulations (ADFs) represent one novel strategy for curbing the potential of opioid abuse. We aim to compare and contrast the characteristics and applications of current abuse-deterrent opioid products in clinical practice. Literature searches were conducted in databases (Pubmed Medline, International Pharmaceutical Abstracts, Google Scholar) and official reports. Relevant data were screened and organized into: 1) epidemiology of opioid abuse, 2) mitigation strategies for reducing opioid abuse, 3) development of ADFs, and 4) clinical experience with these formulations. Increasing trends of opioid abuse and misuse have been reported globally. There are 5 types of abuse-deterrent opioid products: physical chemical barrier, combined agonist/antagonist, sequestered aversive agent, prodrug, and novel delivery system. The advantages and disadvantages of the 5 options are discussed in this review. A total of 9 products with abuse-deterrent labels have been approved by the Food and Drug Administration (FDA). The rates of abuse, diversion, and overdose deaths of these new products are also discussed. A framework for collecting in-time data on the efficacy, benefit and risk ratio, and cost-effectiveness of these new products is suggested to facilitate their optimal use. The present review did not utilize systematic review standards or meta-analytic techniques, given the large heterogeneity of data and outcomes reviewed. ADFs provide an option for inhibiting the abuse or misuse of oral opioid products by hindering extraction of the active ingredient, preventing alternative routes of administration, or causing aversion. Their relatively high costs, uncertain insurance policies, and limited data on pharmacoeconomics warrant collaborative monitoring and assessment by government agencies, pharmaceutical manufacturers, and data analysis services to define their therapeutic role in the future. Opioid abuse, abuse-deterrent formulations, ADF, post-marketing, FDA

State Legal Restrictions and Prescription-Opioid Use among Disabled Adults

PubMed Central

Meara, Ellen; Horwitz, Jill R.; Powell, Wilson; McClelland, Lynn; Zhou, Weiping; O’Malley, A. James; Morden, Nancy E.

2016-01-01

BACKGROUND In response to rising rates of opioid abuse and overdose, U.S. states enacted laws to restrict the prescribing and dispensing of controlled substances. The effect of these laws on opioid use is unclear. METHODS We tested associations between prescription-opioid receipt and state controlled-substances laws. Using Medicare administrative data for fee-for-service disabled beneficiaries 21 to 64 years of age who were alive throughout the calendar year (8.7 million person-years from 2006 through 2012) and an original data set of laws (e.g., prescription-drug monitoring programs), we examined the annual prevalence of beneficiaries with four or more opioid prescribers, prescriptions yielding a daily morphine-equivalent dose (MED) of more than 120 mg, and treatment for nonfatal prescription-opioid overdose. We estimated how opioid outcomes varied according to eight types of laws. RESULTS From 2006 through 2012, states added 81 controlled-substance laws. Opioid receipt and potentially hazardous prescription patterns were common. In 2012 alone, 47% of beneficiaries filled opioid prescriptions (25% in one to three calendar quarters and 22% in every calendar quarter); 8% had four or more opioid prescribers; 5% had prescriptions yielding a daily MED of more than 120 mg in any calendar quarter; and 0.3% were treated for a nonfatal prescription-opioid overdose. We observed no significant associations between opioid outcomes and specific types of laws or the number of types enacted. For example, the percentage of beneficiaries with a prescription yielding a daily MED of more than 120 mg did not decline after adoption of a prescription-drug monitoring program (0.27 percentage points; 95% confidence interval, −0.05 to 0.59). CONCLUSIONS Adoption of controlled-substance laws was not associated with reductions in potentially hazardous use of opioids or overdose among disabled Medicare beneficiaries, a population particularly at risk. PMID:27332619

Healthcare system-wide implementation of opioid-safety guideline recommendations: the case of urine drug screening and opioid-patient suicide- and overdose-related events in the Veterans Health Administration.

PubMed

Brennan, Penny L; Del Re, Aaron C; Henderson, Patricia T; Trafton, Jodie A

2016-12-01

This study provides an example of how healthcare system-wide progress in implementation of opioid-therapy guideline recommendations can be longitudinally assessed and then related to subsequent opioid-prescribed patient health and safety outcomes. Using longitudinal linear mixed effects analyses, we determined that in the Department of Veterans Affairs (VA) healthcare system (n = 141 facilities), over the 4-year interval from 2010 to 2013, a key opioid therapy guideline recommendation, urine drug screening (UDS), increased from 29 to 42 %, with an average within-facility increase rate of 4.5 % per year. Higher levels of UDS implementation from 2010 to 2013 were associated with lower risk of suicide and drug overdose events among VA opioid-prescribed patients in 2013, even after adjusting for patients' 2012 demographic characteristics and medical and mental health comorbidities. Findings suggest that VA clinicians and healthcare policymakers have been responsive to the 2010 VA/Department of Defense (DOD) UDS treatment guideline recommendation, resulting in improved patient safety for VA opioid-prescribed patients.

A nationwide pharmacy chain responds to the opioid epidemic.

PubMed

Shafer, Emily; Bergeron, Nyahne; Smith-Ray, Renae; Robson, Chester; O'Koren, Rachel

To describe the 3-pronged approach taken by a large national retail pharmacy chain to address the opioid epidemic and associated overdoses. Large national retail pharmacy chain with more than 8200 stores in 50 states. Eight million customer interactions daily through in-store and digital settings. This is a company with a long history of responding to public health crises. Initiated 3 programs to respond to the opioid crisis: 1) provide safe medication disposal kiosks; 2) expand national access to naloxone; and 3) provide education on the risk and avoidance of opioid overdose. Used the RE-AIM framework to evaluate and enhance the quality, speed, and public health impact of the interventions. Not applicable. Early results are safe medication disposal kiosks in more than 43 states, naloxone-dispensing program in 33 states, and patient and support system education using the Opioid Overdose Toolkit from the Substance Abuse and Mental Health Services Administration. The availability of safe drug-disposal kiosks, naloxone dispensing at pharmacies, and patient education are key prevention initiatives to address the opioid epidemic and reduce the increasing national burden of opioid overdose. Early results are quantitatively and qualitatively promising. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Synthesis of mixed MOR/KOR efficacy cyclic opioid peptide analogs with antinociceptive activity after systemic administration.

PubMed

Perlikowska, Renata; Piekielna, Justyna; Gentilucci, Luca; De Marco, Rossella; Cerlesi, Maria Camilla; Calo, Girolamo; Artali, Roberto; Tömböly, Csaba; Kluczyk, Alicja; Janecka, Anna

2016-02-15

Cyclic pentapeptide Tyr-c[D-Lys-Phe-Phe-Asp]NH2, based on the structure of endomorphin-2 (EM-2), which shows high affinity to the μ-opioid receptor (MOR) and a very strong antinociceptive activity in mice was used as a parent compound for the structure-activity relationship studies. In this report we synthesized analogs of a general sequence Dmt-c[D-Lys-Xaa-Yaa-Asp]NH2, with D-1- or D-2-naphthyl-3-alanine (D-1-Nal or D-2-Nal) in positions 3 or 4. In our earlier papers we have indicated that replacing a phenylalanine residue by the more extended aromatic system of naphthylalanines may result in increased bioactivities of linear analogs. The data obtained here showed that only cyclopeptides modified in position 4 retained the sub-nanomolar MOR and nanomolar κ-opioid receptor (KOR) affinity, similar but not better than that of a parent cyclopeptide. In the in vivo mouse hot-plate test, the most potent analog, Dmt-c[D-Lys-Phe-D-1-Nal-Asp]NH2, exhibited higher than EM-2 but slightly lower than the cyclic parent peptide antinociceptive activity after peripheral (ip) and also central administration (icv). Conformational analyses in a biomimetic environment and molecular docking studies disclosed the structural determinants responsible for the different pharmacological profiles of position 3- versus position 4-modified analogs. Copyright © 2015. Published by Elsevier Masson SAS.

Accuracy of using Diagnosis Procedure Combination administrative claims data for estimating the amount of opioid consumption among cancer patients in Japan.

PubMed

Iwamoto, Momoko; Higashi, Takahiro; Miura, Hiroki; Kawaguchi, Takahiro; Tanaka, Shigeyuki; Yamashita, Itsuku; Yoshimoto, Tetsusuke; Yoshida, Shigeaki; Matoba, Motohiro

2015-11-01

The state of opioid consumption among cancer patients has never been comprehensively investigated in Japan. The Diagnosis Procedure Combination claims data may be used to measure and monitor opioid consumption among cancer patients, but the accuracy of using the Diagnosis Procedure Combination data for this purpose has never been tested. We aimed to ascertain the accuracy of using the Diagnosis Procedure Combination claims data for estimating total opioid analgesic consumption by cancer patients compared with electronic medical records at Aomori Prefectural Central Hospital. We calculated percent differences between estimates obtained from electronic medical records and Diagnosis Procedure Combination claims data by month and drug type (morphine, oxycodone, fentanyl, buprenorphine, codeine and tramadol) between 1 October 2012 and 30 September 2013, and further examined the causes of discrepancy by reviewing medical and administrative charts between April and July 2013. Percent differences varied by month for drug types with small prescription volumes, but less so for drugs with larger prescription volumes. Differences also tended to diminish when consumption was compared for a year instead of a month. Total percent difference between electronic medical records and Diagnosis Procedure Combination data during the study period was -0.1% (4721 mg per year per hospital), as electronic medical records as baseline. Half of the discrepancy was caused by errors in data entry. Our study showed that Diagnosis Procedure Combination claims data can be used to accurately estimate opioid consumption among a population of cancer patients, although the same conclusion cannot be made for individual estimates or when making estimates for a group of patients over a short period of time. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Impact of the opioid system on the reproductive axis.

PubMed

Böttcher, Bettina; Seeber, Beata; Leyendecker, Gerhard; Wildt, Ludwig

2017-08-01

Endogenous opioids, first described more than 40 years ago, have long been recognized for their main role as important neuromodulators within the central nervous system. More recently endogenous opioids and their receptor have been identified in a variety of reproductive and nonreproductive tissues outside the central nervous system. Their role within these tissues and organs, however, is only incompletely understood. In the central nervous system, endogenous opioids inhibit pulsatile GnRH release, in part mediating the stress response within the central nervous-pituitary gonadal axis, resulting in hypothalamic amenorrhea. In the ovary, the presence of endogenous opioids primarily produced by granulosa cells has been demonstrated within the follicular fluid, likely influencing oocyte maturation. In hypothalamic amenorrhea, normal cycles can be restored by the administration of opioid antagonists, such as naltrexone. In polycystic ovarian syndrome, endogenous opioids have found to be elevated and may stimulate insulin secretion from the endocrine pancreas. This effect can be inhibited by opioid antagonists, resulting in a decrease of circulating insulin levels in response to glucose challenge. Endogenous opioids may also play a role in the pathogenesis of ovarian hyperstimulation syndrome. In summary, endogenous opioids exert a wide variety of actions within the reproductive system and are worthy of further scientific study. Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

NOP Receptor Mediates Anti-analgesia Induced by Agonist-Antagonist Opioids

PubMed Central

Gear, Robert W.; Bogen, Oliver; Ferrari, Luiz F.; Green, Paul G.; Levine, Jon D.

2014-01-01

Clinical studies have shown that agonist-antagonist opioid analgesics that produce their analgesic effect via action on the kappa-opioid receptor, produce a delayed-onset anti-analgesia in men but not women, an effect blocked by co-administration of a low dose of naloxone. We now report the same time-dependent anti-analgesia and its underlying mechanism in an animal model. Using the Randall-Selitto paw-withdrawal assay in male rats, we found that nalbuphine, pentazocine, and butorphanol each produced analgesia during the first hour followed by anti-analgesia starting at ~90 minutes after administration in males but not females, closely mimicking its clinical effects. As observed in humans, co-administration of nalbuphine with naloxone in a dose ratio of 12.5:1 blocked anti-analgesia but not analgesia. Administration of the highly selective kappa-opioid receptor agonist U69,593 produced analgesia without subsequent anti-analgesia, and confirmed by the failure of the selective kappa antagonist nor-binaltorphimine to block nalbuphine-induced anti-analgesia, indicating that anti-analgesia is not mediated by kappa-opioid receptors. We therefore tested the role of other receptors in nalbuphine anti-analgesia. Nociceptin/orphanin FQ (NOP) and sigma-1 and sigma-2 receptors were chosen on the basis of their known anti-analgesic effects and receptor binding studies. The selective NOP receptor antagonists, JTC801, and J113397, but not the sigma receptor antagonist, BD 1047, antagonized nalbuphine anti-analgesia. Furthermore, the NOP receptor agonist NNC 63-0532 produced anti-analgesia with the same delay in onset observed with the three agonist-antagonists, but without producing preceding analgesia and this anti-analgesia was also blocked by naloxone. These results strongly support the suggestion that clinically used agonist-antagonists act at the NOP receptor to produce anti-analgesia. PMID:24188792

Improving the recognition and diagnosis of opioid-induced constipation in clinical practice.

PubMed

Gupta, Anita

2015-10-01

Opioid-induced constipation is a common side effect of opioid therapy that has been under-recognized and undertreated. With the continued increase in opioid use in the United States, along with the growth of the elderly population, more patients will develop OIC, and family physicians will encounter more patients with OIC. OIC negatively affects patient QOL, daily activity, work productivity, and psychological well-being. If not treated effectively, OIC may result in patients attempting to balance their pain relief against their constipation, by self-adjusting their opioid dose. OIC results from opioid actions at enteric opioid receptors. Although commonly prescribed for OIC, laxatives do not target the pathophysiologic mechanism of OIC and have limited efficacy. Specific, effective treatments for OIC, consisting of a subcutaneously administered PAMORA, an oral PAMORA, and an oral chloride channel activator, have been developed and have received US Food and Drug Administration approval. After recognizing the signs and symptoms of OIC to facilitate diagnosis, family physicians can initiate effective treatments in appropriate patients.

m-Trifluoromethyl-diphenyl Diselenide Regulates Prefrontal Cortical MOR and KOR Protein Levels and Abolishes the Phenotype Induced by Repeated Forced Swim Stress in Mice.

PubMed

Rosa, Suzan Gonçalves; Pesarico, Ana Paula; Martini, Franciele; Nogueira, Cristina Wayne

2018-04-05

The present study aimed to investigate the m-trifluoromethyl-diphenyl diselenide [(m-CF 3 -PhSe) 2 ] effects on prefrontal cortical MOR and KOR protein levels and phenotype induced by repeated forced swim stress (FSS) in mice. Adult Swiss mice were subjected to repeated FSS sessions, and after that, they performed the spontaneous locomotor/exploratory activity, tail suspension, and splash tests. (m-CF 3 -PhSe) 2 (0.1 to 5 mg/kg) was administered to mice 30 min before the first FSS session and 30 min before the subsequent repeated FSS. (m-CF 3 -PhSe) 2 abolished the phenotype induced by repeated FSS in mice. In addition, a single FSS session increased μ but reduced δ-opioid receptor contents, without changing the κ content. Mice subjected to repeated FSS had an increase in the μ content when compared to those of naïve group or subjected to single FSS. Repeated FSS induced an increase of δ-opioid receptor content compared to those mice subjected to single FSS. However, the δ-opioid receptor contents were lower than those found in the naïve group. The mice subjected to repeated FSS showed an increase in the κ-opioid receptor content when compared to that of the naïve mice. (m-CF 3 -PhSe) 2 regulated the protein contents of μ and κ receptors in mice subjected to repeated FSS. These findings demonstrate that (m-CF 3 -PhSe) 2 was effective to abolish the phenotype induced by FSS, which was accompanied by changes in the contents of cortical μ- and κ-opioid receptors.

Distribution of bemitil in organs and tissues of rats after single or repeated administration.

PubMed

Sergeeva, S A; Gulyaeva, I L

2006-05-01

After single and repeated peroral administration of bemitil to rats this drug was found in the liver, brain, kidneys, spleen, heart, skeletal muscles, lungs, adipose tissue, and testicles. After single treatment accumulation of bemitil was most pronounced in the liver. After repeated treatment the decrease in bemitil concentration in the liver was probably associated with increased elimination of the drug from liver tissue due to intensification of its biotransformation. We conclude that bemitil can accumulate in the blood, but not in tissues.

Using behavioral economics to predict opioid use during prescription opioid dependence treatment.

PubMed

Worley, Matthew J; Shoptaw, Steven J; Bickel, Warren K; Ling, Walter

2015-03-01

Research grounded in behavioral economics has previously linked addictive behavior to disrupted decision-making and reward-processing, but these principles have not been examined in prescription opioid addiction, which is currently a major public health problem. This study examined whether pre-treatment drug reinforcement value predicted opioid use during outpatient treatment of prescription opioid addiction. Secondary analyses examined participants with prescription opioid dependence who received 12 weeks of buprenorphine-naloxone and counseling in a multi-site clinical trial (N=353). Baseline measures assessed opioid source and indices of drug reinforcement value, including the total amount and proportion of income spent on drugs. Weekly urine drug screens measured opioid use. Obtaining opioids from doctors was associated with lower pre-treatment drug spending, while obtaining opioids from dealers/patients was associated with greater spending. Controlling for demographics, opioid use history, and opioid source frequency, patients who spent a greater total amount (OR=1.30, p<.001) and a greater proportion of their income on drugs (OR=1.31, p<.001) were more likely to use opioids during treatment. Individual differences in drug reinforcement value, as indicated by pre-treatment allocation of economic resources to drugs, reflects propensity for continued opioid use during treatment among individuals with prescription opioid addiction. Future studies should examine disrupted decision-making and reward-processing in prescription opioid users more directly and test whether reinforcer pathology can be remediated in this population. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Using behavioral economics to predict opioid use during prescription opioid dependence treatment

PubMed Central

Worley, Matthew J.; Shoptaw, Steven J.; Bickel, Warren K.; Ling, Walter

2015-01-01

Background Research grounded in behavioral economics has previously linked addictive behavior to disrupted decision-making and reward-processing, but these principles have not been examined in prescription opioid addiction, which is currently a major public health problem. This study examined whether pre-treatment drug reinforcement value predicted opioid use during outpatient treatment of prescription opioid addiction. Methods Secondary analyses examined participants with prescription opioid dependence who received 12 weeks of buprenorphine-naloxone and counseling in a multi-site clinical trial (N = 353). Baseline measures assessed opioid source and indices of drug reinforcement value, including the total amount and proportion of income spent on drugs. Weekly urine drug screens measured opioid use. Results Obtaining opioids from doctors was associated with lower pre-treatment drug spending, while obtaining opioids from dealers/patients was associated with greater spending. Controlling for demographics, opioid use history, and opioid source frequency, patients who spent a greater total amount (OR = 1.30, p < .001) and a greater proportion of their income on drugs (OR = 1.31, p < .001) were more likely to use opioids during treatment. Conclusions Individual differences in drug reinforcement value, as indicated by pre-treatment allocation of economic resources to drugs, reflects propensity for continued opioid use during treatment among individuals with prescription opioid addiction. Future studies should examine disrupted decision-making and reward-processing in prescription opioid users more directly and test whether reinforcer pathology can be remediated in this population. PMID:25622776

Comparative effects of cyclo-oxygenase and nitric oxide synthase inhibition on the development and reversal of spinal opioid tolerance

PubMed Central

Powell, Kelly J; Hosokawa, Akiko; Bell, Andrew; Sutak, Maaja; Milne, Brian; Quirion, Remi; Jhamandas, Khem

1999-01-01

This study examined the effects of the COX inhibitors, ketorolac and ibuprofen, and the NOS inhibitor L-NAME for their potential to both inhibit the development and reverse tolerance to the antinociceptive action of morphine. Repeated administration of intrathecal morphine (15 μg), once daily, resulted in a progressive decline of antinociceptive effect and an increase in the ED50 value in the tailflick and paw pressure tests. Co-administration of ketorolac (30 and 45 μg) or S(+) ibuprofen (10 μg) with morphine (15 μg) prevented the decline of antinociceptive effect and increase in ED50 value. Similar treatment with L-NAME (100 μg) exerted weaker effects. Administration of S(+) but not R(−) ibuprofen (10 mg kg−1) had similar effects on systemic administration of morphine (15 mg kg−1). Intrathecal or systemic administration of the COX or NOS inhibitors did not alter the baseline responses in either tests. Acute keterolac or S(+) ibuprofen also did not potentiate the acute actions of spinal or systemic morphine, but chronic intrathecal administration of these agents increased the potency of acute morphine. In animals already tolerant to intrathecal morphine, subsequent administration of ketorolac (30 μg) with morphine (15 μg) partially restored the antinociceptive effect and ED50 value of acute morphine, reflecting the reversal of tolerance. Intrathecal L-NAME (100 μg) exerted a weaker effect. These data suggest that spinal COX activity, and to a lesser extent NOS activity, contributes to the development and expression of opioid tolerance. Inhibition of COX may represent a useful approach for the prevention as well as reversal of opioid tolerance. PMID:10401553

Opioid gene expression changes and post-translational histone modifications at promoter regions in the rat nucleus accumbens after acute and repeated 3,4-methylenedioxy-methamphetamine (MDMA) exposure.

PubMed

Caputi, Francesca Felicia; Palmisano, Martina; Carboni, Lucia; Candeletti, Sanzio; Romualdi, Patrizia

2016-12-01

The recreational drug of abuse 3,4-methylenedioxymethamphetamine (MDMA) has been shown to produce neurotoxic damage and long-lasting changes in several brain areas. In addition to the involvement of serotoninergic and dopaminergic systems, little information exists about the contribution of nociceptin/orphaninFQ (N/OFQ)-NOP and dynorphin (DYN)-KOP systems in neuronal adaptations evoked by MDMA. Here we investigated the behavioral and molecular effects induced by acute (8mg/kg) or repeated (8mg/kg twice daily for seven days) MDMA exposure. MDMA exposure affected body weight gain and induced hyperlocomotion; this latter effect progressively decreased after repeated administration. Gene expression analysis indicated a down-regulation of the N/OFQ system and an up-regulation of the DYN system in the nucleus accumbens (NAc), highlighting an opposite systems regulation in response to MDMA exposure. Since histone modifications have been strongly associated to the addiction-related maladaptive changes, we examined two permissive (acH3K9 and me3H3K4) and two repressive transcription marks (me3H3K27 and me2H3K9) at the pertinent opioid gene promoter regions. Chromatin immunoprecipitation assays revealed that acute MDMA increased me3H3K4 at the pN/OFQ, pDYN and NOP promoters. Following acute and repeated treatment a significant decrease of acH3K9 at the pN/OFQ promoter was observed, which correlated with gene expression results. Acute treatment caused an acH3K9 increase and a me2H3K9 decrease at the pDYN promoter which matched its mRNA up-regulation. Our data indicate that the activation of the DYNergic stress system together with the inactivation of the N/OFQergic anti-stress system contribute to the neuroadaptive actions of MDMA and offer novel epigenetic information associated with MDMA abuse. Copyright © 2016 Elsevier Ltd. All rights reserved.

Opioid receptor mediated anticonvulsant effect of pentazocine.

PubMed

Khanna, N; Khosla, R; Kohli, J

1998-01-01

Intraperitoneal (i.p.) administration of (+/-) pentazocine (10, 30 & 50 mg/kg), a Sigma opioid agonist, resulted in a dose dependent anticonvulsant action against maximal electroshock seizures in mice. This anticonvulsant effect of pentazocine was not antagonized by both the doses of naloxone (1 and 10 mg/kg) suggesting thereby that its anticonvulsant action is probably mediated by Sigma opiate binding sites. Its anticonvulsant effect was potentiated by both the anticonvulsant drugs viz. diazepam and diphenylhydantoin. Morphine, mu opioid agonist, on the other hand, failed to protect the animals against maximal electroshock seizures when it was given in doses of 10-40 mg/kg body wt.

Monitoring Hospitalized Adult Patients for Opioid-Induced Sedation and Respiratory Depression.

PubMed

Jungquist, Carla R; Smith, Kirsten; Nicely, Kelly L Wiltse; Polomano, Rosemary C

2017-03-01

: Opioid analgesics are commonly administered to hospitalized patients to treat acute pain, but these drugs put patients at risk for serious adverse events, such as unintended advancing sedation, respiratory depression, and death. Nurses play an important role in keeping patients safe by making clinical decisions about the frequency and intensity with which patients receiving IV and epidural opioids should be monitored. To make sound clinical judgments, nurses must be aware of the factors that place patients at elevated risk for adverse opioid-related effects and know how to screen and assess patients for these risks. The authors review the literature on unintended advancing sedation and respiratory depression associated with opioid administration and present evidence-based recommendations for clinical decision making and patient monitoring, using both nursing assessments and electronic technologies.

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

Anhedonia to music and mu-opioids: Evidence from the administration of naltrexone.

PubMed

Mallik, Adiel; Chanda, Mona Lisa; Levitin, Daniel J

2017-02-08

Music's universality and its ability to deeply affect emotions suggest an evolutionary origin. Previous investigators have found that naltrexone (NTX), a μ-opioid antagonist, may induce reversible anhedonia, attenuating both positive and negative emotions. The neurochemical basis of musical experience is not well-understood, and the NTX-induced anhedonia hypothesis has not been tested with music. Accordingly, we administered NTX or placebo on two different days in a double-blind crossover study, and assessed participants' responses to music using both psychophysiological (objective) and behavioral (subjective) measures. We found that both positive and negative emotions were attenuated. We conclude that endogenous opioids are critical to experiencing both positive and negative emotions in music, and that music uses the same reward pathways as food, drug and sexual pleasure. Our findings add to the growing body of evidence for the evolutionary biological substrates of music.

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

CXCL10 Controls Inflammatory Pain via Opioid Peptide-Containing Macrophages in Electroacupuncture

PubMed Central

Wang, Ying; Gehringer, Rebekka; Mousa, Shaaban A.; Hackel, Dagmar; Brack, Alexander; Rittner, Heike L.

2014-01-01

Acupuncture is widely used for pain treatment in patients with osteoarthritis or low back pain, but molecular mechanisms remain largely enigmatic. In the early phase of inflammation neutrophilic chemokines direct opioid-containing neutrophils in the inflamed tissue and stimulate opioid peptide release and antinociception. In this study the molecular pathway and neuroimmune connections in complete Freund's adjuvant (CFA)-induced hind paw inflammation and electroacupuncture for peripheral pain control were analyzed. Free moving Wistar rats with hind paw inflammation were treated twice with electroacupuncture at GB30 (Huan Tiao - gall bladder meridian) (day 0 and 1) and analyzed for mechanical and thermal nociceptive thresholds. The cytokine profiles as well as the expression of opioid peptides were quantified in the inflamed paw. Electroacupuncture elicited long-term antinociception blocked by local injection of anti-opioid peptide antibodies (beta-endorphin, met-enkephalin, dynorphin A). The treatment altered the cytokine profile towards an anti-inflammatory pattern but augmented interferon (IFN)-gamma and the chemokine CXCL10 (IP-10: interferon gamma-inducible protein) protein and mRNA expression with concomitant increased numbers of opioid peptide-containing CXCR3+ macrophages. In rats with CFA hind paw inflammation without acupuncture repeated injection of CXCL10 triggered opioid-mediated antinociception and increase opioid-containing macrophages. Conversely, neutralization of CXCL10 time-dependently decreased electroacupuncture-induced antinociception and the number of infiltrating opioid peptide-expressing CXCR3+ macrophages. In summary, we describe a novel function of the chemokine CXCL10 - as a regulator for an increase of opioid-containing macrophages and antinociceptive mediator in inflammatory pain and as a key chemokine regulated by electroacupuncture. PMID:24732949

Intranasal Opioid Administration in Rhesus Monkeys: PET Imaging and Antinociception.

PubMed

Saccone, Phillip A; Lindsey, Angela M; Koeppe, Robert A; Zelenock, Kathy A; Shao, Xia; Sherman, Phillip; Quesada, Carole A; Woods, James H; Scott, Peter J H

2016-11-01

The goal of this study was to evaluate the effects of intranasally administered opioids in rhesus monkeys using the tail-withdrawal assay, and to correlate these effects with measures of receptor occupancy using positron emission tomography (PET) imaging. Initial experiments characterized the antinociceptive effects of intranasal (IN) fentanyl and buprenorphine relative to intramuscular (IM) injection. Fentanyl (0.010-0.032 mg/kg) and buprenorphine (0.1-1.0 mg/kg) produced dose-dependent increases in tail-withdrawal latency that did not differ between routes of delivery. The second experiment compared the ability of IN and intravenous (IV) naloxone (NLX) to block the antinociceptive effects IV fentanyl, and to measure receptor occupancy at equipotent doses of NLX using PET imaging. IN and IV NLX (0.0032-0.032 mg/kg) produced dose-dependent decreases in fentanyl-induced antinociception. Again, there was no difference observed in overall potency between routes. PET imaging showed that IV and IN NLX produced similar decreases in receptor occupancy as measured by [ 11 C]carfentanil blocking, although there was a trend for IV NLX to produce marginally greater occupancy changes. This study validated the first procedures to evaluate the IN effects of opioids in rhesus monkeys. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Determinants of trends in prescription opioid use in British Columbia, Canada, 2005-2013.

PubMed

Smolina, Kate; Gladstone, Emilie; Morgan, Steven G

2016-05-01

To explore the determinants of total opioid consumption in a Canadian province, and to examine patterns of opioid dispensations by sex, age, and income quintile. We used population-based administrative data on prescription drug dispensations in British Columbia (BC; population ~4 million). We apply an index-based approach to examine how changes in population exposure, type of opioids used, and intensity of use contributed to changes in total morphine equivalents dispensed per 1000 population. Between 2005 and 2013 in BC, opioid consumption increased by 31%, driven by longer duration of opioid therapy and by an increase in the use of stronger opioids. Consumption increased for oxycodone, hydromorphone, fentanyl, and tramadol; and declined for morphine, codeine, and other opioids. While we did not find large sex and age differences, the total level of opioid consumption was three times as high among individuals in the lowest income quintile compared to those in the highest income quintile. Our findings on changes in the type of opioids used and changes in intensity of use suggest that modifications to clinical management of patients on opioid therapy may be warranted. Similar drug utilization statistics, derived from drug information systems, can be reproduced in other jurisdictions to enable a better understanding of the opioid crisis. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Clinical implications of patient-provider agreements in opioid prescribing.

PubMed

Kraus, Carl N; Baldwin, Alan T; Curro, Frederick A; McAllister, R G

2015-01-01

In June, 2012 the United States Food and Drug Administration (FDA) developed a "blueprint" for prescriber education as a means of directing Certified Medical Education (CME) activities that included content which would meet the regulatory requirements of the class-wide, longacting/ extended-release (LA-ER) opioid Risk Evaluation Mitigation Strategies (REMS). Within the blueprint is the suggested adoption of Patient-Provider Agreements (PPAs) to be used in association with opioid prescribing, but, to our knowledge, there have been no reported evaluations of the role played by opioid-agent PPAs in clinical practice, or of the perceptions of this regulatory mandate by clinicians. Therefore, we conducted a survey regarding PPA perceptions by opioid prescribers that was posted for five weeks on a well-trafficked online CME service provider (Medscape). Of the 1,232 respondents (reflecting a 99.5% completion rate), 52.4% treat acute or chronic pain with opioids. The survey identified an improvement of opioid safe-use education (21% of respondents) as the most frequently selected beneficial element of PPAs. Conversely, the challenges to adoption included time constraints (21% of physicians) as well as lack of evidence that PPAs will reduce drug misuse, and the lack of a uniform, patient-friendly PPA. Based on our survey, clinicians consider the PPA of potential value, but data regarding the utility of such an instrument are lacking.

Multiple Sources of Prescription Payment and Risky Opioid Therapy Among Veterans.

PubMed

Becker, William C; Fenton, Brenda T; Brandt, Cynthia A; Doyle, Erin L; Francis, Joseph; Goulet, Joseph L; Moore, Brent A; Torrise, Virginia; Kerns, Robert D; Kreiner, Peter W

2017-07-01

Opioid overdose and other related harms are a major source of morbidity and mortality among US Veterans, in part due to high-risk opioid prescribing. We sought to determine whether having multiple sources of payment for opioids-as a marker for out-of-system access-is associated with risky opioid therapy among veterans. Cross-sectional study examining the association between multiple sources of payment and risky opioid therapy among all individuals with Veterans Health Administration (VHA) payment for opioid analgesic prescriptions in Kentucky during fiscal year 2014-2015. Source of payment categories: (1) VHA only source of payment (sole source); (2) sources of payment were VHA and at least 1 cash payment [VHA+cash payment(s)] whether or not there was a third source of payment; and (3) at least one other noncash source: Medicare, Medicaid, or private insurance [VHA+noncash source(s)]. Our outcomes were 2 risky opioid therapies: combination opioid/benzodiazepine therapy and high-dose opioid therapy, defined as morphine equivalent daily dose ≥90 mg. Of the 14,795 individuals in the analytic sample, there were 81.9% in the sole source category, 6.6% in the VHA+cash payment(s) category, and 11.5% in the VHA+noncash source(s) category. In logistic regression, controlling for age and sex, persons with multiple payment sources had significantly higher odds of each risky opioid therapy, with those in the VHA+cash having significantly higher odds than those in the VHA+noncash source(s) group. Prescribers should examine the prescription monitoring program as multiple payment sources increase the odds of risky opioid therapy.

Anhedonia to music and mu-opioids: Evidence from the administration of naltrexone

PubMed Central

Mallik, Adiel; Chanda, Mona Lisa; Levitin, Daniel J.

2017-01-01

Music’s universality and its ability to deeply affect emotions suggest an evolutionary origin. Previous investigators have found that naltrexone (NTX), a μ-opioid antagonist, may induce reversible anhedonia, attenuating both positive and negative emotions. The neurochemical basis of musical experience is not well-understood, and the NTX-induced anhedonia hypothesis has not been tested with music. Accordingly, we administered NTX or placebo on two different days in a double-blind crossover study, and assessed participants’ responses to music using both psychophysiological (objective) and behavioral (subjective) measures. We found that both positive and negative emotions were attenuated. We conclude that endogenous opioids are critical to experiencing both positive and negative emotions in music, and that music uses the same reward pathways as food, drug and sexual pleasure. Our findings add to the growing body of evidence for the evolutionary biological substrates of music. PMID:28176798

Past-year Prescription Drug Monitoring Program Opioid Prescriptions and Self-reported Opioid Use in an Emergency Department Population With Opioid Use Disorder.

PubMed

Hawk, Kathryn; D'Onofrio, Gail; Fiellin, David A; Chawarski, Marek C; O'Connor, Patrick G; Owens, Patricia H; Pantalon, Michael V; Bernstein, Steven L

2017-11-22

Despite increasing reliance on prescription drug monitoring programs (PDMPs) as a response to the opioid epidemic, the relationship between aberrant drug-related behaviors captured by the PDMP and opioid use disorder is incompletely understood. How PDMP data should guide emergency department (ED) assessment has not been studied. The objective was to evaluate a relationship between PDMP opioid prescription records and self-reported nonmedical opioid use of prescription opioids in a cohort of opioid-dependent ED patients enrolled in a treatment trial. PDMP opioid prescription records during 1 year prior to study enrollment on 329 adults meeting Diagnostic and Statistical Manual IV criteria for opioid dependence entering a randomized clinical trial in a large, urban ED were cross-tabulated with data on 30-day nonmedical prescription opioid use self-report. The association among these two types of data was assessed by the Goodman and Kruskal's gamma; a logistic regression was used to explore characteristics of participants who had PDMP record of opioid prescriptions. During 1 year prior to study enrollment, 118 of 329 (36%) patients had at least one opioid prescription (range = 1-51) in our states' PDMP. Patients who reported ≥15 of 30 days of nonmedical prescription opioid use were more likely to have at least four PDMP opioid prescriptions (20/38; 53%) than patients reporting 1 to 14 days (14/38, 37%) or zero days of nonmedical prescription opioid use (4/38, 11%; p = 0.002). Female sex and having health insurance were significantly more represented in the PDMP (p < 0.05 for both). PDMPs may be helpful in identifying patients with certain aberrant drug-related behavior, but are unable to detect many patients with opioid use disorder. The majority of ED patients with opioid use disorder were not captured by the PDMP, highlighting the importance of using additional methods such as screening and clinical history to identify opioid use disorders in ED patients and the

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.

