Bupropion and Naltrexone in Methamphetamine Use Disorder.

BACKGROUND: The use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied. METHODS: We conducted this multisite, double-blind, two-stage, placebo-controlled trial with the use of a sequential parallel comparison design to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg per day) in adults with moderate or severe methamphetamine use disorder. In the first stage of the trial, participants were randomly assigned in a 0.26:0.74 ratio to receive naltrexone-bupropion or matching injectable and oral placebo for 6 weeks. Those in the placebo group who did not have a response in stage 1 underwent rerandomization in stage 2 and were assigned in a 1:1 ratio to receive naltrexone-bupropion or placebo for an additional 6 weeks. Urine samples were obtained from participants twice weekly. The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of stage 1 or stage 2, and the weighted average of the responses in the two stages is reported. The treatment effect was defined as the between-group difference in the overall weighted responses. RESULTS: A total of 403 participants were enrolled in stage 1, and 225 in stage 2. In the first stage, 18 of 109 participants (16.5%) in the naltrexone-bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone-bupropion group and 2 of 111 (1.8%) in the placebo group had a response. The weighted average response across the two stages was 13.6% with naltrexone-bupropion and 2.5% with placebo, for an overall treatment effect of 11.1 percentage points (Wald z-test statistic, 4.53; P<0.001). Adverse events with naltrexone-bupropion included gastrointestinal disorders, tremor, malaise, hyperhidrosis, and anorexia. Serious adverse events occurred in 8 of 223 participants (3.6%) who received naltrexone-bupropion during the trial. CONCLUSIONS: Among adults with methamphetamine use disorder, the response over a period of 12 weeks among participants who received extended-release injectable naltrexone plus oral extended-release bupropion was low but was higher than that among participants who received placebo. (Funded by the National Institute on Drug Abuse and others; ADAPT-2 ClinicalTrials.gov number, NCT03078075.).

Optimally Choosing Medication Type for Patients With Opioid Use Disorder.

Patients with opioid use disorder (OUD) tend to get assigned to one of 3 medications based on the treatment program to which the patient presents (e.g., opioid treatment programs tend to treat patients with methadone, while office-based practices tend to prescribe buprenorphine). It is possible that optimally matching patients with treatment type would reduce the risk of return to regular opioid use (RROU). We analyzed data from 3 comparative effectiveness trials from the US National Institute on Drug Abuse Clinical Trials Network (CTN0027, 2006-2010; CTN0030, 2006-2009; and CTN0051 2014-2017), in which patients with OUD (n = 1,459) were assigned to treatment with either injection extended-release naltrexone (XR-NTX), sublingual buprenorphine-naloxone (BUP-NX), or oral methadone. We learned an individualized rule by which to assign medication type such that risk of RROU during 12 weeks of treatment would be minimized, and then estimated the amount by which RROU risk could be reduced if the rule were applied. Applying our estimated treatment rule would reduce risk of RROU compared with treating everyone with methadone (relative risk (RR) = 0.79, 95% confidence interval (CI): 0.60, 0.97) or treating everyone with XR-NTX (RR = 0.71, 95% CI: 0.47, 0.96). Applying the estimated treatment rule would have resulted in a similar risk of RROU to that of with treating everyone with BUP-NX (RR = 0.92, 95% CI: 0.73, 1.11).

Clinical and psychosocial outcomes by sex among individuals prescribed buprenorphine-naloxone (BUP-NX) or extended-release naltrexone (XR-NTX) for opioid use disorder.

