Loperamide,the “Poor Man’s Methadone”: Brief Review

Loperamide is widely available as an inexpensive, over-the-counter remedy commonly used for management of diarrhea. Although an opioid, at therapeutic doses it acts primarily on the gastrointestinal tissues; however, larger than recommended amounts facilitate central nervous system (CNS) penetration. Such high doses of loperamide have recently gained popularity among users of opioids to manage withdrawal symptomatology and, less frequently, to achieve psychoactive effects. Chronic loperamide use can result in development of tolerance and, upon abrupt cessation of use, withdrawal. With increasing prevalence of use, side-effects are noted, one particularly being life-threatening cardiac arrhythmias. Users are often not forthcoming and routine drug screens do not detect loperamide, so providers need to be alert to such practices in order to recognize intoxication, be able to screen for use, and facilitate entry into treatment.     

Feasibility of collaborative care treatment of opioid use disorders with buprenorphine during pregnancy

Background: Medication-assisted treatment with buprenorphine or methadone is recommended for pregnant patients with opioid use disorders (OUDs) to minimize adverse maternal and neonatal outcomes. Collaborative care approaches have been successfully utilized with office-based opioid treatment with buprenorphine in primary care settings, but research is significantly limited in the obstetric setting. Our aim with this study is to demonstrate the feasibility of a collaborative care model for pregnant patients with opioid use disorder. Methods: This is a case series of 16 pregnancies in 14 women initiated on office-based opioid treatment with buprenorphine in a perinatal mental health service embedded in 2 obstetric clinics. Patients are treated by a psychiatrist alongside their prenatal care provider and followed for up to 6 months postpartum and referred to ongoing substance abuse treatment to a community prescriber. Results: The average age of the patients was 30.3 years, and an average gestational age of 23.6 weeks at the time of referral. Treatment continued until delivery in 15 (93.8%) pregnancies, with an average duration of treatment of 14.5 weeks. The majority (60%) had a cesarean delivery. Twelve (80%) infants were admitted to the Neonatal Intensive Care Unit (NICU) for monitoring or treatment of neonatal abstinence syndrome, 14 (87.5%) patients continued or resumed treatment with buprenorphine postpartum at the time of discharge from our program, and 13 (81.3%) were referred to a community prescriber. Conclusions: A collaborative care approach to buprenorphine treatment is feasible during pregnancy. Further research is needed to improve the treatment of OUD during pregnancy.     

Pharmacological maintenance treatments of opiate addiction

For people seeking treatment, the course of heroin addiction tends to be chronic and relapsing, and longer duration of treatment is associated with better outcomes. Heroin addiction is strongly associated with deviant behaviour and crime, and the objectives in treating heroin addiction have been a blend of humane support, rehabilitation, public health intervention and crime control. Reduction in street heroin use is the foundation on which all these outcomes are based. The pharmacological basis of maintenance treatment of dependent individuals is to minimize withdrawal symptoms and attenuate the reinforcing effects of street heroin, leading to reduction or cessation of street heroin use. Opioid maintenance treatment can be moderately effective in suppressing heroin use, although deviations from evidence-based approaches, particularly the use of suboptimal doses, have meant that treatment as delivered in practice may have resulted in poorer outcomes than predicted by research. Methadone treatment has been ‘programmatic’, with a one-size-fits-all approach that in part reflects the perceived need to impose discipline on deviant individuals. However, differences in pharmacokinetics and in side-effects mean that many patients do not respond optimally to methadone. Injectable diamorphine (heroin) provides a more reinforcing medication for some ‘nonresponders’ and can be a valuable option in the rehabilitation of demoralized, socially excluded individuals. Buprenorphine, a partial agonist, is a less reinforcing medication with different side-effects and less risk of overdose. Not only is it a different medication, but also it can be used in a different paradigm of treatment, office-based opioid treatment, with less structure and offering greater patient autonomy.     

阿片受体克隆研究新进展

阿片肽是一类结构相似的神经调质，通过神经系统的膜受体对疼痛起重要的调控作用。阿片受体可分为μ、δ、κ３种类型，它们之间既有相同点，又有各自不同的药理特性、解剖定位和功能特性。阿片受体克隆成功打开了将重组ＤＮＡ技术运用到受体水平的通路。本文以克隆受体为主题，集中讨论阿片受体的分子克隆和功能特性，在分子水平上对阿片肽的识别和信号转导机制做一初步探讨。     

U.S. Survey of Shared Decision Making Use for Treating Pregnant Women Presenting with Opioid Use Disorder

