Fentanyl: Receptor pharmacology, abuse potential, and implications for treatment.

Opioid overdoses, many of which are attributed to use of illicit fentanyl, are currently one of the leading causes of death in the U.S. Although fentanyl has been used safely for decades in clinical settings, the widespread use of illicit fentanyl is a recent phenomenon. Starting in 2013, illicitly manufactured fentanyl and its analogs began to appear on the streets. These substances were added to or sold as heroin, often unbeknownst to the user. Because fentanyl is so potent, only small amounts are needed to produce pharmacological effects, but the margin between safe and toxic doses is narrow. Surprisingly little is known about the exact signaling mechanisms underlying fentanyl-related respiratory depression or the effectiveness of naloxone in reversing this effect. Similarly, little is known about the ability of treatment medications such as buprenorphine, methadone, or naltrexone to reduce illicit fentanyl use. The present article reviews the receptor, preclinical and clinical pharmacology of fentanyl, and how its pharmacology may predict the effectiveness of currently approved medications for treating illicit fentanyl use

Non-medical use of opioids among HIV-infected opioid dependent individuals on opioid maintenance treatment: the need for a more comprehensive approach

<p>Abstract</p> <p>Background</p> <p>Opioid maintenance treatment (OMT) has a positive impact on substance use and health outcomes among HIV-infected opioid dependent patients. The present study investigates non-medical use of opioids by HIV-infected opioid-dependent individuals treated with buprenorphine or methadone.</p> <p>Methods</p> <p>The MANIF 2000 study is a longitudinal study that enrolled a cohort of 476 HIV-infected opioid-dependent individuals. Data were collected in outpatient hospital services delivering HIV care in France. The sample comprised all patients receiving OMT (either methadone or buprenorphine) who attended at least one follow-up visit with data on adherence to OMT (N = 235 patients, 1056 visits). Non-medical use of opioids during OMT was defined as having reported use of opioids in a non-medical context, and/or the misuse of the prescribed oral OMT by an inappropriate route of administration (injection or sniffing). After adjusting for the non-random assignment of OMT type, a model based on GEE was then used to identify predictors of non-medical use of opioids.</p> <p>Results</p> <p>Among the 235 patients, 144 (61.3%) and 91 (38.9%) patients were receiving buprenorphine and methadone, respectively, at baseline. Non-medical use of opioids was found in 41.6% of visits for 83% of individual patients. In the multivariate analysis, predictors of non-medical use of opioids were: cocaine, daily cannabis, and benzodiazepine use, experience of opioid withdrawal symptoms, and less time since OMT initiation.</p> <p>Conclusions</p> <p>Non-medical use of opioids was found to be comparable in OMT patients receiving methadone or buprenorphine. The presence of opioid withdrawal symptoms was a determinant of non-medical use of opioids and may serve as a clinical indicator of inadequate dosage, medication, or type of follow-up. Sustainability and continuity of care with adequate monitoring of withdrawal symptoms and polydrug use may contribute to reduced harms from ongoing non-medical use of opioids.</p

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

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

The effects of pioglitazone, a PPARγ receptor agonist, on the abuse liability of oxycodone among nondependent opioid users

Aims: Activation of PPARγ by pioglitazone (PIO) has shown some efficacy in attenuating addictive-like responses in laboratory animals. The ability of PIO to alter the effects of opioids in humans has not been characterized in a controlled laboratory setting. The proposed investigation sought to examine the effects of PIO on the subjective, analgesic, physiological and cognitive effects of oxycodone (OXY). Methods: During this investigation, nondependent prescription opioid abusers (N = 17 completers) were maintained for 2-3 weeks on ascending daily doses of PIO (0 mg, 15 mg, 45 mg) prior to completing a laboratory session assessing the aforementioned effects of OXY [using a within-session cumulative dosing procedure (0, 10, and 20 mg, cumulative dose = 30 mg)]. Results: OXY produced typical mu opioid agonist effects: miosis, decreased pain perception, and decreased respiratory rate. OXY also produced dose-dependent increases in positive subjective responses. Yet, ratings such as: drug "liking," "high," and "good drug effect," were not significantly altered as a function of PIO maintenance dose. Discussion: These data suggest that PIO may not be useful for reducing the abuse liability of OXY. These data were obtained with a sample of nondependent opioid users and therefore may not be applicable to dependent populations or to other opioids. Although PIO failed to alter the abuse liability of OXY, the interaction between glia and opioid receptors is not well understood so the possibility remains that medications that interact with glia in other ways may show more promise