BACKGROUND AND OBJECTIVES: Limited research has explored sex differences in opioid use disorder medication (MOUD) treatment outcomes. The purpose of this study was to examine MOUD initiation onto buprenorphine-naloxone (BUP-NX) versus extended-release naltrexone (XR-NTX) by sex, and sex differences in clinical and psychosocial outcomes. METHODS: Using data from a 24-week open-label comparative effectiveness trial of BUP-NX or XR-NTX, this study examined MOUD initiation (i.e., receiving a minimum one XR-NTX injection or first BUP-NX dose) and 24-week self-report outcomes. We used regression models to estimate the probability of MOUD initiation failure among the intent-to-treat sample (N = 570), and the main and interaction effects of sex on outcomes of interest among the subsample of participants who successfully initiated MOUD (n = 474). RESULTS: In the intent-to-treat sample, the odds of treatment initiation failure were not significantly different by sex. In the subsample of successful MOUD initiates, the effect of treatment on employment at week 24 was significantly moderated by sex (p = .003); odds of employment were not significantly different among males by MOUD type; females randomized to XR-NTX versus BUP-NX had 4.63 times greater odds of employment (p < .001). Males had significantly lower odds of past 30-day exchanging sex for drugs versus females (adjusted odds ratios [aOR] = 0.10, p = .004), controlling for treatment and baseline outcomes. DISCUSSION AND CONCLUSIONS: Further research should explore how to integrate employment support into OUD treatment to improve patient outcomes, particularly among women. SCIENTIFIC SIGNIFICANCE: The current study addressed gaps in the literature by examining sex differences in MOUD initiation and diverse treatment outcomes in a large, national sample.

Baseline- and treatment-associated pain in the X:BOT comparative effectiveness study of extended-release naltrexone versus buprenorphine-naloxone for OUD.

Chronic pain is highly prevalent among patients with opioid use disorder (OUD). However, little is known about how pharmacological treatments for OUD, for example, extended-release naltrexone (XR-NTX) and buprenorphine-naloxone (BUP-NX), affect pain. To begin addressing this question, we performed a secondary analysis of pain data on a large prospective 24-week, open-label, randomized-controlled comparative effectiveness trial of XR-NTX versus BUP-NX (X:BOT trial). Participants' pain status was measured by the EuroQol (EQ-5D). Based on their responses to the pain question at baseline, participants were dichotomized into "Pain" versus "No Pain" categories. Participant's pain status was evaluated every 4 weeks. A mixed effects longitudinal logistic regression model was fitted to examine the differential effect of XR-NTX versus BUP-NX on pain, modelling pain at all available follow-up assessments, adjusted for age, sex, and baseline pain. A total of 474 individuals who were successfully inducted onto their assigned medications were included in this analysis. Among participants endorsing pain at baseline, substantial reductions in pain were observed over the course of the study in both treatment groups. Howecver reduction in pain was slightly greater in the group treated with XR-NTX than the one treated with BUP-NX (OR = 1.60 [95% CI: 1.07-2.40], P = 0.023). Future research using instruments and design specifically focused on pain could extend the present observations and evaluate their clinical significance.

Patient Characteristics Associated with Opioid Abstinence after Participation in a Trial of Buprenorphine versus Injectable Naltrexone.

Background and Objectives: Better understanding of predictors of opioid abstinence among patients with opioid use disorder (OUD) may help to inform interventions and personalize treatment plans. This analysis examined patient characteristics associated with opioid abstinence in the X:BOT (Extended-Release Naltrexone versus Buprenorphine for Opioid Treatment) trial. Methods: This post-hoc analysis examined factors associated with past-month opioid abstinence at the 36-week follow-up visit among participants in the X:BOT study. 428 participants (75% of original sample) attended the visit at 36 weeks. Logistic regression models were used to estimate the probability of opioid abstinence across various baseline sociodemographics, clinical characteristics, and treatment variables. Results: Of the 428 participants, 143 (33%) reported abstinence from non-prescribed opioids at the 36-week follow-up. Participants were more likely to be opioid abstinent if randomized to XR-NTX (compared to BUP-NX), were on XR-NTX at week 36 (compared to those off OUD pharmacotherapy), successfully inducted onto either study medication, had longer time on study medication, reported a greater number of abstinent weeks, or had longer time to relapse during the 24-week treatment trial. Participants were less likely to be abstinent if Hispanic, had a severe baseline Hamilton Depression Rating (HAM-D) score, or had baseline sedative use. Conclusions: A substantial proportion of participants was available at follow-up (75%), was on OUD pharmacotherapy (53%), and reported past-month opioid abstinence (33%) at 36 weeks. A minority of patients off medication for OUD reported abstinence and additional research is needed exploring patient characteristics that may be associated with successful treatment outcomes.

Safety and efficacy of a digital therapeutic for substance use disorder: Secondary analysis of data from a NIDA clinical trials network study.