Background: The incidence of pregnant women with an opioid use disorder (PWOUD) at delivery has quadrupled since 1999. State-specific statutes regarding PWOUD often pose punitive measures to the mother–infant dyad, involving the child welfare and criminal justice systems. Shared decision making (SDM) assists individuals through complex health and recovery processes. Objectives: To determine use of SDM in treating PWOUD and associated factors and to quantify physicians’ review and discussion of child welfare statutes. Methods: The American College of Obstetricians and Gynecologists (ACOG) e-mailed the survey to a random sample of members, with 568 responding. Bivariate analyses to identify factors associated with each outcome were performed using Wilcoxon Rank Sum tests or Fisher’s Exact tests. Variables yielding p values < .20 were included in initial logistic regression models; the final model included only significant (<.05) variables. Results: Sixty-one percent used SDM most of the time. Logistic regression indicated that those using SDM were more likely to have had training in substance use disorder and felt prepared for caring for PWOUD; 39% reviewed statutes, and 54% discussed them with PWOUDs. Conclusion: Survey results provide evidence for patient-centered care approaches that support PWOUD involvement in treatment decision making. The SDM model provides an empowerment framework for women to be involved in the process during their pregnancies and opioid use disorder treatments. Future studies might assess the effectiveness of SDM dialogs with PWOUD and evaluate CME training and medical curricula regarding the SDM model.     

Heteromers of μ-δ opioid receptors: new pharmacology and novel therapeutic possibilities

Several studies suggest that heteromerization between μ (MOP) and δ (DOP) opioid receptors modulates the signalling properties of the individual receptors. For example, whereas activation of MOP receptors by an agonist induces G protein-mediated signalling, the same agonist induces β-arrestin-mediated signalling in the context of the MOP-DOP receptor heteromer. Moreover, heteromer-mediated signalling is allosterically modulated by a combination of MOP and DOP receptor ligands. This has implications in analgesia given that morphine-induced antinociception can be potentiated by DOP receptor ligands. Recently reagents selectively targeting the MOP-DOP receptor heteromer such as bivalent ligands, antibodies or membrane permeable peptides have been generated; these reagents are enabling studies to elucidate the contribution of endogenously expressed heteromers to analgesia as well as to the development of side-effects associated with chronic opioid use. Recent advances in drug screening technology have led to the identification of a MOP-DOP receptor heteromer-biased agonist that activates both G protein-mediated and β-arrestin-mediated signalling. Moreover, this heteromer-biased agonist exhibits potent antinociceptive activity but with reduced side-effects, suggesting that ligands targeting the MOP-DOP receptor heteromer form a basis for the development of novel therapeutics for the treatment of pain. In this review, we summarize findings regarding the biological and functional characteristics of the MOP-DOP receptor heteromer and the in vitro and in vivo properties of heteromer-selective ligands.

LINKED ARTICLES

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2     

Exploring social work student education: The effect of a harm reduction curriculum on student knowledge and attitudes regarding opioid use disorders

Background: This study evaluates the degree to which a harm reduction intervention course module impacted Master of Social Work (MSW) students’ knowledge and attitudes towards addressing opioid use disorder issues and clients. Methods: Using a mixed-methods approach, data from 124 MSW students were collected between 2011 and 2015. Students completed a 3-hour course module that focused on harm reduction philosophy and interventions specifically for opioid use disorders. Students completed pre- and posttest of the Harm Reduction Attitude Scale. Students were also engaged in focus groups to gain a better understanding of how and if their knowledge and attitudes changed. Results: Overall, attitudes towards harm reduction approaches for opioid use disorder shifted favorably following the course module. Paired t-test results show a statistically significant difference in the mean scores for pretest attitudes (M = 2.64, SD = 0.16) and posttest attitudes (M = 2.86, SD = 0.12) among social work students. This trend remained consistent despite treatment orientation and having a family history of substance use. Conclusion: Given the increased capacity for social work students to encounter clients with opioid use disorders, it is important to ensure that students are provided with relevant and accurate information related to client-centered approaches such as the harm reduction model to address opioid use disorders. Moreover, given the dearth of social work programs that have and required substance use disorder courses, it is imperative for schools of social work to ensure that students are provided with more than practical information, which is often gained during field placement.     