Effect of daily morphine administration and its discontinuation on delay discounting of food in rhesus monkeys

PubMed Central

Maguire, David R; Gerak, Lisa R; France, Charles P

2015-01-01

Opioid abusers discount delayed reinforcers more rapidly than non-users; however, it is unclear whether chronic drug administration or its discontinuation impact discounting. This study examined daily morphine administration and its discontinuation on delay discounting of food in rhesus monkeys. Responding on one lever delivered 1 food pellet immediately; responding on another lever delivered 2 food pellets either immediately or after a delay (30–120 sec) that increased within the session. Monkeys (n=3) responded for the large reinforcer when both reinforcers were delivered immediately and more for the smaller, immediately available reinforcer as delay to delivery of the large reinforcer increased. When administered acutely, morphine (0.032–5.6 mg/kg) increased trial omissions and had variable effects on choice, with small doses decreasing and large doses increasing choice of the large delayed reinforcer. Chronic morphine administration (0.1 mg/kg/day to 3.2 mg/kg twice daily) reduced choice of the large delayed reinforcer in two monkeys while increasing choice in a third monkey. Despite the development of tolerance to some effects (i.e., rightward shifts in dose-effect curves for the number of trials omitted) and evidence of mild opioid dependence (e.g., decrease in the number of trials completed as well as body weight), discontinuation of treatment did not appear to systematically impact discounting. Overall, these results suggest that repeated opioid administration causes persistent effects on choice under a delay discounting procedure; however, differences in the direction of effect among individuals suggest factors other than, or in addition to, changes in discounting might play a role. PMID:26397762

High-Dose Opioid Prescribing and Opioid-Related Hospitalization: A Population-Based Study.

PubMed

Fernandes, Kimberly; Martins, Diana; Juurlink, David; Mamdani, Muhammad; Paterson, J Michael; Spooner, Luke; Singh, Samantha; Gomes, Tara

2016-01-01

To examine the impact of national clinical practice guidelines and provincial drug policy interventions on prevalence of high-dose opioid prescribing and rates of hospitalization for opioid toxicity. Interventional time-series analysis. Ontario, Canada, from 2003 to 2014. Ontario Drug Benefit (ODB) beneficiaries aged 15 to 64 years from 2003 to 2014. Publication of Canadian clinical practice guidelines for use of opioids in chronic non-cancer pain (May 2010) and implementation of Ontario's Narcotics Safety and Awareness Act (NSAA; November 2011). Three outcomes were explored: the rate of opioid use among ODB beneficiaries, the prevalence of opioid prescriptions exceeding 200 mg and 400 mg morphine equivalents per day, and rates of opioid-related emergency department visits and hospital admissions. Over the 12 year study period, the rate of opioid use declined 15.2%, from 2764 to 2342 users per 10,000 ODB eligible persons. The rate of opioid use was significantly impacted by the Canadian clinical practice guidelines (p-value = .03) which led to a decline in use, but no impact was observed by the enactment of the NSAA (p-value = .43). Among opioid users, the prevalence of high-dose prescribing doubled (from 4.2% to 8.7%) over the study period. By 2014, 40.9% of recipients of long-acting opioids exceeded daily doses of 200 mg morphine or equivalent, including 55.8% of long-acting oxycodone users and 76.3% of transdermal fentanyl users. Moreover, in the last period, 18.7% of long-acting opioid users exceeded daily doses of 400 mg morphine or equivalent. Rates of opioid-related emergency department visits and hospital admissions increased 55.0% over the study period from 9.0 to 14.0 per 10,000 ODB beneficiaries from 2003 to 2013. This rate was not significantly impacted by the Canadian clinical practice guidelines (p-value = .68) or enactment of the NSAA (p-value = .59). Although the Canadian clinical practice guidelines for use of opioids in chronic non-cancer pain led

Varenicline impairs extinction and enhances reinstatement across repeated cycles of nicotine self-administration in rats.

PubMed

Macnamara, Claire L; Holmes, Nathan M; Westbrook, R Fred; Clemens, Kelly J

2016-06-01

Varenicline is a partial nicotine receptor agonist widely prescribed as a smoking cessation medication. Repeated (or long-term) use of varenicline has been proposed as a treatment option for tobacco addiction. However the effect of repeated varenicline use on motivation for nicotine is unknown. Here the intravenous nicotine self-administration paradigm in rats was used to model the consequences of varenicline treatment across repeated cycles of administration, extinction and reinstatement. Rats acquired nicotine self-administration across 20 days before undergoing 6 days of extinction, where each extinction session was preceded by a single injection of varenicline or saline. This was followed by a single varenicline-free nicotine-primed reinstatement test. All rats then reacquired nicotine self-administration for 10 days followed by a second cycle of extinction. Across this period, rats either received a second cycle of varenicline (VAR-VAR) or saline (SAL-SAL), or the alternative treatment (SAL-VAR, VAR-SAL), followed by a final reinstatement test. Treatment with varenicline increased responding across the first cycle of extinction, but did not affect responding in the reinstatement test. Across the second cycle, varenicline again increased responding across extinction, and critically, rats treated with varenicline across cycle 1 and saline across cycle 2 (Group VAR-SAL) exhibited more reinstatement than rats in any other group. The effect of VAR on nicotine seeking was not due to its effects on locomotor activity. Instead, the results suggest that a history of VAR can increase vulnerability to reinstatement/relapse when its treatment is discontinued. The possible mechanisms of this increased vulnerability are discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Repeated Post- or Presession Cocaine Administration: Roles of Dose and Fixed-Ratio Schedule

ERIC Educational Resources Information Center

Pinkston, Jonathan W.; Branch, Marc N.

2004-01-01

Effects of repeated administration of cocaine to animals behaving under operant contingencies have depended on when the drug is given. Moderate doses given presession have generally led to a decrease in the drug's effect, an outcome usually referred to as tolerance. When these same doses have been given after sessions, the usual result has been no…

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.

Lack of behavioral sensitization to repeated cocaine administration from postnatal days 1 to 10.

PubMed

Meyer, J S; Yacht, A C

1993-09-01

This research determined whether sensitization (or tolerance) to the behavioral effects of cocaine in rat pups would occur following repeated cocaine administration. Rats were injected daily with 20 mg/kg of cocaine HCl s.c. from postnatal day 1 to day 10, injected with saline vehicle only, or left untreated during this period. On day 11, animals from each group were challenged with either 0, .625, 1.25, or 2.50 mg/kg of cocaine and their behavioral responses were recorded. Prior cocaine treatment did not influence the acute effects of cocaine on ultrasonic vocalizations or on any observed motor responses. In contrast, the cocaine- and saline-treated pups differed in a similar manner from the untreated control group on several behavioral measures. These results indicate that the sensitizing effects of repeated cocaine administration are not manifested during the neonatal period. However, the stimulation (stress) of handling and injection may alter the subsequent responsivity of infant rats to a cocaine challenge.

ICI 204448: a kappa-opioid agonist with limited access to the CNS.

PubMed Central

Shaw, J. S.; Carroll, J. A.; Alcock, P.; Main, B. G.

1989-01-01

1. A number of compounds were evaluated in an attempt to identify a kappa-opioid receptor agonist with limited access to the central nervous system. 2. Quaternary derivatives of the kappa-opioid agonists tifluadom, U-50488H and ethylketocyclazocine were essentially devoid of opioid activity in a range of isolated tissue preparations. 3. A novel compound - ICI 204448 - is described which produced a potent and naloxone-reversible inhibition of electrically-evoked contraction of the guinea-pig ileum, mouse vas deferens and rabbit vas deferens preparations. ICI 204448 was shown to displace the binding of the kappa-opioid ligand [3H]-bremazocine from guinea-pig cerebellum membranes. 4. Ex vivo binding studies in mice showed ICI 204448 to be well absorbed following subcutaneous administration. The brain levels achieved by ICI 20448 were substantially lower than those produced by kappa-agonists such as U-50488H and tifluadom. 5. A good correlation was found for a range of opioids between lipophilicity and degree of CNS penetration. PMID:2568146

Implications of prescription drug monitoring and medical cannabis legislation on opioid overdose mortality.

PubMed

Phillips, Elyse; Gazmararian, Julie

To determine whether specific state legislation has an effect on opioid overdose mortality rates compared to states without those types of legislation. Ecological study estimating opioid-related mortality in states with and without a prescription drug monitoring program (PDMP) and/or medical cannabis legislation. Opioid-related mortality rates for 50 states and Washington DC from 2011 to 2014 were obtained from CDC WONDER. PDMP data were obtained from the National Alliance for Model State Drug Laws, and data on medical cannabis legislation from the National Organization for the Reform of Marijuana Laws. The relationship between PDMPs with mandatory access provisions, medical cannabis legislation, and opioid-related mortality rates. Multivariate repeated measures analysis performed with software and services. Medical cannabis laws were associated with an increase of 21.7 percent in mean age-adjusted opioid-related mortality (p < 0.0001). PDMPs were associated with an increase of 11.4 percent in mean age-adjusted opioid-related mortality (p = 0.005). For every additional year since enactment, mean age-adjusted opioid-related mortality rate increased by 1.7 percent in states with medical cannabis (p = 0.049) and 5.8 percent for states with a PDMP (p = 0.005). Interaction between both types of legislation produced a borderline significant decrease of 10.1 percent (p = 0.055). For every year states had both types of legislation, interaction resulted in a 0.6 percent decrease in rate (p = 0.013). When combined with the availability of medical cannabis as an alternative analgesic therapy, PDMPs may be more effective at decreasing opioid-related mortality.

Naloxegol: A Novel Therapy in the Management of Opioid-Induced Constipation.

PubMed

Jones, Rachel; Prommer, Eric; Backstedt, David

2016-11-01

Opioid-related bowel dysfunction is a common and potentially severe adverse effect from treatment with opioid analgesics. Its development is not dose related, nor do patients develop tolerance. Opioid-induced constipation (OIC) can lead to fecal impaction, bowel obstruction, and bowel perforation as well as noncompliance with opioid analgesics and poor quality of life. Routine administration of laxatives is necessary to maintain bowel function, and, in refractory cases, other modalities must be pursued. Available options are limited but include peripherally acting μ-opioid receptor antagonists (PAMORAs), including methylnaltrexone. Naloxegol is a newly developed PAMORA that is available through the oral route. At the therapeutic dose of 25 mg daily, naloxegol is effective and safe, with a limited side effect profile and is associated with preservation of centrally mediated analgesia. In this article, we discuss the pharmacokinetics, pharmacodynamics, adverse effects, clinical trials, and cost considerations of naloxegol. Finally, we discuss its potential role as a novel key treatment for OIC in palliative medicine patients. © The Author(s) 2015.

Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration.

PubMed

Kenward, Hannah; Pelligand, Ludovic; Elliott, Jonathan

2014-08-01

Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies.

Repeated MDMA administration increases MDMA-produced locomotor activity and facilitates the acquisition of MDMA self-administration: role of dopamine D2 receptor mechanisms.

PubMed

van de Wetering, Ross; Schenk, Susan

2017-04-01

Repeated exposure to ±3, 4-methylenedioxymethamphetamine (MDMA) produces sensitization to MDMA-produced hyperactivity, but the mechanisms underlying the development of this sensitized response or the relationship to the reinforcing effects of MDMA is unknown. This study determined the effect of a sensitizing regimen of MDMA exposure on the acquisition of MDMA self-administration and investigated the role of dopamine D 2 receptor mechanisms. Rats received the selective D 2 antagonist, eticlopride (0.0 or 0.3 mg/kg, i.p.) and MDMA (0.0 or 10.0 mg/kg, i.p.) during a five-day pretreatment regimen. Two days following the final session, the locomotor activating effects of MDMA (5 mg/kg, i.p.) and the latency to acquisition of MDMA self-administration were determined. Pretreatment with MDMA enhanced the locomotor activating effects of MDMA and facilitated the acquisition of MDMA self-administration. Administration of eticlopride during MDMA pretreatment completely blocked the development of sensitization to MDMA-produced hyperactivity but failed to significantly alter the facilitated acquisition of MDMA self-administration. Pretreatment with eticlopride alone facilitated the acquisition of self-administration. These data suggest that repeated MDMA exposure sensitized both the locomotor activating and reinforcing effects of MDMA. Activation of D 2 receptors during MDMA pretreatment appears critical for the development of sensitization to MDMA-produced hyperactivity. The role of D 2 receptor mechanisms in the development of sensitization to the reinforcing effects of MDMA is equivocal.

Opioids for neuropathic pain.

PubMed

Katz, Nathaniel; Benoit, Christine

2005-06-01

Whether opioids are effective for neuropathic pain has been a matter of controversy for decades. Within limits, it is clear that opioids in general are effective for neuropathic pain. Furthermore, there is no evidence that opioids are any less effective for neuropathic pain than for non-neuropathic pain, no evidence that opioids are less effective for neuropathic pain than are other medications, and no evidence that one opioid is any more effective than another for neuropathic pain. It remains uncertain whether opioids are effective for central pain, although they may have a role. Although some patients appear to enjoy long-term benefits, most studies have been short-term. Opioids have an important role in the treatment of neuropathic pain; however, skillful opioid use balances the benefits with management of side effects and prevention and treatment of abuse and addiction.

Prevalence of prescription opioid use disorder among chronic opioid therapy patients after health plan opioid dose and risk reduction initiatives.

PubMed

Von Korff, Michael; Walker, Rod L; Saunders, Kathleen; Shortreed, Susan M; Thakral, Manu; Parchman, Michael; Hansen, Ryan N; Ludman, Evette; Sherman, Karen J; Dublin, Sascha

2017-08-01

No studies have assessed the comparative effectiveness of guideline-recommended interventions to reduce risk of prescription opioid use disorder among chronic opioid therapy (COT) patients. We compared the prevalence of prescription opioid use disorder among COT patients from intervention clinics that had implemented opioid dose and risk reduction initiatives for more than 4 years relative to control clinics that had not. After a healthcare system in Washington State implemented interventions to reduce opioid dose and risks, we surveyed 1588 adult primary care COT patients to compare the prevalence of prescription opioid use disorder among COT patients from the intervention and control clinics. Intervention clinics managed COT patients at lower COT doses and with more consistent use of risk reduction practices. Control clinics cared for similar COT patients but prescribed higher opioid doses and used COT risk reduction practices inconsistently. Prescription opioid use disorder was assessed with the Psychiatric Research Interview for Substance and Mental Disorders. The prevalence of prescription opioid use disorder was 21.5% (95% CI=18.9% to 24.4%) among COT patients in the intervention clinics and 23.9% (95% CI=20.5% to 27.6%) among COT patients in the control clinics. The adjusted relative risk of prescription opioid use disorder was 1.08 (95% CI=0.89, 1.32) among the control clinic patients relative to the intervention clinic patients. Long-term implementation of opioid dose and risk reduction initiatives was not associated with lower rates of prescription opioid use disorder among prevalent COT patients. Extreme caution should be exercised by clinicians considering COT for patients with chronic non-cancer pain until benefits of this treatment and attendant risks are clarified. Copyright © 2017 Elsevier B.V. All rights reserved.

Growth In Buprenorphine Waivers For Physicians Increased Potential Access To Opioid Agonist Treatment, 2002-11.

PubMed

Dick, Andrew W; Pacula, Rosalie L; Gordon, Adam J; Sorbero, Mark; Burns, Rachel M; Leslie, Douglas; Stein, Bradley D

2015-06-01

Opioid use disorders are a significant public health problem, affecting two million people in the United States. Treatment with buprenorphine, methadone, or both is predominantly offered in methadone clinics, yet many people do not receive the treatment they need. In 2002 the Food and Drug Administration approved buprenorphine for prescription by physicians who completed a course and received a waiver from the Drug Enforcement Administration, exempting them from requirements in the Controlled Substances Act. To determine the waiver program's impact on the availability of opioid agonist treatment, we analyzed data for the period 2002-11 to identify counties with opioid treatment shortages. We found that the percentage of counties with a shortage of waivered physicians fell sharply, from 98.9 percent in 2002 to 46.8 percent in 2011. As a result, the percentage of the US population residing in what we classified as opioid treatment shortage counties declined from 48.6 percent in 2002 to 10.4 percent in 2011. These findings suggest that the increase in waivered physicians has dramatically increased potential access to opioid agonist treatment. Policy makers should focus their efforts on further increasing the number and geographical distribution of physicians, particularly in more rural counties, where prescription opioid misuse is rapidly growing. Project HOPE—The People-to-People Health Foundation, Inc.

Regulation and Functional Implications of Opioid Receptor Splicing in Opioid Pharmacology and HIV Pathogenesis

PubMed Central

Regan, Patrick M.; Langford, T. Dianne; Khalili, Kamel

2015-01-01

Despite the identification and characterization of four opioid receptor subtypes and the genes from which they are encoded, pharmacological data does not conform to the predications of a four opioid receptor model. Instead, current studies of opioid pharmacology suggest the existence of additional receptor subtypes; however, no additional opioid receptor subtype has been identified to date. It is now understood that this discrepancy is due to the generation of multiple isoforms of opioid receptor subtypes. While several mechanisms are utilized to generate these isoforms, the primary mechanism involves alternative splicing of the pre-mRNA transcript. Extensive alternative splicing patterns for opioid receptors have since been identified and discrepancies in opioid pharmacology are now partially attributed to variable expression of these isoforms. Recent studies have been successful in characterizing the localization of these isoforms as well as their specificity in ligand binding; however, the regulation of opioid receptor splicing specificity is poorly characterized. Furthermore, the functional significance of individual receptor isoforms and the extent to which opioid- and/or HIV-mediated changes in the opioid receptor isoform profile contributes to altered opioid pharmacology or the well-known physiological role of opioids in the exacerbation of HIV neurocognitive dysfunction is unknown. As such, the current review details constitutive splicing mechanisms as well as the specific architecture of opioid receptor genes, transcripts, and receptors in order to highlight the current understanding of opioid receptor isoforms, potential mechanisms of their regulation and signaling, and their functional significance in both opioid pharmacology and HIV-associated neuropathology. PMID:26529364

Trends in the Distribution of Opioids in Puerto Rico, 1999-2013.

PubMed

El Burai Félix, Sausan; Mack, Karin A; Jones, Christopher M

2016-09-01

Limited information has been published about opioid prescribing practices in Puerto Rico. The objective of this study was to create baseline trends of opioids distributed over a period of fourteen years in Puerto Rico. We examined data from the U.S. Drug Enforcement Administration's Automation of Reports and Consolidated Orders System (ARCOS) for the period 1999-2013. ARCOS data reflects the amount of controlled substances legally dispensed. Analyses include the distribution of opioids (in morphine milligram equivalent kg per 10,000 persons) by year and entity (pharmacy, hospital, practitioner). The distribution of four drugs (fentanyl, hydromorphone, methadone, oxycodone) increased over 100% between 1999 and 2013. The distribution of two drugs (hydrocodone and meperidine) declined between 1999 and 2013. Oxycodone distribution grew from 0.13 MME kg grams per 10,000 persons in 1999 to 0.29 MME kg in 2013. ARCOS data showed that the overall amount of opioid pain relievers distributed in Puerto Rico increased by 68% between 1999 and 2013. Currently, prescription opioid pain reliever overdose deaths in Puerto Rico do not appear to be skyrocketing as they are in the mainland U.S. However, the ongoing problem with prescription opioid pain reliever overdoses in certain areas should serve as a warning to monitor consumption of opioid pain relievers, as well as changes in prescription drug abuse, overdoses, and deaths.

Reinstatement of cocaine place-conditioning prevented by the peptide kappa-opioid receptor antagonist arodyn.

PubMed

Carey, A N; Borozny, K; Aldrich, J V; McLaughlin, J P

2007-08-13

Stress contributes to the reinstatement of cocaine-seeking behavior in abstinent subjects. Kappa-opioid receptor antagonists attenuate the behavioral effects of stress, potentially providing therapeutic value in treating cocaine abuse. Presently, the peptide arodyn produced long-lasting kappa-opioid receptor antagonism, suppressing kappa-opioid receptor agonist-induced antinociception at least 3 days after intracerebroventricular administration of 0.3 nmol. C57Bl/6J mice demonstrated cocaine-conditioned place preference, extinction over 3 weeks, and a subsequent reinstatement of place preference. Arodyn pretreatment suppressed stress-induced, but not cocaine-exposed, reinstatement of cocaine place preference. These results verify that arodyn and other kappa-opioid receptor antagonists may be useful therapeutics for cocaine abuse.

Opioid-induced preconditioning: recent advances and future perspectives.

PubMed

Peart, Jason N; Gross, Eric R; Gross, Garrett J

2005-01-01

Opioids, named by Acheson for compounds with morphine-like actions despite chemically distinct structures, have received much research interest, particularly for their central nervous system (CNS) actions involved in pain management, resulting in thousands of scientific papers focusing on their effects on the CNS and other organ systems. A more recent area which may have great clinical importance concerns the role of opioids, either endogenous or exogenous compounds, in limiting the pathogenesis of ischemia-reperfusion injury in heart and brain. The role of endogenous opioids in hibernation provides tantalizing evidence for the protective potential of opioids against ischemia or hypoxia. Mammalian hibernation, a distinct energy-conserving state, is associated with depletion of energy stores, intracellular acidosis and hypoxia, similar to those which occur during ischemia. However, despite the potentially detrimental cellular state induced with hibernation, the myocardium remains resilient for many months. What accounts for the hypoxia-tolerant state is of great interest. During hibernation, circulating levels of opioid peptides are increased dramatically, and indeed, are considered a "trigger" of hibernation. Furthermore, administration of opioid antagonists can effectively reverse hibernation in mammals. Therefore, it is not surprising that activation of opioid receptors has been demonstrated to preserve cellular status following a hypoxic insult, such as ischemia-reperfusion in many model systems including the intestine [Zhang, Y., Wu, Y.X., Hao, Y.B., Dun, Y. Yang, S.P., 2001. Role of endogenous opioid peptides in protection of ischemic preconditioning in rat small intestine. Life Sci. 68, 1013-1019], skeletal muscle [Addison, P.D., Neligan, P.C., Ashrafpour, H., Khan, A., Zhong, A., Moses, M., Forrest, C.R., Pang, C.Y., 2003. Noninvasive remote ischemic preconditioning for global protection of skeletal muscle against infarction. Am. J. Physiol. Heart Circ

Work Enabling Opioid Management.

PubMed

Lavin, Robert A; Kalia, Nimisha; Yuspeh, Larry; Barry, Jill A; Bernacki, Edward J; Tao, Xuguang Grant

2017-08-01

This study describes the relationship between opioid prescribing and ability to work. The opioid prescription patterns of 4994 claimants were studied. Three groups were constructed: 1) at least 3 consecutive months prescribed (chronic opioid therapy; COT); 2) less than 3 consecutive months prescribed (acute opioid therapy; AOT); and 3) no opioids prescribed. Variables included sex, age, daily morphine equivalent dose (MED), days opioids were prescribed, temporary total days (TTDs), and medical/indemnity/total costs. The COT versus AOT claimants had higher opioid costs ($8618 vs $94), longer TTD (636.2 vs 182.3), and average MED (66.8 vs 34.9). Only 2% of the COT cohort were not released to work. Fifty-seven percent of patients in the COT category (64 of 112) were released to work while still receiving opioids. COT does not preclude ability to work when prescribing within established guidelines.

Demographic Trends of Adults in New York City Opioid Treatment Programs--An Aging Population.

PubMed

Han, Benjamin; Polydorou, Soteri; Ferris, Rosie; Blaum, Caroline S; Ross, Stephen; McNeely, Jennifer

2015-01-01

The population of adults accessing opioid treatment is growing older, but exact estimates vary widely, and little is known about the characteristics of the aging treatment population. Further, there has been little research regarding the epidemiology, healt h status, and functional impairments in this population. To determine the utilization of opioid treatment services by older adults in New York City. This study used administrative data from New York State licensed drug treatment programs to examine overall age trends and characteristics of older adults in opioid treatment programs in New York City from 1996 to 2012. We found significant increases in utilization of opioid treatment programs by older adults in New York City. By 2012, those aged 50-59 made up the largest age group in opioid treatment programs. Among older adults there were notable shifts in demographic background including gender and ethnicity, and an increase in self-reported impairments. More research is needed to fully understand the specific characteristics and needs of older adults with opioid dependence.

Distance traveled and frequency of interstate opioid dispensing in opioid shoppers and nonshoppers.

PubMed

Cepeda, M Soledad; Fife, Daniel; Yuan, Yingli; Mastrogiovanni, Greg

2013-10-01

Little is known about how far opioid shoppers travel or how often they cross state lines to fill their opioid prescriptions. This retrospective cohort study evaluated these measures for opioid shoppers and nonshoppers using a large U.S. prescription database. Patients with ≥3 opioid dispensings were followed for 18 months. A subject was considered a shopper when he or she filled overlapping opioid prescriptions written by >1 prescriber at ≥3 pharmacies. A heavy shopper had ≥5 shopping episodes. Outcomes assessed were distance traveled among pharmacies and number of states visited to fill opioid prescriptions. A total of 10,910,451 subjects were included; .7% developed any shopping behavior and their prescriptions accounted for 8.6% of all opioid dispensings. Shoppers and heavy shoppers were younger than the nonshoppers. Shoppers traveled a median of 83.8 miles, heavy shoppers 199.5 miles, and nonshoppers 0 miles. Almost 20% of shoppers or heavy shoppers, but only 4% of nonshoppers, visited >1 state. Shoppers traveled greater distances and more often crossed state borders to fill opioid prescriptions than nonshoppers, and their dispensings accounted for a disproportionate number of opioid dispensings. Sharing of data among prescription-monitoring programs will likely strengthen those programs and may decrease shopping behavior. This study shows that opioid shoppers travel greater distances and more often cross state borders to fill opioid prescriptions than nonshoppers, and their dispensings accounted for a disproportionate number of opioid dispensings. The findings support the need for data sharing among prescription-monitoring programs to deter opioid shopping behavior. Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.

Interpreting labels of abuse-deterrent opioid analgesics.

PubMed

Webster, Lynn R

To provide an overview of available abuse-deterrent opioids (ADOs) and the labeling text that describes abuse-deterrent (AD) properties. A nonsystematic review of ADO literature and regulatory documents guiding their development. A critical assessment and discussion of common routes of opioid abuse, AD methods and properties, US Food and Drug Administration (FDA) study requirements to achieve AD labeling, and brief guide to understanding AD labels. The FDA has issued guidance as incentive and direction to industry to develop ADOs as one component of a multi-pronged public-health strategy to combat opioid abuse and misuse. The guidance describes separate categories of premarket and postmarket studies and makes recommendations for claims that may be made based on study findings. Ten ADOs have FDA-approved labeling attesting to AD properties. Available formulations that fail to conform to FDA guidance in study and labeling recommendations cannot be considered ADO. Formulations with AD properties are expected to reduce risk compared to the same agents without AD properties but cannot prevent all abuse and adverse clinical outcomes.

Association Between Opioid Use and Risk of Erectile Dysfunction: A Systematic Review and Meta-Analysis.

PubMed

Zhao, Shankun; Deng, Tuo; Luo, Lianmin; Wang, Jiamin; Li, Ermao; Liu, Luhao; Li, Futian; Luo, Jintai; Zhao, Zhigang

2017-10-01

Opioid analgesics have been widely used to relieve chronic pain conditions; however, a connection between opioid analgesic administration and increased susceptibility to erectile dysfunction (ED) has been hypothesized. To evaluate whether opioid use was a risk factor for ED in a systematic review and meta-analysis. The PubMed, Cochrane Library, and Embase databases were searched to identify eligible studies concerning opioid use and risk of ED from inception to April 2017. The association between opioid use and risk of ED was summarized using the relative risk with 95% CI. Sensitivity analyses were conducted to assess potential bias. The Begg and Egger tests were used for publication bias analysis. The GRADE evidence profile tool was used to assess the quality of the evidence. The overall combined risk estimates for the effect of opioid use on ED were calculated using a random-effects model. This meta-analysis included 8,829 men (mean age = 41.6 years) from 10 studies, 2,456 of whom received opioid management (duration of intervention = 4 months to 9.5 years). Pooled results demonstrated that the use of opioids was significantly associated with an increased risk of ED (relative risk = 1.96, 95% CI = 1.66-2.32, P < .001). Estimates of the total effects were generally consistent in the sensitivity analysis. No evidence of publication bias was observed. The overall quality of evidence was rated as low. We found that men with opioid use had a significantly increased prevalence of ED, which suggests that patients and clinicians should be aware of the potential role played by opioid administration in the development of ED. This is the first meta-analysis performed to describe the relation between opioid use and ED risk based on all available epidemiologic studies. However, the direction of causality between opioid use and risk of ED should be interpreted with caution because most included studies used a cross-sectional design. Evidence from the included

The effect of repeated diazepam administration on myocardial function in the ischemia-reperfused isolated rat heart.

PubMed

Shackebaei, Dareuosh; Kayhani, Bijan; Godini, Aliashraf; Pourshanazari, Aliasghar; Reshadat, Sohyla

2009-06-01

To evaluate whether repeated diazepam administration affects the heart in ischemia-reperfusion. This study was performed at the Medical Biology Research Center, Kermanshah, Iran, from March to September 2008. Four groups of rats were subjected to a daily injection of diazepam (group 1 [0.5 mg/kg for 21 days], group II [2.5 mg/kg for 5 days], and group III [5 mg/kg for 5 days] intraperitoneally), and saline solution (21 days) in the control groups. Isolated, perfused hearts were subjected to 40 minutes global ischemia, and 45 minutes reperfusion. The left ventricular developed pressure (LVDP), heart rate, and coronary flow were measured. Rate pressure product (RPP) was calculated. In reperfusion, released lactate dehydrogenase (LDH) enzyme in effluent was measured. It was observed that the recovery of the RPP and LVDP in reperfusion significantly decreased in the test group III (n=9) in comparison to the control (n=8). During the reperfusion period, the released LDH significantly increased in test group II (n=8) and group III in comparison with the control. The results show that repeated administration of diazepam (5 mg/kg for 5 days) reduced the cardiac performance in reperfusion, and significantly exacerbated the ischemia-reperfusion injury. It is probably mediated by the changing of cardiac susceptibility in ischemia due to repeated administration of diazepam.

Evaluation of US Federal Legislation for Opioid Abuse: 1973-2016.

PubMed

Ruble, James H

2016-09-01

The 114th Congress (2014-2016) has received recent attention for the high number of legislative bills directed to the public health crisis in prescription opioid abuse. The US government does not have a single source for determining public policy; however, the people expect that there will be some level of efficiency and coordination between federal and state leaders to improve the nation's health. A search of the National Library of Congress database to analyze legislative bills introduced between 1973 and 2016 and which contain the term "opioid" identified 127 bills that characterize consistency and coordination with other governmental efforts in prescription opioid abuse. Despite the recent number of introduced bills, there does not appear to be a close coordination between Congress and Federal Administrative agencies regarding this crisis.

Magnesium enhances opioid-induced analgesia - What we have learnt in the past decades?

PubMed

Bujalska-Zadrożny, Magdalena; Tatarkiewicz, Jan; Kulik, Kamila; Filip, Małgorzata; Naruszewicz, Marek

2017-03-01

Opioids are increasingly used in alleviating pain, including cancer-related pain and postoperative pain. Unfortunately, the development of tolerance, the resistance of neuropathic pain on opioid analgesia or other undesirable effects may limit their utility. In order to reduce opioid doses, and thereby to avoid the risk of side effects and sudden deaths due to overdosing, attempts have been made to introduce co-analgesics. Due to an increasing amount of data concerning a potential enhance of opioid analgesia by the physiological antagonist of N-methyl-d-aspartate receptors, magnesium ions (Mg 2+ ), a concomitant use of such a combination seems to be interesting from a clinical point of view. Therefore, the aim of this review is to provide an analysis of existing preclinical and clinical studies in the context of the benefits of using this combination in clinical practice. A potential mechanism of magnesium - opioid interaction is also suggested. The potential influence of Mg on opioid adverse/side effects as well as conclusions on the safety of combined administration of magnesium and opioid drugs were also summarized. Data from animal studies indicate that magnesium increases opioid analgesia in chronic (e.g., neuropathic, inflammatory) as well as acute pain. In clinical trials, most authors confirmed that magnesium reduces opioid consumption and alleviates postoperative pain scores while not increasing the risk of side effects after opioids. However, more clinical studies are needed concerning an influence of Mg on opioid activity in other difficult to treat types of pain, especially neuropathic and inflammatory. Copyright © 2016 Elsevier B.V. All rights reserved.

Nonopioid substance use disorders and opioid dose predict therapeutic opioid addiction.

PubMed

Huffman, Kelly L; Shella, Elizabeth R; Sweis, Giries; Griffith, Sandra D; Scheman, Judith; Covington, Edward C

2015-02-01

Limited research examines the risk of therapeutic opioid addiction (TOA) in patients with chronic noncancer pain. This study examined TOA among 199 patients undergoing long-term opioid therapy at the time of admission to a pain rehabilitation program. It was hypothesized that nonopioid substance use disorders and opioid dosage would predict TOA. Daily mean opioid dose was 132.85 mg ± 175.39. Patients with nonopioid substance use disorders had 28 times the odds (odds ratio [OR] = 28.58; 95% confidence interval [CI] = 10.86, 75.27) of having TOA. Each 50-mg increase in opioid dose nearly doubled the odds of TOA (OR = 1.73; 95% CI = 1.29, 2.32). A 100-mg increase was associated with a 3-fold increase in odds (OR = 3.00; 95% CI = 1.67, 5.41). Receiver operating characteristic analysis revealed that opioid dose was a moderately accurate predictor (area under the curve = .75; 95% CI = .68, .82) of TOA. The sensitivity (.70) and specificity (.68) of opioid dose in predicting TOA was maximized at 76.10 mg; in addition, 46.00 mg yielded 80% sensitivity in identifying TOA. These results underscore the importance of obtaining a substance use history prior to prescribing and suggest a low screening threshold for TOA in patients who use opioids in the absence of improvement in pain or functional impairment. This article examines TOA in patients with chronic noncancer pain undergoing long-term opioid therapy. Results suggest that patients should be screened for nonopioid substance use disorders prior to prescribing. In the absence of improvement in pain or function, there is a low threshold (∼50 mg daily opioid dose) for addiction screening. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

Parenteral opioids for maternal pain management in labour.