Background: Traditional treatments for substance use disorders (SUDs) rely heavily on face-to-face interactions, which pose substantial limitations for patients. A clinical trial of a digital therapeutic (DT), delivering behavioral therapy demonstrated safety and efficacy in a population including patients with opioid use disorder (OUD) not treated with buprenorphine, which is not a guideline-recommended approach. This study re-analyzed the data excluding patients with OUD to more closely approximate real-world patient populations. Methods: Secondary analysis of patients with substance use disorders related to alcohol, cannabis, cocaine, or other stimulants (n = 399, patients with OUD excluded) from a previously-published randomized controlled trial. Patients received 12-weeks of outpatient treatment-as-usual (TAU; n = 193) or TAU with reduced counseling plus a DT (n = 206) providing computerized cognitive behavioral therapy and contingency management. Primary outcomes were abstinence in weeks 9-12 and retention in treatment. Results: The 399 patients in this analysis (206 in the DT group and 193 in the TAU group) reported substance use disorders related to alcohol, cannabis, cocaine, or other stimulants (e.g., methamphetamines). Demographic and baseline characteristics including age, sex, race, education, and reported primary substance use disorder were balanced between treatment groups. Abstinence was significantly higher in the DT group compared to TAU (40.3 vs. 17.6%; p < 0.001) as was retention in therapy (76.2 vs. 63.2%, p = 0.004). Intergroup adverse event rates were not significantly different (p = 0.68). Conclusions: The results demonstrate that use of a DT safely increased abstinence (reduced substance use) and retention in treatment among patients with substance use disorders related to alcohol, cannabis, cocaine, or other stimulants (including methamphetamines).

Is extended release naltrexone superior to buprenorphine-naloxone to reduce drinking among outpatients receiving treatment for opioid use disorder? A secondary analysis of the CTN X:BOT trial.

BACKGROUND: The comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT) trial showed that following induction, treatment with the sublingual agonist (buprenorphine-naloxone, BUP-NX) or injected antagonist (extended release naltrexone, XR-NTX) produced similar reductions in opioid relapse in injection users with opioid use disorder (OUD). Because XR-NTX reduces drinking in alcohol use disorder (AUD), we conducted a secondary analysis of the X:BOT sample of patients successfully inducted onto treatment to determine whether XR-NTX (n = 204) was superior to BUP-NX (n = 270) in reducing drinking or heavy drinking in patients with OUD. METHODS: Standard drink units consumed were measured using the Timeline Follow-back method. Mixed-models regression was used to examine the monthly frequency of any drinking and heavy drinking over 6 months of treatment. We used a proportional hazard survival analysis to examine the time to first drink. RESULTS: Both treatment groups reduced drinking from baseline to posttreatment (small to medium effect), but no differences between groups were detected. However, only 29% (n = 136) of the sample had AUD and 19% (n = 26/136) of those were abstinent before treatment. Analysis of a subsample enriched for possible drinking included 136 individuals with an AUD diagnosis plus 43 who did not have AUD, but reported at least one day of heavy drinking prior to the study. However, this subsample reported only 32% of days of any drinking with a median of only 13% of days designated as "heavy." Within this subsample, at baseline, the BUP-NX group reported more mean drinks per drinking day than the XR-NTX group (p = 0.03); however, there were no other significant group differences on drinking observed before, during, or at the end of treatment. CONCLUSIONS: There was an overall reduction in drinking during treatment of OUD using both agonist and antagonist medications, so that the hypothesis that XR-NTX would be superior to BUP-NX was not supported. The study is limited by low levels of comorbid AUD or heavy drinking observed in X:BOT trial participants seeking treatment for OUD.

Pilot randomized placebo-controlled clinical trial of high-dose gabapentin for alcohol use disorder.

