Resilience Phenotypes and Psychological Functioning among Individuals with Opioid Use Disorder.

BACKGROUND: Opioid use disorder (OUD) is a heterogeneous disorder. However, there is a lack of deep phenotyping investigations focusing on important psychological constructs such as resilience that may impact OUD. The present study aimed to investigate the relationship between trait resilience and the five-factor model of personality (FFM) among individuals with opioid use disorder (OUD). We also explored whether the FFM and trait resilience form specific phenotypes associated with psychological functioning. METHODS: This secondary analysis of an epigenetic study included participants of African ancestry (n = 72), an understudied population, who met DSM-5 criteria for OUD. Participants completed measures to assess personality traits, trait resilience, current and previous drug use, and psychological functioning (depression, anxiety, and stress). RESULTS: Linear regression revealed a significant relationship between resilience (CD-RISC-25 score) and the FFM, R2 = 0.56, F(5,62) = 15.7, p<.001. Further, a two-cluster classification emerged as the optimal solution from the cluster analysis. Cluster 1 (n = 33, 45.8% of the sample) showed lower resilience (CD-RISC-25 score: M = 58.6, SD = 11.2) compared to Cluster 2 (n = 35, 48.6%; CD-RISC-25 score: M = 76.1, SD = 11.9). The "High-Resilience Cluster" (Cluster 2) was characterized by higher FFM traits of: Extraversion, Openness, Agreeableness, and Conscientiousness, and lower Neuroticism versus Cluster 1. Multivariate analysis of variance revealed statistically significant differences between the two resilience clusters concerning other psychological symptoms, Λ = 0.732, F(4, 50) = 7.05, p < 0.003. CONCLUSIONS: These findings suggest associations between the FFM and trait resilience among individuals with OUD. Two distinct "resilience phenotypes" emerged, with high-resilience individuals displaying less stress, anxiety, and depressive symptoms. Results highlight the clinical importance of resilience as a potential target for intervention in people with OUD.

Sublingual dexmedetomidine (BXCL501) reduces opioid withdrawal symptoms: findings from a multi-site, phase 1b/2, randomized, double-blind, placebo-controlled trial.

Background: Like other alpha-2-adrenergic receptor agonists, dexmedetomidine may reduce the severity of opioid withdrawal but with fewer adverse cardiovascular effects.Objective: This study assessed the safety of sublingual dexmedetomidine (BXCL501) and its preliminary efficacy in treating opioid withdrawal (ClinicalTrials.gov: NCT04470050).Methods: Withdrawal was induced among individuals with physiological dependence on opioids via discontinuation of oral morphine (Days 1-5). Participants were randomized to receive placebo or active BXCL501: 30, 60, 90, 120, 180, and 240 µg twice daily (Days 6-12). Treatment-emergent adverse events (TEAEs) were the primary outcome measure. Secondary outcomes included the Clinical and Subjective Opiate Withdrawal Scales (COWS and SOWS-Gossop, respectively), and the Agitation and Calmness Evaluation Scale (ACES).Results: Of 225 participants enrolled, 90 discontinued during morphine stabilization. Post-BXCL501 randomization (Day 6) data were available from 135 participants (73% male), with 33% completing thru Day 12. In total, 36 subjects reported 1 or more TEAE. Higher doses of BXCL501 (i.e. 180 and 240 µg, twice daily) increased the frequency of: hypotension, orthostatic hypotension, and somnolence. TEAEs related to BXCL501 were mild or moderate in severity, except for one participant in the 120 µg condition whose orthostatic hypotension and bradycardia were classified as severe. Higher BXCL501 dose conditions (120, 180, and 240 µg) resulted in statistically significant reductions in COWS & SOWS scores. Mean ratings on the ACES were between 3 (mild), 4 (normal), and 5 (mild calmness), with few significant differences as a function of dose.Conclusions: These findings support the continued development of BXCL501 for the management of opioid withdrawal.

The effects of acute oral naltrexone pretreatment on the abuse potential of intranasal methamphetamine, and the relationship between reward/punishment sensitivity and methamphetamine's effects.

