Jermaine D. Jones

Risks, management, and monitoring of combination opioid, benzodiazepines, and/or alcohol use.

Abstract The concurrent use of opioids, benzodiazepines (BZDs), and/or alcohol poses a formidable challenge for clinicians who manage chronic pain. While the escalating use of opioid analgesics for the treatment of chronic pain and the concomitant rise in opioid-related abuse and misuse are widely recognized trends, the contribution of combination use of BZDs, alcohol, and/or other sedative agents to opioid-related morbidity and mortality is underappreciated, even when these agents are used appropriately. Patients with chronic pain who use opioid analgesics along with BZDs and/or alcohol are at higher risk for fatal/nonfatal overdose and have more aberrant behaviors. Few practice guidelines for BZD treatment are readily available, especially when they are combined clinically with opioid analgesics and other central nervous system-depressant agents. However, coadministration of these agents produces a defined increase in rates of adverse events, overdose, and death, warranting close monitoring and consideration when treating patients with pain. To improve patient outcomes, ongoing screening for aberrant behavior, monitoring of treatment compliance, documentation of medical necessity, and the adjustment of treatment to clinical changes are essential. In this article, we review the prevalence and pharmacologic consequences of BZDs and/or alcohol use among patients with pain on chronic opioid therapy, as well as the importance of urine drug testing, an indispensable tool for therapeutic drug monitoring, which helps to ensure the continued safety of patients. Regardless of risk or known aberrant drug-related behaviors, patients on chronic opioid therapy should periodically undergo urine drug testing to confirm adherence to the treatment plan.

Glial modulators: a novel pharmacological approach to altering the behavioral effects of abused substances

Introduction: Commonly abused drugs including opioids, stimulants and alcohol activate glia cells, an effect that has been identified across species. Glia, specifically astrocytes and microglia, have been shown to contribute directly to behaviors predictive of the abuse liability of these drugs. Although still in its infancy, research investigating the effects of pharmacological modulation of glial activity on these behaviors has provided encouraging findings suggesting glial cell modulators as potential pharmacotherapies for substance-use disorders. Areas covered: This review first explores the evidence establishing glial-mediated modulations of behaviors associated with opioid, stimulant and alcohol exposure, with emphasis placed on the neuroanatomical substrates for these effects. Next, neurobiological and behavioral studies evaluating the ability of glial cell modulators to prevent and reverse the effects of these abused substances will be considered. Finally, the potential clinical efficacy of glial cell modulators as a novel pharmacological approach to treat substance-use disorders in relation to currently available, conventional pharmacotherapies will be discussed. Expert opinion: Though the relationship between drug-induced glial activity and behaviors indicative of drug abuse and dependence is not yet fully elucidated, the evidence for the association continues to grow. The use of glial modulators as pharmacological tools to investigate this relationship has also yielded findings supporting their potential clinical efficacy for treating substance-use disorders.

Assessment of a formulation designed to be crush-resistant in prescription opioid abusers.

BACKGROUND The extent of prescription opioid abuse has led to the development of formulations that are difficult to crush. The purpose of the present studies was to examine whether experienced prescription opioid abusers (individuals using prescription opioids for non-medical purposes regardless of how they were obtained) were able to prepare a formulation of oxymorphone hydrochloride ER 40 mg designed to be crush-resistant (DCR) for intranasal (study 1) or intravenous abuse (study 2), utilizing a non-crush-resistant formulation of oxymorphone (40 mg; OXM) as a positive control. METHODS No drug was administered in these studies. Participants were provided with DCR and OXM tablets in random order and asked to prepare them for abuse with tools/solutions that they had previously requested. The primary outcome for study 1 was particle size distribution, and the primary outcome for study 2 was percent yield of active drug in the extracts. Other descriptive variables were examined to better understand potential responses to these formulations. RESULTS Fewer DCR than OXM particles were smaller than 1.705 mm (9.8% vs. 97.7%), and thus appropriate for analyses. Percent yield of active drug in extract was low and did not differ between the two formulations (DCR: 1.95%; OXM: 1.29%). Most participants were not willing to snort (92%) or inject (84%) the tampered products. Participants indicated that they found less relative value in the DCR than the OXM formulation across both studies. CONCLUSIONS These data suggest that the oxymorphone DCR formulations may be a promising technology for reducing opioid abuse.

Effects of acute oral naltrexone on the subjective and physiological effects of oral D-amphetamine and smoked cocaine in cocaine abusers.