BACKGROUND: Despite advances in the development of pharmacotherapy for alcohol use disorder (AUD), there remains a need for medications that can be administered to actively drinking outpatients to promote a reduction in harmful alcohol consumption. The primary aim of this pilot study was to determine whether high-dose gabapentin (3600 mg/daily) is more effective than placebo in reducing harmful alcohol consumption in outpatients with AUD. METHODS: Forty patients (27 men) who met DSM-IV-TR criteria for alcohol dependence and reporting at least 4 heavy drinking days (HDD) per week were recruited at a single site. Participants were actively drinking at study entry and received double-blind gabapentin (3600 mg/day; n = 19) or placebo (n = 20) for 8 weeks. Study medication was titrated over 5 days and administered in three divided doses (1200 mg three times per day). The proportion of HDD (primary outcome) and percent days abstinent (PDA; secondary outcome) were analyzed using generalized longitudinal mixed models with the predictors being study arm, week, study arm by week interaction, and corresponding baseline drinking measure. RESULTS: There was a significant interaction between study arm and week for the proportion of HDD per week, F (7, 215) = 3.33, p = 0.002 . There was also a significant interaction between study arm and week for PDA per week, F (7, 215) = 3.11, p = 0.004. The overall retention rate was 67.5% with no significant difference in time-to-dropout between treatment groups. There were no serious adverse events. No participants were removed from the trial due to the development of moderate-to-severe alcohol withdrawal (CIWA-Ar ≥ 13). CONCLUSIONS: Gabapentin treatment rapidly titrated to a dosage of 3600 mg/day is associated with a reduction in the proportion of HDD per week and an increase in PDA per week in actively drinking outpatients with AUD. High-dose gabapentin is potentially a feasible approach to treating AUD and deserving of further study.

The utility of a formative one-station objective structured clinical examination for Substance use disorders in a dental curriculum.

Substance use disorders (SUD) are chronic relapsing medical conditions characterised by compulsive substance seeking and use. They constitute a substantial disease burden globally. Labelling of persons with SUD has created barriers to treatment but there are effective management strategies. The dental profession has embraced reforms designed to address the SUD epidemic by promoting continuing education for practitioners and initiating curriculum changes in dental schools. Screening, Brief Intervention and Referral to Treatment (SBIRT) is an evidence-based model for managing patients with SUD. The use of a formative 1-station Objective Structured Clinical Examination (OSCE) for learning and assessment in SBIRT, operationalised with the MD3 rating scale is presented in this study. In 3 years of implementation, the SBIRT OSCE successfully integrated into the curriculum of the College of Dental Medicine, Columbia University. Mean score of total adherent behaviours was 11.80 (SD =4.23) (range: 2 - 24) and Cronbach's coefficient alpha for across-items reliability in adherent behaviours was 0.66. Adherent behaviours correlated with the global ratings (r = 0.66). Mean of global rating scores were 2.90 (SD =1.01) for collaboration and 2.97 (SD =1.00) for empathy and the global rating scores correlated with each other (r = 0.85). Histograms of global rating scores resembled normal distribution. The 1-station OSCE is a good model for learning about SBIRT. Psychometric analysis was useful in understanding the underlying construct of the MD3 rating scale and supported its reliability, validity and utility in dental education.

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.

Addiction Psychiatry and Addiction Medicine: The Evolution of Addiction Physician Specialists.

Addiction Psychiatry and Addiction Medicine are two physician subspecialities recognized by the American Board of Medical Specialties (ABMS) that focus on providing care for patients with substance use disorders. Their shared and distinct historical roots are reviewed, and their respective ABMS board examination content areas and Accreditation Council on Graduate Medical Education (ACGME) fellowship training program requirements are compared. Addiction Psychiatry, a subspecialty under the American Board of Psychiatry and Neurology, began certifying diplomates in 1993, currently has 1202 active diplomates, and certifies around 150 diplomates every 2 years through 50 ACGME-accredited fellowships. Addiction Medicine, a subspecialty under the American Board of Preventive Medicine, began certifying diplomates in 2018, has 2604 diplomates with more expected before the practice pathway closes (anticipated in 2021), after which a fellowship training becomes required. Currently there are 78 accredited Addiction Medicine fellowships and more under development. The fields display substantial overlap between their respective examination content areas and fellowship training requirements, covering similar knowledge and skills for evaluation and treatment of substance use disorders and psychiatric and medical comorbidities across the full range of clinical settings, from general medical to addiction specialty settings. Key differences include that Addiction Psychiatry is open only to Board-certified psychiatrists and places extra emphasis on psychotherapeutic and psychopharmacological management strategies. Addiction Medicine is open to any ABMS primary specialty, including psychiatry. Opportunities for collaboration are discussed as both fields pursue the common goal of providing a well-trained workforce of physicians to meet the public health challenge presented by addiction. (Am J Addict 2020;00:00-00).