One potential medication for treating methamphetamine use disorder is the opioid antagonist naltrexone (NLTX). Despite encouraging preclinical findings, the results of clinical studies have been mixed. The primary aim of the current trial was to examine the effects of acute NLTX pretreatment on the subjective and reinforcing effects of intranasal methamphetamine. Nonmedical psychostimulant users completed outpatient testing sessions in which they received oral placebo (0 mg) or NLTX (50 mg) before intranasal methamphetamine (30 mg/70 kg). Primary outcome measures were peak positive subjective effects (e.g. drug 'Liking') assessed on a visual analog scale (0-100), and methamphetamine self-administration using an operant self-administration task. Participants also completed a probabilistic categorization task to assess reward and punishment learning sensitivity. Complete data were available from 13 male and 1 transgender (male-to-female) participant (age: 33.4 ± 7.6 years). Intranasal methamphetamine significantly increased subjective ratings of drug 'Liking', 'Good Effect' and 'High' from baseline (P's < 0.01), but did not significantly vary as a function of placebo or NLTX pretreatment. Similarly, methamphetamine self-administration did not vary between the placebo and NLTX pretreatment conditions. This sample did not demonstrate a significant 'bias' in learning from positive and negative outcomes (i.e. reward and punishment sensitivity), and reward/punishment sensitivity was not correlated with the effects of methamphetamine or the effects of NLTX on methamphetamine. The current study argues against the use of NLTX as a stand-alone medication for treating methamphetamine use disorder.

Emotional reactions of trained overdose responders who use opioids following intervention in an overdose event.

Background: Our aim was to explore emotional reactions to intervening in an overdose event from the perspective of individuals who use opioids (peer responders). In addition, we were interested in the impact this experience may have on peer responders' feelings about helping in an overdose situation in the future. Methods: For this qualitative sub-study of a randomized controlled trial (RCT), data from 61 interviews were analyzed thematically using an inductive approach. Results: Peer responders had diverse emotional reactions to the overdose event. These ranged from a sense of pride and other positive feelings associated with their ability to help to ambivalence about being involved in situations perceived as challenging and burdensome. There were few reports of the overdose event as an exclusively negative experience. Many peer responders perceived it as their duty to use naloxone again if required. However, some had ambivalent feelings toward this responsibility, which may be related to negative experiences with previous intervention efforts. Conclusions: The capacity of people who use opioids to help reduce the harms associated with opioid overdose is experienced as empowering by some. Nonetheless, engaging peer responders in strategies to reduce opioid-related mortality should be coupled with appropriate resources to process their experiences and emotional responses.

UNDERSTANDING PREFERENCES FOR TYPE OF TAKE-HOME NALOXONE DEVICE: INTERNATIONAL QUALITATIVE ANALYSIS OF THE VIEWS OF PEOPLE WHO USE OPIOIDS.

Background: Take-home naloxone (THN) is provided to non-medically trained people to reverse potential opioid overdoses. There is an increasing range of effective intramuscular (IM) and intranasal (IN) naloxone devices and this paper explores the types preferred by people who use opioids, using consumer behaviour literature to interpret the findings. Methods: Data derive from two unconnected qualitative studies involving audio-recorded semi-structured interviews. Study 1 was conducted in the United States (n=21 users of non-medical/illicit opioids). Study 2 was conducted in Australia (n=42 users of non-medical/illicit or prescribed opioids). Findings: Most participants preferred IN naloxone. Preferences were based on the ease, speed, safety and comfort of each device and underpinned by accounts of overdose revivals as being very rushed and frightening situations. Preferences related to complex interactions between the naloxone device ('product'); the knowledge, skills, experience and attitudes of the lay responder ('consumer'), and when, where and how naloxone was to be used ('usage situation'). Conclusions: THN programs should offer choice of device when possible and nasal naloxone if resources permit. Asking people which devices they prefer and why and treating them as valued consumers of naloxone products can generate insights that improve future naloxone technology and increase THN uptake and usage.

The Increasing Prevalence of Fentanyl: A Urinalysis-Based Study Among Individuals With Opioid Use Disorder in New York City.