PubMed

Smith, Lesley A; Burns, Ethel; Cuthbert, Anna

2018-06-05

Parenteral opioids (intramuscular and intravenous drugs including patient-controlled analgesia) are used for pain relief in labour in many countries throughout the world. This review is an update of a review first published in 2010. To assess the effectiveness, safety and acceptability to women of different types, doses and modes of administration of parenteral opioid analgesia in labour. A second objective is to assess the effects of opioids in labour on the baby in terms of safety, condition at birth and early feeding. We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (11 May 2017) and reference lists of retrieved studies. We included randomised controlled trials examining the use of intramuscular or intravenous opioids (including patient-controlled analgesia) for women in labour. Cluster-randomised trials were also eligible for inclusion, although none were identified. We did not include quasi-randomised trials. We looked at studies comparing an opioid with another opioid, placebo, no treatment, other non-pharmacological interventions (transcutaneous electrical nerve stimulation (TENS)) or inhaled analgesia. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of each evidence synthesis using the GRADE approach. We included 70 studies that compared an opioid with placebo or no treatment, another opioid administered intramuscularly or intravenously or compared with TENS applied to the back. Sixty-one studies involving more than 8000 women contributed data to the review and these studies reported on 34 different comparisons; for many comparisons and outcomes only one study contributed data. All of the studies were conducted in hospital settings, on healthy women with uncomplicated pregnancies at 37 to 42 weeks' gestation. We excluded studies focusing on women with pre

Physician Introduction to Opioids for Pain Among Patients with Opioid Dependence and Depressive Symptoms

PubMed Central

Tsui, Judith I.; Herman, Debra S.; Kettavong, Malyna; Alford, Daniel; Anderson, Bradley J.; Stein, Michael D.

2011-01-01

This study determined the frequency of reporting being introduced to opioids by a physician among opioid dependent patients. Cross-sectional analyses were performed using baseline data from a cohort of opioid addicts seeking treatment with buprenorphine. The primary outcome was response to the question: “Who introduced you to opiates?” Covariates included sociodemographics, depression, pain, current and prior substance use. Of 140 participants, 29% reported that they had been introduced to opioids by a physician. Of those who were introduced to opioids by a physician, all indicated that they had initially used opioids for pain, versus only 11% of those who did not report being introduced to opioids by a physician (p<0.01). There was no difference in current pain (78% vs. 85%, p=0.29), however participants who were introduced to opioids by a physician were more likely to have chronic pain (63% vs. 43%, p=0.04). A substantial proportion of individuals with opioid dependence seeking treatment may have been introduced to opioids by a physician. PMID:20727704

Delay discounting in opioid use disorder: Differences between heroin and prescription opioid users.

PubMed

Karakula, Sterling L; Weiss, Roger D; Griffin, Margaret L; Borges, Allison M; Bailey, Allen J; McHugh, R Kathryn

2016-12-01

Among those with opioid use disorder, heroin use is associated with poorer prognosis relative to use of prescription opioids alone. However, relatively little is known about distinguishing features between those who use heroin relative to those who use prescription opioids. In the present study we evaluated differences in delay discounting in those with opioid use disorder based on primary opioid of use. Delay discounting is associated with a range of negative outcomes and is an important therapeutic target in this population. Treatment-seeking adults with opioid dependence completed self-report measures including past-month opioid use and the Monetary Choice Questionnaire (Kirby and Marakovic, 1996; Kirby et al., 1999), a measure of delay discounting. Participants were divided into two groups based on whether they used any heroin in the past 30days or only prescription opioids, and delay discounting scores were compared between the groups. Group differences in sociodemographic or clinical variables were included in the analysis as covariates. Results from a forward stepwise linear regression indicated that heroin use was associated with significantly higher delay discounting (B=-0.99, SE B =0.34, t=-2.88, p=0.005), even when considering covariates. Adults with opioid dependence who exclusively used prescription opioids had lower delay discounting relative to those who used heroin. This finding contributes further to the literature suggesting that heroin use is associated with greater clinical severity among those with opioid use disorder. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

[Effect of repeated cycles of tetraolean and oleandomycin administration on the indices of nonspecific resistence of the body in experimental staphylococcal sepsis].

PubMed

Plaksin, A I; Plaksina, A N

1975-02-01

The effect of repeated cycles of tetracycline and oleandomycin administration on the complement titer, content of lysozyme and bactericidal properties of the serum in rabbits with experimental staphylococcal sepsis was studied. It was shown that the septic process induced by intravenous inoculation of staphylococci was accompanied by stimulation of the host nonspecific resistance. However, repeated inoculations of the animals resulted in exhaustion of the host protective forces and decreased non-specific resistance. The use of tetracycline in experimental staphylococcal sepsis was accompanied by an increase in the complement titer, lysozyme content and bactericidal properties of the serum after both the 1st and 2nd cycles of the drug administration. The use of oleaudomycin induced an increase in the contents of the complement, lysozyme and bactericidal properties of the serum at the background of staphylococcal sepsis only after the 1st cycle. The repeated cycle of oleandomycin administration was accompanied by a decrease in the above indices. Such conditions should be taken into account in choosing the antibiotic for treatment of septic cases especially when repeated cycles of the drug administration are used.

Opioid intoxication

MedlinePlus

... treat severe cough or diarrhea. The illegal drug heroin is also an opioid. When abused , opioids cause ... Abuse. What are the medical complications of chronic heroin use? National Institute on Drug Abuse Web site. ...

Does naltrexone affect craving in abstinent opioid-dependent patients?

PubMed

Dijkstra, Boukje A G; De Jong, Cor A J; Bluschke, Sarah M; Krabbe, Paul F M; van der Staak, Cees P F

2007-06-01

Naltrexone blocks the opioid receptors that modulate the release of dopamine in the brain reward system and therefore blocks the rewarding effects of heroin and alcohol. It is generally assumed that naltrexone leads to reduction of craving, but few studies have been performed to prove this. The purpose of the present study was to examine the effect of the administration of naltrexone on craving level after rapid opioid detoxification induced by naltrexone. A naturalistic study was carried out in which patients were followed during 10 months after rapid detoxification. Data about abstinence, relapse, and naltrexone use were collected by means of urine specimens. Craving was measured by the visual analogue scale craving, the Obsessive Compulsive Drug Use Scale, and the Desires for Drug Questionnaire. Results showed that patients who relapsed in opioid use experienced obviously more craving than abstinent people. Patients who took naltrexone did not experience significant less craving than those who did not. These results suggest that the use of opioids is associated with increased craving and that abstinence for opioids is associated with less craving, independent of the use of naltrexone. This is in contrast to the general opinion. Because of the naturalistic design of the study, no firm conclusions can be drawn, but the results grounded the needs of an experimental study.

Opioid analgesics: does potency matter?

PubMed

Passik, Steven D; Webster, Lynn

2014-01-01

Prescription opioid analgesics with a wide range of potencies are currently used for the treatment of chronic pain. Yet understanding the clinical relevance and therapeutic consequences of opioid potency remains ill defined. Both patients and clinicians alike have misperceptions about opioid potency, expecting that less-potent opioids will be less effective or fearing that more-potent opioids are more dangerous or more likely to be abused. In this review, common myths about the potency of opioid analgesics will be discussed. Clinicians should understand that pharmacologic potency per se does not necessarily imply more effective analgesia or higher abuse liability. Published dose conversion tables may not accurately calculate the dose for effective and safe rotation from one opioid to another in patients receiving long-term opioid therapy because they are based on limited data that may not apply to chronic pain. Differences in pharmacologic potency are largely accounted for by the actual doses prescribed, according to individualized patient need. Factors for achieving effective analgesia and reducing the risks involved with opioid use include careful medication selection based on patient characteristics, appropriate dosing titration and opioid rotation practices, knowledge of product formulation characteristics (eg, extended release, immediate release, and tamper-resistant features), and an awareness of differences in opioid pharmacokinetics and metabolism. Clinicians should remain vigilant in monitoring patients on any opioid medication, regardless of classification along the opioid potency continuum.

Opioid withdrawal suppression efficacy of oral dronabinol in opioid dependent humans

PubMed Central

Lofwall, Michelle R.; Babalonis, Shanna; Nuzzo, Paul A.; Elayi, Samy Claude; Walsh, Sharon L.

2016-01-01

Background The cannabinoid (CB) system is a rational novel target for treating opioid dependence, a significant public health problem around the world. This proof-of-concept study examined the potential efficacy of a CB1 receptor partial agonist, dronabinol, in relieving signs and symptoms of opioid withdrawal. Methods Twelve opioid dependent adults participated in this 5-week, inpatient, double-blind, randomized, placebo-controlled study. Volunteers were maintained on double-blind oxycodone (30mg oral, four times/day) and participated in a training session followed by 7 experimental sessions, each testing a single oral test dose (placebo, oxycodone 30 and 60mg, dronabinol 5, 10, 20, and 30mg [decreased from 40mg]). Placebo was substituted for oxycodone maintenance doses for 21 hours before each session in order to produce measurable opioid withdrawal. Outcomes included observer- and participant-ratings of opioid agonist, opioid withdrawal and psychomotor/cognitive performance. Results Oxycodone produced prototypic opioid agonist effects (i.e., suppressing withdrawal and increasing subjective effects indicative of abuse liability). Dronabinol 5 and 10mg produced effects most similar to placebo, while the 20 and 30mg doses produced modest signals of withdrawal suppression that were accompanied by dose-related increases in high, sedation, bad effects, feelings of heart racing, and tachycardia. Dronabinol was not liked more than placebo, showed some impairment in cognitive performance, and was identified as marijuana with increasing dose. Conclusion CB1 receptor activation is a reasonable strategy to pursue for the treatment of opioid withdrawal; however, dronabinol is not a likely candidate given its modest withdrawal suppression effects of limited duration and previously reported tachycardia during opioid withdrawal. PMID:27234658

Peripheral kappa-opioid agonist, ICI 204448, evokes hypothermia in cold-exposed rats.

PubMed

Rawls, Scott M; Ding, Zhe; Gray, Alex M; Cowan, Alan

2005-05-01

ICI 204448, a selective kappa-opioid agonist with limited CNS access, can be used to discriminate central and peripheral opioid actions on physiological systems such as pain and thermoregulation. Therefore, we investigated the effect of ICI 204448 (2.5, 5, and 10 mg/kg, s.c.) on male Sprague-Dawley rats exposed to ambient temperatures of 5, 20, or 32 degrees C. ICI 204448 did not alter the body temperature of rats maintained at 20 or 32 degrees C. However, 5 and 10 mg/kg of ICI 204448 evoked significant hypothermia in rats exposed to 5 degrees C. The i.c.v. administration of nor-BNI, a kappa-opioid antagonist, did not affect the hypothermia produced by the systemic injection of ICI 204448. Thus, an involvement of brain kappa-opioid receptors in ICI 204448-evoked hypothermia is unlikely. The present data demonstrate for the first time that ICI 204448 produces hypothermia in cold-exposed rats and suggest that the role of peripheral kappa-opioid receptors in thermoregulation becomes more significant at cold ambient temperatures. Copyright (c) 2005 S. Karger AG, Basel.

Mindfulness Meditation Modulates Pain Through Endogenous Opioids.

PubMed

Sharon, Haggai; Maron-Katz, Adi; Ben Simon, Eti; Flusser, Yuval; Hendler, Talma; Tarrasch, Ricardo; Brill, Silviu

2016-07-01

Recent evidence supports the beneficial effects of mindfulness meditation on pain. However, the neural mechanisms underlying this effect remain poorly understood. We used an opioid blocker to examine whether mindfulness meditation-induced analgesia involves endogenous opioids. Fifteen healthy experienced mindfulness meditation practitioners participated in a double-blind, randomized, placebo-controlled, crossover study. Participants rated the pain and unpleasantness of a cold stimulus prior to and after a mindfulness meditation session. Participants were then randomized to receive either intravenous naloxone or saline, after which they meditated again, and rated the same stimulus. A (3) × (2) repeated-measurements analysis of variance revealed a significant time effect for pain and unpleasantness scores (both P <.001) as well as a significant condition effect for pain and unpleasantness (both P <.2). Post hoc comparisons revealed that pain and unpleasantness scores were significantly reduced after natural mindfulness meditation and after placebo, but not after naloxone. Furthermore, there was a positive correlation between the pain scores following naloxone vs placebo and participants' mindfulness meditation experience. These findings show, for the first time, that meditation involves endogenous opioid pathways, mediating its analgesic effect and growing resilient with increasing practice to external suggestion. This finding could hold promising therapeutic implications and further elucidate the fine mechanisms involved in human pain modulation. Copyright © 2016 Elsevier Inc. All rights reserved.

Sex differences in opioid analgesia and addiction: interactions among opioid receptors and estrogen receptors

PubMed Central

2013-01-01

Opioids are widely used as the pain reliever and also notorious for being addictive drugs. Sex differences in the opioid analgesia and addiction have been reported and investigated in human subjects and animal models. Yet, the molecular mechanism underlying the differences between males and females is still unclear. Here, we reviewed the literature describing the sex differences in analgesic responses and addiction liabilities to clinically relevant opioids. The reported interactions among opioids, estrogens, opioid receptors, and estrogen receptors are also evaluated. We postulate that the sex differences partly originated from the crosstalk among the estrogen and opioid receptors when stimulated by the exogenous opioids, possibly through common secondary messengers and the downstream gene transcriptional regulators. PMID:24010861

Resistance exercise decreases heroin self-administration and alters gene expression in the nucleus accumbens of heroin-exposed rats.

PubMed

Smith, Mark A; Fronk, Gaylen E; Abel, Jean M; Lacy, Ryan T; Bills, Sarah E; Lynch, Wendy J

2018-04-01

Preclinical studies consistently report that aerobic exercise decreases drug self-administration and other forms of drug-seeking behavior; however, relatively few studies have examined other types of physical activity. The purpose of the present study was to examine the effects of resistance exercise (i.e., strength training) on heroin self-administration and mRNA expression of genes known to mediate opioid reinforcement and addictive behavior in the nucleus accumbens (NAc) of heroin-exposed rats. Female rats were obtained during late adolescence and divided into two groups. Resistance exercise rats were trained to climb a vertical ladder wearing a weighted vest; sedentary control rats were placed repeatedly on the ladder oriented horizontally on its side. All rats were implanted with intravenous catheters and trained to self-administer heroin on a fixed ratio (FR1) schedule of reinforcement. mRNA expression in the NAc core and shell was examined following behavioral testing. Resistance exercise significantly decreased heroin self-administration, resulting in a downward shift in the dose-effect curve. Resistance exercise also reduced mRNA expression for mu opioid receptors and dopamine D1, D2, and D3 receptors in the NAc core. Resistance exercise increased mRNA expression of dopamine D5 receptors in the NAc shell and increased mRNA expression of brain-derived neurotrophic factor (exons I, IIB, IIC, IV, VI, IX) in the NAc core. These data indicate that resistance exercise decreases the positive reinforcing effects of heroin and produces changes in opioid and dopamine systems in the NAc of heroin-exposed rats.

Co-morbid pain and opioid addiction: Long term effect of opioid maintenance on acute pain

PubMed Central

Wachholtz, Amy; Gonzalez, Gerardo

2014-01-01

Introduction Medication assisted treatment for opioid dependence alters the pain experience. This study will evaluate changes pain sensitivity and tolerance with opioid treatments; and duration of this effect after treatment cessation. Method 120 individuals with chronic pain were recruited in 4 groups (n=30): 1-methadone for opioid addiction; 2-buprenorphine for opioid addiction; 3-history of opioid maintenance treatment for opioid addiction but with prolonged abstinence (M=121 weeks; SD=23.3); and 4-opioid naïve controls. Participants completed a psychological assessment and a cold water task including, time to first pain (sensitivity) and time to stopping the pain task (tolerance). Data analysis used survival analyses. Results A Kaplan-Meier-Cox survival analysis showed group differences for both pain sensitivity (Log rank=15.50; p<.001) and tolerance (Log rank=20.11; p<.001). Current or historical use of opioid maintenance resulted in differing pain sensitivity compared to opioid naïve (p’s<.01). However, tolerance to pain was better among those with a history of opioid maintenance compared to active methadone patients (p<.05), with the highest tolerance found among opioid naïve control group participants (p’s<.001). Correlations within the prolonged abstinent group indicated pain tolerance was significantly improved as length of opioid abstinence increased (R=.37; p<.05); but duration of abstinence did not alter sensitivity (ns). Conclusion Among individuals with a history of prolonged opioid maintenance, there appears to be long-term differences in pain sensitivity that do not resolve with discontinuation of opioid maintenance. Although pain sensitivity does not change, pain tolerance does improve after opioid maintenance cessation. Implications for treating co-morbid opioid addiction and pain (acute and chronic) are discussed. PMID:25456326

Co-morbid pain and opioid addiction: long term effect of opioid maintenance on acute pain.

PubMed

Wachholtz, Amy; Gonzalez, Gerardo

2014-12-01

Medication assisted treatment for opioid dependence alters the pain experience. This study will evaluate changes pain sensitivity and tolerance with opioid treatments; and duration of this effect after treatment cessation. 120 Individuals with chronic pain were recruited in 4 groups (N = 30): 1-methadone for opioid addiction; 2-buprenorphine for opioid addiction; 3-history of opioid maintenance treatment for opioid addiction but with prolonged abstinence (M = 121 weeks; SD = 23.3); and 4-opioid naïve controls. Participants completed a psychological assessment and a cold water task including, time to first pain (sensitivity) and time to stopping the pain task (tolerance). Data analysis used survival analyses. A Kaplan-Meier-Cox survival analysis showed group differences for both pain sensitivity (log rank = 15.50; p < .001) and tolerance (log rank = 20.11; p < .001). Current or historical use of opioid maintenance resulted in differing pain sensitivity compared to opioid naïve (p's < .01). However, tolerance to pain was better among those with a history of opioid maintenance compared to active methadone patients (p < .05), with the highest tolerance found among opioid naïve control group participants (p's < .001). Correlations within the prolonged abstinent group indicated pain tolerance was significantly improved as length of opioid abstinence increased (R = .37; p < .05); but duration of abstinence did not alter sensitivity (ns). Among individuals with a history of prolonged opioid maintenance, there appears to be long-term differences in pain sensitivity that do not resolve with discontinuation of opioid maintenance. Although pain sensitivity does not change, pain tolerance does improve after opioid maintenance cessation. Implications for treating co-morbid opioid addiction and pain (acute and chronic) are discussed. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

[Psycho-emotional changes in women during delivery under the influence of opioid analgesics].

PubMed

Kiselev, A G; Polushin, Iu S

2010-01-01

A study of psycho-emotional condition was carried out in 408 women during opioid analgesia in different delivery stages with estimation of the changes in reactive and personal anxiety and rank pain index (RPI). The obtained data suppose that analgetic effect of opioids is carried out especially through the sensor component of RPI. On the other hand, the evaluated (targeted) and the effector components of psycho-emotional condition after administration of opioids have changed insignificantly and not evidently. The effect of medicamental analgetics on emotional component of pain perception in every stage of labour had it own features. This should be taken in account while practical work.

Long-Term Opioid Therapy Reconsidered

PubMed Central

Von Korff, Michael; Kolodny, Andrew; Deyo, Richard A.; Chou, Roger

2012-01-01

In the past 20 years, primary care physicians have greatly increased prescribing of long-term opioid therapy. However, the rise in opioid prescribing has outpaced the evidence regarding this practice. Increased opioid availability has been accompanied by an epidemic of opioid abuse and overdose. The rate of opioid addiction among patients receiving long-term opioid therapy remains unclear, but research suggests that opioid misuse is not rare. Recent studies report increased risks for serious adverse events, including fractures, cardiovascular events, and bowel obstruction, although further research on medical risks is needed. New data indicate that opioid-related risks may increase with dose. From a societal perspective, higher-dose regimens account for the majority of opioids dispensed, so cautious dosing may reduce both diversion potential and patient risks for adverse effects. Limiting long-term opioid therapy to patients for whom it provides decisive benefits could also reduce risks. Given the warning signs and knowledge gaps, greater caution and selectivity are needed in prescribing long-term opioid therapy. Until stronger evidence becomes available, clinicians should err on the side of caution when considering this treatment. PMID:21893626

42 CFR 8.34 - Court review of final administrative action; exhaustion of administrative remedies.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 1 2013-10-01 2013-10-01 false Court review of final administrative action; exhaustion of administrative remedies. 8.34 Section 8.34 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS CERTIFICATION OF OPIOID TREATMENT PROGRAMS Procedures for...

42 CFR 8.34 - Court review of final administrative action; exhaustion of administrative remedies.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 1 2012-10-01 2012-10-01 false Court review of final administrative action; exhaustion of administrative remedies. 8.34 Section 8.34 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS CERTIFICATION OF OPIOID TREATMENT PROGRAMS Procedures for...

42 CFR 8.34 - Court review of final administrative action; exhaustion of administrative remedies.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 1 2014-10-01 2014-10-01 false Court review of final administrative action; exhaustion of administrative remedies. 8.34 Section 8.34 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS CERTIFICATION OF OPIOID TREATMENT PROGRAMS Procedures for...

Opioid Prescribing Education in Surgical Residencies: A Program Director Survey.

PubMed

Yorkgitis, Brian K; Bryant, Elizabeth; Raygor, Desiree; Brat, Gabriel; Smink, Douglas S; Crandall, Marie

Opioid abuse and misuse is a public health crisis. A national effort to reduce this phenomenon is ongoing. Residents represent a large pool of opioid prescribers but, are often not the target for opioid prescribing education (OPE). We developed a survey to assess current opioid prescribing practices and education among surgical residents. An Institutional Review Board and Association of Program Directors in Surgery approved survey was electronically mailed to surgical program directors (PDs). The survey included questions regarding residency type, location, number of graduates per year, perceived value of OPE, residency policy on prescribing outpatients controlled substances, presence of OPE, and preferred method of OPE. A total of 248 PDs were e-mailed the survey with 110 complete responses (44.4%). Of all 104 (94.5%) allow residents to prescribe outpatient opioids with 24 (23.1%) limiting the opioid class prescribed. A total of 29 (27.9%) programs require residents to obtain their own Drug Enforcement Administration registration. Only 22 (20.0%) programs had in place mandatory OPE, 7 (6.4%) PDs were unsure if OPE was a mandatory educational requirement. Furthermore, 70 (79.5%) of programs currently without OPE are considering adding it. Didactic lecture (18, 81.8%) is the most common modality for OPE. The mode time dedicated to OPE was 1 hour. When PDs were asked about which method would be best to deliver OPE, the most common response was case-based scenarios (39, 35.5%). Bivariate statistics were performed and no association was found between OPE and program characteristics'. Most surgical residency programs allow residents to prescribe outpatient opioids, very few require OPE. The most common method of OPE was didactic lectures. To enhance a resident's knowledge in prescribing opioids, programs should incorporate OPE into their curriculum. Copyright © 2017 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.

Opioid Utilization and Opioid-Related Adverse Events in Non-Surgical Patients in U.S. Hospitals

PubMed Central

Herzig, Shoshana J.; Rothberg, Michael B.; Cheung, Michael; Ngo, Long H.; Marcantonio, Edward R.

2014-01-01

Background Recent studies in the outpatient setting have demonstrated high rates of opioid prescribing and overdose-related deaths. Prescribing practices in hospitalized patients are unexamined. Objective To investigate patterns and predictors of opioid utilization in non-surgical admissions to U.S. hospitals, variation in use, and the association between hospital-level use and rates of severe opioid-related adverse events. Design, Setting, and Patients Adult non-surgical admissions to 286 U.S. hospitals. Measurements Opioid exposure and severe opioid-related adverse events during hospitalization, defined using hospital charges and ICD-9-CM codes. Results Of 1.14 million admissions, opioids were used in 51%. The mean ± s.d. daily dose received in oral morphine equivalents (OME) was 68 ± 185 mg; 23% of exposed received a total daily dose of ≥ 100 mg OME. Opioid prescribing rates ranged from 5% in the lowest to 72% in the highest prescribing hospital (mean 51% ± 10%). After adjusting for patient characteristics, the adjusted opioid prescribing rates ranged from 33–64% (mean 50% ± s.d. 4%). Among exposed, 0.97% experienced severe opioid-related adverse events. Hospitals with higher opioid prescribing rates had higher adjusted relative risk of a severe opioid-related adverse event per patient exposed (RR 1.23 [1.14–1.33] for highest compared to lowest prescribing quartile). Conclusions The majority of hospitalized non-surgical patients were exposed to opioids, often at high doses. Hospitals that used opioids most frequently had increased adjusted risk of a severe opioid-related adverse event per patient exposed. Interventions to standardize and enhance the safety of opioid prescribing in hospitalized patients should be investigated. PMID:24227700

Repeated arterial occlusion, delta-opioid receptor (DOR) plasticity and vagal transmission within the sinoatrial node of the anesthetized dog.

PubMed

Deo, Shekhar H; Barlow, Matthew A; Gonzalez, Leticia; Yoshishige, Darice; Caffrey, James L

2009-01-01

Brief interruptions in coronary blood flow precondition the heart, engage delta-opioid receptor (DOR) mechanisms and reduce the damage that typically accompanies subsequent longer coronary occlusions. Repeated short occlusions of the sinoatrial (SA) node artery progressively raised nodal methionine-enkephalin-arginine-phenylalanine (MEAP) and improved vagal transmission during subsequent long occlusions in anesthetized dogs. The DOR type-1 (DOR-1) antagonist, BNTX reversed the vagotonic effect. Higher doses of enkephalin interrupted vagal transmission through a DOR-2 mechanism. The current study tested whether the preconditioning (PC) protocol, the later occlusion or a combination of both was required for the vagotonic effect. The study also tested whether evolving vagotonic effects included withdrawal of competing DOR-2 vagolytic influences. Vagal transmission progressively improved during successive SA nodal artery occlusions. The vagotonic effect was absent in sham animals and after DOR-1 blockade. After completing the PC protocol, exogenously applied vagolytic doses of MEAP reduced vagal transmission under both normal and occluded conditions. The magnitude of these DOR-2 vagolytic effects was small compared to controls and repeated MEAP challenges rapidly eroded vagolytic responses further. Prior DOR-1 blockade did not alter the PC mediated, progressive loss of DOR-2 vagolytic responses. In conclusion, DOR-1 vagotonic responses evolved from signals earlier in the PC protocol and erosion of competing DOR-2 vagolytic responses may have contributed to an unmasking of vagotonic responses. The data support the hypothesis that PC and DOR-2 stimulation promote DOR trafficking, and down regulation of the vagolytic DOR-2 phenotype in favor of the vagotonic DOR-1 phenotype. DOR-1 blockade may accelerate the process by sequestering newly emerging receptors.

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.

On subclasses of opioid analgesics.

PubMed

Raffa, Robert B

2014-12-01

The history of discovery of analgesic drugs has followed a trajectory from original serendipitous discovery of plant-derived substances to laboratory creation of customized molecules that are intentionally designed to interact with specific receptors of neurotransmitters involved in either the transmission of the pain signal or the attenuation of such a signal. The drugs most recently developed have been designed to provide incremental greater separation between pain relief and adverse effects. The result has been drugs that have individualized pharmacodynamic and pharmacokinetic characteristics that represent specific advances in basic science and translate into unique clinical profiles. Several of the drugs include non-opioid components. They retain some of the features of opioids, but have distinct clinical characteristics that differentiate them from traditional opioids. Thus they defy simple classification as opioids. A summary is provided of the development of the modern view of multi-mechanistic pain and its treatment using analgesics that have multi-mechanisms of action (consisting of both opioid and non-opioid components). Descriptions of examples of such current analgesics and of those that have pharmacokinetic characteristics that result in atypical opioid clinical profiles are given. By serendipity or design, several current strong analgesics have opioid components of action, but have an additional non-opioid mechanism of action or some pharmacokinetic feature that gives them an atypical opioid clinical profile and renders them not easily classified as classical opioids. An appreciation that there are now opioid analgesics that differentiate from classical opioids in ways that defy their simplistic classification as opioids suggests that recognition of subclasses of opioid analgesics would be more accurate scientifically and would be more informative for healthcare providers and regulators. This would likely lead to positive outcomes for the clinical

Repeated chlorpromazine administration increases a behavioural response of rats to 5-hydroxytryptamine receptor stimulation.

PubMed Central

Green, A R

1977-01-01

1 The hyperactivity syndrome produced in rats by administration of tranylcypromine (20 mg/kg i.p.) followed 30 min later by L-tryptophan (50 mg/kg i.p.) is generally considered to be due to increased 5-hydroxytryptamine (5-HT) functional activity. It is inhibited by chlorpromazine (30 mg/kg i.p.) injected 60 min before the tranylcypromine. However, chlorpromazine injection for 4 days either at a dose of 30 mg/kg once daily or 5 mg/kg twice daily results in an enhanced hyperactivity response to tranylcypromine and L-tryptophan administration 24 h after the final dose of chlorpromazine. 2 One injection of chlorpromazine (30 mg/kg) did not produce enhancement 24 h later and the inhibition of the tranylcypromine/L-tryptophan hyperactivity observed after acute chlorpromazine injection was seen if the rats were given tranylcypromine and L-tryptophan 1 h after the fourth chlorpromazine (30 mg/kg) dose. 3 Chlorpromazine (30 mg/kg) once daily or 5 mg/kg twice daily for 4 days resulted in rats displaying enhanced behavioral responses to the suggested 5-HT agonist 5-methoxy N,N-dimethyltryptamine (2 mg/kg) on day 5. 4 Chlorpromazine (30 mg/kg) once daily for 4 days produces a slight increase in brain 5-hydroxytryptamine (5-HT) concentration on day 5, but no difference in the rate of brain 5-HT synthesis or the rate of 5-HT accumulation after tranylcypromine and L-tryptophan administration. 5. There is some evidence that chlorpromazine blocks 5-HT receptors. It has also been observed that several other neuroleptic drugs do not produce enhanced 5-HT responses after repeated administration. It is suggested therefore that the enhanced behavioural response to 5-HT receptor stimulation following repeated chlorpromazine administration may be because this drug blocks 5-HT receptors. PMID:264797

Association between intraoperative opioid administration and 30-day readmission: a pre-specified analysis of registry data from a healthcare network in New England.

PubMed

Long, D R; Lihn, A L; Friedrich, S; Scheffenbichler, F T; Safavi, K C; Burns, S M; Schneider, J C; Grabitz, S D; Houle, T T; Eikermann, M

2018-05-01

The use of intraoperative opioids may influence the rate of postoperative complications. This study evaluated the association between intraoperative opioid dose and the risk of 30-day hospital readmission. We conducted a pre-specified analysis of existing registry data for 153 902 surgical cases performed under general anaesthesia at Massachusetts General Hospital and two affiliated medical centres. We examined the association between total intraoperative opioid dose (categorised in quintiles) and 30-day hospital readmission, controlling for several patient-, anaesthetist-, and case-specific factors. Compared with low intraoperative opioid dosing [quintile 1, median (inter-quartile range): 8 (4-9) mg morphine equivalents], exposure to high-dose opioids during surgery [quintile 5: 32 (27-41) equivalents] is an independent predictor of 30-day readmission [odds ratio (OR) 1.15 (95% confidence interval 1.07-1.24); P<0.001]. Ambulatory surgery patients receiving high opioid doses were found to have the greatest adjusted risk of readmission (OR 1.75; P<0.001) with a clear dose-response effect across quintiles (P for trend <0.05), and were more likely to be readmitted early (postoperative days 0-2 vs 3-30; P<0.001). Opioid class modified the association between total opioid dose and readmission, with longer-acting opioids demonstrating a stronger influence (P<0.001). We observed significant practice variability across individual anaesthetists in the utilisation of opioids that could not be explained by patient- and case-specific factors. High intraoperative opioid dose is a modifiable anaesthetic factor that varies in the practice of individual anaesthetists and affects postoperative outcomes. Conservative standards for intraoperative opioid dosing may reduce the risk of postoperative readmission, particularly in ambulatory surgery. Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

New developments in managing opioid addiction: impact of a subdermal buprenorphine implant

PubMed Central

Itzoe, MariaLisa; Guarnieri, Michael

2017-01-01

Opioid addiction to prescription and illicit drugs is a serious and growing problem. In the US alone, >2.4 million people suffer from opioid use disorder. Government and pharmaceutical agencies have begun to address this crisis with recently released and revised task forces and medication-assisted therapies (MAT). For decades, oral or intravenous (IV) MATs have helped patients in their recovery by administration of opioid agonists (methadone, buprenorphine, oxycodone), antagonists (naltrexone, naloxone), and combinations of the two (buprenorphine/naloxone). While shown to be successful, particularly when combined with psychological counseling, oral and IV forms of treatment come with constraints and challenges. Patients can become addicted to the agonists themselves, and there is increased risk for diversion, abuse, or missed dosages. Consequently, long-acting implants have begun to be developed as a potentially preferable method of agonist delivery. To date, the newest implant approved by the US Food and Drug Administration (May 2016) is Probuphine®, which delivers steady-state levels of buprenorphine over the course of 6 months. Numerous studies have demonstrated its efficacy and safety. Yet, implants come with their own risks such as surgical site irritation, possible movement, and protrusion of implant out of skin. This review introduces the opioid abuse epidemic, examines existing medications used for therapy, and highlights Probuphine as a new treatment option. Costs associated with MATs are also discussed. PMID:28546740

New developments in managing opioid addiction: impact of a subdermal buprenorphine implant.

PubMed

Itzoe, MariaLisa; Guarnieri, Michael

2017-01-01

Opioid addiction to prescription and illicit drugs is a serious and growing problem. In the US alone, >2.4 million people suffer from opioid use disorder. Government and pharmaceutical agencies have begun to address this crisis with recently released and revised task forces and medication-assisted therapies (MAT). For decades, oral or intravenous (IV) MATs have helped patients in their recovery by administration of opioid agonists (methadone, buprenorphine, oxycodone), antagonists (naltrexone, naloxone), and combinations of the two (buprenorphine/naloxone). While shown to be successful, particularly when combined with psychological counseling, oral and IV forms of treatment come with constraints and challenges. Patients can become addicted to the agonists themselves, and there is increased risk for diversion, abuse, or missed dosages. Consequently, long-acting implants have begun to be developed as a potentially preferable method of agonist delivery. To date, the newest implant approved by the US Food and Drug Administration (May 2016) is Probuphine ® , which delivers steady-state levels of buprenorphine over the course of 6 months. Numerous studies have demonstrated its efficacy and safety. Yet, implants come with their own risks such as surgical site irritation, possible movement, and protrusion of implant out of skin. This review introduces the opioid abuse epidemic, examines existing medications used for therapy, and highlights Probuphine as a new treatment option. Costs associated with MATs are also discussed.

Involvement of central opioid systems in human interferon-α induced immobility in the mouse forced swimming test

PubMed Central

Makino, Mitsuhiro; Kitano, Yutaka; Komiyama, Chika; Hirohashi, Masaaki; Takasuna, Kiyoshi

2000-01-01

We investigated the mechanism by which human interferon-α (IFN-α) increases the immobility time in a forced swimming test, an animal model of depression.Central administration of IFN-α (0.05–50 IU per mouse, i.cist.) increased the immobility time in the forced swimming test in mice in a dose-dependent manner.Neither IFN-β nor -γ possessed any effect under the same experimental conditions.Pre-treatment with an opioid receptor antagonist, naloxone (1 mg kg−1, s.c.) inhibited the prolonged immobility time induced by IFN-α (60 KIU kg−1, i.v. or 50 IU per mouse. i.cist.).Peripheral administration of naloxone methiodide (1 mg kg−1, s.c.), which does not pass the blood–brain barrier, failed to block the effect of IFN-α, while intracisternal administration of naloxone methiodide (1 nmol per mouse) completely blocked.The effect of IFN-α was inhibited by a μ1-specific opioid receptor antagonist, naloxonazine (35 mg kg−1, s.c.) and a μ1/μ2 receptor antagonist, β-FNA (40 mg kg−1, s.c.). A selective δ-opioid receptor antagonist, naltrindole (3 mg kg−1, s.c.) and a κ-opioid receptor antagonist, nor-binaltorphimine (20 mg kg−1, s.c.), both failed to inhibit the increasing effect of IFN-α.These results suggest that the activator of the central opioid receptors of the μ1-subtype might be related to the prolonged immobility time of IFN-α, but δ and κ-opioid receptors most likely are not involved. PMID:10903965

The role of endogenous opioids in mediating pain reduction by orally administered glucose among newborns.