Research design considerations for clinical studies of abuse-deterrent opioid analgesics: IMMPACT recommendations

Opioids are essential to the management of pain in many patients, but they also are associated with potential risks for abuse, overdose, and diversion. A number of efforts have been devoted to the development of abuse-deterrent formulations of opioids to reduce these risks. This article summarizes a consensus meeting that was organized to propose recommendations for the types of clinical studies that can be used to assess the abuse deterrence of different opioid formulations. Due to the many types of individuals who may be exposed to opioids, an opioid formulation will need to be studied in several populations using various study designs in order to determine its abuse-deterrent capabilities. It is recommended that the research conducted to evaluate abuse deterrence should include studies assessing: (1) abuse liability; (2) the likelihood that opioid abusers will find methods to circumvent the deterrent properties of the formulation; (3) measures of misuse and abuse in randomized clinical trials involving pain patients with both low risk and high risk of abuse; and (4) post-marketing epidemiological studies

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Sustained-release naltrexone: novel treatment for opioid dependence

The devastating costs of opioid abuse and dependence underscore theneed for effective treatments for these disorders. At present, several different maintenance medications exist for treating opioid dependence, including methadone, buprenorphine and naltrexone. Of these, naltrexone is theonly one that possesses no opioid agonist effects. Instead, naltrexoneoccupies opioid receptors and prevents or reverses the effects produced by opioid agonists. Despite its clear pharmacologic effectiveness, its clinical effectiveness in treating opioid dependence has been disappointing, primarily due to non-compliance with taking the medication. However, the recent availability of sustained-release formulations of naltrexone has renewed interest in this medication. The present paper describes the development of sustained-release naltrexone formulations and discusses the clinical issues associated with their use in treating opioid dependence

Multi-informant Implementation and Intervention Outcomes of Opioid Overdose Education and Naloxone Distribution in New York City

Overdose Education and Naloxone Distribution (OEND) is an effective public health intervention to reduce opioid overdose fatalities (McDonald and Strang, Addiction 111:1177–1187, 2016). However, we know little about OEND implementation outcomes (i.e., indicators of implementation success), specifically the fidelity of training delivery, and how these may relate to intervention outcomes (i.e., indicators of the success or effectiveness of an intervention), such as overdose knowledge and attitudes. This study evaluated 16 OEND trainings conducted at different Opioid Overdose Prevention Programs in New York City. Trainees (N = 75) completed the Opioid Overdose Knowledge and Attitude Scales before and after training (intervention outcomes). Implementation outcomes were fidelity (competence and adherence of the trainer, N = 10; modified Fidelity Checklist) and acceptability of OEND (Acceptability of Intervention Measure), assessed from multiple perspectives (trainees, trainers, and an independent observer). Trainees’ overdose knowledge, t(71) = − 8.12, p < 0.001, 95% CI [− 6.54, − 3.96], and attitudes, t(65) = − 6.85, p < 0.001, 95% CI [− 0.59, − 0.33], improved significantly from pre- to post-training. Stepwise multiple regression models indicated that adherence of the trainer rated from the observer perspective added significantly to the prediction of changes in overdose knowledge, F(1, 67) = 9.81, p = 0.003, and explained 13% of the variance in outcome. However, fidelity measures from the perspective of trainees or trainers and acceptability of OEND were not associated with changes in trainees’ overdose knowledge or attitudes. OEND implementation outcomes and their relationship with intervention outcomes differed depending on the role of the fidelity rater in relation to the intervention. Specifically, our findings indicate that fidelity should be measured from an independent perspective (i.e., an individual who is experienced with fidelity rating but not directly involved in the intervention)