BACKGROUND AND OBJECTIVES: Opioid-related overdose deaths in North America have increased drastically, partially due to the increased prevalence of illicitly manufactured fentanyl. The current study sought to assess the prevalence and intentionality of fentanyl use among individuals with opioid use disorder (OUD). METHODS: For this secondary analysis (study 1) we screened a total of 1118 urine samples from 316 participants with OUD from 2016 to 2019. Fentanyl knowledge and intentionality of use were assessed in a separate OUD sample (study 2; N = 33). RESULTS: In study 1, 34.6% of all urine samples tested positive for fentanyl. Overall, 149 (47.2%) participants provided more than or equal to one urine sample that tested fentanyl-positive, and 93 (29.4%) provided more than or equal to two fentanyl-positive samples. The number of fentanyl-positive samples, relative to the number of samples tested each year, increased by 330% from year 1 to 3. Study 2 found all participants had pre-existing knowledge that drugs may be adulterated with fentanyl, yet 67% were surprised by their own fentanyl-positive test result. DISCUSSION AND CONCLUSIONS: Like previous studies, our data indicate the high prevalence of fentanyl exposure and low perception of fentanyl-related risk among individuals with OUD, respectively, suggesting that opioid overdose harm reduction efforts may need to focus more on drug users' understanding of risks related to fentanyl use and adulteration of drugs. SCIENTIFIC SIGNIFICANCE: The current studies provide longitudinal data on fentanyl exposure prevalence and risk perception that is uniquely granular by assessing OUD treatment status, and by identifying potential associations between fentanyl exposure with the presence of other drug use and nonfatal overdose. (Am J Addict 2021;30:65-71).

Intervention in an opioid overdose event increases interest in treatment among individuals with opioid use disorder.

Background: This study sought to explore whether intervening in suspected cases of opioid overdose alters interest in treatment for opioid use disorder (OUD). Data were collected as a part of a trial comparing the effects of different overdose education and naloxone distribution (OEND) training curricula on overdose outcomes. Methods: Following OEND training, participants completed four in-person follow-up visits at 1-, 3-, 6- and 12-months. Participants were also regularly contacted to inquire about overdose events they responded to, witnessed, or experienced themselves. Other assessments included the Addiction Severity Index that queries participants' perceived importance of drug treatment on a scale of: 0 (Not at All) to 4 (Extremely). For the current secondary data analysis, treatment importance was assessed at the time points most immediately preceding and following participant intervention in an overdose event using naloxone. Results: The sample reported a mean duration of opioid use of 14.9 (± 11.5) years, with 67% having witnessed an overdose event prior to the study. Of the 321 enrolled, 92 participants used naloxone in response to 166 suspected cases of an opioid overdose. For the entire sample, mean treatment importance did not significantly change throughout the study. Among participants who utilized naloxone, treatment importance increased following the event (Before: 3.03, After: 3.39, p = 0.02). Due to the amount of time between the overdose event and assessment of post-event treatment importance (40.5 days, ±40.2), the current study most likely underestimates this effect. Conclusions: The current study suggests that responding to an overdose event increases interest in OUD treatment. Currently only considered an acute intervention to reduce overdose morbidity and mortality, OEND may have the potential to increase enrollment in medications to treat OUD. However, a prospective investigation needs to determine if the impact of an overdose event could be utilized to increase treatment engagement.

A randomized, double-blind, placebo-controlled study of the kappa opioid receptor antagonist, CERC-501, in a human laboratory model of smoking behavior.

Preclinical data indicate that selective kappa opioid receptor antagonists reduce nicotine self-administration and withdrawal symptoms. The aim of the current study was to determine whether treatment with CERC-501, an orally available, potent, and selective kappa opioid receptor antagonist, could alleviate nicotine withdrawal and craving and mitigate mood alterations associated with nicotine withdrawal in humans. Healthy, adult cigarette smokers were enrolled into this randomized, multisite, double-blind, placebo-controlled, crossover study. Participants completed two 8-day treatment phases during which they received either CERC-501 (15 mg, p.o., once daily) or placebo. On the seventh day of each dosing phase, participants were admitted as inpatients for an 18-hour cigarette abstinence period followed by experimental testing. The primary outcome measures were (a) performance on the McKee Smoking Lapse test (ie, latency to smoke in exchange for money) and (b) number of cigarettes self-administered during a 60-minute ad lib smoking period. Other outcomes included measures of craving, mood, anxiety, nicotine withdrawal, and subjective effects of cigarette smoking. A total of 71 participants who smoked an average of approximately 23 cigarettes per day were enrolled, and 56 subjects completed the study. CERC-501 was well tolerated, but it did not significantly alter the latency to start smoking (CERC-501: 16.5 min vs placebo: 17.7 min) or the number of cigarettes smoked (CERC-501: 3.3 cigarettes vs placebo: 3.1 cigarettes). Compared with placebo, CERC-501 also did not affect cigarette craving, mood, anxiety, nicotine withdrawal, or subjective effects of smoking. These findings do not support a role for CERC-501 in the treatment of nicotine use disorder.