PubMed

Gradin, Maria; Schollin, Jens

2005-04-01

It has been demonstrated clearly that sweet-tasting solutions given before a painful intervention can reduce pain among newborns. There is no fully accepted explanation for this effect, but activation of endogenous opioids has been suggested as a possible mechanism. The aim of this study was to obtain deeper knowledge of the underlying mechanism by investigating whether administration of an opioid antagonist would reduce the effect of orally administered glucose at heel stick among term newborns. A randomized, placebo-controlled, double-blind trial with a validated, neonatal, pain-rating scale. The trial included 30 term newborns undergoing heel stick, who were assigned randomly to 1 of 2 groups, ie, group I, with naloxone hydrochloride (opioid antagonist) 0.01 mg/kg administered intravenously before oral administration of 1 mL of 30% glucose, or group II, with a corresponding amount of placebo (saline solution) administered intravenously before oral administration of glucose. Pain-related behavior during blood sampling was measured with the Premature Infants Pain Profile. Crying time and heart rate were also recorded. The 2 groups did not differ significantly in Premature Infant Pain Profile scores during heel stick. The median crying time during the first 3 minutes was 14 seconds (range: 0-174 seconds) for the naloxone group and 105 seconds (range: 0-175 seconds) for the placebo group. There was no significant difference in heart rate between the 2 groups. Administration of an opioid antagonist did not decrease the analgesic effect of orally administered glucose given before blood sampling.

Combination of intrathecal opioids with bupivacaine attenuates opioid dose escalation in chronic noncancer pain patients.

PubMed

Veizi, I Elias; Hayek, Salim M; Narouze, Samer; Pope, Jason E; Mekhail, Nagy

2011-10-01

The purpose of this study was to examine the effect of intrathecal (IT) coadministration of bupivacaine with opioids during the initial phase of opioid titration and up to 1 year after implantation of an IT drug delivery system (IDDS). The study was designed as a retrospective study. OUTCOMES ANALYZED: The outcomes analyzed for this study were pain relief, oral opioid consumption, IT opioid, and bupivacaine dosage. METHODS AND PATIENT POPULATION: The patient population for this study were consecutively implanted patients over a period of 6 years in a tertiary single center with multiple practitioners. In this retrospective study, 126 consecutive noncancer intractable pain patients were implanted with IDDS and initiated with an IT opioid (O) as a single medication or an IT opioid and bupivacaine (O + B). Pain intensity, amount of oral opioids, dose, rate, and concentration of IT opioids and bupivacaine, and number and type of IT medication used were recorded at preimplant, implant, and at 3, 6, and 12 months postimplant. The intervention used for the study was the IT delivery device implant. Significant reduction in pain intensity was observed in both groups at 12 months postimplant (O group: baseline 7.42 ± 2.1 to 5.85 ± 2.8 [n = 72, P < 0.001]; O + B group 7.35 ± 2 to 5.03 ± 2.4 (n = 54; P < 0.001]). The combination of opioids with bupivacaine from the start of IT infusion treatment resulted in a reduced progression of opioid dose escalation in comparison to patients started with opioids (O group). The rate of increase of IT opioids in the O group at 12 months was 535 ± 180%, whereas in the O + B, the dose increase was significantly lower at 185 ± 85% (P < 0.004). In both groups, there was a statistically significant decrease in oral opioid consumption compared with preimplant doses. Concomitant initial coadministration of IT bupivacaine with opioids blunts the rate of IT opioid dose escalation during the first year after implant of an IDDS. More studies are

Using Opioids Safely After Surgery

MedlinePlus

... Adult , Geriatric Using Opioids Safely After Surgery Using Opioids Safely After Surgery Stick to the lowest dose ... need opioid pain medicine. If your doctor says opioids aren’t necessary. If your doctor thinks you ...

Opioids and Opioid Maintenance Therapies: Their Impact on Monocyte-Mediated HIV Neuropathogenesis

PubMed Central

Jaureguiberry-Bravo, Matias; Wilson, Rebecca; Carvallo, Loreto; Berman, Joan W.

2017-01-01

Background HIV-1 enters the CNS within two weeks after peripheral infection and results in chronic neuroinflammation that leads to HIV associated neurocognitive disorders (HAND) in more than 50% of infected people. HIV enters the CNS by transmigration of infected monocytes across the blood brain barrier. Intravenous drug abuse is a major risk factor for HIV-1 infection, and opioids have been shown to alter the progression and severity of HAND. Methadone and buprenorphine are opioid derivates that are used as opioid maintenance therapies. They are commonly used to treat opioid dependency in HIV infected substance abusers, but their effects on monocyte migration relevant to the development of cognitive impairment are not well characterized. Conclusion Here, we will discuss the effects of opioids and opioid maintenance therapies on the inflammatory functions of monocytes and macrophages that are related to the development of neuroinflammation in the context of HIV infection. PMID:27009099

Performance Measures of Diagnostic Codes for Detecting Opioid Overdose in the Emergency Department.

PubMed

Rowe, Christopher; Vittinghoff, Eric; Santos, Glenn-Milo; Behar, Emily; Turner, Caitlin; Coffin, Phillip O

2017-04-01

specificity of 99.9% (95% CI = 99.8% to 100.0%). Expanding the ICD-9-CM codes to include both nonspecified and general (i.e., without a decimal modifier) drug poisoning and drug abuse codes identified overdose ED visits with a sensitivity of 56.8% (95% CI = 43.6%-72.7%) and specificity of 96.2% (95% CI = 94.8%-97.2%). Additional ICD-9-CM codes not explicitly relevant to opioid overdose were necessary to further enhance sensitivity. Among the 44 overdose ED visits, neither naloxone administration during the visit, whether the patient responded to the naloxone, nor the specific opioids involved were associated with the assignment of an opioid poisoning ICD-9-CM code (p ≥ 0.05). Tracking opioid overdose ED visits by diagnostic coding is fairly specific but insensitive, and coding was not influenced by administration of naloxone or the specific opioids involved. The reason for the high rate of missed cases is uncertain, although these results suggest that a more clearly defined case definition for overdose may be necessary to ensure effective opioid overdose surveillance. Changes in coding practices under ICD-10 might help to address these deficiencies. © 2016 by the Society for Academic Emergency Medicine.

Opioid Abuse and Addiction

MedlinePlus

Opioids, sometimes called narcotics, are a type of drug. They include strong prescription pain relievers, such as ... tramadol. The illegal drug heroin is also an opioid. Some opioids are made from the opium plant, ...

Understanding the Opioid Epidemic

MedlinePlus

... Opioid Overdose Deaths Preventing Overdose Deaths Opioid Overdose Deaths From 1999-2016, more than 350,000 people ... counterfeit pills, and cocaine. 1,3 Preventing Overdose Deaths Combatting the Opioid Overdose Epidemic CDC is committed ...

Repeated N-Acetylcysteine Administration Alters Plasticity-Dependent Effects of Cocaine

PubMed Central

Madayag, Aric; Lobner, Doug; Kau, Kristen S.; Mantsch, John R.; Abdulhameed, Omer; Hearing, Matthew; Grier, Mark D.; Baker, David A.

2010-01-01

Cocaine produces a persistent reduction in cystine-glutamate exchange via system xc- in the nucleus accumbens that may contribute to pathological glutamate signaling linked to addiction. System xc- influences glutamate neurotransmission by maintaining basal, extracellular glutamate in the nucleus accumbens which, in turn, shapes synaptic activity by stimulating group II metabotropic glutamate autoreceptors. In the present study, we tested the hypothesis that a long-term reduction in system xc- activity is part of the plasticity produced by repeated cocaine that results in the establishment of compulsive drug seeking. To test this, the cysteine prodrug N-acetylcysteine was administered prior to daily cocaine to determine the impact of increased cystine-glutamate exchange on the development of plasticity-dependent cocaine seeking. Although N-acetylcysteine administered prior to cocaine did not alter the acute effects of cocaine on self-administration or locomotor activity, it prevented behaviors produced by repeated cocaine including escalation of drug intake, behavioral sensitization, and cocaine-primed reinstatement. Because sensitization or reinstatement was not evident even 2–3 weeks after the last injection of N-acetylcysteine, we examined whether N-acetylcysteine administered prior to daily cocaine also prevented the persistent reduction in system xc- activity produced by repeated cocaine. Interestingly, N-acetylcysteine pretreatment prevented cocaine-induced changes in 35S cystine transport via system xc-, basal glutamate, and cocaine-evoked glutamate in the nucleus accumbens when assessed at least three weeks after the last N-acetylcysteine pretreatment. These findings indicate that N-acetylcysteine selectively alters plasticity-dependent behaviors and that normal system xc- activity prevents pathological changes in extracellular glutamate that may be necessary for compulsive drug seeking. PMID:18094234

Risk factors for severe respiratory depression from prescription opioid overdose.

PubMed

Fox, Lindsay M; Hoffman, Robert S; Vlahov, David; Manini, Alex F

2018-01-01

Prescription opioid overdose is a leading cause of injury-related morbidity and mortality in the United States. We aimed to identify characteristics associated with clinical severity in emergency department patients with prescription opioid overdose. This was a secondary data analysis of adult prescription opioid overdoses from a large prospective cohort of acute overdoses. We examined elements of a typical emergency department evaluation using a multivariable model to determine which characteristics were associated with clinical severity, specifically severe respiratory depression (SRD). This study was conducted at two urban academic emergency departments in New York City, USA. Adult patients who presented with acute prescription opioid overdose between 2009 and 2013 were included in the current study. We analyzed 307 patients (mean age = 44.7, 42% female, 2.0% mortality). Patient demographics, reported substances ingested, suspected intent for ingesting the substance, vital signs, laboratory data, treatments including antidotes and intubation and outcome of death were recorded by trained research assistants. Intent was categorized into four mutually exclusive categories: suicide, misuse, therapeutic error and undetermined. The primary outcome was SRD, defined as administration of either (a) naloxone or (b) endotracheal intubation (ETI). A total of 109 patients suffered SRD with 90 patients receiving naloxone alone, nine ETI alone and 10 both naloxone and ETI. The most common opioids were oxycodone (n = 124) and methadone (n = 116). Mean age was higher in patients with SRD (51.1 versus 41.1, P < 0.001). Opioid misuse was associated with SRD in the multivariable analysis [odds ratio (OR) = 2.07, 95% confidence interval (CI) = 1.21-3.55]. The unadjusted relative risk of SRD was high for fentanyl (83.3% SRD) and lowest for codeine (3.6% SRD). In emergency department patients in the United States with prescription opioid overdose, worse clinical severity

Opioids in people with cancer-related pain

PubMed Central

2008-01-01

Introduction Up to 80% of people with cancer experience pain at some time during their illness, and most will need opioid analgesics. This review assesses how different opioid analgesics compare, in terms of both pain control and adverse effects, in people with cancer. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical question: what are the effects of opioids in treating cancer-related pain? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 22 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review, we present information relating to the effectiveness and safety of the following interventions: codeine, dihydrocodeine, transdermal fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. PMID:19445735

Craving and subsequent opioid use among opioid dependent patients who initiate treatment with buprenorphine

PubMed Central

Tsui, Judith I.; Anderson, Bradley J.; Strong, David R.; Stein, Michael D.

2016-01-01

Background Few studies have directly assessed associations between craving and subsequent opioid use among treated patients. Our objective was to prospectively evaluate the relative utility of two craving questionnaires to predict opioid use among opioid dependent patients in treatment. Method Opioid dependent patients (n=147) initiating buprenorphine treatment were assessed for three months. Craving was measured using: 1) the Desires for Drug Questionnaire (DDQ) and 2) the Penn Alcohol-Craving Scale adapted for opioid craving (PCS) for this study. Multi-level logistic regression models estimated the effects of craving on the likelihood of opioid use after adjusting for gender, age, ethnicity, education, opioid of choice, frequency of use, pain and depression. In these analyses craving assessed at time t was entered as a time-varying predictor of opioid use at time t+1. Results In adjusted regression models, a 1-point increase in PCS scores (on a 7-point scale) was associated with a significant increase in the odds of opioid use at the subsequent assessment (OR = 1.27, 95% CI 1.08; 1.49, p < .01). The odds of opioid use at the subsequent follow-up assessment increased significantly as DDQ desire and intention scores increased (OR = 1.25, 95%CI 1.03; 1.51, p< .05), but was not associated significantly with DDQ negative reinforcement (OR = 1.01, 95%CI 0.88; 1.17, p > .05) or DDQ control (OR = 0.97, 95%CI 0.85; 1.11, p > .05) scores. Conclusion Self-reported craving for opioids was associated with subsequent lapse to opioid use among a cohort of patients treated with buprenorphine. PMID:24521036

Low-dose naltrexone targets the opioid growth factor-opioid growth factor receptor pathway to inhibit cell proliferation: mechanistic evidence from a tissue culture model.

PubMed

Donahue, Renee N; McLaughlin, Patricia J; Zagon, Ian S

2011-09-01

Naltrexone (NTX) is an opioid antagonist that inhibits or accelerates cell proliferation in vivo when utilized in a low (LDN) or high (HDN) dose, respectively. The mechanism of opioid antagonist action on growth is not well understood. We established a tissue culture model of LDN and HDN using short-term and continuous opioid receptor blockade, respectively, in human ovarian cancer cells, and found that the duration of opioid receptor blockade determines cell proliferative response. The alteration of growth by NTX also was detected in cells representative of pancreatic, colorectal and squamous cell carcinomas. The opioid growth factor (OGF; [Met(5)]-enkephalin) and its receptor (OGFr) were responsible for mediating the action of NTX on cell proliferation. NTX upregulated OGF and OGFr at the translational but not at the transcriptional level. The mechanism of inhibition by short-term NTX required p16 and/or p21 cyclin-dependent inhibitory kinases, but was not dependent on cell survival (necrosis, apoptosis). Sequential administration of short-term NTX and OGF had a greater inhibitory effect on cell proliferation than either agent alone. Given the parallels between short-term NTX in vitro and LDN in vivo, we now demonstrate at the molecular level that the OGF-OGFr axis is a common pathway that is essential for the regulation of cell proliferation by NTX.

Opioid dependence - management in general practice.

PubMed

Frei, Matthew

2010-08-01

Addiction to opioids, or opioid dependence, encompasses the biopsychosocial dysfunction seen in illicit heroin injectors, as well as aberrant behaviours in patients prescribed opioids for chronic nonmalignant pain. To outline the management of opioid dependence using opioid pharmacotherapy as part of a comprehensive chronic illness management strategy. The same principles and skills general practitioners employ in chronic illness management underpin the care of patients with opioid dependence. Opioid pharmacotherapy, with the substitution medications methadone and buprenorphine, is an effective management of opioid dependence. Training and regulatory requirements for prescribing opioid pharmacotherapies vary between jurisdictions, but this treatment should be within the scope of most Australian GPs.

Opioid Attentional Bias and Cue-Elicited Craving Predict Future Risk of Prescription Opioid Misuse Among Chronic Pain Patients*

PubMed Central

Garland, Eric L.; Howard, Matthew O.

2014-01-01

Background Some chronic pain patients receiving long-term opioid analgesic pharmacotherapy are at risk for misusing opioids. Like other addictive behaviors, risk of opioid misuse may be signaled by an attentional bias (AB) towards drug-related cues. The purpose of this study was to examine opioid AB as a potential predictor of opioid misuse among chronic pain patients following behavioral treatment. Methods Chronic pain patients taking long-term opioid analgesics (N = 47) completed a dot probe task designed to assess opioid AB, as well as self-report measures of opioid misuse and pain severity, and then participated in behavioral treatment. Regression analyses examined opioid AB and cue-elicited craving as predictors of opioid misuse at 3-months posttreatment follow-up. Results Patients who scored high on a measure of opioid misuse risk following treatment exhibited significantly greater opioid AB scores than patients at low risk for opioid misuse. Opioid AB for 200 ms cues and cue-elicited craving significantly predicted opioid misuse risk 20 weeks later, even after controlling for pre-treatment opioid dependence diagnosis, opioid misuse, and pain severity (Model R2 = .50). Conclusion Biased initial attentional orienting to prescription opioid cues and cue-elicited craving may reliably signal future opioid misuse risk following treatment. These measures may therefore provide potential prognostic indicators of treatment outcome. PMID:25282309

Postsurgical prescriptions for opioid naive patients and association with overdose and misuse: retrospective cohort study

PubMed Central

Agniel, Denis; Beam, Andrew; Yorkgitis, Brian; Bicket, Mark; Homer, Mark; Fox, Kathe P; Knecht, Daniel B; McMahill-Walraven, Cheryl N; Palmer, Nathan; Kohane, Isaac

2018-01-01

Abstract Objective To quantify the effects of varying opioid prescribing patterns after surgery on dependence, overdose, or abuse in an opioid naive population. Design Retrospective cohort study. Setting Surgical claims from a linked medical and pharmacy administrative database of 37 651 619 commercially insured patients between 2008 and 2016. Participants 1 015 116 opioid naive patients undergoing surgery. Main outcome measures Use of oral opioids after discharge as defined by refills and total dosage and duration of use. The primary outcome was a composite of misuse identified by a diagnostic code for opioid dependence, abuse, or overdose. Results 568 612 (56.0%) patients received postoperative opioids, and a code for abuse was identified for 5906 patients (0.6%, 183 per 100 000 person years). Total duration of opioid use was the strongest predictor of misuse, with each refill and additional week of opioid use associated with an adjusted increase in the rate of misuse of 44.0% (95% confidence interval 40.8% to 47.2%, P<0.001), and 19.9% increase in hazard (18.5% to 21.4%, P<0.001), respectively. Conclusions Each refill and week of opioid prescription is associated with a large increase in opioid misuse among opioid naive patients. The data from this study suggest that duration of the prescription rather than dosage is more strongly associated with ultimate misuse in the early postsurgical period. The analysis quantifies the association of prescribing choices on opioid misuse and identifies levers for possible impact. PMID:29343479

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…

Opioid modulation of reflex versus operant responses following stress in the rat.

PubMed

King, C D; Devine, D P; Vierck, C J; Mauderli, A; Yezierski, R P

2007-06-15

In pre-clinical models intended to evaluate nociceptive processing, acute stress suppresses reflex responses to thermal stimulation, an effect previously described as stress-induced "analgesia." Suggestions that endogenous opioids mediate this effect are based on demonstrations that stress-induced hyporeflexia is enhanced by high dose morphine (>5 mg/kg) and is reversed by naloxone. However, reflexes and pain sensations can be modulated differentially. Therefore, in the present study direct comparisons were made of opioid agonist and antagonist actions, independently and in combination with acute restraint stress in Long Evans rats, on reflex lick-guard (L/G) and operant escape responses to nociceptive thermal stimulation (44.5 degrees C). A high dose of morphine (>8 mg/kg) was required to reduce reflex responding, but a moderate dose of morphine (1 mg/kg) significantly reduced escape responding. The same moderate dose (and also 5 mg/kg) of morphine significantly enhanced reflex responding. Naloxone (3 mg/kg) significantly enhanced escape responding but did not affect L/G responding. Restraint stress significantly suppressed L/G reflexes (hyporeflexia) but enhanced escape responses (hyperalgesia). Stress-induced hyperalgesia was significantly reduced by morphine and enhanced by naloxone. In contrast, stress-induced hyporeflexia was blocked by both naloxone and 1 mg/kg of morphine. Thus, stress-induced hyperalgesia was opposed by endogenous opioid release and by administration of morphine. Stress-induced hyporeflexia was dependent upon endogenous opioid release but was counteracted by a moderate dose of morphine. These data demonstrate a differential modulation of reflex and operant outcome measures by stress and by separate or combined opioid antagonism or administration of morphine.

42 CFR 8.34 - Court review of final administrative action; exhaustion of administrative remedies.

Code of Federal Regulations, 2010 CFR

2010-10-01

... HEALTH AND HUMAN SERVICES GENERAL PROVISIONS CERTIFICATION OF OPIOID TREATMENT PROGRAMS Procedures for... Withdrawal of Approval of an Accreditation Body § 8.34 Court review of final administrative action...

42 CFR 8.34 - Court review of final administrative action; exhaustion of administrative remedies.

Code of Federal Regulations, 2011 CFR

2011-10-01

... HEALTH AND HUMAN SERVICES GENERAL PROVISIONS CERTIFICATION OF OPIOID TREATMENT PROGRAMS Procedures for... Withdrawal of Approval of an Accreditation Body § 8.34 Court review of final administrative action...

Clinical and forensic signs related to opioids abuse.

PubMed

Dinis-Oliveira, Ricardo Jorge; Carvalho, Felix; Moreira, Roxana; Duarte, Jose Alberto; Proenca, Jorge Brandao; Santos, Agostinho; Magalhaes, Teresa

2012-12-01

For a good performance in Clinical and Forensic Toxicology it is important to be aware of the biological and non-biological signs and symptoms related to xenobiotic exposure. This manuscript highlights and analyzes clinical and forensic imaging related to opioids abuse critically. Particularly, respiratory depression, track marks and hemorrhages, skin "popping", practices of phlebotomy, tissue necrosis and ulceration, dermatitis, tongue hyperpigmentation, "coma blisters", intra-arterial administration, candidiasis, wounds associated with anthrax or clostridium contaminated heroin, desomorphine related lesions and characteristic non-biological evidences are some commonly reported findings in opioids abuse, which will be discussed. For this purpose, clinical and forensic cases from our database (National Institute of Legal Medicine and Forensic Sciences, North Branch, Portugal), in addition to literature data, are reviewed.

Opioids in Preclinical and Clinical Trials

NASA Astrophysics Data System (ADS)

Nagase, Hiroshi; Fujii, Hideaki

Since 1952, when Gates determined the stereo structure of morphine, numerous groups have focused on discovering a nonnarcotic opioid drug [1]. Although several natural, semisynthetic, and synthetic opioid ligands (alkaloids and peptides) have been developed in clinical studies, very few were nonnarcotic opioid drugs [2]. One of the most important studies in the opioid field appeared in 1976, when Martin and colleagues [3] established types of opioid receptors (these are now classified into μ, δ, and κ types). Later, Portoghese discovered a highly selective μ type opioid receptor antagonist, β-funaltrexamine [4]. This led to the finding that the μ type opioid receptor was correlated to drug dependence [5]. Consequently, δ, and particularly κ, opioid agonists were expected to lead to ideal opioid drugs. Moreover, opioid antagonists were evaluated for the treatment of symptoms related to undesirable opioid system activation. In this chapter, we provide a short survey of opioid ligands in development and describe the discovery of the two most promising drugs, TRK-851 [6] and TRK-820 (nalfurafine hydrochloride) [7].

Analysis of inflammation-induced depression of home cage wheel running in rats reveals the difference between opioid antinociception and restoration of function

PubMed Central

Kandasamy, Ram; Calsbeek, Jonas J.; Morgan, Michael M.

2016-01-01

Opioids are effective at inhibiting responses to noxious stimuli in rodents, but have limited efficacy and many side effects in chronic pain patients. One reason for this disconnect is that nociception is typically assessed using withdrawal from noxious stimuli in animals, whereas chronic pain patients suffer from abnormal pain that disrupts normal activity. We hypothesized that assessment of home cage wheel running in rats would provide a much more clinically relevant method to assess opioid efficacy to restore normal behavior. Intraplantar injection of Complete Freund’s Adjuvant (CFA) into the right hindpaw depressed wheel running and caused mechanical allodynia measured with the von Frey test in both male and female rats. Administration of an ED50 dose of morphine (3.2 mg/kg) reversed mechanical allodynia, but did not reverse CFA-induced depression of wheel running. In contrast, administration of a low dose of morphine (1.0 mg/kg) restored running for one hour in both sexes, but had no effect on mechanical allodynia. Administration of the atypical opioid buprenorphine had no effect on inflammation-induced depression of wheel running in male or female rats, but attenuated mechanical allodynia in male rats. Administration of buprenorphine and higher doses of morphine depressed wheel running in non-inflamed rats, suggesting that the side effects of opioids interfere with restoration of function. These data indicate that restoration of pain-depressed function requires antinociception in the absence of disruptive side effects. The disruptive side effects of opioids are consistent with the major limitation of opioid use in human pain patients. PMID:27746208

Measuring quality of life in opioid-dependent people: a systematic review of assessment instruments.

PubMed

Strada, Lisa; Vanderplasschen, Wouter; Buchholz, Angela; Schulte, Bernd; Muller, Ashley E; Verthein, Uwe; Reimer, Jens

2017-12-01

Opioid dependence is a chronic relapsing disorder. Despite increasing research on quality of life (QOL) in people with opioid dependence, little attention has been paid to the instruments used. This systematic review examines the suitability of QOL instruments for use in opioid-dependent populations and the instruments' quality. A systematic search was performed in the databases Medline, PsycInfo, The Cochrane Library, and CINAHL. Articles were eligible if they assessed QOL of opioid-dependent populations using a validated QOL instrument. Item content relevance to opioid-dependent people was evaluated by means of content analysis, and instrument properties were assessed using minimum standards for patient-reported outcome measures. Eighty-nine articles were retrieved, yielding sixteen QOL instruments, of which ten were assessed in this review. Of the ten instruments, six were disease specific, but none for opioid dependence. Two instruments had good item content relevance. The conceptual and measurement model were described in seven instruments. Four instruments were developed with input from the respective target population. Eight instruments had low respondent and administrator burden. Psychometric properties were either not assessed in opioid-dependent populations or were inconclusive or moderate. No instrument scored perfectly on both the content and properties. The limited suitability of instruments for opioid-dependent people hinders accurate and sensitive measurement of QOL in this population. Future research is in need of an opioid dependence-specific QOL instrument to measure the true impact of the disease on people's lives and to evaluate treatment-related services.

COMPARATIVE METABOLISM OF ARSENIC IN MICE AFTER A SINGLE OR REPEATED ORAL ADMINISTRATION OF ARSENATE

EPA Science Inventory

COMPARATIVE METABOLISM OF ARSENIC IN MICE AFTER A SINGLE OR REPEATED ORAL ADMINISTRATION OF ARSENATE
Michael F. Hughes*1, Elaina M. Kenyon1, Brenda C. Edwards1, Carol T. Mitchell1, Luz Maria Del Razo2 and David J. Thomas1
1US EPA, ORD, NHEERL, ETD, PKB, Research Triangle Pa...

Repeated administration of amitriptyline reduces oxaliplatin-induced mechanical allodynia in rats.

PubMed

Sada, Hikaru; Egashira, Nobuaki; Ushio, Soichiro; Kawashiri, Takehiro; Shirahama, Masafumi; Oishi, Ryozo

2012-01-01

Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes acute and chronic neuropathies in patients. Amitriptyline has widely been used in patients with painful neuropathy. In this study, we investigated the effect of amitriptyline on the oxaliplatin-induced neuropathy in rats. Repeated administration of amitriptyline (5 and 10 mg/kg, p.o., once a day) reduced the oxaliplatin-induced mechanical allodynia but not cold hyperalgesia and reversed the oxaliplatin-induced increase in the expression of NR2B protein and mRNA in rat spinal cord. These results suggest that amitriptyline is useful for the treatment of oxaliplatin-induced neuropathy clinically.

Single-dose evaluation of safety, tolerability and pharmacokinetics of newly formulated hydromorphone immediate-release and hydrophilic matrix extended-release tablets in healthy Japanese subjects without co-administration of an opioid antagonist.

PubMed

Toyama, Kaoru; Uchida, Naoki; Ishizuka, Hitoshi; Sambe, Takehiko; Kobayashi, Shinichi

2015-09-01

This single dose, open-label study investigated the safety, tolerability and pharmacokinetics of single oral doses of newly formulated immediate-release (IR) and hydrophilic matrix extended-release (ER) hydromorphone tablets in healthy Japanese subjects without co-administration of an opioid antagonist under fasting and fed conditions. Plasma and urinary concentrations of hydromorphone and metabolites were measured by liquid-chromatography tandem mass-spectroscopy. Following administration of the ER tablet, plasma concentrations of hydromorphone slowly increased with a median tmax of 5.0 h and the Cmax decreased to 37% of the IR tablet, while the AUC0-inf was comparable with that of the IR tablet when administered at the same dose. The degree of fluctuation in the plasma concentration for the ER tablet was much lower than that of the IR tablet and certain levels of plasma concentrations were maintained after 24 h of ER dosing. The AUC0-inf and Cmax increased with food for both IR and ER tablets. The AUC0-inf of hydromorphone-3-glucoside was one-tenth of that of hydromorphone-3-glucuronide. A single oral administration of the hydromorphone tablets would be well-tolerated in healthy Japanese subjects despite a lack of co-administration of an opioid antagonist and the newly developed ER hydromorphone tablets may have the appropriate PK characteristics for once-daily dosing. © 2015, The American College of Clinical Pharmacology.

Current status and evolving role of abuse-deterrent opioids in managing patients with chronic pain.

PubMed

Webster, Lynn; St Marie, Barbara; McCarberg, Bill; Passik, Steven D; Panchal, Sunil J; Voth, Eric

2011-01-01

Opioids are widely used for the treatment of patients with chronic pain; yet, the increase in their abuse, misuse, and diversion is an ongoing focus of regulatory, governmental, and legal scrutiny. As a consequence, clinicians are faced with numerous challenges in an effort to use opioids in appropriate patients with pain while minimizing the potential for opioid abuse, misuse, and diversion. Policies and programs such as state prescription monitoring programs, which have been in existence for decades, are but one attempt to address some of the issues regarding the prescribing of opioids. Another is a risk evaluation and mitigation strategy for opioids under consideration by the US Food and Drug Administration. At the clinical level, a universal precautions and risk management package that includes risk assessment and patient monitoring is a recommended approach. This approach can also include the use of abuse-deterrent and abuse-resistant formulations designed to reduce the nonmedical use of opioids. Several of these opioid formulations have been approved or should soon be on the market for use in the United States; however, their role and other questions regarding their use remain unanswered. The authors offer their clinical perspective on several of these key questions.

Risk of Prolonged Opioid Use Among Opioid-Naïve Patients Following Common Hand Surgery Procedures.

PubMed

Johnson, Shepard P; Chung, Kevin C; Zhong, Lin; Shauver, Melissa J; Engelsbe, Michael J; Brummett, Chad; Waljee, Jennifer F

2016-10-01

To evaluate prolonged opioid use in opioid-naïve patients after common hand surgery procedures in the United States. We studied insurance claims from the Truven MarketScan databases to identify opioid-naïve adult patients (no opioid exposure 11 months before the perioperative period) who underwent an elective (carpal tunnel release, carpometacarpal arthroplasty/arthrodesis, cubital tunnel release, or trigger finger release) or trauma-related (closed distal radius fracture fixation, flexor tendon repair, metacarpal fracture fixation, or phalangeal fracture fixation) hand surgery procedure between 2010 and 2012 (N = 77,573 patients). Patients were observed for 6 months to determine the number, timing, duration, and oral morphine equivalent dosage of postoperative opioid prescriptions. We assessed prolonged postoperative opioid use, defined as patients who filled a perioperative opioid prescription followed by a prescription between 90 and 180 days after surgery, and evaluated associated risk factors using multivariable logistic regression. In this cohort, 59,725 opioid-naïve patients (77%) filled a perioperative opioid prescription. Of these, 13% of patients continued to fill prescriptions between 90 and 180 days after surgery. Elective surgery patients were more likely to continue to fill opioid prescriptions after 90 days compared with trauma patients (13.5% vs 10.5%). Younger age, female gender, lower income, comprehensive insurance, higher Elixhauser comorbidity index, mental health disorders, and tobacco dependence or abuse were associated with prolonged opioid use. Approximately 13% of opioid-naïve patients continue to fill opioid prescriptions after hand surgery procedures 90 days after surgery. Preoperative interventions centered on opioid alternatives and early cessation, particularly among patients at risk for long-term use, is critical to addressing the prescription opioid crisis in the United States. The current national opioid use epidemic requires

Opioid system and human emotions.

PubMed

Nummenmaa, Lauri; Tuominen, Lauri

2017-04-10

Emotions are states of vigilant readiness that guide human and animal behaviour during survival-salient situations. Categorical models of emotions posit neurally and physiologically distinct basic human emotions (anger, fear, disgust, happiness, sadness and surprise) that govern different survival functions. Opioid receptors are expressed abundantly in the mammalian emotion circuit, and the opioid system modulates a variety of functions related to arousal and motivation. Yet, its specific contribution to different basic emotions has remained poorly understood. Here, we review how the endogenous opioid system and particularly the μ receptor contribute to emotional processing in humans. Activation of the endogenous opioid system is consistently associated with both pleasant and unpleasant emotions. In general, exogenous opioid agonists facilitate approach-oriented emotions (anger, pleasure) and inhibit avoidance-oriented emotions (fear, sadness). Opioids also modulate social bonding and affiliative behaviour, and prolonged opioid abuse may render both social bonding and emotion recognition circuits dysfunctional. However, there is no clear evidence that the opioid system is able to affect the emotions associated with surprise and disgust. Taken together, the opioid systems contribute to a wide array of positive and negative emotions through their general ability to modulate the approach versus avoidance motivation associated with specific emotions. Because of the protective effects of opioid system-mediated prosociality and positive mood, the opioid system may constitute an important factor contributing to psychological and psychosomatic resilience. © 2017 The British Pharmacological Society.

Opioid Use Disorders

PubMed Central

Sharma, Bikash; Bruner, Ann; Barnett, Gabrielle; Fishman, Marc

2016-01-01

Opioid use and addiction in adolescents and young adults, including heroin and non-medical use of prescription opioids, is a serious and growing health problem of epidemic proportions. Opioid use has devastating consequences for youth and their families, including: progression to full addiction, severe psychosocial impairment, HCV and HIV transmission with injection use, exacerbation of co-occurring psychiatric disorders, overdose, and death. This chapter will provide an overview of opioid use disorders (OUDs) in youth, including: etiologic factors, epidemiology, consequences, clinical presentation and course, assessment and diagnosis, overdose, detoxification, and treatment. Opioid overdose is a life-threatening emergency. Respiratory depression should be treated with naloxone, and respiratory support if necessary. Overdose should always be utilized as an opportunity to initiate addiction treatment. Opioid withdrawal management (detoxification) is often a necessary, but never sufficient, component of treatment for OUDs. Medications used in the treatment of withdrawal may include buprenorphine, clonidine and others for relief of symptoms. Treatment for OUDs is effective but treatment capacity is alarmingly limited and under-developed. Although there is a limited evidence base for youth specific treatment, emerging consensus supports the incorporation of relapse prevention medications such as buprenorphine and extended release naltrexone into comprehensive psychosocial treatment including counseling and family involvement. PMID:27338968

Fatal and non-fatal opioid overdose in opioid dependent patients treated with methadone, buprenorphine or implant naltrexone.