Despite the prevalent worldwide abuse of stimulants, such as amphetamines and cocaine, no medications are currently approved for treating this serious public health problem. Both preclinical and clinical studies suggest that the opioid antagonist naltrexone (NTX) is effective in reducing the abuse liability of amphetamine, raising the question of whether similar positive findings would be obtained for cocaine. The purpose of this study was to evaluate the ability of oral NTX to alter the cardiovascular and subjective effects of D-amphetamine (D-AMPH) and cocaine (COC). Non-treatment-seeking COC users (N=12) completed this 3-week inpatient, randomized, crossover study. Participants received 0, 12.5, or 50 mg oral NTX 60 min before active or placebo stimulant administration during 10 separate laboratory sessions. Oral AMPH (0, 10, and 20 mg; or all placebo) was administered in ascending order within a laboratory session using a 60-min interdose interval. Smoked COC (0, 12.5, 25, and 50 mg; or all placebo) was administered in ascending order within a laboratory session using a 14-min interdose interval. Active COC and AMPH produced dose-related increases in cardiovascular function that were of comparable magnitude. In contrast, COC, but not AMPH, produced dose-related increases in several subjective measures of positive drug effect (eg, high, liking, and willingness to pay for the drug). NTX did not alter the cardiovascular effects of AMPH or COC. NTX also did not alter positive subjective ratings after COC administration, but it did significantly reduce ratings of craving for COC and tobacco during COC sessions. These results show that (1) oral AMPH produces minimal abuse-related subjective responses in COC smokers, and (2) NTX reduces craving for COC and tobacco during COC sessions. Future studies should continue to evaluate NTX as a potential anti-craving medication for COC dependence.

A comparison among tapentadol tamper-resistant formulations (TRF) and OxyContin® (non-TRF) in prescription opioid abusers

AIMS To examine whether tamper-resistant formulations (TRFs) of tapentadol hydrochloride extended-release (ER) 50 mg (TAP50) and tapentadol hydrochloride 250 mg (TAP250) could be converted into forms amenable to intranasal (study 1) or intravenous abuse (study 2). DESIGN Randomized, repeated-measures study designs were employed. A non-TRF of OxyContin® 40 mg (OXY40) served as a positive control. No drug was taken in either study. SETTING The studies took place in an out-patient setting in New York, NY. PARTICIPANTS Twenty-five experienced, healthy ER oxycodone abusers participated in each study. MEASUREMENTS The primary outcome for study 1 was the percentage of participants who indicated that they would snort the tampered tablets, while the primary outcome for study 2 was the percentage yield of active drug in solution. Other descriptive variables, such as time spent manipulating the tablets, were also examined to characterize tampering behaviors more clearly. FINDINGS Tampered TRF tablets were less desirable than the tampered OXY40 tablets. Few individuals were willing to snort the TRF particles (TAP50: 24%, TAP250: 16%; OXY40: 100% P < 0.001). There was less drug extracted from the TAP50 tablet than from the OXY40 tablet (3.52 versus 37.02%, P = 0.008), and no samples from the TAP250 tablets contained analyzable solutions of the drug. It took participants longer to tamper with the TAPs (study 1: TAP50 versus OXY40, P < 0.01; TAP250 versus OXY40, P < 0.01; study 2: TAP250 versus OXY40, P < 0.05). CONCLUSIONS Tamper-resistant formulations of taptentadol (pain relief) tablets do not appear to be well-liked by individuals who tamper regularly with extended-release oxycodone tablets. Employing tamper-resistant technology may be a promising approach towards reducing the abuse potential of tapentadol extended-release.

The Pharmacogenetics of Alcohol Use Disorder

BACKGROUND Annually, the use and abuse of alcohol contributes to millions of deaths and billions of dollars in societal costs. To determine the impact of genetic variation on the susceptibility to the disorder and its response to treatment, studies have been conducted to assess the contribution of a variety of candidate genetic variants. These variants, which we review here, were chosen based upon their observed or hypothesized functional relevance to alcohol use disorder (AUD) risk or to the mechanism by which medications used to treat the disorder exert their effects. METHODS This qualitative review examines studies in which candidate polymorphisms were tested as moderator variables to identify pharmacogenetic effects on either the subjective response to alcohol or the outcomes of pharmacotherapy. RESULTS Although findings from these studies provide evidence of a number of clinically relevant pharmacogenetic effects, the literature is limited and there are conflicting findings that require resolution. CONCLUSIONS Pharmacogenetic studies of AUD treatment that use greater methodological rigor and better statistical controls, such as corrections for multiple testing, may help to resolve inconsistent findings. These procedures could also lead to the discovery of more robust and clinically meaningful moderator effects. As the field evolves through methodological standardization and the use of larger study samples, pharmacogenetic research has the potential to inform clinical care by enhancing therapeutic effects and personalizing treatments. These efforts may also provide insights into the mechanisms by which medications reduce heavy drinking or promote abstinence in patients with an AUD.

Buprenorphine/naloxone as a promising therapeutic option for opioid abusing patients with chronic pain: reduction of pain, opioid withdrawal symptoms, and abuse liability of oral oxycodone.