Naloxone-Induced Withdrawal in Individuals With and Without Fentanyl-Positive Urine Samples.

BACKGROUND AND OBJECTIVE: This retrospective analysis of data from heroin users screening for clinical research, sought to determine if more naloxone is needed to precipitate opioid withdrawal among those who regularly use heroin with fentanyl, as opposed to those who use heroin without fentanyl. METHODS: Over the course of three to five screening visits, participants completed assessments of drug use, along with urine toxicology tests at each visit. To test for opioid dependence, 29 participants completed a modified Wang test (score: 0-150) during which an intramuscular dose of naloxone (0.2-0.4 mg) was administered and the severity of withdrawal was quantified. RESULTS: The severity of opioid withdrawal was compared between individuals whose urine toxicology regularly tested positive for fentanyl (N = 15), and those only positive for other opioids (N = 14). No significant differences were found in demographic or drug use between the fentanyl-positive (mean: age 41.1 years, 9.1 bags heroin/d) and fentanyl-negative (42.0 years, 10.0 bags heroin/d) groups. Intramuscular naloxone-precipitated robust withdrawal in both samples (P < .01) with no significant difference (P = .8) in the severity (fentanyl positive [100.6 ± 13.4]; fentanyl negative [82.7 ± 9.6]). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: These data suggest that a standard naloxone dose can be equally effective at precipitating withdrawal in individuals using heroin with fentanyl compared to heroin without fentanyl. These data contribute to our understanding of how naloxone antagonizes the effects of fentanyl and may have significant implications for the clinical laboratory and opioid overdose. A prospective clinical laboratory study with the proper opioid maintenance controls is needed to provide a more definitive finding. (Am J Addict 2019;00:00-00).

Chronic pain and opioid abuse: Factors associated with health-related quality of life.

BACKGROUND AND OBJECTIVES: While research on the separate relationships between health-related quality of life (HRQOL) and chronic pain, and HRQOL and opioid abuse has been sparse, even less work has investigated the factors associated with HRQOL in individuals who have both chronic pain and meet criteria for opioid use disorder. The data presented in this analysis should allow a better understanding the factors important to quality of life among this dual-diagnosed population. METHODS: Individuals with dual diagnoses of chronic pain and opioid use disorder were recruited for clinical research studies at Columbia University Medical Center. Participants (n = 47) completed inventories to assess pain (Brief Pain Inventory), opioid (ab)use, and depression (Beck Depression Inventory). Variable from these and other inventories, along with demographic factors (age, race, sex, pain severity, depressive symptoms, duration of opioid use, route of opioid use, amount of opioid use) were entered into a regression analysis in order to identify the strongest predictors of SF-36 Health Survey score. RESULTS: In the bivariate analysis we found that demographic and drug use variables were rarely associated with HRQOL. Typically, ratings of pain severity and pain interference were the best predictors. In the multivariate analysis, we found that across the several HRQOL dimensions greater Brief Pain Inventory (BPI) ratings of pain "interference" and Beck Depression Inventory (BDI) scores were consistently associated with lower HRQOL. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: These data suggest that insufficient pain management and depression are significant variables contributing to lower quality of life among individuals with chronic pain and opioid use disorder. (Am J Addict 2017;26:815-821).

The effects of ibudilast, a glial activation inhibitor, on opioid withdrawal symptoms in opioid-dependent volunteers.