From education to practice: Addressing opioid misuse through health care provider training: A special issue of Substance Abuse journal

ABSTRACT

Opioid misuse may be ignored by providers who are unwilling or not confident in engaging the complex nature of substance use disorders among their patient populations. Addiction is a complex disease, and although providers often are comfortable in identifying, assessing, and treating the complex diseases of their patients, basic knowledge and skills of identification, assessment, and treatment expertise involving opioids for pain, addressing opioid misuse, and treatment of opioid use disorder are lacking. Initiatives to improve knowledge of opioid use, misuse, and opioid use disorder among health care providers are emerging. In this issue of the Substance Abuse journal, we examine the science and evidence base of educational interventions and public initiatives addressing opioid use and addiction. These initiatives include naloxone rescue awareness and programs, community-based training initiatives, and system or public health approaches to improve student, trainee, and clinician education/training revolving around opioid misuse and opioid use disorder. We call on stakeholders to fund more research to investigate and implement the proven means to educate undergraduate students, graduate trainees, and clinicians regarding pain and addiction. We also recognize the 2016 peer reviewers of our journal who have performed meritorious, volunteer service to advance the science of addiction.     

吗啡联合小剂量阿片受体拮抗剂应用研究进展

吗啡是临床常用的强效阿片类镇痛药，临床应用中出现恶心、呕吐、镇静、瘙痒、便秘、尿潴留、呼吸抑制等副作用，长期应用又出现耐受和依赖。大剂量阿片受体拮抗剂能拮抗吗啡所产生的全部效应，而小剂量的阿片受体拮抗剂不仅能减少或减轻吗啡所致的副作用，还能增强吗啡的镇痛效能。本文就小剂量阿片受体拮抗剂与吗啡的联合应用、小剂量阿片受体拮抗剂增强吗啡镇痛效能、减弱吗啡耐受和依赖的作用机制，以及拮抗副作用等方面的研究进展进行综述。     

Clinical outcomes of concomitant rifamycin and opioid therapy: A systematic review

Opioids are one of the most prescribed classes of analgesic medications. Their narrow therapeutic index and metabolism through cytochrome p450 (CYP) enzymes can result in a drug interaction when used concomitantly with rifamycins. In clinical scenarios where concurrent therapy with an opioid and a rifamycin occurs, there is no standardized guidance for managing the interaction. The objective of this review was to examine literature which evaluates the concomitant use of opioids and rifamycins with clinically relevant CYP-inducing properties. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria was performed. PubMed, Scopus, and OVID Embase were queried for studies from database inception to January 2020 related to rifamycin and opioid medications. Only full-text, peer-reviewed, English language articles addressing clinical outcomes from concomitant rifamycin and opioid therapy were included. The review isolated 12 articles for data extraction from an original 2260 citations identified. Rifampin (11; 92%) and rifabutin (2; 17%) were the rifamycins studied along with seven different opioids. Decreased effect of opioids with concomitant rifampin therapy manifested as withdrawal in numerous patients on methadone and a decreased analgesic effect from tramadol, morphine, and, most notably, oxycodone. Only the combinations of rifampin with buccal fentanyl and rifabutin with buprenorphine and methadone were found to have no clinically measurable interaction. Available literature suggests that a decrease in opioid clinical effects is appreciated with concomitant rifamycin therapy. Further research is needed to focus on specific mitigation strategies beyond opioid agent selection, such as dosing adjustment recommendations.     

Managing opioid withdrawal precipitated by buprenorphine with buprenorphine

Buprenorphine is a partial opioid agonist commonly used to treat opioid dependence. The pharmacology of buprenorphine increases the risk of a precipitated opioid withdrawal when commencing patients on buprenorphine treatment, particularly when transferring from long acting opioids (e.g. methadone). There is little documented experience regarding the management of precipitated withdrawal. In our case, a patient developed a significant precipitated opioid withdrawal following buprenorphine administration, and was able to be successfully treated in hospital with further buprenorphine. This demonstrates that rapid increases in buprenorphine dose can be used as an effective treatment for buprenorphine-induced precipitated opioid withdrawal. The use of buprenorphine to manage withdrawal then allows the individual to continue on this highly effective treatment.     

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

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.     

Opioid blockade attenuates acquisition and expression of cocaine-induced place preference conditioning in rats

Endogenous opioid systems have been implicated in experimental cocaine addiction. One aspect of this involvement may be the modulation of the motivational properties of cocaine by endogenous opioids. The present study assessed the effect of opioid blockade with naloxone (NLX) on cocaine's motivational properties using the conditioned place preference procedure. Treatment with doses of NLX that did not induce place aversion (0.01–1.0 mg/kg^–1, SC), dose-dependently attenuated place preference induced by cocaine (10 or 20 mg/kg^–1, IP). This effect of NLX was present when administered during acquisition of cocaine-induced place preference and when administered before expression of cocaine's motivational effects. These data support the notion that the (conditioned) motivational properties of cocaine are modulated through activation of opioid systems by endogenous opioid peptides. Furthermore, it is suggested that an interaction between endogenous opioid systems and dopaminergic systems in the brain might be of importance in the motivational facilitation of experimental cocaine addiction.