•Illicit fentanyl is sold as an adulterant to heroin and other drugs. The extent to which fentanyl alone is sold or sought out by drug users is unclear.•Fentanyl is a potent mu opioid agonist with ...high efficacy. Compared to morphine, it may produce greater activation of beta-arrestin complexes.•Naloxone and naltrexone antagonize the effects of most commonly abused opioids, including fentanyl, through a competitive interaction.•Opioid cross-tolerance is smaller to opioids with high compared to low efficacy.•Research on the optimal doses and regimens of naltrexone, methadone, and buprenorphine for treating illicit fentanyl use is urgently needed.
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.
Vaccines offer a promising therapeutic strategy to treat substance use disorders (SUD). Vaccines have shown extensive preclinical proof of selectivity, safety, and efficacy against opioids, nicotine, ...cocaine, methamphetamine, and designer drugs. Despite clinical evaluation of vaccines targeting nicotine and cocaine showing proof of concept for this approach, no vaccine for SUD has yet reached the market. This review first discusses how vaccines for treatment of opioid use disorders (OUD) and reduction of opioid-induced fatal overdoses fit within the current medication assisted treatment (MAT) portfolio, and then summarizes ongoing efforts toward translation of vaccines targeting heroin, oxycodone, fentanyl, and other opioids.
This article is part of the Special Issue entitled ‘New Vistas in Opioid Pharmacology’.
•Vaccines are a promising strategy to treat opioid use disorders (OUD) and prevent overdose.•Vaccines offer benefits complementary to approved Medication Assisted Treatment (MAT).•Pre-clinical studies provide proof of efficacy, safety and selectivity for vaccines for OUD.•Translation of vaccines for OUD is challenging, but necessary to validate this approach.
Abstract This paper reviews studies examining the pharmacological interactions and epidemiology of the combined use of opioids and benzodiazepines (BZDs). A search of English language publications ...from 1970 to 2012 was conducted using PubMed and PsycINFO® . Our search found approximately 200 articles appropriate for inclusion in this paper. While numerous reports indicate that the co-abuse of opioids and BZDs is ubiquitous around the world, the reasons for the co-abuse of these medications are not entirely clear. Though the possibility remains that opioid abusers are using BZDs therapeutically to self-medicate anxiety, mania or insomnia, the data reviewed in this paper suggest that BZD use is primarily recreational. For example, co-users report seeking BZD prescriptions for the purpose of enhancing opioid intoxication or “high,” and use doses that exceed the therapeutic range. Since there are few clinical studies investigating the pharmacological interaction and abuse liability of their combined use, this hypothesis has not been extensively evaluated in clinical settings. As such, our analysis encourages further systematic investigation of BZD abuse among opioid abusers. The co-abuse of BZDs and opioids is substantial and has negative consequences for general health, overdose lethality, and treatment outcome. Physicians should address this important and underappreciated problem with more cautious prescribing practices, and increased vigilance for abusive patterns of use.
Background
Cocaine use contines to be a significant public health problem world‐wide. However, despite substantial research efforts, no pharmacotherapies are approved for the treatment of cocaine use ...disorder (CUD).
Argument
Studies have identified positive signals for a range of medications for treating CUD. These include long‐acting amphetamine formulations, modafinil, topiramate, doxazosin and combined topiramate and mixed amphetamine salts extended‐release (MAS‐ER). However, valid conclusions about a medication's clinical efficacy require nuanced approaches that take into account behavioural phenotypes of the target population (frequency of use, co‐abuse of cocaine and other substances, genetic subgroups, psychiatric comorbidity), variables related to the medication (dose, short‐/long‐acting formulations, titration speed, medication adherence) and other factors that may affect treatment outcomes. Meta‐analyses frequently do not account for these co‐varying factors, which contributes to a somewhat nihilistic view on pharmacotherapeutic options for CUD. In addition, the predominant focus on abstinence, which is difficult for most patients to achieve, may overshadow more nuanced therapeutic signals.
Conclusion
While there is an emphasis on finding new medications with novel mechanisms of action for treating CUD, currently available medications deserve further investigation based on the existing literature. Evaluating refined metrics of treatment success in well‐defined subgroups of patients, and further exploring combination therapies and their synergy with behavioural/psychosocial interventions, are promising avenues to establishing effective therapies for CUD.