Substance Use and Mental Health in Emerging Adult Vs Older Adult Men and Women With Opioid Use Disorder.

BACKGROUND AND OBJECTIVES: We examined age differences across genders in clinical characteristics in emerging adult (≤25 years) vs older adult patients (26+ years) with opioid use disorder (OUD). METHODS: Participants (N = 570; 30% female) entering a comparative effectiveness medication trial of buprenorphine vs extended-release naltrexone. RESULTS: Differences in clinical characteristics in emerging adult vs older participants were similar across genders. However, women 26+ years reported more mental health problems compared with women ≤25, while men ≤25 years reported more mental health problems compared with men 26+ years. DISCUSSION AND CONCLUSION: Different strategies for emerging adult and older patients seeking OUD treatment may be necessary to address psychiatric comorbidities that differ across genders in this population. SCIENTIFIC SIGNIFICANCE: Comprehensive psychiatric assessment should be systematically included in OUD treatment for all genders. Treatment should focus on the emerging adult developmental phase when appropriate, with psychiatric treatment tailored for women and men, separately, across the lifespan. (Am J Addict 2020;29:536-542).

Cost-Effectiveness of Buprenorphine-Naloxone Versus Extended-Release Naltrexone to Prevent Opioid Relapse.

Background: Not enough evidence exists to compare buprenorphine-naloxone with extended-release naltrexone for treating opioid use disorder. Objective: To evaluate the cost-effectiveness of buprenorphine-naloxone versus extended-release naltrexone. Design: Cost-effectiveness analysis alongside a previously reported randomized clinical trial of 570 adults in 8 U.S. inpatient or residential treatment programs. Data Sources: Study instruments. Target Population: Adults with opioid use disorder. Time Horizon: 24-week intervention with an additional 12 weeks of observation. Perspective: Health care sector and societal. Interventions: Buprenorphine-naloxone and extended-release naltrexone. Outcome Measures: Incremental costs combined with incremental quality-adjusted life-years (QALYs) and incremental time abstinent from opioids. Results of Base-Case Analysis: Use of the health care sector perspective and a willingness-to-pay threshold of $100 000 per QALY showed buprenorphine-naloxone to be preferable to extended-release naltrexone in 97% of bootstrap replications at 24 weeks and in 85% at 36 weeks. Similar results were obtained with incremental time abstinent from opioids as an outcome and with use of the societal perspective. Results of Sensitivity Analysis: The base-case results were sensitive to the cost of the 2 treatments and the success of randomized treatment initiation. Limitation: Relatively short follow-up for a chronic condition, substantial missing data, no information on patient out-of-pocket and social service costs. Conclusion: Buprenorphine-naloxone is preferred to extended-release naltrexone as first-line treatment when both options are clinically appropriate and patients require detoxification before initiating extended-release naltrexone. Primary Funding Source: National Institute on Drug Abuse, National Institutes of Health.

A week-long outpatient induction onto XR-naltrexone in patients with opioid use disorder.

BACKGROUND: Extended-release (XR) naltrexone can prevent relapse to opioid use disorder following detoxification. However, one of the barriers to initiating XR-naltrexone is the recommendation for a 7-10-day period of abstinence from opioids prior to the first dose. OBJECTIVES: The current study evaluated the feasibility of an XR-naltrexone induction protocol that can be implemented over 1 week in the outpatient clinic. METHODS: Participants (N = 44) were seen in the clinic daily. On Day 1, after abstaining from opioids for at least 12 h, they received buprenorphine 6-8 mg. Adjunctive medications (clonidine, clonazepam, zolpidem, trazodone, and prochlorperazine) were dispensed on Days 2-5, while ascending oral doses of naltrexone were given on Days 3-5 starting with 1 mg dose. An injection of XR-naltrexone was given on Day 5, 1 h after receiving and tolerating naltrexone 24 mg. RESULTS: Of the 44 participants (38 males), 35 (80%) were heroin users and 9 (20%) used prescription opioids. A total of 26 participants (59%) completed the induction and received their first injection of XR-naltrexone. XR-naltrexone was initiated in 54% (19/35) of heroin users and 78% (7/9) of prescription opioid users. CONCLUSION: The results support the feasibility of a week-long outpatient induction onto XR-naltrexone with ascending doses of naltrexone and standing doses of adjunctive medications. By circumventing the need for a protracted period of abstinence and mitigating the severity of withdrawal symptoms experienced during naltrexone titration, this strategy has the potential to increase patient acceptability and access to relapse prevention treatment with XR-naltrexone.