Glial activation is hypothesized to contribute directly to opioid withdrawal. This study investigated the dose-dependent effects of a glial cell modulator, ibudilast, on withdrawal symptoms in opioid-dependent volunteers after abrupt discontinuation of morphine administration. Non-treatment-seeking heroin-dependent volunteers (n = 31) completed the in-patient, double-blind, placebo-controlled, within-subject and between-group study. Volunteers were maintained on morphine (30 mg, QID) for 14 days and placebo (0 mg, QID) for the last 7 days of the 3-week study. Volunteers also received placebo (0 mg, PO, BID) capsules on days 1-7. On days 8-21, volunteers were randomized to receive ibudilast (20 or 40 mg, PO, BID) or placebo capsules. Subjective and clinical ratings of withdrawal symptoms were completed daily using daily using the Subjective Opioid Withdrawal Scale (SOWS) and Clinical Opioid Withdrawal Scale (COWS). Medication side effects were also monitored. Relative to the first 2 weeks, all groups exhibited withdrawal during the third week as assessed by the SOWS and COWS (P ≤ 0.0001). Although overall SOWS scores did not differ between groups, exploratory analyses pooling the two ibudilast groups demonstrated that they had lower ratings of withdrawal symptoms on SOWS items ('anxious,' 'perspiring,' 'restless,' 'stomach cramps') during detoxification relative to the placebo group. Ibudilast was well tolerated; no serious adverse events occurred during the study. Pharmacological modulation of glial activity with ibudilast decreased some subjective ratings of opioid withdrawal symptoms. These exploratory findings are the first to demonstrate the potential clinical utility of glial modulators for treating opioid withdrawal in humans.

Searching for evidence of genetic mediation of opioid withdrawal by opioid receptor gene polymorphisms.

BACKGROUND: Previous research has identified many genetic polymorphisms that appear to mediate the effects of opioid drugs. However, the relationship between genetic polymorphisms and the severity of opioid withdrawal has not yet been characterized. METHODS: Data were collected from 48 daily heroin users who previously completed a standardized abstinence-induced or naloxone-precipitated withdrawal procedure to assess opioid dependence. The total withdrawal severity score (based on the COWS) from this procedure was correlated with genotype information for variants of OPRM1 (rs1799971; rs6848893), OPRD1 (rs10753331; rs2234918; rs581111; rs678849; rs1042114), and OPRK1 (rs6473797; rs963549). Genotype and other participant variables (age, race, sex, duration of drug use, concomitant drug use, route of opioid use) were used as predictors. RESULTS: Of these variables, those individually correlated with a p < .2 were entered into a multivariate regression in order to identify the most predictive model. Three polymorphisms were significantly associated with severity of abstinence-induced withdrawal (n = 19) in the bivariate analysis (R): OPRM1 rs6848893 (.45), OPRD1 rs10753331 (.03), and rs678849 (.08), but only the OPRM1 rs6848893 was retained in the multivariate model (p < .001). For participants who underwent naloxone-precipitated withdrawal (n = 29) only OPRK1 rs6473797 (-.23) was significant in the bivariate analysis, though not retained in the final model. CONCLUSIONS: These data provide evidence for genetic modulation of opioid withdrawal severity, and suggest there may be qualitative differences between withdrawal resulting from abstinence and antagonist-precipitated withdrawal. SCIENTIFIC SIGNIFICANCE: This study demonstrates the importance and feasibility of incorporating genetic information into clinical addiction research.

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.

Abuse potential of intranasal buprenorphine versus buprenorphine/naloxone in buprenorphine-maintained heroin users.

In spite of the clinical utility of buprenorphine, parenteral abuse of this medication has been reported in several laboratory investigations and in the real world. Studies have demonstrated lower abuse liability of the buprenorphine/naloxone combination relative to buprenorphine alone. However, clinical research has not yet examined the utility of the combined formulation to deter intranasal use in a buprenorphine-maintained population. Heroin-using volunteers (n = 12) lived in the hospital for 8-9 weeks and were maintained on each of three sublingual buprenorphine doses (2, 8, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intranasal doses of buprenorphine (8, 16 mg), buprenorphine/naloxone (8/2, 8/8, 8/16, 16/4 mg) and controls (placebo, heroin 100 mg, naloxone 4 mg) were assessed. Intranasal buprenorphine alone typically produced increases in positive subjective effects and the 8 mg dose was self-administered above the level of placebo. The addition of naloxone dose dependently reduced positive subjective effects and increased aversive effects. No buprenorphine/naloxone combination dose was self-administered significantly more than placebo. These data suggest that within a buprenorphine-dependent population, intranasal buprenorphine/naloxone has reduced abuse potential in comparison to buprenorphine alone. These data strongly argue in favor of buprenorphine/naloxone rather than buprenorphine alone as the more reasonable option for managing the risk of buprenorphine misuse.