PubMed

Kelty, Erin; Hulse, Gary

2017-08-01

Illicit opioid use is associated with high rates of fatal and non-fatal opioid overdose. This study aims to compare rates of fatal and serious but non-fatal opioid overdose in opioid dependent patients treated with methadone, buprenorphine or implant naltrexone, and to identify risk factors for fatal opioid overdose. Opioid dependent patients treated with methadone (n=3515), buprenorphine (n=3250) or implant naltrexone (n=1461) in Western Australia for the first time between 2001 and 2010, were matched against state mortality and hospital data. Rates of fatal and non-fatal serious opioid overdoses were calculated and compared for the three treatments. Risk factors associated with fatal opioid overdose were examined using multivariate cox proportional hazard models. No significant difference was observed between the three groups in terms of crude rates of fatal or non-fatal opioid overdoses. During the first 28days of treatment, rates of non-fatal opioid overdose were high in all three groups, as were fatal opioid overdoses in patients treated with methadone. However, no fatal opioid overdoses were observed in buprenorphine or naltrexone patients during this period. Following the first 28 days, buprenorphine was shown to be protective, particularly in terms of non-fatal opioid overdoses. After the cessation of treatment, rates of fatal and non-fatal opioid overdoses were similar between the groups, with the exception of lower rates of non-fatal opioid overdose in the naltrexone treated patients compared with the methadone treated patients. After the commencement of treatment, gender, and hospitalisations with a diagnosis of opioid poisoning, cardiovascular or mental health problems were significant predictors of subsequent fatal opioid overdose. Rates of fatal and non-fatal opioid overdose were not significantly different in patients treated with methadone, buprenorphine or implant naltrexone. Gender and prior cause-specific hospitalisations can be used to identify

Costs and Work Loss Burden of Diagnosed Opioid Abuse Among Employees on Workers Compensation or Short-term Disability.

PubMed

Johnston, Stephen S; Alexander, Andrea H; Masters, Elizabeth T; Mardekian, Jack; Semel, David; Malangone-Monaco, Elisabetta; Riehle, Ellen; Wilson, Kathleen; Sadosky, Alesia

2016-11-01

To compare 12-month healthcare costs between employees with versus without diagnosed opioid abuse within 12 months after an injury-related workers' compensation (WC) or short-term disability (STD) claim. Retrospective study using 2003 to 2014 US insurance claims linked to administrative data on WC/STD claims. Multivariable models compared healthcare costs between employees with versus without diagnosed opioid abuse. Study included 107,975 opioid-treated employees with an injury-related WC or STD claim. Mean number of opioid prescription fills and adjusted total healthcare costs were substantially greater in employees with diagnosed opioid abuse versus without (WC: 13.4 vs. 4.5, P < 0.001; $18,073 vs. $8470, P < 0.001; STD: 13.7 vs. 4.5, P < 0.001; $25,693 vs. $14,939, P < 0.001). Opioids are commonly prescribed to employees with injury-related WC/STD claims. Employers may benefit from proactively addressing the issue of opioid abuse in these populations.

Genetics of Opioid Dependence: A Review of the Genetic Contribution to Opioid Dependence

PubMed Central

Mistry, Chetna J; Bawor, Monica; Desai, Dipika; Marsh, David C; Samaan, Zainab

2014-01-01

This narrative review aims to provide an overview of the impact of opioid dependence and the contribution of genetics to opioid dependence. Epidemiological data demonstrate that opioid dependence is a global trend with far-reaching effects on the social, economic, and health care systems. A review of classical genetic studies of opioid use suggests significant heritability of drug use behavior, however the evidence from molecular genetic studies is inconclusive. Nonetheless, certain genetic variants are important to consider given their role in the pathophysiology of addictive behavior. We undertook a literature review to identify the current state of knowledge regarding the role of genes in opioid dependence. Determining the association of genetic markers could change the current understanding of the various factors contributing to opioid dependence and therefore may improve recognition of individuals at risk for the disorder and prevention and treatment strategies. PMID:25242908

Methylnaltrexone mechanisms of action and effects on opioid bowel dysfunction and other opioid adverse effects.

PubMed

Yuan, Chun-Su

2007-06-01

To review the mechanisms of action of methylnaltrexone and its effects on opioid bowel dysfunction, as well as its effects on other opioid-induced adverse effects (ADEs), and its potential roles in clinical practice. A literature search using the MEDLINE and Cochrane Collaboration databases for articles published between 1966 and March 2007 was performed. Additional data sources were obtained from manual searches of recent journal articles, book chapters, and monographs. An updated literature search showed no additional publications. Abstracts and original preclinical and clinical research reports published in the English language were identified for review. Review articles, commentaries, and news reports of this compound were excluded. Literature related to opioids, opioid receptors, opioid antagonists, methylnaltrexone, opioid-induced bowel dysfunction, constipation, nausea, and vomiting was evaluated and selected based on consideration of the support shown for the proof of concept, mechanistic findings, and timeliness. Fifty-eight original articles from preclinical studies and clinical trials using methylnaltrexone were identified. Pharmacologic action, benefits, and ADEs of methylnaltrexone were reviewed, with a focus on its effects on bowel dysfunction after opioids. Emphases were placed on its receptor binding activities and therapeutically relevant sites of action (peripheral vs central), in which peripheral opioid receptors in the body contribute to physiological and drug-induced effects. Morphine and related opioids are associated with a number of limiting ADEs, including opioid-induced bowel dysfunction. Methylnaltrexone, a quaternary derivative of naltrexone, blocks peripheral effects of opioids while sparing central analgesic effects. It is currently under late-stage clinical investigation for the treatment of opioid-induced constipation in patients with advanced illness. Reported results showed the drug to be generally well-tolerated. The rapid

Personality as a risk factor for illicit opioid use and a protective factor for illicit opioid dependence.

PubMed

Zaaijer, Eline R; Bruijel, Jessica; Blanken, Peter; Hendriks, Vincent; Koeter, Maarten W J; Kreek, Mary Jeanne; Booij, Jan; Goudriaan, Anna E; van Ree, Jan M; van den Brink, Wim

2014-12-01

Most studies investigating the role of personality as a risk factor for the development of opioid dependence compare dependent opioid users with healthy controls who never used heroin. In order to understand the potential protective role of personality, it is crucial to compare illicit opioid users who never became dependent with dependent opioid users. This study aims to examine the role of personality as a risk factor for opioid use and as a protective factor for the development of opioid dependence. Comparing personality factors between three groups: (1) 161 never-dependent illicit opioid users who have been using illicit opioids but never became opioid dependent; (2) 402 dependent opioid users in methadone maintenance treatment or heroin-assisted treatment; and (3) 135 healthy controls who never used heroin. Personality was assessed with a short version of Cloninger's Temperament and Character Inventory. Never-dependent opioid users reported more Novelty Seeking and Harm Avoidance and less Self-Directedness and Cooperativeness than healthy controls and more Reward Dependence and Self-Directedness, and less Harm Avoidance than dependent opioid users. Furthermore, never-dependent opioid users reported more Self-Transcendence than both dependent opioid users and healthy controls. Never-dependent opioid users may have started to use opioids partly due to their tendency to seek novel and/or spiritual experiences (high Novelty Seeking, high Self-Transcendence) and their tendency to avoid aversive stimuli (high Harm Avoidance), whereas they may have been protected against the development of dependence by their need for social approval (high Reward Dependence) and their self-efficacy (high Self-Directedness). Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Prescription drug monitoring program data tracking of opioid addiction treatment outcomes in integrated dual diagnosis care involving injectable naltrexone.

PubMed

Sajid, Ayesha; Whiteman, Aaron; Bell, Richard L; Greene, Marion S; Engleman, Eric A; Chambers, R Andrew

2016-10-01

Fourfold increases in opioid prescribing and dispensations over 2 decades in the U.S. has paralleled increases in opioid addictions and overdoses, requiring new preventative, diagnostic, and treatment strategies. This study examines Prescription Drug Monitoring Program (PDMP) tracking as a novel measure of opioid addiction treatment outcomes in a university-affiliated integrated mental health-addiction treatment clinic. Repeated measure parametrics examined PDMP and urine drug screening (UDS) data before and after first injection for all patients (N = 68) who received at least one long-acting naltrexone injection (380 mg/IM) according to diagnostic groupings of having either (i) alcohol (control); (ii) opioid; or (iii) combined alcohol and opioid use disorders. There were no group differences post-injection in treatment days, injections delivered, or treatment service encounters. UDS and PDMP measures of opioid exposures were greater in opioid compared to alcohol-only patients. Post-first injection, UDS's positive for opioids declined (p < .05) along with PDMP measures of opioid prescriptions (p < .001), doses (p < .01), types (p < .001), numbers of dispensing prescribers (p < .001) and pharmacies (p < .001). Opioid patients without alcohol disorders showed the best outcomes with 50% to 80% reductions in PDMP-measures of opioids, down to levels of alcohol-only patients. This study shows PDMP utility for measuring opioid addiction treatment outcomes, supporting the routine use of PDMPs in clinical and research settings. These findings demonstrate that opioid addiction in patients with complex addictions and mental illnesses comorbidities can show effective treatment responses as measured by PDMP tracking of decreases in opioid prescriptions to those patients. (Am J Addict 2016;25:557-564). © 2016 The Authors. The American Journal on Addictions Published by Wiley Periodicals, Inc. on behalf of The American Academy of Addiction

Prescription drug monitoring program data tracking of opioid addiction treatment outcomes in integrated dual diagnosis care involving injectable naltrexone

PubMed Central

Sajid, Ayesha; Whiteman, Aaron; Bell, Richard L.; Greene, Marion S.; Engleman, Eric A.

2016-01-01

Background and Objectives Fourfold increases in opioid prescribing and dispensations over 2 decades in the U.S. has paralleled increases in opioid addictions and overdoses, requiring new preventative, diagnostic, and treatment strategies. This study examines Prescription Drug Monitoring Program (PDMP) tracking as a novel measure of opioid addiction treatment outcomes in a university‐affiliated integrated mental health‐addiction treatment clinic. Methods Repeated measure parametrics examined PDMP and urine drug screening (UDS) data before and after first injection for all patients (N = 68) who received at least one long‐acting naltrexone injection (380 mg/IM) according to diagnostic groupings of having either (i) alcohol (control); (ii) opioid; or (iii) combined alcohol and opioid use disorders. Results There were no group differences post‐injection in treatment days, injections delivered, or treatment service encounters. UDS and PDMP measures of opioid exposures were greater in opioid compared to alcohol‐only patients. Post‐first injection, UDS's positive for opioids declined (p < .05) along with PDMP measures of opioid prescriptions (p < .001), doses (p < .01), types (p < .001), numbers of dispensing prescribers (p < .001) and pharmacies (p < .001). Opioid patients without alcohol disorders showed the best outcomes with 50% to 80% reductions in PDMP‐measures of opioids, down to levels of alcohol‐only patients. Conclusions This study shows PDMP utility for measuring opioid addiction treatment outcomes, supporting the routine use of PDMPs in clinical and research settings. Scientific Significance These findings demonstrate that opioid addiction in patients with complex addictions and mental illnesses comorbidities can show effective treatment responses as measured by PDMP tracking of decreases in opioid prescriptions to those patients. (Am J Addict 2016;25:557–564) PMID:27647699

Opioid Abuse and Addiction - Multiple Languages

MedlinePlus

... Opioid addiction, part 8 - español (Spanish) MP4 Healthy Roads Media Comorbidity or dual diagnosis - Opioid addiction, part 9 - English PDF Comorbidity or ... addiction, part 9 - English MP4 Comorbidity or dual diagnosis - Opioid ... MP4 Healthy Roads Media Pregnancy and opioids - Opioid addiction, part 10 - ...

Repeated Famotidine Administration Results in a Diminished Effect on Intragastric pH in Dogs.

PubMed

Tolbert, M K; Graham, A; Odunayo, A; Price, J; Steiner, J M; Newkirk, K; Hecht, S

2017-01-01

Famotidine is an acid suppressant commonly administered to dogs. Prolonged famotidine use in people results in decreased efficacy, but the effect in dogs is unknown. To compare the effect of repeated oral administration of famotidine or placebo on intragastric pH and serum gastrin in dogs. We hypothesized that famotidine would have a diminished effect on intragastric pH on day 13 compared to day 1. Six healthy adult colony Beagles. Randomized, 2-factor repeated-measures crossover design. All dogs received oral placebo or 1.0 mg/kg famotidine q12h for 14 consecutive days. Intragastric pH monitoring was used to continuously record intragastric pH on treatment days 1-2 and 12-13. Mean pH as well as mean percentage time (MPT) that intragastric pH was ≥3 or ≥4 were compared between and within groups by analysis of variance. Serum gastrin was measured on days 0, 3, and 12 for each treatment. Continued administration of famotidine resulted in a significant decrease in mean pH, MPT ≥3, and MPT ≥4 (P < .0001) on day 12 and 13. This resulted in a mean decrease in pH by 1.63 on days 12 and 13 compared to days 1 and 2. Furthermore, a mean decrease of MPT ≥3 and MPT ≥4 by 33 and 45% was observed for the same time period, respectively. Continued administration of famotidine results in a diminished effect on intragastric pH in dogs. Caution is advised when recommending long-term, daily oral administration of famotidine to dogs. Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Hyperthermic responses to central injections of some peptide and non-peptide opioids in the guinea-pig

NASA Technical Reports Server (NTRS)

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

1983-01-01

The intracerebroventricular administration of prototype nonpeptide opioid receptor (mu, kappa, and sigma) agonists, morphine, ketocyclazocine, and N-allyl normetazocine and an agonist at both kappa and sigma receptors, pentazocine, was found to induce hyperthermia in guinea pigs. The similar administration of peptide opioids like beta endorphin, methionine endkephalin, leucine endkephaline, and several of their synthetic analogues was also found to cause hyperthermia. Only the liver-like transport system of the three anion transport systems (iodide, hippurate, and liver-like) present in the choroid plexus was determined to be important to the central inactivation of beta-endorphin and two synthetic analogues. Prostaglandins and norepinephrine (NE) as well as cAMP were not involved in peptide and nonpeptide opioid-induced hyperthermia. Naloxone-sensitive receptors were found to be involved in the induction of hyperthermia by morphine and beta-endorphin, while hyperthermic responses to ketocyclazocine, N-allyl normetazocine, pentazocine, Met-enkephalin, Leu-enkephalin, and two of the synthetic analogues were not antagonized by nalozone. The lack of antagonism of naloxone on pyrogen, arachidonic acid, PGE2, dibutyryl cAMP, and NE-induced hyperthermia shows that endogenous opioid peptides are not likely to be central mediators of the hyperthermia induced by these agents.

The Rewarding and Locomotor-Sensitizing Effects of Repeated Cocaine Administration are Distinct and Separable in Mice

PubMed Central

Riday, Thorfinn T.; Kosofsky, Barry E.; Malanga, C.J.

2011-01-01

Repeated psychostimulant exposure progressively increases their potency to stimulate motor activity in rodents. This behavioral or locomotor sensitization is considered a model for some aspects of drug addiction in humans, particularly drug craving during abstinence. However, the role of increased motor behavior in drug reward remains incompletely understood. Intracranial self-stimulation (ICSS) was measured concurrently with locomotor activity to determine if acute intermittent cocaine administration had distinguishable effects on motor behavior and perception of brain stimulation-reward (BSR) in the same mice. Sensitization is associated with changes in neuronal activity and glutamatergic neurotransmission in brain reward circuitry. Expression of AMPA receptor subunits (GluR1 and GluR2) and CRE binding protein (CREB) was measured in the ventral tegmental area (VTA), dorsolateral striatum (STR) and nucleus accumbens (NAc) before and after a sensitizing regimen of cocaine, with and without ICSS. Repeated cocaine administration sensitized mice to its locomotor stimulating effects but not its ability to potentiate BSR. ICSS increased GluR1 in the VTA but not NAc or STR, demonstrating selective changes in protein expression with electrical stimulation of discrete brain structures. Repeated cocaine reduced GluR1, GluR2 and CREB expression in the NAc, and reductions of GluR1 and GluR2 but not CREB were further enhanced by ICSS. These data suggest that the effects of repeated cocaine exposure on reward and motor processes are dissociable in mice, and that reduction of excitatory neurotransmission in the NAc may predict altered motor function independently from changes in reward perception. PMID:22197517

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.

Comparative effectiveness of senna to prevent problematic constipation in pediatric oncology patients receiving opioids: a multicenter study of clinically detailed administrative data.

PubMed

Feudtner, Chris; Freedman, Jason; Kang, Tammy; Womer, James W; Dai, Dingwei; Faerber, Jennifer

2014-08-01

Pediatric oncology patients often receive prolonged courses of opioids, which can result in constipation. Comparing patients who received senna matched with similar patients who received other oral bowel medications, determine the subsequent risk of "problematic constipation," assessed as the occurrence of the surrogate markers of receiving an enema, escalation of oral bowel medications, and abdominal radiographic imaging. This was a retrospective cohort study of hospitalized pediatric oncology patients less than 21 years of age in 78 children's and adult hospitals between 2006 and 2011 who were started on seven consecutive days or more of opioid therapy and were started on an oral bowel medication within the first two days of opioid therapy. Clinically detailed administrative data were used from the Pediatric Health Information System and the Premier Perspective Database. After performing propensity score matching of similar patients who started senna and who started a different oral bowel medication, Cox regression modeling was used to compare the subsequent hazard of the surrogate markers. The final matched sample of 586 patients averaged 11.5 years of age (range 0-20 years); 41.8% (n = 245) had blood cancer, 50.3% (n = 295) had solid tumor cancer, and 7.9% (n = 46) had brain cancer. Initiating senna therapy within two days of starting the prolonged opioid course, compared with initiating another oral bowel medication, was significantly associated with a lower hazard during the ensuing five days for receipt of an enema (hazard ratio [HR], 0.31; 95% CI, 0.11-0.91) or undergoing abdominal radiographic imaging (HR, 0.74; 95% CI, 0.55-0.98), was marginally associated with a lower hazard of oral bowel medicine escalation (HR, 0.78; 95% CI, 0.59-1.03), and overall was significantly associated with a lower hazard of the composite end point of problematic constipation (HR, 0.70; 95% CI, 0.56-0.88). Initiating senna therapy, compared with other oral bowel

Alteration in metabolism and toxicity of acetaminophen upon repeated administration in rats.

PubMed

Kim, Sun J; Lee, Min Y; Kwon, Do Y; Kim, Sung Y; Kim, Young C

2009-10-01

Our previous studies showed that administration of a subtoxic dose of acetaminophen (APAP) to female rats increased generation of carbon monoxide from dichloromethane, a metabolic reaction catalyzed mainly by cytochrome P450 (CYP) 2E1. In this study we examined the changes in metabolism and toxicity of APAP upon repeated administration. An intraperitoneal dose of APAP (500 mg/kg) alone did not increase aspartate aminotransferase, alanine aminotransferase, or sorbitol dehydrogenase activity in serum, but was significantly hepatotoxic when the rats had been pretreated with an identical dose of APAP 18 h earlier. The concentrations and disappearance of APAP and its metabolites in plasma were monitored for 8 h after the treatment. APAP pretreatment reduced the elevation of APAP-sulfate, but increased APAP-cysteine concentrations in plasma. APAP or APAP-glucuronide concentrations were not altered. Administration of a single dose of APAP 18 h before sacrifice increased microsomal CYP activities measured with p-nitrophenol, p-nitroanisole, and aminopyrine as probes. Expression of CYP2E1, CYP3A, and CYP1A proteins in the liver was also elevated significantly. The results suggest that administration of APAP at a subtoxic dose may result in an induction of hepatic CYP enzymes, thereby altering metabolism and toxicological consequences of various chemical substances that are substrates for the same enzyme system.

Variants of opioid system genes are associated with non-dependent opioid use and heroin dependence.

PubMed

Randesi, Matthew; van den Brink, Wim; Levran, Orna; Blanken, Peter; Butelman, Eduardo R; Yuferov, Vadim; da Rosa, Joel Correa; Ott, Jurg; van Ree, Jan M; Kreek, Mary Jeanne

2016-11-01

Heroin addiction is a chronic, relapsing brain disease. Genetic factors are involved in the development of drug addiction. The aim of this study was to determine whether specific variants in genes of the opioid system are associated with non-dependent opioid use and heroin dependence. Genetic information from four subject groups was collected: non-dependent opioid users (NOD) [n=163]; opioid-dependent (OD) patients in methadone maintenance treatment (MMT) [n=143]; opioid-dependent MMT-resistant patients in heroin-assisted treatment (HAT) [n=138]; and healthy controls with no history of opioid use (HC) [n=153]. Eighty-two variants in eight opioid system genes were studied. To establish the role of these genes in (a) non-dependent opioid use, and (b) heroin dependence, the following groups were compared: HC vs. NOD; HC vs. OD (MMT+HAT); and NOD vs. OD (MMT+HAT). Five unique SNPs in four genes showed nominally significant associations with non-dependent opioid use and heroin dependence. The association of the delta opioid receptor (OPRD1) intronic SNP rs2236861 with non-dependent opioid use (HC vs. NOD) remained significant after correction for multiple testing (OR=0.032; p corrected =0.015). This SNP exhibited a significant gene-gene interaction with prepronociceptin (PNOC) SNP rs2722897 (OR=5.24; p corrected =0.041) (HC vs. NOD). This study identifies several new and some previously reported associations of variants with heroin dependence and with non-dependent opioid use, an important and difficult to obtain group not extensively studied previously. Further studies are warranted to confirm and elucidate the potential roles of these variants in the vulnerability to illicit drug use and drug addiction. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Novel Oral Therapies for Opioid-induced Bowel Dysfunction in Patients with Chronic Noncancer Pain.

PubMed

Holder, Renee M; Rhee, Diane

2016-03-01

Opioid analgesics are frequently prescribed and play an important role in chronic pain management. Opioid-induced bowel dysfunction, which includes constipation, hardened stool, incomplete evacuation, gas, and nausea and vomiting, is the most common adverse event associated with opioid use. Mu-opioid receptors are specifically responsible for opioid-induced bowel dysfunction, resulting in reduced peristaltic and secretory actions. Agents that reverse these actions in the bowel without reversing pain control in the central nervous system may be preferred over traditional laxatives. The efficacy and safety of these agents in chronic noncancer pain were assessed from publications identified through Ovid and PubMed database searches. Trials that evaluated the safety and efficacy of oral agents for opioid-induced constipation or opioid-induced bowel dysfunction, excluding laxatives, were reviewed. Lubiprostone and naloxegol are approved in the United States by the Food and Drug Administration for use in opioid-induced constipation. Axelopran (TD-1211) and sustained-release naloxone have undergone phase 2 and phase 1 studies, respectively, for the same indication. Naloxegol and axelopran are peripherally acting μ-opioid receptor antagonists. Naloxone essentially functions as a peripherally acting μ-opioid receptor antagonist when administered orally in a sustained-release formulation. Lubiprostone is a locally acting chloride channel (CIC-2) activator that increases secretions and peristalsis. All agents increase spontaneous bowel movements and reduce other bowel symptoms compared with placebo in patients with noncancer pain who are chronic opioid users. The most common adverse events were gastrointestinal in nature, and none of the drugs were associated with severe adverse or cardiovascular events. Investigations comparing these agents to regimens using standard laxative and combination therapy and trials in special populations and patients with active cancer are

Analysis of inflammation-induced depression of home cage wheel running in rats reveals the difference between opioid antinociception and restoration of function.

PubMed

Kandasamy, Ram; Calsbeek, Jonas J; Morgan, Michael M

2017-01-15

Opioids are effective at inhibiting responses to noxious stimuli in rodents, but have limited efficacy and many side effects in chronic pain patients. One reason for this disconnect is that nociception is typically assessed using withdrawal from noxious stimuli in animals, whereas chronic pain patients suffer from abnormal pain that disrupts normal activity. We hypothesized that assessment of home cage wheel running in rats would provide a much more clinically relevant method to assess opioid efficacy to restore normal behavior. Intraplantar injection of Complete Freund's Adjuvant (CFA) into the right hindpaw depressed wheel running and caused mechanical allodynia measured with the von Frey test in both male and female rats. Administration of an ED 50 dose of morphine (3.2mg/kg) reversed mechanical allodynia, but did not reverse CFA-induced depression of wheel running. In contrast, administration of a low dose of morphine (1.0mg/kg) restored running for one hour in both sexes, but had no effect on mechanical allodynia. Administration of the atypical opioid buprenorphine had no effect on inflammation-induced depression of wheel running in male or female rats, but attenuated mechanical allodynia in male rats. Administration of buprenorphine and higher doses of morphine depressed wheel running in non-inflamed rats, suggesting that the side effects of opioids interfere with restoration of function. These data indicate that restoration of pain-depressed function requires antinociception in the absence of disruptive side effects. The disruptive side effects of opioids are consistent with the major limitation of opioid use in human pain patients. Copyright © 2016 Elsevier B.V. All rights reserved.

Routes of abuse of prescription opioid analgesics: a review and assessment of the potential impact of abuse-deterrent formulations.

PubMed

Gasior, Maciej; Bond, Mary; Malamut, Richard

2016-01-01

Prescription opioid analgesics are an important treatment option for patients with chronic pain; however, misuse, abuse and diversion of these medications are a major global public health concern. Prescription opioid analgesics can be abused via intended and non-intended routes of administration, both intact or after manipulation of the original formulation to alter the drug-delivery characteristics. Available data indicate that ingestion (with or without manipulation of the prescribed formulation) is the most prevalent route of abuse, followed by inhalation (snorting, smoking and vaping) and injection. However, reported routes of abuse vary considerably between different formulations. A number of factors have been identified that appear to be associated with non-oral routes of abuse, including a longer duration of abuse, younger age, male sex and a rural or socially deprived location. The development of abuse-deterrent formulations of prescription opioid analgesics is an important step toward reducing abuse of these medications. Available abuse-deterrent formulations aim to hinder extraction of the active ingredient, prevent administration through alternative routes and/or make abuse of the manipulated product less attractive, less rewarding or even aversive. There are currently five opioid analgesics with a Food and Drug Administration abuse-deterrent label, and a number of other products are under review. A growing body of evidence suggests that introduction of abuse-deterrent opioid analgesics in the USA has been associated with decreased rates of abuse of these formulations. The availability of abuse-deterrent formulations therefore appears to represent an important step toward curbing the epidemic of abuse of prescription opioid analgesics, while ensuring the availability of effective pain medications for patients with legitimate medical need.

Racial-Ethnic Disparities in Opioid Prescriptions at Emergency Department Visits for Conditions Commonly Associated with Prescription Drug Abuse.

PubMed

Singhal, Astha; Tien, Yu-Yu; Hsia, Renee Y

2016-01-01

Prescription drug abuse is a growing problem nationally. In an effort to curb this problem, emergency physicians might rely on subjective cues such as race-ethnicity, often unknowingly, when prescribing opioids for pain-related complaints, especially for conditions that are often associated with drug-seeking behavior. Previous studies that examined racial-ethnic disparities in opioid dispensing at emergency departments (EDs) did not differentiate between prescriptions at discharge and drug administration in the ED. We examined racial-ethnic disparities in opioid prescription at ED visits for pain-related complaints often associated with drug-seeking behavior and contrasted them with conditions objectively associated with pain. We hypothesized a priori that racial-ethnic disparities will be present among opioid prescriptions for conditions associated with non-medical use, but not for objective pain-related conditions. Using data from the National Hospital Ambulatory Medical Care Survey for 5 years (2007-2011), the odds of opioid prescription during ED visits made by non-elderly adults aged 18-65 for 'non-definitive' conditions (toothache, back pain and abdominal pain) or 'definitive' conditions (long-bone fracture and kidney stones) were modeled. Opioid prescription at discharge and opioid administration at the ED were the primary outcomes. We found significant racial-ethnic disparities, with non-Hispanic Blacks being less likely (adjusted odds ratio ranging from 0.56-0.67, p-value < 0.05) to receive opioid prescription at discharge during ED visits for back pain and abdominal pain, but not for toothache, fractures and kidney stones, compared to non-Hispanic whites after adjusting for other covariates. Differential prescription of opioids by race-ethnicity could lead to widening of existing disparities in health, and may have implications for disproportionate burden of opioid abuse among whites. The findings have important implications for medical provider education

A statewide effort to reduce high-dose opioid prescribing through coordinated care organizations.

PubMed

Hartung, Daniel M; Alley, Lindsey; Leichtling, Gillian; Korthuis, P Todd; Hildebran, Christi

2018-05-01

Oregon's Medicaid program is delivered through 16 Coordinated Care Organizations (CCOs) participating in a statewide performance improvement program to reduce high-dose opioid prescribing. CCOs were allowed flexibility to develop their own dose targets and any policies, trainings, guidelines, and/or materials to meet these targets. In this study, we characterize CCO strategies to reduce high-dose opioid prescribing across the 16 CCOs. We reviewed relevant CCO documents and conducted semi-structured interviews with CCO administrators to acquire opioid-related policies, practices, timelines and contextual factors. We applied a systematic coding procedure to develop a comprehensive description of each CCO's strategy. We used administrative data from the state to summarize contextual utilization data for each CCO. Most CCOs selected a target daily morphine milligram equivalent (MME) dose of 90 mg. Sixteen issued quantity limits related to dose, eight restricted specific drug formulations (short-acting or long-acting), and 11 allowed for time-limited taper plan periods for patients over threshold. Many CCOs also employed provider trainings, feedback reports, and/or onsite technical assistance. Other innovations included incentive measures, electronic health record alerts, and toolkits with materials on local alternative therapy resources and strategies for patient communication. CCOs leveraging collaborations with regional partners appeared to mount a greater intensity of interventions than independently operating CCOs. CCOs developed a diversity of interventions to confront high-risk opioid prescribing within their organization. As healthcare systems mount interventions to reduce risky opioid prescribing, it is critical to carefully describe these activities and examine their impact on process and health outcomes. Copyright © 2018 Elsevier Ltd. All rights reserved.

Pain outcomes in children who received intrathecal vs intravenous opioids for pain control following major urologic surgery: a retrospective review.

PubMed

Putnam, Elizabeth M; Koppera, Prabhat; Malviya, Shobha; Voepel-Lewis, Terri

2015-12-01

Intrathecal (IT) opioid administration has been associated with postoperative benefits including reduced pain and opioid use in children. However, the postoperative benefits and risks of IT opioid administration during major urologic surgery in children remain unclear. The aim of this study was to compare postoperative pain and adverse event outcomes among children who received IT vs intravenous (IV) opioids during major urologic surgery. We reviewed the medical records of children 3-17 years of age who underwent ureteroneocystostomy or pyeloplasty between 2006 and 2012. Electronically captured anesthetic and surgical data, postanesthesia care recovery unit (PACU) and nursing flowsheets, and daily progress notes through hospital discharge were reviewed. Analgesic techniques (i.e., IT or IV patient/nurse controlled opioids), all analgesic drugs and doses were recorded. Outcome measures included pain scores, need for rescue analgesics, opioid-related adverse events, and their treatments. Seventy-seven children received IT opioids and 51 received IV opioids. More children in the IV group required rescue analgesics and had higher pain scores at PACU discharge. Children in the IV group required rescue opioids more frequently than the IT group from 0 to 8 h and 8 to 16 h after PACU discharge, but rates were similar by 16-24 h 70% of children in IT group transitioned directly to oral opioids. Seven IT placements were considered as failed due to early need for rescue opioids. Four (8%) of the IV group and seven (9%) of the IT group experienced oxygen desaturation. Two of these, both in IT group required naloxone and one was admitted to ICU for observation. The IT group experienced a higher incidence of pruritus, constipation and hypotension. We observed better postoperative pain control in children who received IT vs IV opioids for the first 16 h with no discernible difference thereafter. The intrathecal group experienced higher incidences of pruritus, constipation, and

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.

Opioid system of the brain and ethanol.

PubMed

Gogichadze, M; Mgaloblishvili-Nemsadze, M; Oniani, N; Emukhvary, N; Basishvili, T

2009-04-01

Influence of blocking of opioid receptors with concomitant intraperitoneal injections of Naloxone (20 mg/kg) (non-selective antagonist of opioid system) on the outcomes of anesthetic dose of ethanol (4,25 ml /kg 25% solution) was investigated in the rats. The sleep-wakefulness cycle (SWC) was used as a model for identification of the effects. Alterations of the SWC structure adequately reflect the neuro-chemical changes, which may develop during pharmacological and non-pharmacological impact. Administration of anesthetic dose of ethanol evoked considerable modification of spontaneous EEG activity of the neocortex. The EEG activity was depressed and full inhibition of spinal reflexes and somatic muscular relaxation did occur. During EEG depression regular SWC did not develop. All phases of SWC were reduced. The disturbances of SWC, such as decrease of slow wave sleep and paradoxical sleep duration and increase of wakefulness, remained for several days. At concomitant administration of Naloxone and ethanol, duration of EEG depression decreased significantly. Generation of normal SWC was observed on the same experimental day. However, it should be noted that complete abolishment of ethanol effects by Naloxone was not observed. The results obtained suggest that Naloxone partially blocks ethanol depressogenic effects and duration of this effect is mediated by GABA-ergic system of the brain.

Morphine sensitization as a model of mania: comparative study of the effects of repeated lithium or carbamazepine administration.

PubMed

Grappi, Silvia; Marchese, Giovanna; Secci, Maria Elena; De Montis, Maria Graziella; Gambarana, Carla; Scheggi, Simona

2011-10-01

Repeated unavoidable stress induces in rats decreased reactivity to avoidable stressors and an anhedonia-like condition that are reverted by long-term antidepressant treatments and regarded as models of core symptoms of depression. Morphine-sensitized rats present resilience to stress-induced behavioral deficits and, if hyporeactivity to stress models a depressive symptom, stress resistance can be regarded as a manic symptom. This hypothesis is supported by the observation that long-term lithium administration reinstates sensitivity to stress in sensitized rats. The first aim of the study was to examine the effects of carbamazepine, a standard antimanic treatment, on the stress resilience of sensitized rats, to further characterize morphine sensitization as a model of manic symptom. Carbamazepine administration abolished stress resilience but did not interfere with the expression of sensitization. The second aim of the study was to assess whether repeated carbamazepine treatment affected the dopaminergic and behavioral responses to a natural reward, a palatable food (vanilla sugar, VS), in non food-deprived sensitized and control rats and compare these possible effects with those of repeated lithium administration. Control and sensitized rats showed increased extraneuronal dopamine levels in the nucleus accumbens shell after VS consumption and competence to acquire an instrumental VS-sustained appetitive behavior (VAB). Repeated carbamazepine treatment abolished the dopaminergic response to VS consumption and disrupted the competence to acquire VAB in control rats. Lithium-treated rats showed a dopaminergic response to VS and easily acquired the appetitive behavior. In sensitized rats, neither carbamazepine nor lithium administration interfered with the dopaminergic response to VS and the acquisition of VAB. In summary, the effect of carbamazepine on the stress resilience of sensitized rats further supported the hypothesis that morphine sensitization might model

QUINIDINE AND DOMPERIDONE INTERACTIONS IN THE RAT EXPERIMENTAL MODEL OF REPEATED ADMINISTRATION.

PubMed

Bamburowicz-Klimkowska, Magdalena; Szost, Tadeusz; Małkowska, Anna; Szutowski, Mirosław

2016-07-01

This study has investigated domperidone (DOM) and quinidine (QD) interaction in the Wistar rat experimental model of repeated administration. We used nonconventional administration model consistent with occasional administration method. Difference in administration was related to sequence of domperidone alone or with quinidine dosage. Expected domperidone-quinidine interactions could have its origin both in the ability of quinidine to inhibit P-glycoprotein (P-gp) activity as well as cytochrome P450-mediated metabolism of both compounds. There also were examined kinetics of acetaminophen (PAM) administered (30 mg/kg) with domperidone as an indicator of gastric emptying, showing domperidone prokinetic activity, as well as quinidine anticholinergic activity. Domperidone (30 mg/kg) with PAM and with/without quinidine (25 mg/kg) was administered orally according to the disposition regiment different for six examined rat groups. DOM and PAM concentrations in plasma were assayed by HPLC method. Following changes were observed: domperidone did not modify the duration of the uptake phase of acetaminophen; quinidine prolongs gastric emptying time (as a result of anticholinergic action); quinidine given as the fourth or fifth dose with domperidone promotes growth of its concentration in plasma; analysis of changes in the value of AUC(0-2) at the initial three weeks of experiment suggests intensity of domperidone absorption processes, the following week increase in the value AUC(4-6) suggests inhibition of domperidone hepatic biotransformation and the mechanism of induction of absorption during domperidone administration is different from the absorption - inducing effects of quinidine. Both effects are superimposed and produce large, 2, 3-fold change in domperidone's AUC(0-6).