&NA; In opioid‐dependent individuals with chronic pain, buprenorphine/naloxone may be an effective therapeutic option using adequate dose and paying attention to withdrawal symptoms and pain. &NA; Few studies have examined abuse of prescription opioids among individuals with chronic pain under buprenorphine/naloxone (Bup/Nx) maintenance. The current 7‐week inpatient study assessed oral oxycodone self‐administration by patients with chronic pain who had a history of opioid abuse. Participants (n = 25) were transitioned from their preadmission prescribed opioid to Bup/Nx. All of the participants were tested under each of the sublingual Bup/Nx maintenance doses (2/0.5, 8/2 or 16/4 mg) in random order. During each maintenance period, participants could self‐administer oxycodone orally (0, 10, 20, 40 or 60 mg prescription opioids) or receive money during laboratory sessions. Drug choice (percentage) was the primary dependent variable. Subjective ratings of clinical pain and withdrawal symptoms also were measured. Mann‐Whitney tests compared percentage of drug choice for each active oxycodone dose to placebo. Logistic regression analyses identified correlates of oxycodone preference, defined as 60% or greater choice of oxycodone compared to money. Pain was significantly reduced while participants were maintained on Bup/Nx compared to preadmission ratings. No differences in percentage drug choice were observed between the active oxycodone doses and placebo under each Bup/Nx maintenance dose. However, factors associated with oxycodone preference were lower Bup/Nx maintenance dose, more withdrawal symptoms and more pain. These data suggest that Bup/Nx was effective in reducing pain and supplemental oxycodone use. Importantly, adequate management of pain and withdrawal symptoms by Bup/Nx may reduce oxycodone preference in this population.

A review of human drug self-administration procedures.

Drug self-administration procedures in laboratory settings allow us to closely model drug-taking behavior in real-world settings. This review provides an overview of many of the common self-administration methods used in human laboratory research. Typically, self-administration studies provide a quantifiable measure of the reinforcing effect of a drug, which is believed to be predictive of its potential for abuse. Several adaptations of the self-administration paradigm exist, the simplest of which allows participants free access to the drug under investigation. Free-access procedures allow investigators to observe patterns of drug self-administration and drug effects in a controlled setting. Allowing participants to choose between two simultaneously available reinforcers (choice procedures) is another well-established method of assessing the reinforcing effects of a drug. Offering a choice between two reinforcers (e.g. two different doses of the same drug, two different drugs, or drug and nondrug reinforcers) provides researchers with a point of comparison (e.g. between a drug of known abuse potential and a novel drug). When combined with other endpoints, such as subjective effects ratings, physiological responses, and cognitive performance, human self-administration paradigms have contributed significantly to our understanding of the factors that contribute to, maintain, and alter drug-taking behavior including: craving, positive subjective effects, toxicity, drug interactions and abstinence. This area of research has also begun to incorporate other techniques such as imaging and genetics to further understand the multifaceted nature of substance abuse. The present paper summarizes the different self-administration techniques that are commonly used today and the application of other procedures that may complement interpretation of the drug self-administration findings.

The Subjective, Reinforcing, and Analgesic Effects of Oxycodone in Patients with Chronic, Non-Malignant Pain who are Maintained on Sublingual Buprenorphine/Naloxone

Some sources suggest that significant misuse of opioid drugs exists among patients with chronic pain. However, the risk factors and motivation behind their abuse may differ from those of other opioid abusers. This study sought to examine the abuse liability of oxycodone among patients with chronic, non-malignant pain who met the DSM-IV criteria for opioid abuse. Eighteen opioid-dependent patients with chronic pain lived on an in-patient unit of the New York State Psychiatric Institute during the 7-week study. Participants were given oral oxycodone (0, 10, 20, 40, and 60 mg/70 kg) while maintained on various doses of sublingual buprenorphine/naloxone (Bup/Nx; 2/0.5, 8/2, and 16/4 mg/day). Doses of both medications were administered under double-blind conditions. Oxycodone produced an overall positive, but less robust, subjective profile than previously reported in recreational opioid users without pain. Furthermore, unlike our findings in recreational opioid users and more similar to effects in non-drug-abusing individuals, oxycodone failed to serve as a reinforcer. As for the maintenance drug, Bup/Nx produced a dose-related reduction in some of the effects of acutely administered oxycodone. These data suggest that sublingual Bup/Nx has the potential as an analgesic medication and further research should investigate its use in treating patients with chronic pain who abuse opioids.

Oxycodone Abuse in New York City: Characteristics of Intravenous and Intranasal Users

This pilot study sought to characterize typical nonmedical oxycodone use in the New York Metropolitan area. Accordingly, a clinical interview was administered to 25 intranasal (IN) and 25 intravenous (IV) oxycodone abusers to capture demographics and patterns of use within the region. IN and IV abusers shared a number of similar characteristics including age, proportion of men and women, criminal history, drug use history, and current recreational drug use. However, the two populations also differed in a number of aspects. IV oxycodone users had lower rates of employment, earlier onset of illicit drug use, and more current heroin use. Although IN users reported somewhat more frequent use of oxycodone weekly, IV users were more likely to supplement their oxycodone use with other opioid drugs, most notably heroin. Additional research is needed to confirm these observed differences, yet these data may assist treatment efforts by providing information to guide targeted treatment and population-specific interventions.