Empirical assessment of wounds among people who use substances.

BACKGROUND: Wounds are a significant source of morbidity among people who use substances (PWUS). This project sought to identify the incidence and severity of wounds among PWUS in the South Bronx, a region of New York City with one of the highest morbidities of substance use disorder. METHODS: This study recruited PWUS within the past 30 days. Research staff were trained to document the presence and severity of wounds. The primary outcome measure was the incidence of wounds. Acceptability of on-the-street wound care was assessed by the number of participants encountered. The association between participant characteristics and wounds was also evaluated. RESULTS: In total, 586 PWUS were assessed (19.4 % female: 69 % Hispanic; 23 % Black; 5 % White). Heroin (65.7 %) and psychostimulants (58.3 %) were the most commonly used drugs. Approximately 23 % of outreach recipients disclosed a wound. Among those with a wound, 60.9 % reported one wound, 27.8 % had two wounds, and 11.3 % had three or more wounds. Small wounds (approximately the size of a cherry) were the most common (78.6 %). Recent use of stimulants or heroin, along with intravenous use of any substance were significantly associated with having a wound. CONCLUSIONS: This study found that drug-related wounds were common among PWUS. Toxicology data from other sources indicate that xylazine was present in the NYC market at the time, though its prevalence among the current sample is difficult to determine. The occurrence and severity of substance-related wounds in NYC should continue to be monitored as a function of changes in the xylazine adulteration.

The influence of drug class on reward in substance use disorders.

In the United States, the societal costs associated with drug use surpass $500 billion annually. The rewarding and reinforcing properties that drive the use of these addictive substances are typically examined concerning the neurobiological effects responsible for their abuse potential. In this review, terms such as "abuse potential," "drug," and "addictive properties" are used due to their relevance to the methodological, theoretical, and conceptual framework for understanding the phenomenon of drug-taking behavior and the associated body of preclinical and clinical literature. The use of these terms is not intended to cast aspersions on individuals with substance use disorders (SUD). Understanding what motivates substance use has been a focus of SUD research for decades. Much of this corpus of work has focused on the shared effects of each drug class to increase dopaminergic transmission within the central reward pathways of the brain, or the "reward center." However, the precise influence of each drug class on dopamine signaling, and the extent thereof, differs considerably. Furthermore, the aforementioned substances have effects on several neurobiological targets that mediate and modulate their addictive properties. The current manuscript sought to review the influence of drug class on the rewarding effects of each of the major pharmacological classes of addictive drugs (i.e., psychostimulants, opioids, nicotine, alcohol, and cannabinoids). Our review suggests that even subtle differences in drug effects can result in significant variability in the subjective experience of the drug, altering rewarding and other reinforcing effects. Additionally, this review will argue that reward (i.e., the attractive and motivational property of a stimulus) alone is not sufficient to explain the abuse liability of these substances. Instead, abuse potential is best examined as a function of both positive and negative reinforcing drug effects (i.e., stimuli that the subject will work to attain and stimuli that the subject will work to end or avoid, respectively). Though reward is central to drug use, the factors that motivate and maintain drug taking are varied and complex, with much to be elucidated.

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.

Comparison of a drug versus money and drug versus drug self-administration choice procedure with oxycodone and morphine in opioid addicts.