Pharmacists’ experiences with dispensing opioids

PubMed Central

Kahan, Meldon; Wilson, Lynn; Wenghofer, Elizabeth Francis; Srivastava, Anita; Resnick, Anne; Janecek, Eva; Sheehan, Carolynn

2011-01-01

Abstract Objective To explore pharmacists’ beliefs, practices, and experiences regarding opioid dispensing. Design Mailed survey. Setting The province of Ontario. Participants A total of 1011 pharmacists selected from the Ontario College of Pharmacists’ registration list. Main outcome measures Pharmacists’ experiences with opioid-related adverse events (intoxication and aberrant drug-related behaviour) and their interactions with physicians. Results A total of 652 pharmacists returned the survey, for a response rate of 64%. Most (86%) reported that they were concerned about several or many of their patients who were taking opioids; 36% reported that at least 1 patient was intoxicated from opioids while visiting their pharmacies within the past year. Reasons for opioid intoxication included the patient taking more than prescribed (84%), the patient using alcohol or sedating drugs along with the opioid (69.9%), or the prescribed dose being too high (34%). Participants’ most common concerns in the 3 months before the survey were patients coming in early for prescription refills, suspected double-doctoring, and requests for replacement doses for lost medication (reported frequently by 39%, 12%, and 16% of respondents, respectively). Pharmacists were concerned about physician practices, such as prescribing benzodiazepines along with opioids. Pharmacists reported difficulty in reaching physicians directly by telephone (43%), and indicated that physicians frequently did not return their calls promptly (28%). The strategies rated as most helpful for improving opioid dispensing were a provincial prescription database and opioid prescribing guidelines. Conclusion Pharmacists commonly observe opioid intoxication and aberrant drug-related behaviour in their patients but have difficulty communicating their concerns to physicians. System-wide strategies are urgently needed to improve the safety of opioid prescribing and to enhance communication between physicians and

Opioid dependence and substitution therapy: thymoquinone as potential novel supplement therapy for better outcome for methadone maintenance therapy substitution therapy

PubMed Central

Adnan, Liyana Hazwani Mohd; Bakar, Nor Hidayah Abu; Mohamad, Nasir

2014-01-01

Methadone is widely being used for opioid substitution therapy. However, the administration of methadone to opioid dependent individual is frequently accompanied by withdrawal syndrome and chemical dependency develops. Other than that, it is also difficult to retain patients in the treatment programme making their retention rates are decreasing over time. This article is written to higlights the potential use of prophetic medicines, Nigella sativa, as a supplement for opioid dependent receiving methadone. It focuses on the potential role of N. sativa and its major active compound, Thymoquinone (TQ) as a calcium channel blocking agent to reduce withdrawal syndrome and opioid dependency. PMID:25859295

Opioid-Induced Bowel Dysfunction

PubMed Central

Cheng, Vivian; Lembo, Anthony

2013-01-01

Opioid-induced bowel dysfunction (OIBD) is a potentially debilitating side effect of chronic opioid use. It refers to a collection of primarily gastrointestinal motility disorders induced by opioids, of which opioid-induced constipation (OIC) is the most common. Management of OIBD is difficult, and affected patients will often limit their opioid intake at the expense of experiencing more pain, to reduce the negative impact of OIBD on their quality of life. Effective pharmacologic therapy for OIC is considered an unmet need and several agents have recently been given priority review and approval for OIC. Furthermore, multiple agents currently in development show promise in treating OIC without significant impact on analgesia or precipitation of withdrawal symptoms. The approval and availability of such medications would represent a significant improvement in the management of OIC and OIBD in patients with chronic pain. PMID:23900996

The opioid manager: a point-of-care tool to facilitate the use of the Canadian Opioid Guideline.

PubMed

Furlan, Andrea D; Reardon, Rhoda; Salach, Lena

2012-01-01

The Opioid Manager is designed to be used as a point-of-care tool for providers prescribing opioids for chronic noncancer pain. It condenses the key elements from the Canadian Opioid Guideline and can be used as a chart insert. The Opioid Manager has been validated and is available for download from the Guideline's Web site http://nationalpaincentre.mcmaster.ca/opioidmanager/. The Opioid Manager is divided into the following four parts: A) before you write the first script, B) initiation trial, C) maintenance and monitoring, and D) when is it time to decrease the dose or stop the opioid completely? The Opioid Manager has been downloaded by 1,432 users: 47 percent family physicians, 18 percent pharmacists, 13 percent other physicians, and 22 percent miscellaneous. To show how to use the Opioid Manager, the authors created a 10-minute video that is available on the Internet. The Opioid Manager is being translated to French, Spanish, Portuguese, and Farsi.

Current Research on Opioid Receptor Function

PubMed Central

Feng, Yuan; He, Xiaozhou; Yang, Yilin; Chao, Dongman; Lazarus, Lawrence H.; Xia, Ying

2012-01-01

The use of opioid analgesics has a long history in clinical settings, although the comprehensive action of opioid receptors is still less understood. Nonetheless, recent studies have generated fresh insights into opioid receptor-mediated functions and their underlying mechanisms. Three major opioid receptors (μ-opioid receptor, MOR; δ-opioid receptor, DOR; and κ-opioid receptor, KOR) have been cloned in many species. Each opioid receptor is functionally sub-classified into several pharmacological subtypes, although, specific gene corresponding each of these receptor subtypes is still unidentified as only a single gene has been isolated for each opioid receptor. In addition to pain modulation and addiction, opioid receptors are widely involved in various physiological and pathophysiological activities, including the regulation of membrane ionic homeostasis, cell proliferation, emotional response, epileptic seizures, immune function, feeding, obesity, respiratory and cardiovascular control as well as some neurodegenerative disorders. In some species, they play an essential role in hibernation. One of the most exciting findings of the past decade is the opioid-receptor, especially DOR, mediated neuroprotection and cardioprotection. The up-regulation of DOR expression and DOR activation increase the neuronal tolerance to hypoxic/ischemic stress. The DOR signal triggers (depending on stress duration and severity) different mechanisms at multiple levels to preserve neuronal survival, including the stabilization of homeostasis and increased pro-survival signaling (e.g., PKC-ERK-Bcl 2) and anti-oxidative capacity. In the heart, PKC and KATP channels are involved in the opioid receptor-mediated cardioprotection. The DOR-mediated neuroprotection and cardioprotection have the potential to significantly alter the clinical pharmacology in terms of prevention and treatment of life-threatening conditions like stroke and myocardial infarction. The main purpose of this article

Safety and efficacy of an oxycodone vaccine: Addressing some of the unique considerations posed by opioid abuse

PubMed Central

Peterson, S. J.; Laudenbach, M.; Baruffaldi, F.; Carroll, F. I.; Comer, S. D.; Navarro, H. A.; Langston, T. L.; Runyon, S. P.; Winston, S.; Pravetoni, M.; Pentel, P. R.

2017-01-01

Among vaccines aimed at treating substance use disorders, those targeting opioids present several unique medication development challenges. 1) Opioid overdose is a common complication of abuse, so it is desirable for an opioid vaccine to block the toxic as well as the addictive effects of opioids. 2) It is important that an opioid vaccine not interfere with the action of opioid antagonists used to reverse opioid overdose or treat addiction. 3) Some opioids are immunosuppressive and chronic ongoing opioid use could interfere with vaccine immunogenicity. 4) Although antibody-bound oxycodone is unable to enter the brain because of its size, it might still be able to activate peripheral opioid receptors. To assess vaccine impact on opioid toxicity, rats vaccinated with oxycodone conjugated to keyhole limpet hemocyanin subunit dimer (OXY-dKLH) adsorbed to alum or controls vaccinated with dKLH were compared with regard to oxycodone-induced hotplate analgesia and oxycodone-induced respiratory depression and bradycardia. Vaccination shifted the dose-response curves to the right, representing protection, for each of these endpoints. Naloxone was equally effective in both OXY-dKLH and control groups, providing complete and rapid reversal of respiratory depression. The administration of a long-acting naltrexone formulation during vaccination did not impair vaccine immunogenicity in mice. Similarly, serum anti-oxycodone antibody titers were not altered by continuous morphine infusion during vaccination compared to opioid-naïve controls. Competitive ELISA assay showed negligible or low affinity of immune antiserum for endogenous opioids or opioid antagonists. In vitro receptor binding assays showed that antibody-bound oxycodone does not activate mu opioid receptors. These data support further study of OXY-dKLH as a potential treatment for oxycodone abuse and suggest that vaccination might also reduce the severity of oxycodone overdose. PMID:29194445

Chronic Opioid Use After Surgery: Implications for Perioperative Management in the Face of the Opioid Epidemic.

PubMed

Hah, Jennifer M; Bateman, Brian T; Ratliff, John; Curtin, Catherine; Sun, Eric

2017-11-01

Physicians, policymakers, and researchers are increasingly focused on finding ways to decrease opioid use and overdose in the United States both of which have sharply increased over the past decade. While many efforts are focused on the management of chronic pain, the use of opioids in surgical patients presents a particularly challenging problem requiring clinicians to balance 2 competing interests: managing acute pain in the immediate postoperative period and minimizing the risks of persistent opioid use after the surgery. Finding ways to minimize this risk is particularly salient in light of a growing literature suggesting that postsurgical patients are at increased risk for chronic opioid use. The perioperative care team, including surgeons and anesthesiologists, is poised to develop clinical- and systems-based interventions aimed at providing pain relief in the immediate postoperative period while also reducing the risks of opioid use longer term. In this paper, we discuss the consequences of chronic opioid use after surgery and present an analysis of the extent to which surgery has been associated with chronic opioid use. We follow with a discussion of the risk factors that are associated with chronic opioid use after surgery and proceed with an analysis of the extent to which opioid-sparing perioperative interventions (eg, nerve blockade) have been shown to reduce the risk of chronic opioid use after surgery. We then conclude with a discussion of future research directions.

Persistent opioid use following Cesarean delivery: patterns and predictors among opioid naïve women

PubMed Central

Bateman, Brian T.; Franklin, Jessica M.; Bykov, Katsiaryna; Avorn, Jerry; Shrank, William H.; Brennan, Troyen A.; Landon, Joan E.; Rathmell, James P.; Huybrechts, Krista F.; Fischer, Michael A.; Choudhry, Niteesh K.

2016-01-01

Background The incidence of opioid-related death in women has increased five-fold over the past decade. For many women, their initial opioid exposure will occur in the setting of routine medical care. Approximately 1 in 3 deliveries in the U.S. is by Cesarean and opioids are commonly prescribed for post-surgical pain management. Objective The objective of this study was to determine the risk that opioid naïve women prescribed opioids after Cesarean delivery will subsequently become consistent prescription opioid users in the year following delivery, and to identify predictors for this behavior. Study Design We identified women in a database of commercial insurance beneficiaries who underwent Cesarean delivery and who were opioid-naïve in the year prior to delivery. To identify persistent users of opioids, we used trajectory models, which group together patients with similar patterns of medication filling during follow-up, based on patterns of opioid dispensing in the year following Cesarean delivery. We then constructed a multivariable logistic regression model to identify independent risk factors for membership in the persistent user group. Results 285 of 80,127 (0.36%, 95% confidence interval 0.32 to 0.40), opioid-naïve women became persistent opioid users (identified using trajectory models based on monthly patterns of opioid dispensing) following Cesarean delivery. Demographics and baseline comorbidity predicted such use with moderate discrimination (c statistic = 0.73). Significant predictors included a history of cocaine abuse (risk 7.41%; adjusted odds ratio 6.11, 95% confidence interval 1.03 to 36.31) and other illicit substance abuse (2.36%; adjusted odds ratio 2.78, 95% confidence interval 1.12 to 6.91), tobacco use (1.45%; adjusted odds ratio 3.04, 95% confidence interval 2.03 to 4.55), back pain (0.69%; adjusted odds ratio 1.74, 95% confidence interval 1.33 to 2.29), migraines (0.91%; adjusted odds ratio 2.14, 95% confidence interval 1.58 to 2

Individual variation in the motivational and neurobiological effects of an opioid cue.

PubMed

Yager, Lindsay M; Pitchers, Kyle K; Flagel, Shelly B; Robinson, Terry E

2015-03-13

A discrete cue associated with intravenous injections of cocaine acquires greater control over motivated behavior in some rats ('sign-trackers', STs) than others ('goal-trackers', GTs). It is not known, however, if such variation generalizes to cues associated with other drugs. We asked, therefore, whether a discrete cue (a light) associated with the intravenous administration of an opioid drug (the short-acting mu receptor agonist, remifentanil) acquires incentive motivational properties differently in STs and GTs, as indicated by tests of Pavlovian conditioned approach and conditioned reinforcement. Consistent with studies using cocaine, STs approached a classically conditioned opioid cue more readily than GTs, and in a test of conditioned reinforcement worked more avidly to get it. Interestingly, STs and GTs did not differ in the acquisition of a conditioned orienting response. In addition, the performance of conditioned approach behavior, but not conditioned orientation, was attenuated by pretreatment with the dopamine receptor antagonist, flupenthixol, into the core of the nucleus accumbens. Lastly, food and opioid cues engaged similar amygdalo-striatal-thalamic circuitry to a much greater extent in STs than GTs, as indicated by Fos expression. Taken together, these data demonstrate that, similar to food and cocaine cues: (1) a discrete opioid cue attains greater incentive motivational value in STs than GTs; (2) the attribution of incentive motivational properties to an opioid cue is dopamine dependent; and (3) an opioid cue engages the so-called 'motive circuit' only if it is imbued with incentive salience.

Specifying the non-specific factors underlying opioid analgesia: Expectancy, attention, and affect

PubMed Central

Atlas, Lauren Y.; Wielgosz, Joseph; Whittington, Robert A.; Wager, Tor D.

2013-01-01

Rationale Psychological processes such as expectancy, attention, and affect directly influence clinical outcomes. These factors are grouped together as “nonspecific” factors, or placebo effects, in the medical literature, and their individual contributions are rarely considered. The pain-reducing effects of analgesic treatments may reflect changes in these psychological factors, rather than pure drug effects on pain. Furthermore, drug effects may not be isolated by drug vs. placebo comparisons if drugs interact with relevant psychological processes. Objectives To determine whether the analgesic effects of opioid and placebo treatment are mediated by changes in attention, expectancy, or affect. Methods We crossed intravenous administration of a potent opioid analgesic, remifentanil, with information about drug delivery (treatment expectancy, or placebo) using a balanced placebo design. We measured drug and treatment expectancy effects on pain, attention, and responses to emotional images. We also examined interactions with cue-based expectations about noxious stimulation, or stimulus expectancy. Results Pain was additively influenced by treatment expectancy, stimulus expectancy, and drug concentration. Attention performance showed a small but significant interaction between drug and treatment expectancy. Finally, remifentanil enhanced responses to both positive and negative emotional images. Conclusions The pain-relieving effects of opioid drugs are unlikely to be mediated by changes in threat or affective processing. Standard open-label opioid administration influences multiple clinically relevant cognitive and emotional processes. Psychological factors can combine with drug effects to influence multiple outcomes in distinct ways. The influence of specific psychological factors should be considered when developing and testing pharmacological treatments. PMID:24096537

Ketamine as an Adjunct to Opioids for Acute Pain in the Emergency Department: A Randomized Controlled Trial.

PubMed

Bowers, Karen J; McAllister, Kelly B; Ray, Meredith; Heitz, Corey

2017-06-01

(mean ± SD = 9.95 ± 4.83 mg) compared to placebo (mean ± SD = 12.81 ± 6.81 mg; p = 0.02). Satisfaction did not differ between groups. Fewer patients in the ketamine group required additional opioid doses. More patients reported light-headedness and dizziness in the ketamine group. Ketamine, as an adjunct to opioid therapy, was more effective at reducing pain over 120 minutes and resulted in a lower total opioid dose as well as fewer repeat doses of analgesia. More side effects were reported in the ketamine group (51% vs. 19%), but the side effect profile appears tolerable. © 2017 by the Society for Academic Emergency Medicine.

Characteristics of opioid-users whose death was related to opioid-toxicity: a population-based study in Ontario, Canada.

PubMed

Madadi, Parvaz; Hildebrandt, Doris; Lauwers, Albert E; Koren, Gideon

2013-01-01

The impact of the prescription opioid public health crisis has been illustrated by the dramatic increase in opioid-related deaths in North America. We aimed to identify patterns and characteristics amongst opioid-users whose cause of death was related to opioid toxicity. This was a population-based study of Ontarians between the years 2006 and 2008. All drug-related deaths which occurred during this time frame were reviewed at the Office of the Chief Coroner of Ontario, and opioid-related deaths were identified. Medical, toxicology, pathology, and police reports were comprehensively reviewed. Narratives, semi-quantitative, and quantitative variables were extracted, tabulated, and analyzed. Out of 2330 drug-related deaths in Ontario, 58% were attributed either in whole or in part, to opioids (n = 1359). Oxycodone was involved in approximately one-third of all opioid-related deaths. At least 7% of the entire cohort used opioids that were prescribed for friends and/or family, 19% inappropriately self-administered opioids (injection, inhalation, chewed patch), 3% were recently released from jail, and 5% had been switched from one opioid to another near the time of death. Accidental deaths were significantly associated with personal history of substance abuse, enrollment in methadone maintenance programs, cirrhosis, hepatitis, and cocaine use. Suicides were significantly associated with mental illness, previous suicide attempts, chronic pain, and a history of cancer. These results identify novel, susceptible groups of opioid-users whose cause of death was related to opioids in Ontario and provide the first evidence to assist in quantifying the contribution of opioid misuse and diversion amongst opioid-related mortality in Canada. Multifaceted prevention strategies need to be developed based on subpopulations of opioid users.

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

ER/LA Opioid Analgesics REMS: Overview of Ongoing Assessments of Its Progress and Its Impact on Health Outcomes.

PubMed

Cepeda, M Soledad; Coplan, Paul M; Kopper, Nathan W; Maziere, Jean-Yves; Wedin, Gregory P; Wallace, Laura E

2017-01-01

Opioid abuse is a serious public health concern. In response, the Food and Drug Administration (FDA) determined that a risk evaluation and mitigation strategy (REMS) for extended-release and long-acting (ER/LA) opioids was necessary to ensure that the benefits of these analgesics continue to outweigh the risks. Key components of the REMS are training for prescribers through accredited continuing education (CE), and providing patient educational materials. The impact of this REMS has been assessed using diverse metrics including evaluation of prescriber and patient understanding of the risks associated with opioids; patient receipt and comprehension of the medication guide and patient counseling document; patient satisfaction with access to opioids; drug utilization and changes in prescribing patterns; and surveillance of ER/LA opioid misuse, abuse, overdose, addiction, and death. The results of these assessments indicate that the increasing rates of opioid abuse, addiction, overdose, and death observed prior to implementation of the REMS have since leveled off or started to decline. However, these benefits cannot be attributed solely to the ER/LA opioid analgesics REMS since many other initiatives to prevent abuse occurred contemporaneously. These improvements occurred while preserving patient access to opioids as a large majority of patients surveyed expressed satisfaction with their access to opioids. © 2016 American Academy of Pain Medicine.

ER/LA Opioid Analgesics REMS: Overview of Ongoing Assessments of Its Progress and Its Impact on Health Outcomes

PubMed Central

Cepeda, M. Soledad; Kopper, Nathan W.; Maziere, Jean-Yves; Wedin, Gregory P.; Wallace, Laura E.

2017-01-01

Objective. Opioid abuse is a serious public health concern. In response, the Food and Drug Administration (FDA) determined that a risk evaluation and mitigation strategy (REMS) for extended-release and long-acting (ER/LA) opioids was necessary to ensure that the benefits of these analgesics continue to outweigh the risks. Key components of the REMS are training for prescribers through accredited continuing education (CE), and providing patient educational materials. Methods. The impact of this REMS has been assessed using diverse metrics including evaluation of prescriber and patient understanding of the risks associated with opioids; patient receipt and comprehension of the medication guide and patient counseling document; patient satisfaction with access to opioids; drug utilization and changes in prescribing patterns; and surveillance of ER/LA opioid misuse, abuse, overdose, addiction, and death. Results and Conclusions. The results of these assessments indicate that the increasing rates of opioid abuse, addiction, overdose, and death observed prior to implementation of the REMS have since leveled off or started to decline. However, these benefits cannot be attributed solely to the ER/LA opioid analgesics REMS since many other initiatives to prevent abuse occurred contemporaneously. These improvements occurred while preserving patient access to opioids as a large majority of patients surveyed expressed satisfaction with their access to opioids. PMID:27373304

Long-Acting Injectable Naltrexone Induction: A Randomized Trial of Outpatient Opioid Detoxification With Naltrexone Versus Buprenorphine.

PubMed

Sullivan, Maria; Bisaga, Adam; Pavlicova, Martina; Choi, C Jean; Mishlen, Kaitlyn; Carpenter, Kenneth M; Levin, Frances R; Dakwar, Elias; Mariani, John J; Nunes, Edward V

2017-05-01

At present there is no established optimal approach for transitioning opioid-dependent adults to extended-release injection naltrexone (XR-naltrexone) while preventing relapse. The authors conducted a trial examining the efficacy of two methods of outpatient opioid detoxification for induction to XR-naltrexone. Participants were 150 opioid-dependent adults randomly assigned 2:1 to one of two outpatient detoxification regimens, naltrexone-assisted detoxification or buprenorphine-assisted detoxification, followed by an injection of XR-naltrexone. Naltrexone-assisted detoxification lasted 7 days and included a single day of buprenorphine followed by ascending doses of oral naltrexone along with clonidine and other adjunctive medications. Buprenorphine-assisted detoxification included a 7-day buprenorphine taper followed by a week-long delay before administration of XR-naltrexone, consistent with official prescribing information for XR-naltrexone. Participants from both groups received behavioral therapy focused on medication adherence and a second dose of XR-naltrexone. Compared with participants in the buprenorphine-assisted detoxification condition, participants assigned to naltrexone-assisted detoxification were significantly more likely to be successfully inducted to XR-naltrexone (56.1% compared with 32.7%) and to receive the second injection at week 5 (50.0% compared with 26.9%). Both models adjusted for primary type of opioid use, route of opioid administration, and morphine equivalents at baseline. These results demonstrate the safety, efficacy, and tolerability of low-dose naltrexone, in conjunction with single-day buprenorphine dosing and adjunctive nonopioid medications, for initiating adults with opioid dependence to XR-naltrexone. This strategy offers a promising alternative to the high rates of attrition and relapse currently observed with agonist tapers in both inpatient and outpatient settings.

Brief Opioid Overdose Knowledge (BOOK): A Questionnaire to Assess Overdose Knowledge in Individuals Who Use Illicit or Prescribed Opioids.

PubMed

Dunn, Kelly E; Barrett, Frederick S; Yepez-Laubach, Claudia; Meyer, Andrew C; Hruska, Bryce J; Sigmon, Stacey C; Fingerhood, Michael; Bigelow, George E

2016-01-01

Opioid overdose is a public health crisis. This study describes efforts to develop and validate the Brief Opioid Overdose Knowledge (BOOK) questionnaire to assess patient knowledge gaps related to opioid overdose risks. Two samples of illicit opioid users and a third sample of patients receiving an opioid for the treatment of chronic pain (total N = 848) completed self-report items pertaining to opioid overdose risks. A 3-factor scale was established, representing Opioid Knowledge (4 items), Opioid Overdose Knowledge (4 items), and Opioid Overdose Response Knowledge (4 items). The scale had strong internal and face validity. Patients with chronic pain performed worse than illicit drug users in almost all items assessed, highlighting the need to increase knowledge of opioid overdose risk to this population. This study sought to develop a brief, internally valid method for quickly assessing deficits in opioid overdose risk areas within users of illicit and prescribed opioids, to provide an efficient metric for assessing and comparing educational interventions, facilitate conversations between physicians and patients about overdose risks, and help formally identify knowledge deficits in other patient populations.

Illicit Opioid Intoxication: Diagnosis and Treatment

PubMed Central

Fareed, A.; Stout, S.; Casarella, J.; Vayalapalli, S.; Cox, J.; Drexler, K.

2011-01-01

Opioid intoxications and overdose are associated with high rates of morbidity and mortality. Opioid overdose may occur in the setting of intravenous or intranasal heroin use, illicit use of diverted opioid medications, intentional or accidental misuse of prescription pain medications, or iatrogenic overdose. In this review, we focused on the epidemiology of illict opioid use in the United States and on the mechanism of action of opioid drugs. We also described the signs and symptoms, and diagnoses of intoxication and overdose. Lastly, we updated the reader about the most recent recommendations for treatment and prevention of opioid intoxications and overdose. PMID:22879747

Methadone Management of Withdrawal Associated With Loperamide-related Opioid Use Disorder.

PubMed

Leo, Raphael J; Ghazi, Muhammad A; Jaziri, Kelly S

: Loperamide hydrochloride is an over-the-counter anti-diarrheal agent, acting via mu-opioid receptor agonist effects in the intestinal myenteric plexus. Although preclinical investigations suggested that abuse liability associated with loperamide use is low, there are increasing numbers of cases reported to the US Food and Drug Administration, of abuse, dependence, and withdrawal associated with loperamide use. A case of a patient with opioid use disorder, that is, in the form of protracted loperamide excess use, requiring management of withdrawal with methadone is presented. Management of withdrawal from abrupt loperamide discontinuation has not been discussed in the literature. Long-term treatment issues are also described.

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.

The Influence of Prescription Opioid Use Duration and Dose on Development of Treatment Resistant Depression

PubMed Central

Scherrer, Jeffrey F.; Salas, Joanne; Sullivan, Mark D.; Schneider, F. David; Bucholz, Kathleen K.; Burroughs, Thomas; Copeland, Laurel; Ahmedani, Brian; Lustman, Patrick J.

2016-01-01

Long-term prescription opioid use is associated both with new-onset and recurrence of depression. Whether chronic opioid use interferes with depression management has not been reported, therefore we determined whether patients’ longer duration of opioid use and higher opioid dose are associated with new-onset treatment resistant depression (TRD) after controlling for confounding from pain and other variables. Data was obtained from Veteran Health Administration (VHA) de-identified patient medical records. We used a retrospective cohort design from 2000–2012. Eligible subjects (n=6,169) were 18–80 years of age, free of cancer and HIV, diagnosed with depression and opioid-free for the 24-month interval prior to the observation period. Duration of a new prescription for opioid analgesic was categorized as 1–30 days, 31–90 days and >90 days. Morphine-equivalent dose (MED) during follow-up categorized as ≤50 mg versus >50 mg per day. Pain and other sources of confounding were controlled by propensity scores and inverse probability of treatment weighting. Cox proportional hazard models were computed to estimate the association between duration and dose of opioid and onset of TRD. After removing confounding by weighting data, opioid use for 31–90 days and for >90 days, compared to 1–30 days, was significantly associated with new onset TRD (HR=1.25; 95%CI: 1.09–1.45 and HR=1.52; 95%CI: 1.32–1.74, respectively). MED was not associated with new onset TRD. The risk of developing TRD increased as time spent on opioid analgesics increased. Long-term opioid treatment of chronic pain may interfere with treatment of depression. PMID:27497660

Blocking of opioid receptors in experimental formaline-inactivated respiratory syncytial virus (FI-RSV) immunopathogenesis: from beneficial to harmful impacts.

PubMed

Salimi, Vahid; Mirzaei, Habib; Ramezani, Ali; Tahamtan, Alireza; Jamali, Abbas; Shahabi, Shahram; Golaram, Maryam; Minaei, Bagher; Gharagozlou, Mohammad Javad; Mahmoodi, Mahmood; Bont, Louis; Shokri, Fazel; Mokhtari-Azad, Talat

2018-04-01

Opioid system plays a significant role in pathophysiological processes, such as immune response and impacts on disease severity. Here, we investigated the effect of opioid system on the immunopathogenesis of respiratory syncytial virus (RSV) vaccine (FI-RSV)-mediated illness in a widely used mouse model. Female Balb/c mice were immunized at days 0 and 21 with FI-RSV (2 × 10 6  pfu, i.m.) and challenged with RSV-A2 (3 × 10 6  pfu, i.n.) at day 42. Nalmefene as a universal opioid receptors blocker administered at a dose of 1 mg/kg in combination with FI-RSV (FI-RSV + NL), and daily after live virus challenge (RSV + NL). Mice were sacrificed at day 5 after challenge and bronchoalveolar lavage (BAL) fluid and lungs were harvested to measure airway immune cells influx, T lymphocyte subtypes, cytokines/chemokines secretion, lung histopathology, and viral load. Administration of nalmefene in combination with FI-RSV (FI-RSV + NL-RSV) resulted in the reduction of the immune cells infiltration to the BAL fluid, the ratio of CD4/CD8 T lymphocyte, the level of IL-5, IL-10, MIP-1α, lung pathology, and restored weight loss after RSV infection. Blocking of opioid receptors during RSV infection in vaccinated mice (FI-RSV-RSV + NL) had no significant effects on RSV immunopathogenesis. Moreover, administration of nalmefene in combination with FI-RSV and blocking opioid receptors during RSV infection (FI-RSV + NL-RSV + NL) resulted in an increased influx of the immune cells to the BAL fluid, increases the level of IFN-γ, lung pathology, and weight loss in compared to control condition. Although nalmefene administration within FI-RSV vaccine decreases vaccine-enhanced infection during subsequent exposure to the virus, opioid receptor blocking during RSV infection aggravates the host inflammatory response to RSV infection. Thus, caution is required due to beneficial/harmful functions of opioid systems while targeting as potentially therapies.

What do providers want to know about opioid prescribing? A qualitative analysis of their questions.

PubMed

Cushman, Phoebe A; Liebschutz, Jane M; Hodgkin, Joseph G; Shanahan, Christopher W; White, Julie L; Hardesty, Ilana; Alford, Daniel P

2017-01-01

In 2012, the US Food and Drug Administration (FDA) responded to the opioid crisis with a Risk Evaluation and Mitigation Strategy, requiring manufacturers of extended-release/long-acting opioids to fund continuing medical education based on the "FDA Blueprint for Prescriber Education." Topics in the Blueprint are "Assessing Patients for Treatment," "Initiating Therapy, Modifying Dosing, and Discontinuing Use," "Managing Therapy," "Counseling Patients and Caregivers about Safe Use," "General Drug Information," and "Specific Drug Information." Based on the FDA Blueprint, Boston University School of Medicine's "Safe and Competent Opioid Prescribing Education" (SCOPE of Pain) offers live trainings for physicians and other prescribers. During trainings, participants submit written questions about the curriculum and/or their clinical experiences. The objective was to compare themes that arose from questions asked by SCOPE of Pain participants with content of the FDA Blueprint in order to evaluate how well the Blueprint answers prescribers' concerns. The authors conducted qualitative analyses of all 1309 questions submitted by participants in 29 trainings across 16 states from May 2013 to May 2015, using conventional content analysis to code the questions. Themes that emerged from participants' questions were then compared with the Blueprint. Most themes fell into the topic categories of the Blueprint. Five main themes diverged: Participants sought information on (1) safe alternatives to opioids, (2) overcoming barriers to safe opioid prescribing, (3) government regulations of opioid prescribing, (4) the role of marijuana in opioid prescribing, and (5) maintaining a positive provider-patient relationship while prescribing opioids. In addition to learning the mechanics of safe opioid prescribing, providers want to understand government regulations and effective patient communication skills. Aware of the limitations of opioids in managing chronic pain, providers seek advice

Ketamine as an adjuvant to opioids for cancer pain.

PubMed

Bell, Rae F; Eccleston, Christopher; Kalso, Eija A

2017-06-28

This is an update of a review first published in 2003 and updated in 2012.Ketamine is a commonly used anaesthetic agent, and in subanaesthetic doses is also given as an adjuvant to opioids for the treatment of refractory cancer pain, when opioids alone or in combination with appropriate adjuvant analgesics prove to be ineffective. Ketamine is known to have psychomimetic (including hallucinogenic), urological, and hepatic adverse effects. To determine the effectiveness and adverse effects of ketamine as an adjuvant to opioids for refractory cancer pain in adults. For this update, we searched MEDLINE (OVID) to December 2016. We searched CENTRAL (CRSO), Embase (OVID) and two clinical trial registries to January 2017. The intervention considered by this review was the addition of ketamine, given by any route of administration, in any dose, to pre-existing opioid treatment given by any route and in any dose, compared with placebo or active control. We included studies with a group size of at least 10 participants who completed the trial. Two review authors independently assessed the search results and performed 'Risk of bias' assessments. We aimed to extract data on patient-reported pain intensity, total opioid consumption over the study period; use of rescue medication; adverse events; measures of patient satisfaction/preference; function; and distress. We also assessed participant withdrawal (dropout) from trial. We assessed the quality of the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation). One new study (185 participants) was identified by the updated search and included in the review. We included a total of three studies in this update.Two small studies, both with cross-over design, with 20 and 10 participants respectively, were eligible for inclusion in the original review. One study with 20 participants examined the addition of intrathecal ketamine to intrathecal morphine, compared with intrathecal morphine alone. The

The opioid epidemic and national guidelines for opioid therapy for chronic noncancer pain: a perspective from different continents.

PubMed

Häuser, Winfried; Schug, Stephan; Furlan, Andrea D

2017-05-01

A marked rise in opioid prescriptions for patients with chronic noncancer pain (CNCP) with a parallel increase in opioid abuse/misuse, and resulting deaths was noted in the Unites states in the past decade (opioid epidemic). In response, the US Center of Diseases Control (CDC) developed a guideline for prescribing of opioids for patients with CNCP. To assess (1) if there is an opioid epidemic in Australia, Canada, and Germany (2) to compare Australian, Canadian, German, and Center of Diseases Control guidelines recommendations for long-term opioid therapy for CNCP. National evidence-based guidelines and PubMed were searched for recommendations for opioid prescriptions for CNCP. There are signs of an opioid epidemic in Australia and Canada, but not in Germany. Guidelines in all 4 countries provide similar recommendations: opioids are not the first-line therapy for patients with CNCP; regular clinical assessments of benefits and harms are necessary; excessive doses should be avoided (recommended morphine equivalent daily doses range from 50 to 200 mg/d); stopping rules should be followed. All guidelines do not recommend the use of opioids in chronic pain conditions without an established nociceptive or neuropathic cause such as fibromyalgia and primary headache. Implementation of opioid prescribing guidelines should ensure that physicians prescribe opioids only for appropriate indications in limited doses for selected patients and advice patients on their safe use. These measures could contribute to reduce prescription opioid misuse/abuse and deaths.

Prospects of Using of κ-Opioid Receptor Agonists U-50,488 and ICI 199,441 for Improving Heart Resistance to Ischemia/Reperfusion.

PubMed

Tsibulnikov, S Yu; Maslov, L N; Mukhomedzyanov, A V; Krylatov, A V; Tsibulnikova, M R; Lishmanov, Yu B

2015-10-01

We studied the ability of the agonist of κ1-opioid receptors U-50,488 in doses of 0.1 and 1 mg/kg to simulate ischemic pre- and postconditioning of the heart and κ-opioid receptors ICI 199,441 in a dose of 0.1 mg/kg to simulate the antiarrhythmic effect of heart preconditioning. The duration of ischemia was 10 or 45 min and the duration of reperfusion was 10 min or 2 h. Administration of 1 mg/kg U-50,488 both before ischemia and 5 min before reperfusion produced a pronounced antiarrhythmic effect. U-50,488 injected 5 min before reperfusion 2-fold reduced the ratio of infarction to risk area. Administration of ICI 199,441 in a dose of 0.1 mg/kg 15 min before ischemia produced a potent antiarrhythmic effect. Antiarrhythmic effect of κ-opioid receptor agonists depended on activation of κ-opioid receptors.