Cannabinoids combined with opioids produce synergistic antinociceptive effects, decreasing the lowest effective antinociceptive opioid dose (i.e., opioid-sparing effects) in laboratory animals. ...Although pain patients report greater analgesia when cannabis is used with opioids, no placebo-controlled studies have assessed the direct effects of opioids combined with cannabis in humans or the impact of the combination on abuse liability. This double-blind, placebo-controlled, within-subject study determined if cannabis enhances the analgesic effects of low dose oxycodone using a validated experimental model of pain and its effects on abuse liability. Healthy cannabis smokers (N = 18) were administered oxycodone (0, 2.5, and 5.0 mg, PO) with smoked cannabis (0.0, 5.6% Δ
tetrahydrocannabinol THC) and analgesia was assessed using the Cold-Pressor Test (CPT). Participants immersed their hand in cold water (4 °C); times to report pain (pain threshold) and withdraw the hand from the water (pain tolerance) were recorded. Abuse-related effects were measured and effects of oxycodone on cannabis self-administration were determined. Alone, 5.0 mg oxycodone increased pain threshold and tolerance (p ≤ 0.05). Although active cannabis and 2.5 mg oxycodone alone failed to elicit analgesia, combined they increased pain threshold and tolerance (p ≤ 0.05). Oxycodone did not increase subjective ratings associated with cannabis abuse, nor did it increase cannabis self-administration. However, the combination of 2.5 mg oxycodone and active cannabis produced small, yet significant, increases in oxycodone abuse liability (p ≤ 0.05). Cannabis enhances the analgesic effects of sub-threshold oxycodone, suggesting synergy, without increases in cannabis's abuse liability. These findings support future research into the therapeutic use of opioid-cannabinoid combinations for pain.
Opioid use disorder (OUD) presents a serious public health concern, with dramatic increases in opioid-overdose mortality in recent years and a small percentage of those with OUD accessing or ...remaining engaged with available treatments. Efforts are currently underway to identify vaccines targeting opioids, which could provide a novel and complimentary approach. The current review provides an overview of existing literature, practical considerations for designing and conducting clinical trials with vaccines for opioids, and future directions.
This review covers the following themes: clinical trial design and selection of endpoints, timepoint selection, practical considerations and lessons learned from the first (ongoing) trial of a vaccine targeting opioids, and future directions.
Efforts to develop and test vaccines targeting OUD are based on a foundation of preclinical work and close collaboration between preclinical and clinical researchers. Efforts to learn from shortcomings of prior clinical trials of vaccines for other substances are essential in designing and testing effective vaccines for OUD. Design and implementation of clinical trials for a vaccine for OUD requires careful balance of participant safety and strategies for retention and efforts to gather viable data to inform future work.
Highlights • We review data on BUP-induced changes in mu -opioid receptor ( μ OR) availability, pharmacokinetics and clinical efficacy. • Opioid withdrawal suppression appears to require ≤50% μ OR ...availability, associated with BUP plasma concentrations ≥1 ng/mL. • Blocking opioid reinforcement requires <20% μ OR availability, or BUP plasma levels ≥3 ng/mL. • Blockade of opioid use for many patients may require total BUP daily doses ≥16 mg, although other factors contribute. • Data suggest that fixed limits on BUP doses in clinical care or limits on reimbursement for this care are unwarranted.
Terminology related to prescription drug misuse and abuse is inconsistently defined. An expert panel developed consensus classifications and definitions for use in clinical trials.
As the ...nontherapeutic use of prescription medications escalates, serious associated consequences have also increased. This makes it essential to estimate misuse, abuse, and related events (MAREs) in the development and postmarketing adverse event surveillance and monitoring of prescription drugs accurately. However, classifications and definitions to describe prescription drug MAREs differ depending on the purpose of the classification system, may apply to single events or ongoing patterns of inappropriate use, and are not standardized or systematically employed, thereby complicating the ability to assess MARE occurrence adequately. In a systematic review of existing prescription drug MARE terminology and definitions from consensus efforts, review articles, and major institutions and agencies, MARE terms were often defined inconsistently or idiosyncratically, or had definitions that overlapped with other MARE terms. The Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, Opportunities, and Networks (ACTTION) public–private partnership convened an expert panel to develop mutually exclusive and exhaustive consensus classifications and definitions of MAREs occurring in clinical trials of analgesic medications to increase accuracy and consistency in characterizing their occurrence and prevalence in clinical trials. The proposed ACTTION classifications and definitions are designed as a first step in a system to adjudicate MAREs that occur in analgesic clinical trials and postmarketing adverse event surveillance and monitoring, which can be used in conjunction with other methods of assessing a treatment’s abuse potential.
Development and implementation of effective treatments for opioid use disorder (OUD) and prevention of overdose are urgent public health needs. Though existing medications for OUD (MOUD) are ...effective, barriers to initiation and retention in treatment persist. Therefore, development of novel treatments, especially those may complement existing treatments, is needed.
This review provides an overview of vaccines for substance use disorders (SUD) and mechanisms underlying their function and efficacy. Next, we focus on existing preclinical and clinical trials of SUD vaccines. We focus briefly on related strategies before providing an expert opinion on prior, current, and future work on vaccines for OUD. We included published findings from preclinical and clinical trials found on PubMed and ScienceDirect as well as ongoing or initiated trials listed on ClinicalTrials.gov.
The present opioid overdose and OUD crises necessitate urgent development and implementation of effective treatments, especially those that offer protection from overdose and can serve as adjuvants to existing medications. Promising preclinical trial results paired with careful efforts to develop vaccines that account for prior SUD vaccine shortcomings offer hope for current and future clinical trials of opioid vaccines. Clinical advantages of opioid vaccines appear to outnumber disadvantages, which may result in improved treatment options.
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