This double-blind, placebo-controlled study investigated the effects of oral morphine (0, 45, 135 mg/70 kg) and oral oxycodone (0, 15, 45 mg/70 kg) on buprenorphine-maintained opioid addicts. As a 3: 1 morphine : oxycodone oral dose ratio yielded equivalent subjective and physiological effects in nondependent individuals, this ratio was used in the present study. Two self-administration laboratory procedures - that is, a drug versus money and a drug versus drug procedure - were assessed. Study participants (N=12) lived in the hospital and were maintained on 4 mg/day sublingual buprenorphine. When participants chose between drug and money, money was preferred over all drug doses; only high-dose oxycodone was self-administered more than placebo. When participants chose between drug and drug, both drugs were chosen more than placebo, high doses of each drug were chosen over low doses, and high-dose oxycodone was preferred over high-dose morphine. The subjective, performance-impairing, and miotic effects of high-dose oxycodone were generally greater than those of high-dose morphine. The study demonstrated that a 3: 1 oral dose ratio of morphine : oxycodone was not equipotent in buprenorphine-dependent individuals. Both self-administration procedures were effective for assessing the relative reinforcing effects of drugs; preference for one procedure should be driven by the specific research question of interest.

Opioid-like effects of the neurokinin 1 antagonist aprepitant in patients maintained on and briefly withdrawn from methadone.

BACKGROUND: Although opioid substitution therapy is an effective clinical tool used to manage opioid abuse and dependence, concerns regarding the current FDA-approved medications have lead to a search for efficacious, non-opioid medications. Preclinical data indicate that neurokinin 1 (NK1) receptor activity may modulate opioid effects and withdrawal. This investigation sought to examine the ability of the NK1 antagonist aprepitant to alter the effects of methadone as well as withdrawal symptoms induced by brief methadone discontinuation. METHODS: This blinded, placebo-controlled, within-subjects study consisted of placebo and aprepitant conditions. Experimental assessments occurred on the first three days (days 1-3: placebo or aprepitant + methadone) and again on days 8-10 (aprepitant or placebo + methadone). Fifteen methadone-maintained patients completed the investigation. Outcome measures were the assessments of opioid withdrawal, as well as subjective measures of opioid-like effects. RESULTS: Statistical trends indicated that aprepitant may reduce opioid withdrawal symptoms. When an active dose of aprepitant was administered an hour before methadone, participants reported less desire to use methadone. However, ratings of methadone "Liking" also appeared to increase. CONCLUSIONS: These data tentatively suggest that aprepitant has some ability to alleviate withdrawal following methadone abstinence, but also appears to increase subjective indicators of methadone's abuse liability. Since few of the differences between aprepitant and placebo reached statistical significance, these data should only be viewed as preliminary. Findings from other studies indicate that higher doses of aprepitant may be more clinically effective. Further clinical investigations are needed in order to determine whether aprepitant is useful for alleviating opioid withdrawal.

A pilot study examining the relationship between chronic heroin use and telomere length among individuals of African ancestry.

BACKGROUND: Prior research has suggested a possible link between heroin use and shortened telomere length (TL), a marker of cellular aging and genomic stability. We sought to replicate these findings by examining the relationship between TL and heroin use among individuals of African ancestry. METHODS: This cross-sectional study examined TL among 57 participants [17.5 % female; mean age 48.0 (±6.80) years] of African ancestry with Opioid Use Disorder (OUD) and a mean heroin use duration of 18.2 (±10.7) years. Quantitative polymerase chain reaction (qPCR) was used to calculate TL as the ratio between telomere repeat copy number (T) and a single-copy gene, copy number (S). The primary dependent variable was TL (T/S Ratio) measured in kilobase pairs. Covariates included heroin use years and personality traits. Using a hybrid approach, multiple linear regression and Bayesian linear regression examined the association of chronological age, heroin use years and personality traits with TL. RESULTS: The multiple linear regression model fit the data well, R2 = 0.265, F(7,49) = 2.53, p < .026. Chronological age (ß = -0.36, p = .017), neuroticism (ß = 0.46, p = .044), and conscientiousness (ß = 0.52, p = .040) were significant predictors of TL. Bayesian linear regression provided moderate support for the alternate hypothesis that chronological age and TL are associated, BF10 = 5.77, R2 = 0.120. The posterior summary of the coefficient was M = 0.719 (SD = 0.278, 95 % credible interval [-1.28, -0.163]). CONCLUSIONS: Contrary to prior studies, these findings suggest that heroin use duration may not be significantly associated with TL among individuals of African ancestry, highlighting the need for more rigorous research to elucidate the complexity of this relationship.