Characteristics of Opioid-Users Whose Death Was Related to Opioid-Toxicity: A Population-Based Study in Ontario, Canada

PubMed Central

Madadi, Parvaz; Hildebrandt, Doris; Lauwers, Albert E.; Koren, Gideon

2013-01-01

Background The impact of the prescription opioid public health crisis has been illustrated by the dramatic increase in opioid-related deaths in North America. We aimed to identify patterns and characteristics amongst opioid-users whose cause of death was related to opioid toxicity. Methods This was a population-based study of Ontarians between the years 2006 and 2008. All drug-related deaths which occurred during this time frame were reviewed at the Office of the Chief Coroner of Ontario, and opioid-related deaths were identified. Medical, toxicology, pathology, and police reports were comprehensively reviewed. Narratives, semi-quantitative, and quantitative variables were extracted, tabulated, and analyzed. Results Out of 2330 drug-related deaths in Ontario, 58% were attributed either in whole or in part, to opioids (n = 1359). Oxycodone was involved in approximately one-third of all opioid-related deaths. At least 7% of the entire cohort used opioids that were prescribed for friends and/or family, 19% inappropriately self-administered opioids (injection, inhalation, chewed patch), 3% were recently released from jail, and 5% had been switched from one opioid to another near the time of death. Accidental deaths were significantly associated with personal history of substance abuse, enrollment in methadone maintenance programs, cirrhosis, hepatitis, and cocaine use. Suicides were significantly associated with mental illness, previous suicide attempts, chronic pain, and a history of cancer. Significance/Conclusion These results identify novel, susceptible groups of opioid-users whose cause of death was related to opioids in Ontario and provide the first evidence to assist in quantifying the contribution of opioid misuse and diversion amongst opioid-related mortality in Canada. Multifaceted prevention strategies need to be developed based on subpopulations of opioid users. PMID:23577131

"Weak" opioid analgesics. Codeine, dihydrocodeine and tramadol: no less risky than morphine.

PubMed

2016-02-01

So-called weak opioid analgesics are often used to treat severe pain, or when paracetamol or a nonsteroidal anti-inflammatory drug (NSAID) proves inadequate. But are weak opioids any more effective than paracetamol or NSAIDs on nociceptive pain, and are they better tolerated than morphine? To answer these questions, we conducted a review of literature using the standard Prescrire methodology. The potency of codeine and tramadol is strongly influenced by the cytochrome P450 isoenzyme CYP2D6 genotype, which varies widely from one person to another. This explains reports of overdosing or underdosing after administration of standard doses of the two drugs. The potency of morphine and that of buprenorphine, an opioid receptor agonist-antagonist, appears to be independent of CYP2D6 activity. All "weak" opioids can have the same dose-dependent adverse effects as morphine. There is no evidence that, at equivalent analgesic efficacy, weak opioids carry a lower risk of addiction than low-dose morphine. Respiratory depression can occur in ultrarapid metabolisers after brief exposure to standard doses of codeine or tramadol. Similar cases have been reported with dihydrocodeine in patients with renal failure. In addition, tramadol can cause a serotonin syndrome, hypoglycaemia, hyponatraemia and seizures. Several trials have compared different weak opioids in patients with post-operative pain. A single dose of a weak opioid, possibly combined with paracetamol, has greater analgesic efficacy than paracetamol alone but is not more effective than an NSAID alone. There is a dearth of evidence on weak opioids in patients with chronic pain. Available trials fail to show that a weak opioid has markedly superior analgesic efficacy to paracetamol or an NSAID. Sublingual buprenorphine at analgesic doses appears less likely to cause respiratory depression, but it seems to have weak analgesic efficacy. In practice, when opioid therapy is needed, there is no evidence that codeine

Discharge prescribing of enteral opioids after initiation as a weaning strategy from continuous opioid infusions in the Intensive Care Unit.

PubMed

Kram, Bridgette; Weigel, Kylie M; Kuhrt, Michelle; Gilstrap, Daniel L

To evaluate the proportion of patients receiving a hospital discharge prescription for a scheduled enteral opioid following initiation as a weaning strategy from a continuous opioid infusion in the Intensive Care Unit (ICU). Retrospective, observational study. Five adult ICUs at a large, quaternary care academic medical center. Endotracheally intubated, opioid-naive adults receiving a continuous opioid infusion with a concomitant scheduled enteral opioid initiated. Exclusion criteria were receipt of fewer than two enteral opioid doses, documentation of a long-acting opioid as a home medication, the indication for the enteral opioid was not a weaning strategy, death during hospital admission or discharge to hospice. None. The proportion of ICU and hospital survivors who received a discharge prescription for a scheduled enteral opioid, total duration of continuous opioid infusion, duration of continuous opioid infusion after initiation of an enteral opioid therapy, total duration of enteral therapy, ICU and hospital length of stay. Of 62 included patients, 19 patients (30.6 percent) received a new prescription for a scheduled enteral opioid at hospital discharge. The median duration of enteral opioid therapy was longer for patients who received a discharge prescription compared to those who did not (20.09 vs 8.89 days, p = 0.02), though the remaining endpoints were not different. Utilizing scheduled enteral opioids as a weaning strategy from continuous opioid infusions may place patients at risk of ICU-acquired physical dependence on opioids.

Macroeconomic conditions and opioid abuse.

PubMed

Hollingsworth, Alex; Ruhm, Christopher J; Simon, Kosali

2017-12-01

We examine how deaths and emergency department (ED) visits related to use of opioid analgesics (opioids) and other drugs vary with macroeconomic conditions. As the county unemployment rate increases by one percentage point, the opioid death rate per 100,000 rises by 0.19 (3.6%) and the opioid overdose ED visit rate per 100,000 increases by 0.95 (7.0%). Macroeconomic shocks also increase the overall drug death rate, but this increase is driven by rising opioid deaths. Our findings hold when performing a state-level analysis, rather than county-level; are primarily driven by adverse events among whites; and are stable across time periods. Copyright © 2017 Elsevier B.V. All rights reserved.

Targinact--opioid pain relief without constipation?

PubMed

2010-12-01

Targinact (Napp Pharmaceuticals Ltd) is a modified-release combination product containing the strong opioid oxycodone plus the opioid antagonist naloxone. It is licensed for "severe pain, which can be adequately managed only with opioid analgesics".1 The summary of product characteristics (SPC) states that "naloxone is added to counteract opioid-induced constipation by blocking the action of oxycodone at opioid receptors locally in the gut". Advertising for the product claims "better pain relief", "superior GI [gastrointestinal] tolerability" and "improved quality of life" "compared to previous treatment in a clinical practice study (n=7836)". Here we consider whether Targinact offers advantages over using strong opioids plus laxatives where required.

Parent and Metabolite Opioid Drug Concentrations in Unintentional Deaths Involving Opioid and Benzodiazepine Combinations*†‡

PubMed Central

Fields, Marcia D.; Abate, Marie A.; Hu, Lan; Long, D. Leann; Blommel, Matthew L.; Haikal, Nabila A.; Kraner, James C.

2016-01-01

Effects of benzodiazepines on postmortem opioid parent and parent/metabolite blood concentration ratios were determined for fentanyl-, hydrocodone-, methadone-, or oxycodone-related accidental deaths. These opioids are partially metabolized by the CYP3A4 enzyme system, which is also affected by diazepam and alprazolam. Opioid/metabolite combinations examined were as follows: fentanyl/norfentanyl, hydrocodone/dihydrocodeine, methadone/EDDP, and oxycodone/oxymorphone. Parent opioid concentrations were analyzed for 877 deaths. Parent/metabolite concentration ratios were analyzed for 349 deaths, excluding cases with co-intoxicants present known to interfere with opioid elimination. Alprazolam in combination with diazepam significantly decreased median hydrocodone concentrations by 48% (p = 0.01) compared to hydrocodone alone. The methadone parent/metabolite concentration ratio was reduced by 35% in the presence of diazepam compared to methadone alone (p = 0.03). Benzodiazepines did not statistically significantly affect fentanyl or oxycodone concentrations. Possible factors affecting opioid concentrations and possible toxicity development, including any differential effects on specific opioids, should continue to be explored. PMID:26223761

Concomitant use of opioid medications with triptans or serotonergic antidepressants in US office-based physician visits.

PubMed

Molina, Kyle C; Fairman, Kathleen A; Sclar, David A

2018-01-01

Opioids are not recommended for routine treatment of migraine because their benefits are outweighed by risks of medication overuse headache and abuse/dependence. A March 2016 US Food and Drug Administration (FDA) safety communication warned of the risk of serotonin syndrome from using opioids concomitantly with 5-hydroxytryptamine receptor agonists (triptans) or serotonergic antidepressants: selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Epidemiological information about co-prescribing of these medications is limited. The objective of this study was to estimate the nationwide prevalence of co-prescribing of an opioid with a serotonergic antidepressant and/or triptan in US office-based physician visits made by 1) all patients and 2) patients diagnosed with migraine. National Ambulatory Medical Care Survey (NAMCS) data were obtained for 2013 and 2014. Physician office visits that included the new or continued prescribing of ≥1 opioid medication with a triptan or an SSRI/SNRI were identified. Co-prescribed opioids were stratified by agent to determine the proportion of co-prescriptions with opioids posing a higher risk of serotonergic agonism (meperidine, tapentadol, and tramadol). Of an annualized mean 903.6 million office-based physician visits in 2013-2014, 17.7 million (2.0% of all US visits) resulted in the prescribing of ≥1 opioid medication with a triptan or an SSRI/SNRI. Opioid-SSRI/SNRI was co-prescribed in 16,044,721 visits, while opioid-triptan was co-prescribed in 1,622,827 visits. One-fifth of opioid co-prescribing was attributable to higher-risk opioids, predominantly tramadol (18.6% of opioid-SSRI/SNRI, 21.8% of opioid-triptan). Of 7,672,193 visits for patients diagnosed with migraine, 16.3% included opioid prescribing and 2.0% included co-prescribed opioid-triptan. During a period approximately 2 years prior to an FDA warning about the risk of serotonin syndrome from opioid-SSRI/SNRI or

Huperzine A inhibits immediate addictive behavior but not behavioral sensitization following repeated morphine administration in rats.

PubMed

Sun, Jinling; Tian, Lin; Cui, Ruisi; Li, Xinwang

2017-04-01

Acetylcholinesterase inhibitors are regarded as promising therapeutic agents to treat addiction. The current study aimed to examine the effects of huperzine A, a cholinesterase inhibitor, on behavioral sensitization induced by repeated morphine administration and relapse induced by contextual conditioning. The present study also assessed whether the state-dependency hypothesis may explain the results. Adult rats were divided into four groups (n=8) and intraperitoneally injected with 0.2, 0.3 or 0.4 mg/kg huperzine A or saline (1 ml/kg, control), for 5 days. The effect of repeated huperzine A administration alone on locomotor activity was assessed. For the experiments that analyzed the development of morphine-induced sensitization, 40 rats were divided into five groups (n=8): Saline+Saline, Saline+Morphine, 0.2, 0.3 and 0.4 mg/kg huperzine A+Morphine. Following a withdrawal period of 7 days, all animals were administered saline or morphine, as appropriate. To test the state-dependency hypothesis, the rats in the Saline+Morphine group were injected with saline and morphine, while the other three groups were administered different doses of huperzine A and morphine. To examine the effect of huperzine A on the expression of morphine-induced sensitization, the rats in huperzine A+Morphine groups were injected with appropriate concentrations of huperzine A, and morphine. The current results indicated that the administration of huperzine A alone did not affect locomotor activity, while higher doses of huperzine A inhibited the addictive behavior induced by morphine at the development phase. Additionally, huperzine A administration during the expression phase of morphine sensitization did not inhibit the relapse induced by administration of saline. Furthermore, 0.4 mg/kg huperzine A inhibited the expression of morphine-induced behavioral sensitization. Therefore, the results of the current study do not support the state-dependency hypothesis.

Huperzine A inhibits immediate addictive behavior but not behavioral sensitization following repeated morphine administration in rats

PubMed Central

Sun, Jinling; Tian, Lin; Cui, Ruisi; Li, Xinwang

2017-01-01

Acetylcholinesterase inhibitors are regarded as promising therapeutic agents to treat addiction. The current study aimed to examine the effects of huperzine A, a cholinesterase inhibitor, on behavioral sensitization induced by repeated morphine administration and relapse induced by contextual conditioning. The present study also assessed whether the state-dependency hypothesis may explain the results. Adult rats were divided into four groups (n=8) and intraperitoneally injected with 0.2, 0.3 or 0.4 mg/kg huperzine A or saline (1 ml/kg, control), for 5 days. The effect of repeated huperzine A administration alone on locomotor activity was assessed. For the experiments that analyzed the development of morphine-induced sensitization, 40 rats were divided into five groups (n=8): Saline+Saline, Saline+Morphine, 0.2, 0.3 and 0.4 mg/kg huperzine A+Morphine. Following a withdrawal period of 7 days, all animals were administered saline or morphine, as appropriate. To test the state-dependency hypothesis, the rats in the Saline+Morphine group were injected with saline and morphine, while the other three groups were administered different doses of huperzine A and morphine. To examine the effect of huperzine A on the expression of morphine-induced sensitization, the rats in huperzine A+Morphine groups were injected with appropriate concentrations of huperzine A, and morphine. The current results indicated that the administration of huperzine A alone did not affect locomotor activity, while higher doses of huperzine A inhibited the addictive behavior induced by morphine at the development phase. Additionally, huperzine A administration during the expression phase of morphine sensitization did not inhibit the relapse induced by administration of saline. Furthermore, 0.4 mg/kg huperzine A inhibited the expression of morphine-induced behavioral sensitization. Therefore, the results of the current study do not support the state-dependency hypothesis. PMID:28413513

Alcohol Screening among Opioid Agonist Patients in a Primary Care Clinic and an Opioid Treatment Program.

PubMed

Klimas, Jan; Muench, John; Wiest, Katharina; Croff, Raina; Rieckman, Traci; McCarty, Dennis

2015-01-01

Problem alcohol use is associated with adverse health and economic outcomes, especially among people in opioid agonist treatment. Screening, brief intervention, and referral to treatment (SBIRT) are effective in reducing alcohol use; however, issues involved in SBIRT implementation among opioid agonist patients are unknown. To assess identification and treatment of alcohol use disorders, we reviewed clinical records of opioid agonist patients screened for an alcohol use disorder in a primary care clinic (n = 208) and in an opioid treatment program (n = 204) over a two-year period. In the primary care clinic, 193 (93%) buprenorphine patients completed an annual alcohol screening and six (3%) had elevated AUDIT scores. In the opioid treatment program, an alcohol abuse or dependence diagnosis was recorded for 54 (27%) methadone patients. Practitioner focus groups were completed in the primary care (n = 4 physicians) and the opioid treatment program (n = 11 counselors) to assess experience with and attitudes towards screening opioid agonist patients for alcohol use disorders. Focus groups suggested that organizational, structural, provider, patient, and community variables hindered or fostered alcohol screening. Alcohol screening is feasible among opioid agonist patients. Effective implementation, however, requires physician training and systematic changes in workflow.

Role of opioid receptors in the reinstatement of opioid-seeking behavior: an overview.

PubMed

Fattore, Liana; Fadda, Paola; Antinori, Silvia; Fratta, Walter

2015-01-01

Opioid abuse in humans is characterized by discontinuous periods of drug use and abstinence. With time, the probability of falling into renewed drug consumption becomes particularly high and constitutes a considerable problem in the management of heroin addicts. The major problem in the treatment of opioid dependence still remains the occurrence of relapse, to which stressful life events, renewed use of heroin, and exposure to drug-associated environmental cues are all positively correlated. To study the neurobiology of relapse, many research groups currently use the reinstatement animal model, which greatly contributed to disentangle the mechanisms underlying relapse to drug-seeking in laboratory animals. The use of this model is becoming increasingly popular worldwide, and new versions have been recently developed to better appreciate the differential contribution of each opioid receptor subtype to the relapse phenomenon. In this chapter we review the state of the art of our knowledge on the specific role of the opioid receptors as unrevealed by the reinstatement animal model of opioid-seeking behavior.

The effect of state laws designed to prevent nonmedical prescription opioid use on overdose deaths and treatment.

PubMed

Popovici, Ioana; Maclean, Johanna Catherine; Hijazi, Bushra; Radakrishnan, Sharmini

2018-02-01

Nonmedical use of prescription opioids has reached epidemic levels in the United States and globally. In response, federal, state, and local governments are taking actions to address substantial increases in prescription opioid addiction and its associated harms. This study examines the effect of two state laws specifically designed to curtail access to prescription opioids to nonmedical users: pain management clinic and doctor shopping laws. We use administrative data on overdose deaths and admissions to specialty substance use disorder treatment coupled with a differences-in-differences design. Our findings suggest that both pain management clinic and doctor shopping laws have the potential to reduce prescription opioid overdose deaths. Moreover, doctor shopping laws appear to reduce prescription opioid treatment admissions. As many states have adopted these laws in recent years, the full effects of the laws may not yet be realized. Future research using more postlaw passage data should reevaluate the effectiveness of these laws. Copyright © 2017 John Wiley & Sons, Ltd.

Trends in Opioid Use Disorder Diagnoses and Medication Treatment Among Veterans With Posttraumatic Stress Disorder.

PubMed

Shiner, Brian; Leonard Westgate, Christine; Bernardy, Nancy C; Schnurr, Paula P; Watts, Bradley V

2017-01-01

Despite long-standing interest in posttraumatic stress disorder (PTSD) and opioid use disorder comorbidity, there is a paucity of data on the prevalence of opioid use disorder in patients with PTSD. Therefore, there is limited understanding of the use of medications for opioid use disorder in this population. We determined the prevalence of diagnosed opioid use disorder and use of medications for opioid use disorder in a large cohort of patients with PTSD. We obtained administrative and pharmacy data for veterans who initiated PTSD treatment in the Department of Veterans Affairs (VA) between 2004 and 2013 (N = 731,520). We identified those with a comorbid opioid use disorder diagnosis (2.7%; n = 19,998) and determined whether they received a medication for opioid use disorder in the year following their initial clinical PTSD diagnosis (29.6%; n = 5,913). Using logistic regression, we determined the predictors of receipt of opioid use disorder medications. Comorbid opioid use disorder diagnoses increased from 2.5% in 2004 to 3.4% in 2013. Patients with comorbid opioid use disorder used more health services and had more comorbidities than other patients with PTSD. Among patients with PTSD and comorbid opioid use disorder, use of medications for opioid use disorder increased from 22.6% to 35.1% during the same time period. Growth in the use of buprenorphine (2.0% to 22.7%) was accompanied by relative decline in use of methadone (19.3% to 12.7%). Patients who received buprenorphine were younger and more likely to be rural, White, and married. Patients who received methadone were older, urban, unmarried, from racial and ethnic minorities, and more likely to see substance abuse specialists. While use of naltrexone increased (2.8% to 8.6%), most (87%) patients who received naltrexone also had an alcohol use disorder. Controlling for patient factors, there was a substantial increase in the use of buprenorphine, a substantial decrease in the use of methadone, and no change

National and State Treatment Need and Capacity for Opioid Agonist Medication-Assisted Treatment

PubMed Central

Campopiano, Melinda; Baldwin, Grant; McCance-Katz, Elinore

2015-01-01

Objectives. We estimated national and state trends in opioid agonist medication-assisted treatment (OA-MAT) need and capacity to identify gaps and inform policy decisions. Methods. We generated national and state rates of past-year opioid abuse or dependence, maximum potential buprenorphine treatment capacity, number of patients receiving methadone from opioid treatment programs (OTPs), and the percentage of OTPs operating at 80% capacity or more using Substance Abuse and Mental Health Services Administration data. Results. Nationally, in 2012, the rate of opioid abuse or dependence was 891.8 per 100 000 people aged 12 years or older compared with national rates of maximum potential buprenorphine treatment capacity and patients receiving methadone in OTPs of, respectively, 420.3 and 119.9. Among states and the District of Columbia, 96% had opioid abuse or dependence rates higher than their buprenorphine treatment capacity rates; 37% had a gap of at least 5 per 1000 people. Thirty-eight states (77.6%) reported at least 75% of their OTPs were operating at 80% capacity or more. Conclusions. Significant gaps between treatment need and capacity exist at the state and national levels. Strategies to increase the number of OA-MAT providers are needed. PMID:26066931

Comparative Pharmacokinetics of Cefquinome (Cobactan 2.5%) following Repeated Intramuscular Administrations in Sheep and Goats

PubMed Central

El-Hewaity, Mohamed; Abd El Latif, Amera

2014-01-01

The comparative pharmacokinetic profile of cefquinome was studied in sheep and goats following repeated intramuscular (IM) administrations of 2 mg/kg body weight. Cefquinome concentrations in serum were determined by microbiological assay technique using Micrococcus luteus (ATCC 9341) as test organism. Following intramuscular injection of cefquinome in sheep and goats, the disposition curves were best described by two-compartment open model in both sheep and goats. The pharmacokinetics of cefquinome did not differ significantly between sheep and goats; similar intramuscular dose rate of cefquinome should therefore be applicable to both species. On comparing the data of serum levels of repeated intramuscular injections with first intramuscular injection, it was revealed that repeated intramuscular injections of cefquinome have cumulative effect in both species sheep and goats. The in vitro serum protein-binding tendency was 15.65% in sheep and 14.42% in goats. The serum concentrations of cefquinome along 24 h after injection in this study were exceeding the MICs of different susceptible microorganisms responsible for serious disease problems. These findings indicate successful use of cefquinome in sheep and goats. PMID:26464946

The opioid systems--panacea and nemesis.

PubMed

Terenius, Lars; Johansson, Björn

2010-05-21

This mini-review outlines the opioid systems and their roles primarily as related to reward and compulsive drug/alcohol intake. The central role is taken by the mu-opioid receptor, target for opiate analgesics and also a central target in compulsive alcohol abuse, alcoholism. The mu-opioid receptor and the cognate opioid neuropeptides from proenkephalin and proopiomelancortin are members of a superfamily of opioid systems, each with unique and still to be defined roles in the central nervous system. 2010. Published by Elsevier Inc.

Amphiphysin I but not dynamin I nor synaptojanin mRNA expression increased after repeated methamphetamine administration in the rat cerebrum and cerebellum.

PubMed

Hamamura, Mitsuko; Okouchi, Jiro; Ozawa, Hidetoshi; Kimuro, Yoshihiko; Iwaki, Akiko; Fukumaki, Yasuyuki

2013-07-01

Dopamine increases/decreases synaptic vesicle recycling and in schizophrenia the proteins/mRNA is decreased. We isolated cDNA clone, similar to amphiphysin 1 (vesicle protein) mRNA from the neocortex of rats injected repeatedly with methamphetamine using polymerase chain reaction (PCR) differential display. This clone is highly homologous to the 3' region of the human amphiphysin gene. PCR extension study using a primer specific for the rat amphiphysin 1 gene and a primer located within the clone revealed that it is the 3' UTR region of the rat amphiphysin 1 gene. Furthermore, in situ hybridization revealed that amphiphysin 1 mRNA is expressed in the cerebrum, medial thalamus, hippocampus and cerebellum. In the cerebellum, amphiphysin mRNA expression was confined to upper granule cell layer. Repeated methamphetamine administration increased amphiphysin I mRNA expression in both anterior part of the cerebrum, and the cerebellum. However, the repeated administration did not alter mRNA expression of the other vesicle proteins, synaptotagmin I, synapsin I, synaptojanin and dynamin I, we conclude that the repeated administration selectively increased amphiphysin 1 mRNA expression. Thus, amphiphysin 1 does not work as synaptic recycling, but it is suggested, as a part of pathogenesis of brain tissue injury (under Ca²⁺ and Mg²⁺ devoid environment) in repeated methamphetamine-injected states, the gene regulate actin-asssembly, learning, cell stress signaling and cell polarity.

Probabilistic reward- and punishment-based learning in opioid addiction: Experimental and computational data.

PubMed

Myers, Catherine E; Sheynin, Jony; Balsdon, Tarryn; Luzardo, Andre; Beck, Kevin D; Hogarth, Lee; Haber, Paul; Moustafa, Ahmed A

2016-01-01

Addiction is the continuation of a habit in spite of negative consequences. A vast literature gives evidence that this poor decision-making behavior in individuals addicted to drugs also generalizes to laboratory decision making tasks, suggesting that the impairment in decision-making is not limited to decisions about taking drugs. In the current experiment, opioid-addicted individuals and matched controls with no history of illicit drug use were administered a probabilistic classification task that embeds both reward-based and punishment-based learning trials, and a computational model of decision making was applied to understand the mechanisms describing individuals' performance on the task. Although behavioral results showed that opioid-addicted individuals performed as well as controls on both reward- and punishment-based learning, the modeling results suggested subtle differences in how decisions were made between the two groups. Specifically, the opioid-addicted group showed decreased tendency to repeat prior responses, meaning that they were more likely to "chase reward" when expectancies were violated, whereas controls were more likely to stick with a previously-successful response rule, despite occasional expectancy violations. This tendency to chase short-term reward, potentially at the expense of developing rules that maximize reward over the long term, may be a contributing factor to opioid addiction. Further work is indicated to better understand whether this tendency arises as a result of brain changes in the wake of continued opioid use/abuse, or might be a pre-existing factor that may contribute to risk for addiction. Copyright © 2015 Elsevier B.V. All rights reserved.

Nurses' Role in Preventing Prescription Opioid Diversion.

PubMed

Manworren, Renee C B; Gilson, Aaron M

2015-08-01

Prescription opioid abuse is at epidemic levels. Opioids diverted from friends and family members who have legitimate prescriptions are a major source of abused prescription opioids. Nurses are vital to any effort to combat this public health crisis because they have the opportunity to provide essential anticipatory guidance every time a patient receives prescription medication. The purpose of this article is to inform nurses of the magnitude of opioid diversion, the nonmedical use of opioids, and opioids' inappropriate disposal. The authors propose three potential interventions in which nurses can play a critical role: teaching patients about the risks of opioid diversion, providing patients with information on the safekeeping and proper disposal of opioids, and tracking patients' analgesic use to improve our knowledge of prescription analgesic requirements for pain management. Nurses are in an ideal position to help reverse the occurrence and potentially fatal consequences of prescription opioid diversion.

Improved memory for reward cues following acute buprenorphine administration in humans.

PubMed

Syal, Supriya; Ipser, Jonathan; Terburg, David; Solms, Mark; Panksepp, Jaak; Malcolm-Smith, Susan; Bos, Peter A; Montoya, Estrella R; Stein, Dan J; van Honk, Jack

2015-03-01

In rodents, there is abundant evidence for the involvement of the opioid system in the processing of reward cues, but this system has remained understudied in humans. In humans, the happy facial expression is a pivotal reward cue. Happy facial expressions activate the brain's reward system and are disregarded by subjects scoring high on depressive mood who are low in reward drive. We investigated whether a single 0.2mg administration of the mixed mu-opioid agonist/kappa-antagonist, buprenorphine, would influence short-term memory for happy, angry or fearful expressions relative to neutral faces. Healthy human subjects (n38) participated in a randomized placebo-controlled within-subject design, and performed an emotional face relocation task after administration of buprenorphine and placebo. We show that, compared to placebo, buprenorphine administration results in a significant improvement of memory for happy faces. Our data demonstrate that acute manipulation of the opioid system by buprenorphine increases short-term memory for social reward cues. Copyright © 2015. Published by Elsevier Ltd.

Opioid analgesia on the battlefield: a retrospective review of data from Operation HERRICK.

PubMed

Lewis, Pip; Wright, C; Hooper, C

2018-04-06

Acute pain secondary to trauma is commonly encountered on the battlefield. The use of morphine to manage pain during combat has been well established since the 19th century. Despite this, there is relatively little research on analgesia use in this environment. This study aims to review the use and complications of morphine and other opioids during Operation HERRICK. A database search of the Joint Theatre Trauma Registry was completed looking for all incidences of morphine, fentanyl or naloxone use from February 2007 to September 2014. Microsoft Excel was used to analyse the results. Opioid analgesia was administered to 5801 casualties. Morphine was administered 6742 times to 3808 patients. Fentanyl was administered 9672 times to 4318 patients. Naloxone was used 18 times on 14 patients, giving a complication rate of 0.24%. Opioid doses prior to naloxone administration range from 0 to 72 mg of morphine and from 0 to 100 mcg of fentanyl. Four casualties (two local civilians and two coalition forces) received naloxone despite no recorded opioids being administered. Opium abuse was prevalent among the local population in Afghanistan, and this could explain the rationale behind two local national casualties receiving naloxone without any documented opioids being given. The use of opioids in a battlefield environment is extremely safe. Complication rates are similar to previously published data which is reassuring. The efficacy of different opioids was not covered by this study, and further analysis is required, particularly following the introduction of oral transmucosal fentanyl citrate and the availability of novel non-opioid analgesics. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Repeated aripiprazole administration attenuates cocaine seeking in a rat model of relapse.

PubMed

Feltenstein, Matthew W; Do, Phong H; See, Ronald E

2009-12-01

Aripiprazole (Abilify) is an atypical antipsychotic drug characterized by partial agonist activity at dopamine (DA) D(2)/D(3) receptors and a low side-effect profile. While we previously demonstrated that acute aripiprazole blocked the reinstatement of cocaine seeking in an animal model of relapse, clinical treatment of relapse prevention necessitates testing the effects of aripiprazole following prolonged abstinence, as well as after repeated administration during withdrawal from cocaine. We assessed the effects of repeated aripiprazole treatment on cocaine seeking after abstinence and during conditioned cue-induced and cocaine-primed reinstatement in rats. Rats self-administered intravenous cocaine paired with a light + tone stimulus for 10-14 days, followed by 2 weeks of abstinence. Following post-abstinence relapse testing, lever responding was allowed to extinguish, with subsequent reinstatement testing occurring either in the presence of the conditioned stimulus, or after a cocaine-priming injection (10 mg/kg, intraperitoneal (IP)). Following 3 or 7 days of pretreatment, rats received an injection of aripiprazole (0.25, 0.5, and 1.0 mg/kg, IP) or vehicle prior to post-abstinence relapse and reinstatement testing. Vehicle-pretreated animals showed robust cocaine seeking during relapse and reinstatement testing, an effect that was significantly attenuated by aripiprazole pretreatment, although no lasting effects were found in the absence of acute injection. These findings support the possibility that repeated aripiprazole may be an effective therapeutic agent for the prevention of relapse in abstinent cocaine users. Based on its antipsychotic profile, aripiprazole may be particularly useful for individuals diagnosed with comorbid psychoses, such as schizophrenia or bipolar disorder.

Blunted Endogenous Opioid Release Following an Oral Amphetamine Challenge in Pathological Gamblers

PubMed Central

Mick, Inge; Myers, Jim; Ramos, Anna C; Stokes, Paul R A; Erritzoe, David; Colasanti, Alessandro; Gunn, Roger N; Rabiner, Eugenii A; Searle, Graham E; Waldman, Adam D; Parkin, Mark C; Brailsford, Alan D; Galduróz, José C F; Bowden-Jones, Henrietta; Clark, Luke; Nutt, David J; Lingford-Hughes, Anne R

2016-01-01

Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability. The aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [11C]carfentanil PET with an oral amphetamine challenge. Fourteen PG and 15 healthy volunteers (HV) underwent two [11C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [11C]carfentanil binding between baseline and post-amphetamine scans (ΔBPND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [11C]carfentanil BPND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BPND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may have an important role in the pathophysiology of addictions. PMID:26552847

Opioid analgesia in mechanically ventilated children: results from the multicenter Measuring Opioid Tolerance Induced by Fentanyl study.

PubMed

Anand, Kanwaljeet J S; Clark, Amy E; Willson, Douglas F; Berger, John; Meert, Kathleen L; Zimmerman, Jerry J; Harrison, Rick; Carcillo, Joseph A; Newth, Christopher J L; Bisping, Stephanie; Holubkov, Richard; Dean, J Michael; Nicholson, Carol E

2013-01-01

To examine the clinical factors associated with increased opioid dose among mechanically ventilated children in the pediatric intensive care unit. Prospective, observational study with 100% accrual of eligible patients. Seven pediatric intensive care units from tertiary-care children's hospitals in the Collaborative Pediatric Critical Care Research Network. Four hundred nineteen children treated with morphine or fentanyl infusions. None. Data on opioid use, concomitant therapy, demographic and explanatory variables were collected. Significant variability occurred in clinical practices, with up to 100-fold differences in baseline opioid doses, average daily or total doses, or peak infusion rates. Opioid exposure for 7 or 14 days required doubling of the daily opioid dose in 16% patients (95% confidence interval 12%-19%) and 20% patients (95% confidence interval 16%-24%), respectively. Among patients receiving opioids for longer than 3 days (n = 225), this occurred in 28% (95% confidence interval 22%-33%) and 35% (95% confidence interval 29%-41%) by 7 or 14 days, respectively. Doubling of the opioid dose was more likely to occur following opioid infusions for 7 days or longer (odds ratio 7.9, 95% confidence interval 4.3-14.3; p < 0.001) or co-therapy with midazolam (odds ratio 5.6, 95% confidence interval 2.4-12.9; p < 0.001), and it was less likely to occur if morphine was used as the primary opioid (vs. fentanyl) (odds ratio 0.48, 95% confidence interval 0.25-0.92; p = 0.03), for patients receiving higher initial doses (odds ratio 0.96, 95% confidence interval 0.95-0.98; p < 0.001), or if patients had prior pediatric intensive care unit admissions (odds ratio 0.37, 95% confidence interval 0.15-0.89; p = 0.03). Mechanically ventilated children require increasing opioid doses, often associated with prolonged opioid exposure or the need for additional sedation. Efforts to reduce prolonged opioid exposure and clinical practice variation may prevent the complications of

Effects of Repeated 3,4-Methylenedioxymethamphetamine Administration on Neurotransmitter Efflux and Sensory-Evoked Discharge in the Ventral Posterior Medial ThalamusS⃞

PubMed Central

Starr, M. A.; Page, M. E.

2012-01-01

3,4-Methylenedioxymethamphetamine (MDMA) is known to enhance tactile sensory perception, an effect that contributes to its popularity as a recreational drug. The neurophysiological basis for the effects of MDMA on somatosensation are unknown. However, MDMA interactions with the serotonin transporter (SERT) and subsequent enhancement of serotonin neurotransmission are well known. The rat trigeminal somatosensory system receives serotonergic afferents from the dorsal raphe nucleus. Because these fibers express SERT, they should be vulnerable to MDMA-induced effects. We found that administration of a challenge injection of MDMA (3 mg/kg i.p.) after repeated MDMA treatment (3 mg/kg per day for 4 days) elicits both serotonin and norepinephrine efflux in the ventral posterior medial (VPM) thalamus of Long-Evans hooded rats, the main relay along the lemniscal portion of the rodent trigeminal somatosensory pathway. We evaluated the potential for repeated MDMA administration to modulate whisker-evoked discharge of individual neurons in this region. After surgically implanting stainless steel eight-wire multichannel electrode bundles, we recorded spike train activity of single cells while activating the whisker pathway using a piezoelectric mechanical stimulator. We found that repeated MDMA administration increased the spontaneous firing rate but reduced both the magnitude and duration of whisker-evoked discharge in individual VPM thalamic neurons. The time course of drug action on neuronal firing patterns was generally consistent with fluctuations in neurotransmitter efflux as shown from our microdialysis studies. On the basis of these results, we propose that single use and repeated administration of MDMA may “distort,” rather than enhance, tactile experiences in humans, in part, by disrupting normal spike firing patterns through somatosensory thalamic relay circuits. PMID:21984836

The Opioid Rotation Ratio of Hydrocodone to Strong Opioids in Cancer Patients

PubMed Central

Yennurajalingam, Sriram; Desai, Hem; Reddy, Suresh; de la Cruz, Maxine; Wu, Jimin; Liu, Diane; Rodriguez, Eden Mae; Waletich, Jessica; Shin, Seong Hoon; Gayle, Vicki; Patel, Pritul; Dalal, Shalini; Vidal, Marieberta; Tanco, Kimberson; Arthur, Joseph; Tallie, Kimmie; Williams, Janet; Silvestre, Julio; Bruera, Eduardo

2014-01-01

Purpose. Cancer pain management guidelines recommend initial treatment with intermediate-strength analgesics such as hydrocodone and subsequent escalation to stronger opioids such as morphine. There are no published studies on the process of opioid rotation (OR) from hydrocodone to strong opioids in cancer patients. Our aim was to determine the opioid rotation ratio (ORR) of hydrocodone to morphine equivalent daily dose (MEDD) in cancer outpatients. Patients and Methods. We reviewed the records of consecutive patient visits at our supportive care center in 2011–2012 for OR from hydrocodone to stronger opioids. Data regarding demographics, Edmonton Symptom Assessment Scale (ESAS), and MEDD were collected from patients who returned for follow-up within 6 weeks. Linear regression analysis was used to estimate the ORR between hydrocodone and MEDD. Successful OR was defined as 2-point or 30% reduction in the pain score and continuation of the new opioid at follow-up. Results. Overall, 170 patients underwent OR from hydrocodone to stronger opioid. The median age was 59 years, and 81% had advanced cancer. The median time between OR and follow-up was 21 days. We found 53% had a successful OR with significant improvement in the ESAS pain and symptom distress scores. In 100 patients with complete OR and no worsening of pain at follow-up, the median ORR from hydrocodone to MEDD was 1.5 (quintiles 1–3: 0.9–2). The ORR was associated with hydrocodone dose (r = −.52; p < .0001) and was lower in patients receiving ≥40 mg of hydrocodone per day (p < .0001). The median ORR of hydrocodone to morphine was 1.5 (n = 44) and hydrocodone to oxycodone was 0.9 (n = 24). Conclusion. The median ORR from hydrocodone to MEDD was 1.5 and varied according to hydrocodone dose. PMID:25342316

Investigational opioid antagonists for treating opioid-induced bowel dysfunction.

PubMed

Mozaffari, Shilan; Nikfar, Shekoufeh; Abdollahi, Mohammad

2018-03-01

Opioids have been highlighted for their role in pain relief among cancer and non-cancer patients. Novel agents have been investigated to reduce opioid-induced constipation (OIC) as the main adverse effect that may lead to treatment discontinuation. Development of peripherally acting mu-opioid receptor antagonists (PAMORA) has resulted in a novel approach to preserve the efficacy of pain control along with less OIC. Areas covered: Clinical evidence for investigational PAMORAs was reviewed and clinical trials on investigational agents to reduce OIC were included. TD-1211 is currently being evaluated in Phase II clinical trial. Oxycodone-naltrexone and ADL-5945 went through Phase III clinical trials, but have been discontinued. Expert opinion: There is a substantial need to develop agents with specific pharmacokinetic properties to meet the needs of patients with underlying diseases. Holding the efficacy of a medicine with the highest selectivity on targeted receptors and the least adverse effects is the main approach in upcoming investigations to improve patients' quality of life (QoL). Novel agents to reduce opioid-induced bowel dysfunction (OIBD) that do not reverse peripherally mediated pain analgesia are of great interest. Direct comparison of available agents in this field is lacking in the literature.

Opioid management of pain: the impact of the prescription opioid abuse epidemic.

PubMed

Rauenzahn, Sherri; Del Fabbro, Egidio

2014-09-01

The greater emphasis on pain control over the last decade has been accompanied by increased opioid prescriptions and an epidemic of opioid abuse. This review examines the financial, regulatory, and clinical practice impact of the epidemic, the factors contributing to its growth, and strategies that may counter this public health crisis. Despite the call for urgent practice change and the introduction of new initiatives such as electronic prescription monitoring and additional education programs for providers and patients, the evidence for improved outcomes are limited. There are also concerns that some patients may suffer from underprescribing as an unintended consequence of more stringent state and federal regulations. There is consensus that some form of universal precautions should be adopted for all patients, including those being treated for cancer-related pain, in order to better identify and manage those at risk of opioid abuse. The opioid prescription abuse epidemic has precipitated calls for increased regulation. Clinicians can improve patient care and diminish opioid abuse by identifying patient risk factors, increasing vigilance and structure for those at risk, and providing interdisciplinary care for any patients coping in a maladaptive manner.

Kratom: a dangerous player in the opioid crisis.

PubMed

Tayabali, Khadija; Bolzon, Colin; Foster, Paul; Patel, Janki; Kalim, Mohammad Omar

2018-01-01

Kratom use as a herbal supplement is on the rise in the United States, with reported medical outcomes and lethal effects suggesting a public health threat. Even though the Drug Enforcement Administration has included kratom on its drugs of concern list and the FDA has published a press release to identify it as an opioid with a potential for abuse, its therapeutic and side effects are still not well defined in the literature. Here, we present a case of a 32-year-old man with a history of kratom use who became acutely ill with a brief prodromal illness, followed by jaundice and elevated liver enzymes showing a cholestatic picture, and his successful treatment. In this case, we emphasize the need for awareness of kratom exposure as a key contributor in the expansion of the opioid crisis, with therapeutic benefits earned at the expense of potentially lethal side effects.

The association between negative affect and prescription opioid misuse in patients with chronic pain: The mediating role of opioid craving

PubMed Central

Martel, MO; Dolman, AJ; Edwards, RR; Jamison, RN; Wasan, AD

2013-01-01

Over the past decade, considerable research has accumulated showing that chronic pain patients experiencing high levels of negative affect (i.e., anxiety, depression) are at increased risk for prescription opioid misuse. The primary objective of the present study was to examine the factors that underlie the association between negative affect (NA) and prescription opioid misuse among patients with chronic pain. In this study, 82 patients with chronic musculoskeletal pain being prescribed opioid medication completed the Current Opioid Misuse Measure (COMM), a well-validated self-report questionnaire designed to assess prescription opioid misuse. Patients were also asked to complete self-report measures of pain intensity, NA, and opioid craving. A bootstrapped multiple mediation analysis was used to examine the mediating role of patients’ pain intensity and opioid craving in the association between NA and prescription opioid misuse. Consistent with previous research, we found a significant association between NA and prescription opioid misuse. Interestingly, results revealed that opioid craving, but not pain intensity, mediated the association between NA and opioid misuse. Discussion addresses the potential psychological and neurobiological factors that might contribute to the inter-relationships between NA, opioid craving, and prescription opioid misuse in patients with pain. The clinical implications of our findings are also discussed. PMID:24295876

Use of Opioid Analgesics in Older Australians.

PubMed

Veal, Felicity C; Bereznicki, Luke R E; Thompson, Angus J; Peterson, Gregory M

2015-08-01

To identify potential medication management issues associated with opioid use in older Australians. Retrospective cross-sectional review of the utilization of analgesics in 19,581 people who underwent a medication review in Australia between 2010 and 2012. Australian residents living in the community deemed at risk for adverse medication outcomes or any resident living fulltime in an aged care facility. Patient characteristics in those taking regularly dosed opioids and not and those taking opioid doses >120 mg and ≤120 mg MEQ/day were compared. Multivariable binary logistic regression was used to analyze the association between regular opioid and high dose opioid usage and key variables. Additionally, medication management issues associated with opioids were identified. Opioids were taken by 31.8% of patients, with 22.1% taking them regularly. Several major medication management issues were identified. There was suboptimal use of multimodal analgesia, particularly a low use of non-opioid analgesics, in patients taking regular opioids. There was extensive use (45%) of concurrent anxiolytics/hypnotics among those taking regular opioid analgesics. Laxative use in those prescribed opioids regularly was low (60%). Additionally, almost 12% of patients were taking doses of opioid that exceeded Australian recommendations. A significant evidence to practice gap exists regarding the use of opioids amongst older Australians. These findings highlight the need for a quick reference guide to support prescribers in making appropriate decisions regarding pain management in older patients with persistent pain. This should also be combined with patient and caregiver education about the importance of regular acetaminophen to manage persistent pain. Wiley Periodicals, Inc.

From morphine clinics to buprenorphine: regulating opioid agonist treatment of addiction in the United States.

PubMed

Jaffe, Jerome H; O'Keeffe, Charles

2003-05-21

The practice of prescribing opioid drugs for opioid dependent patients in the U.S. has been subjected to special government scrutiny for almost 100 years. From 1920 until 1964, doctors who used opioids to treat addicts risked federal and/or state criminal prosecution. Although that period ended when oral methadone maintenance was established as legitimate medical practice, public concern about methadone diversion and accidental overdose fatalities, combined with political pressure from both hostile bureaucracies and groups committed to drug-free treatments, led to the development of unprecedented and detailed Food and Drug Administration (FDA) regulations that specified the manner in which methadone (and later, levo-alpha-acetyl methadol, or levomethadyl acetate, (LAAM)) could be provided. In 1974, Congress gave the Drug Enforcement Administration (DEA) additional oversight of methadone treatment programs. Efforts to liberalize the FDA regulations over the past 30 years have been resisted by both the DEA and existing treatment providers. Additional flexibility for clinicians may evolve from the most recent effort to create an accreditation system to replace some of the FDA regulations. The development of buprenorphine, a partial opioid agonist, as an effective treatment for opioid addiction reopened the possibility for having a less burdensome oversight process, especially because of its reduced toxicity if ingested by non-tolerant individuals. New legislation, the Drug Addiction Treatment Act (DATA) of 2000, created an opportunity for clinicians with special training to be exempted from both federal methadone regulations and the requirement to obtain a special DEA license when using buprenorphine to treat addicts. Some details of how the DATA was developed, moved through Congress, and signed into law are described.

Prescription of Opioid and Non-opioid Analgesics for Dental Care in Emergency Departments: Findings from the National Hospital Ambulatory Medical Care Survey

PubMed Central

Okunseri, Christopher; Okunseri, Elaye; Xiang, Qun; Thorpe, Joshua M.; Szabo, Aniko

2014-01-01

Objective The aim of this study was to examine trends and associated factors in the prescription of opioid analgesics, non-opioid analgesics, opioid and non-opioid analgesic combinations and no analgesics by emergency physicians for nontraumatic dental condition (NTDC)-related visits. Our secondary aim was to investigate whether race/ethnicity is a possible predictor of receiving a prescription for either type of medication for NTDC visits in emergency departments (EDs) after adjustment for potential covariates. Methods We analyzed data from the National Hospital Ambulatory Medical Care Survey for 1997–2000 and 2003–2007, and used multinomial multivariate logistic regression to estimate the probability of receiving a prescription for opioid analgesics, non-opioid analgesics, or a combination of both compared to receiving no analgesics for NTDC-related visits. Results During 1997–2000 and 2003–2007, prescription of opioid analgesics and combinations of opioid and non-opioid analgesics increased and that of no analgesics decreased over time. The prescription rates for opioid analgesics, non-opioid analgesics, opioid and non-opioid analgesic combinations and no analgesics for NTDC-related visits in EDs were 43%, 20%, 12% and 25% respectively. Majority of patients categorized as having severe pain received prescriptions for opioids for NTDC-related visits in EDs. After adjusting for covariates, patients with self-reported dental reasons for visit and severe pain had a significantly higher probability of receiving prescriptions for opioid analgesics and opioid and non-opioid analgesic combinations. Conclusion Prescription of opioid analgesics increased over time. ED physicians were more likely to prescribe opioid analgesics and opioid and non-opioid analgesic combinations for NTDC-related visits with reported severe pain. PMID:24863407

Geographic and specialty distribution of US physicians trained to treat opioid use disorder.

PubMed

Rosenblatt, Roger A; Andrilla, C Holly A; Catlin, Mary; Larson, Eric H

2015-01-01

The United States is experiencing an epidemic of opioid-related deaths driven by excessive prescribing of opioids, misuse of prescription drugs, and increased use of heroin. Buprenorphine-naloxone is an effective treatment for opioid use disorder and can be provided in office-based settings, but this treatment is unavailable to many patients who could benefit. We sought to describe the geographic distribution and specialties of physicians obtaining waivers from the Drug Enforcement Administration (DEA) to prescribe buprenorphine-naloxone to treat opioid use disorder and to identify potential shortages of physicians. We linked physicians authorized to prescribe buprenorphine on the July 2012 DEA Drug Addiction Treatment Act (DATA) Waived Physician List to the American Medical Association Physician Masterfile to determine their age, specialty, rural-urban status, and location. We then mapped the location of these physicians and determined their supply for all US counties. Sixteen percent of psychiatrists had received a DEA DATA waiver (41.6% of all physicians with waivers) but practiced primarily in urban areas. Only 3.0% of primary care physicians, the largest group of physicians in rural America, had received waivers. Most US counties therefore had no physicians who had obtained waivers to prescribe buprenorphine-naloxone, resulting in more than 30 million persons who were living in counties without access to buprenorphine treatment. In the United States opioid use and related unintentional lethal overdoses continue to rise, particularly in rural areas. Increasing access to office-based treatment of opioid use disorder--particularly in rural America--is a promising strategy to address rising rates of opioid use disorder and unintentional lethal overdoses. © 2015 Annals of Family Medicine, Inc.

[The endogenous opioid system and drug addiction].

PubMed

Maldonado, R

2010-01-01

Drug addiction is a chronic brain disorder leading to complex adaptive changes within the brain reward circuits. Several neurotransmitters, including the endogenous opioid system are involved in these changes. The opioid system plays a pivotal role in different aspects of addiction. Thus, opioid receptors and endogenous opioid peptides are largely distributed in the mesolimbic system and modulate dopaminergic activity within the reward circuits. Opioid receptors and peptides are selectively involved in several components of the addictive processes induced by opioids, cannabinoids, psychostimulants, alcohol and nicotine. This review is focused on the contribution of each component of the endogenous opioid system in the addictive properties of the different drugs of abuse. Copyright 2010 Elsevier Masson SAS. All rights reserved.

Effects of opioid- and non-opioid analgesics on responses to psychosocial stress in humans.

PubMed

Bershad, Anya K; Miller, Melissa A; Norman, Greg J; de Wit, Harriet

2018-06-01

Both preclinical and clinical evidence suggests that the endogenous opioid system is involved in responses to stress. For example, in animal models opioid agonists reduce isolation distress whereas opioid antagonists increase isolation distress. We recently reported that the mixed mu agonist and kappa antagonist buprenorphine dampened responses to acute psychosocial stress in humans. Now we extend this to study the effects of a pure mu-opioid agonist, hydromorphone, and a non-opioid analgesic, acetaminophen, on response to social stress. We compared the effect of hydromorphone (2 and 4 mg), acetaminophen (1000 mg) to a placebo using a between subject design. Healthy adult volunteers were randomly assigned to receive placebo (N = 13), 2 mg hydromorphone (N = 12), 4 mg hydromorphone (N = 12), or 1000 mg acetaminophen (paracetamol; N = 13) under double-blind conditions before undergoing a stress task or a control task on two separate sessions. The stress task, consisting of a standardized speaking task and the non-stressful control task were presented in counterbalanced order. Dependent measures included mood ratings, subjective appraisal of the stress (or no-stress) task, salivary cortisol, pupil diameter, heart rate, and blood pressure. The stress task produced its expected increase in heart rate, blood pressure, salivary cortisol, pupil diameter, and subjective ratings of anxiety and negative mood. Hydromorphone dose-dependently dampened cortisol responses to stress, and decreased ratings of how "challenging" participants found the task. Acetaminophen did not affect physiological responses, but, like hydromorphone, decreased ratings of how "challenging" the task was. The hydromorphone results support the idea that the mu-opioid system is involved in physiological responses to acute stress in humans, in line with results from preclinical studies. The non-opioid analgesic acetaminophen did not dampen physiological responses, but did reduce

Will abuse-deterrent formulations of opioid analgesics be successful in achieving their purpose?

PubMed

Bannwarth, Bernard

2012-09-10

During the last 2 decades, there has been a dramatic increase in the use of strong opioids for chronic non-cancer pain. This increase has been accompanied by a steep increase in abuse, misuse, and both fatal and non-fatal overdoses involving prescription opioids. The situation is already alarming in the US. Prescription opioid-related harm is a complex, multifactorial issue that requires a multifaceted solution. In this respect, formulations of opioid analgesics designed to resist or deter abuse may be a useful component of a comprehensive opioid risk minimization programme. Such formulations have or are being developed. Abuse-resistant opioids include those that use some kind of physical barrier to prevent tampering with the formulation. Abuse-deterrent opioids are not necessarily resistant to tampering, but contain substances that are designed to make the formulation less attractive to abusers. This article focuses on two products intended to deter abuse that were reviewed by the US Food and Drug Administration (FDA). The first (Embeda®) consists of extended-release morphine with sequestered naltrexone, an opioid antagonist that is released if the tablet is compromised by chewing or crushing. Although Embeda® exhibited abuse-deterrent features, its label warns that it can be abused in a manner similar to other opioid agonists. Furthermore, tampering with Embeda® will result in the release of naltrexone, which may precipitate withdrawal in opioid-tolerant individuals. In March 2011, all dosage forms of Embeda® were recalled because the product failed to meet routine stability standards, and its return date to the market is currently unknown. The second product (Acurox®) was intended to be both tamper resistant and abuse deterrent. It consisted of an immediate-release oxycodone tablet with subtherapeutic niacin as an aversive agent and used a gel-forming ingredient designed to inhibit inhalation and prevent extraction of the drug for injection. The new drug

Medication for Opioid Use Disorder After Nonfatal Opioid Overdose and Association With Mortality: A Cohort Study.

PubMed

Larochelle, Marc R; Bernson, Dana; Land, Thomas; Stopka, Thomas J; Wang, Na; Xuan, Ziming; Bagley, Sarah M; Liebschutz, Jane M; Walley, Alexander Y

2018-06-19

Opioid overdose survivors have an increased risk for death. Whether use of medications for opioid use disorder (MOUD) after overdose is associated with mortality is not known. To identify MOUD use after opioid overdose and its association with all-cause and opioid-related mortality. Retrospective cohort study. 7 individually linked data sets from Massachusetts government agencies. 17 568 Massachusetts adults without cancer who survived an opioid overdose between 2012 and 2014. Three types of MOUD were examined: methadone maintenance treatment (MMT), buprenorphine, and naltrexone. Exposure to MOUD was identified at monthly intervals, and persons were considered exposed through the month after last receipt. A multivariable Cox proportional hazards model was used to examine MOUD as a monthly time-varying exposure variable to predict time to all-cause and opioid-related mortality. In the 12 months after a nonfatal overdose, 2040 persons (11%) enrolled in MMT for a median of 5 months (interquartile range, 2 to 9 months), 3022 persons (17%) received buprenorphine for a median of 4 months (interquartile range, 2 to 8 months), and 1099 persons (6%) received naltrexone for a median of 1 month (interquartile range, 1 to 2 months). Among the entire cohort, all-cause mortality was 4.7 deaths (95% CI, 4.4 to 5.0 deaths) per 100 person-years and opioid-related mortality was 2.1 deaths (CI, 1.9 to 2.4 deaths) per 100 person-years. Compared with no MOUD, MMT was associated with decreased all-cause mortality (adjusted hazard ratio [AHR], 0.47 [CI, 0.32 to 0.71]) and opioid-related mortality (AHR, 0.41 [CI, 0.24 to 0.70]). Buprenorphine was associated with decreased all-cause mortality (AHR, 0.63 [CI, 0.46 to 0.87]) and opioid-related mortality (AHR, 0.62 [CI, 0.41 to 0.92]). No associations between naltrexone and all-cause mortality (AHR, 1.44 [CI, 0.84 to 2.46]) or opioid-related mortality (AHR, 1.42 [CI, 0.73 to 2.79]) were identified. Few events among naltrexone recipients

Sustained Benefits of Exercise-based Motivational Interviewing, but Only among Nonusers of Opioids in Patients with Fibromyalgia.

PubMed

Kim, Sunghye; Slaven, James E; Ang, Dennis C

2017-04-01

Given the known side effects of opioids and their potential effects on cognition, we sought to evaluate the benefits of motivational interviewing (MI) to promote physical activity on 2 subsets of participants with fibromyalgia (FM): nonusers and users of opioids. This was a secondary data analysis of a 36-week randomized controlled trial to assess the efficacy of MI to promote physical activity among participants with FM. Participants were randomized to 1 of 2 treatment arms: 6 phone-based MI sessions (n = 107) or 6 sessions of FM self-management instructions [attention control (AC), n = 109]. The primary outcomes were changes in physical function (Medical Outcomes Study Short Form-36), pain severity (Brief Pain Inventory), global FM symptom severity (Fibromyalgia Impact Questionnaire), and the amount of light to moderate physical activity (LMPA) from baseline to each followup visit. At study entry, subjects were categorized as opioid nonusers versus users. Repeated measures ANOVA was used to assess treatment effects adjusting for potential confounders. Of the 216 participants, 145 (67%) were nonusers and 71 (33%) were opioid users. Among nonusers, MI was associated with improved physical function, reduced pain severity, and global FM severity, and increased LMPA at 6-month followup. Among opioid users, there were no significant differences in any outcome measures between the MI and AC groups. Exercise-based MI was associated with sustained clinical benefits 6 months after completion of therapy, but only for those who were not taking opioids.

Dysregulation of endogenous opioid emotion regulation circuitry in major depression in women.

PubMed

Kennedy, Susan E; Koeppe, Robert A; Young, Elizabeth A; Zubieta, Jon-Kar

2006-11-01

There is extensive evidence implicating dysfunctions in stress responses and adaptation to stress in the pathophysiological mechanism of major depressive disorder (MDD) in humans. Endogenous opioid neurotransmission activating mu-opioid receptors is involved in stress and emotion regulatory processes and has been further implicated in MDD. To examine the involvement of mu-opioid neurotransmission in the regulation of affective states in volunteers with MDD and its relationship with clinical response to antidepressant treatment. Measures of mu-opioid receptor availability in vivo (binding potential [BP]) were obtained with positron emission tomography and the mu-opioid receptor selective radiotracer carbon 11-labeled carfentanil during a neutral state. Changes in BP during a sustained sadness challenge were obtained by comparing it with the neutral state, reflecting changes in endogenous opioid neurotransmission during the experience of that emotion. Clinics and neuroimaging facilities at a university medical center. Fourteen healthy female volunteers and 14 individually matched patient volunteers diagnosed with MDD were recruited via advertisement and through outpatient clinics. Sustained neutral and sadness states, randomized and counterbalanced in order, elicited by the cued recall of an autobiographical event associated with that emotion. Following imaging procedures, patients underwent a 10-week course of treatment with 20 to 40 mg of fluoxetine hydrochloride. Changes in mu-opioid receptor BP during neutral and sustained sadness states, negative and positive affect ratings, plasma cortisol and corticotropin levels, and clinical response to antidepressant administration. The sustained sadness condition was associated with a statistically significant decrease in mu-opioid receptor BP in the left inferior temporal cortex of patients with MDD and correlated with negative affect ratings experienced during the condition. Conversely, a significant increase in mu-opioid

Assessment of palliative care team activities--survey of medications prescribed immediately before and at the beginning of opioid usage.

PubMed

Myotoku, Michiaki; Murayama, Yoko; Nakanishi, Akiko; Hashimoto, Norio; Koyama, Fumiko; Irishio, Keiko; Kawaguchi, Syunichi; Yamaguchi, Seiji; Ikeda, Kenji; Hirotani, Yoshihiko

2008-02-01

We established the Terminal Care Study Group, consisting of physicians, pharmacists, and nurses, in September 2001, and developed the group into the Palliative Care Team. We have surveyed the state of concomitant medications immediately before and at the beginning of opioid usage (except injections) to assess the role of the Palliative Care Team. The survey period was 3 years from October 1, 2002 to September 30, 2005. While the frequency of the prescription of non-steroidal anti-inflammatory drugs (NSAIDs), laxatives, or antiemetics before the beginning of opioid administration did not differ significantly among the 3 periods, that at the beginning of opioid administration increased significantly in 2003 compared with 2002, and increased further in 2004. Many of the drugs used were those that were recommended in our cancer pain management program. Thus, the activities of the Palliative Care Team are considered to have led to proper measures for the control of the major adverse effects of opioids such as constipation and nausea/vomiting in addition to pain control in accordance with the WHO's pain ladder, and also contributed to improvements of the patients' QOL.

Factors associated with opioid dose increases: a chart review of patients’ first year on long-term opioids

PubMed Central

Bautista, Christopher A.; Iosif, Ana-Maria; Wilsey, Barth L.; Melnikow, Joy A.; Crichlow, Althea; Henry, Stephen G.

2016-01-01

OBJECTIVE To examine encounter-level factors associated with opioid dose increases during patients’ first year on opioid therapy for chronic pain. DESIGN Case-control study analyzing all opioid prescriptions for patients with chronic pain during their first year after opioid initiation. Cases were patients who experienced an overall dose escalation of ≥30 mg morphine equivalents over the 1-year period; controls did not experience overall dose escalation. Main measures were encounter type; opioid dose change; documented prescribing rationale; documentation of guideline-concordant opioid prescribing practices. Two coders reviewed all encounters associated with opioid prescriptions. Analysis of factors associated with dose increases and provider documentation of prescribing rationale was conducted using multiple logistic regression. RESULTS 674 encounters were coded for 66 patients (22 cases, 44 controls). Fifty-three percent of opioid prescriptions were associated with telephone encounters; 13% were associated with email encounters. No prescribing rationale was documented for 43% of all opioid prescriptions and 25% of dose increases. Likelihood of dose increase and documentation of prescribing rationale did not significantly differ for cases versus controls. Compared to face-to-face encounters, dose increases were significantly less likely for telephone (OR 0.18, 95%CI 0.11 – 0.28) and email (OR 0.23, 95%CI 0.12 – 0.47) encounters; documentation of prescribing rationale was significantly more likely for email (OR 5.06, 95%CI 1.87–13.72) and less likely for telephone (OR 0.30, 95%CI 0.18–0.51) encounters. CONCLUSION Most opioid prescriptions were written without face-to-face encounters. One quarter of dose increases contained no documented prescribing rationale. Documented encounter-level factors were not significantly associated with overall opioid dose escalation. PMID:27477581

Efficacy of opioids versus placebo in chronic pain: a systematic review and meta-analysis of enriched enrollment randomized withdrawal trials.

PubMed

Meske, Diana S; Lawal, Oluwadolapo D; Elder, Harrison; Langberg, Valerie; Paillard, Florence; Katz, Nathaniel

2018-01-01

Opioids have been used for millennia for the treatment of pain. However, the long-term efficacy of opioids to treat chronic non-cancer pain continues to be debated. To evaluate opioids' efficacy in chronic non-cancer pain, we performed a meta-analysis of published clinical trials for μ-opioid receptor agonists performed for US Food and Drug Administration approval. MEDLINE and Cochrane trial register were searched for enriched enrollment randomized withdrawal studies (before June 2016). Selection criteria included: adults, ≥10 subjects per arm, any chronic pain condition, double-blind treatment period lasting ≥12 weeks, and all μ-agonist opioids approved in the USA. Fifteen studies met criteria. Opioid efficacy was statistically significant ( p <0.001) versus placebo for pain intensity (standardized mean difference: -0.416), ≥30% and ≥50% improvement in pain (risk difference: 0.166 and 0.137), patient global impression of change (0.163), and patient global assessment of study medication (0.194). There were minor benefits on physical function and no effect on mental function. Opioids are efficacious in the treatment of chronic non-cancer pain for up to 3 months in randomized controlled trials. This should be considered, alongside data on opioid safety, in the use of opioids for the treatment of chronic pain.

Probuphine® (buprenorphine implant): a promising candidate in opioid dependence

PubMed Central

Barnwal, Preeti; Das, Saibal; Mondal, Somnath; Ramasamy, Anand; Maiti, Tanay; Saha, Arunava

2016-01-01

Opioid dependence leads to physical dependence and addiction which finally results in profound medical, psychological and social dysfunction. One of the useful medications for opioid dependence is buprenorphine, the partial opioid agonist, which is used alone or in combination with naloxone. However, buprenorphine is the victim of its own success due to its illicit use and accidental poisoning in children. Also, buprenorphine typically requires daily self-administration and its effectiveness heavily depends on patient adherence. So, poor treatment adherence results in ineffective treatment manifesting as craving and withdrawal symptoms. Short-term use of buprenorphine in opioid dependence is also often followed by relapse. Buprenorphine when used sublingually often results in inadequate or fluctuating blood concentrations and poorer treatment retention compared with methadone. All of these led to the development of Probuphine®, a polymeric matrix composed of ethylene vinyl acetate and buprenorphine in the form of implants, that are implanted subdermally in office practice and deliver the active drug over 6 months. Buprenorphine release from such implant is fairly consistent, avoiding plasma peaks and troughs, and the implant is also reported to be safe. In this review article, we have highlighted these aspects of treatment of opioid addiction, stressing on the pharmacology of buprenorphine and Probuphine®, and relevant clinical trials addressing the efficacy and safety of Probuphine®. This sustained-release implantable formulation of buprenorphine has the potential to be a suitable alternative to daily or alternate day sublingual buprenorphine which can thereby eliminate the need for daily supervision, minimizing fluctuations in plasma concentrations, and allowing these patients to reduce clinic or pharmacy visits. PMID:28348732

Probuphine® (buprenorphine implant): a promising candidate in opioid dependence.

PubMed

Barnwal, Preeti; Das, Saibal; Mondal, Somnath; Ramasamy, Anand; Maiti, Tanay; Saha, Arunava

2017-03-01

Opioid dependence leads to physical dependence and addiction which finally results in profound medical, psychological and social dysfunction. One of the useful medications for opioid dependence is buprenorphine, the partial opioid agonist, which is used alone or in combination with naloxone. However, buprenorphine is the victim of its own success due to its illicit use and accidental poisoning in children. Also, buprenorphine typically requires daily self-administration and its effectiveness heavily depends on patient adherence. So, poor treatment adherence results in ineffective treatment manifesting as craving and withdrawal symptoms. Short-term use of buprenorphine in opioid dependence is also often followed by relapse. Buprenorphine when used sublingually often results in inadequate or fluctuating blood concentrations and poorer treatment retention compared with methadone. All of these led to the development of Probuphine®, a polymeric matrix composed of ethylene vinyl acetate and buprenorphine in the form of implants, that are implanted subdermally in office practice and deliver the active drug over 6 months. Buprenorphine release from such implant is fairly consistent, avoiding plasma peaks and troughs, and the implant is also reported to be safe. In this review article, we have highlighted these aspects of treatment of opioid addiction, stressing on the pharmacology of buprenorphine and Probuphine®, and relevant clinical trials addressing the efficacy and safety of Probuphine®. This sustained-release implantable formulation of buprenorphine has the potential to be a suitable alternative to daily or alternate day sublingual buprenorphine which can thereby eliminate the need for daily supervision, minimizing fluctuations in plasma concentrations, and allowing these patients to reduce clinic or pharmacy visits.

Creating opioid dependence in the emergency department.

PubMed

Upadhye, Suneel

2018-01-01

Clinical question What is the risk of creating opioid dependence from an ED opioid prescription? Article chosen Barnett ML, Olenski AR, Jena AB. Opioid-prescribing patterns of emergency physicians and risk of long-term use. N Engl J Med 2017;376:663-73, doi:10.1056/NEJMsa1610524. This study examined the risk of creating long-term opioid dependence from a prescription written in an opioid-naive patient in the ED.

Effects on Hedonic Feeding, Energy Expenditure and Balance of the Non-opioid Peptide DYN-A2-17.

PubMed

Alvarez, B; Barrientos, T; Gac, L; Teske, J A; Perez-Leighton, C E

2018-02-10

The dynorphin (DYN) peptide family includes opioid and non-opioid peptides, yet the physiological role of the non-opioid DYN peptides remains poorly understood. Recent evidence shows that administering the non-opioid peptide DYN-A 2-17 into the paraventricular hypothalamic nucleus (PVN) simultaneously increased short-term intake of standard rodent chow and spontaneous physical activity (SPA). The present studies aimed to expand upon the mechanisms and role of DYN-A 2-17 on food intake and energy expenditure. Injection of DYN-A 2-17 in PVN increased SPA, energy expenditure and wheel running in the absence of food. Repeated DYN-A 2-17 injection in PVN increased short-term chow intake, but this effect habituated over time and failed to alter cumulative food intake, body weight or adiposity. Pre-treatment with a CRF receptor antagonist into PVN blocked the effects of DYN-A 2-17 on food intake while injection of DYN-A 2-17 in PVN increased plasma ACTH. Finally, as DYN peptides are co-released with orexin peptides, we compared the effects of DYN-A 2-17 to orexin-A and the opioid peptide DYN-A 1-13 on food choice and intake in PVN when palatable snacks and chow were available. DYN-A 1-13 selectively increased intake of palatable snacks. DYN-A 2-17 and orexin-A decreased palatable snack intake while orexin-A also increased chow intake. These findings demonstrate that the non-opioid peptide DYN-A 2-17 acutely regulates physical activity, energy expenditure and food intake without long-term effects on energy balance. These data also propose different roles of opioid, non-opioid DYN and orexin peptides on food choice and intake when palatable and non-palatable food options are available. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Using prescription monitoring program data to characterize out-of-pocket payments for opioid prescriptions in a state Medicaid program.

PubMed

Hartung, Daniel M; Ahmed, Sharia M; Middleton, Luke; Van Otterloo, Joshua; Zhang, Kun; Keast, Shellie; Kim, Hyunjee; Johnston, Kirbee; Deyo, Richard A

2017-09-01

Out-of-pocket payment for prescription opioids is believed to be an indicator of abuse or diversion, but few studies describe its epidemiology. Prescription drug monitoring programs (PDMPs) collect controlled substance prescription fill data regardless of payment source and thus can be used to study this phenomenon. To estimate the frequency and characteristics of prescription fills for opioids that are likely paid out-of-pocket by individuals in the Oregon Medicaid program. Cross-sectional analysis using Oregon Medicaid administrative claims and PDMP data (2012 to 2013). Continuously enrolled nondually eligible Medicaid beneficiaries who could be linked to the PDMP with two opioid fills covered by Oregon Medicaid. Patient characteristics and fill characteristics for opioid fills that lacked a Medicaid pharmacy claim. Fill characteristics included opioid name, type, and association with indicators of high-risk opioid use. A total of 33 592 Medicaid beneficiaries filled a total of 555 103 opioid prescriptions. Of these opioid fills, 74 953 (13.5%) could not be matched to a Medicaid claim. Hydromorphone (30%), fentanyl (18%), and methadone (15%) were the most likely to lack a matching claim. The 3 largest predictors for missing claims were opioid fills that overlapped with other opioids (adjusted odds ratio [aOR] 1.37; 95% confidence interval [CI], 1.34-1.4), long-acting opioids (aOR 1.52; 95% CI, 1.47-1.57), and fills at multiple pharmacies (aOR 1.45; 95% CI, 1.39-1.52). Prescription opioid fills that were likely paid out-of-pocket were common and associated with several known indicators of high-risk opioid use. Copyright © 2017 John Wiley & Sons, Ltd.