Variants of opioid genes and response to treatment of opioid use disorder with buprenorphine-naloxone versus extended-release naltrexone in Caucasians.

Background: Sublingual buprenorphine-naloxone (BUP-NX), an FDA-approved treatment for opioid use disorder (OUD), combines buprenorphine (a partial mu/kappa agonist) with naloxone (a mu/ kappa antagonist). Extended-release injection naltrexone (XR-NTX; a mu receptor antagonist and kappa receptor partial agonist) is also an FDA-approved treatment for OUD. However, while some patients respond well to these medications, many others leave treatment and relapse. Objectives: Determine whether gene variants in the opioid gene system are associated with better or worse treatment response. Methods: In a 24-week, multisite, randomized, comparative effectiveness trial of daily, sublingual self-administration of BUP-NX versus monthly injection of XR-NTX conducted in the National Drug Abuse Clinical Trials Network, DNA was collected and four opioid gene variants were evaluated: (1) mu opioid receptor 118A>G; (2) 68-bp repeat in prodynorphin; (3) prodynorphin SNP rs910080; and (4) kappa opioid receptor SNP rs6473797. In non-Hispanic Caucasians (N = 334), two outcomes measures were assessed: received first dose (yes/no) and received last dose (yes/no). Separate logistic regressions were used to model each outcome measure as a function of treatment (XR-NTX vs BUP-NX), each gene variant, and their interaction. Results: There were no significant main effects of gene variant on receiving first dose or last dose. There were also no significant gene variant by treatment interactions. Conclusions: The outcome of treatment of OUD with medications is likely a complex function of multiple factors, including environmental, psychosocial, and possibly genetic, such that major effects of genetic variants may be unlikely.

Exploring gender differences among treatment-seekers who use opioids versus alcohol and other drugs.

Identifying clinical differences between opioid users (OU) and alcohol and other drug users (AOD) may help to tailor treatment to OU, particularly among the majority of OU who are not on opioid agonist treatments. Given the dearth of research on these differences, this study explored gender differences in demographic and clinical characteristics between OU and AOD. Participants (N = 506) were from a multisite, randomized controlled clinical trial of an Internet-delivered psychosocial intervention conducted in 2010-2011. Logistic regression models explored differences in demographic and clinical characteristics by substance use category within and between women and men. Women OU were more likely to be younger, White, employed, benzodiazepine users, and less likely to have children or use cocaine and cannabis than women AOD. Men OU, compared to men AOD, were more likely to be younger, White, younger at first abuse/dependence, benzodiazepine users, and reported greater psychological distress, but were less likely to be involved in criminal justice or use stimulants. Interactions by gender and substance use were also detected for age of first abuse/dependence, employment, and criminal justice involvement. These findings provide a nuanced understanding of gender differences within substance use groups to inform providers for OU seeking treatment.

Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Extended-release naltrexone (XR-NTX), an opioid antagonist, and sublingual buprenorphine-naloxone (BUP-NX), a partial opioid agonist, are pharmacologically and conceptually distinct interventions to prevent opioid relapse. We aimed to estimate the difference in opioid relapse-free survival between XR-NTX and BUP-NX. METHODS: We initiated this 24 week, open-label, randomised controlled, comparative effectiveness trial at eight US community-based inpatient services and followed up participants as outpatients. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 opioid use disorder, and had used non-prescribed opioids in the past 30 days. We stratified participants by treatment site and opioid use severity and used a web-based permuted block design with random equally weighted block sizes of four and six for randomisation (1:1) to receive XR-NTX or BUP-NX. XR-NTX was monthly intramuscular injections (Vivitrol; Alkermes) and BUP-NX was daily self-administered buprenorphine-naloxone sublingual film (Suboxone; Indivior). The primary outcome was opioid relapse-free survival during 24 weeks of outpatient treatment. Relapse was 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use. This trial is registered with ClinicalTrials.gov, NCT02032433. FINDINGS: Between Jan 30, 2014, and May 25, 2016, we randomly assigned 570 participants to receive XR-NTX (n=283) or BUP-NX (n=287). The last follow-up visit was Jan 31, 2017. As expected, XR-NTX had a substantial induction hurdle: fewer participants successfully initiated XR-NTX (204 [72%] of 283) than BUP-NX (270 [94%] of 287; p<0·0001). Among all participants who were randomly assigned (intention-to-treat population, n=570) 24 week relapse events were greater for XR-NTX (185 [65%] of 283) than for BUP-NX (163 [57%] of 287; hazard ratio [HR] 1·36, 95% CI 1·10-1·68), most or all of this difference accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures. Among participants successfully inducted (per-protocol population, n=474), 24 week relapse events were similar across study groups (p=0·44). Opioid-negative urine samples (p<0·0001) and opioid-abstinent days (p<0·0001) favoured BUP-NX compared with XR-NTX among the intention-to-treat population, but were similar across study groups among the per-protocol population. Self-reported opioid craving was initially less with XR-NTX than with BUP-NX (p=0·0012), then converged by week 24 (p=0·20). With the exception of mild-to-moderate XR-NTX injection site reactions, treatment-emergent adverse events including overdose did not differ between treatment groups. Five fatal overdoses occurred (two in the XR-NTX group and three in the BUP-NX group). INTERPRETATION: In this population it is more difficult to initiate patients to XR-NTX than BUP-NX, and this negatively affected overall relapse. However, once initiated, both medications were equally safe and effective. Future work should focus on facilitating induction to XR-NTX and on improving treatment retention for both medications. FUNDING: NIDA Clinical Trials Network.

Extended-Release Naltrexone to Prevent Opioid Relapse in Criminal Justice Offenders.

BACKGROUND: Extended-release naltrexone, a sustained-release monthly injectable formulation of the full mu-opioid receptor antagonist, is effective for the prevention of relapse to opioid dependence. Data supporting its effectiveness in U.S. criminal justice populations are limited. METHODS: In this five-site, open-label, randomized trial, we compared a 24-week course of extended-release naltrexone (Vivitrol) with usual treatment, consisting of brief counseling and referrals for community treatment programs, for the prevention of opioid relapse among adult criminal justice offenders (i.e., persons involved in the U.S. criminal justice system) who had a history of opioid dependence and a preference for opioid-free rather than opioid maintenance treatments and who were abstinent from opioids at the time of randomization. The primary outcome was the time to an opioid-relapse event, which was defined as 10 or more days of opioid use in a 28-day period as assessed by self-report or by testing of urine samples obtained every 2 weeks; a positive or missing sample was computed as 5 days of opioid use. Post-treatment follow-up occurred at weeks 27, 52, and 78. RESULTS: A total of 153 participants were assigned to extended-release naltrexone and 155 to usual treatment. During the 24-week treatment phase, participants assigned to extended-release naltrexone had a longer median time to relapse than did those assigned to usual treatment (10.5 vs. 5.0 weeks, P<0.001; hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.68), a lower rate of relapse (43% vs. 64% of participants, P<0.001; odds ratio, 0.43; 95% CI, 0.28 to 0.65), and a higher rate of opioid-negative urine samples (74% vs. 56%, P<0.001; odds ratio, 2.30; 95% CI, 1.48 to 3.54). At week 78 (approximately 1 year after the end of the treatment phase), rates of opioid-negative urine samples were equal (46% in each group, P=0.91). The rates of other prespecified secondary outcome measures--self-reported cocaine, alcohol, and intravenous drug use, unsafe sex, and reincarceration--were not significantly lower with extended-release naltrexone than with usual treatment. Over the total 78 weeks observed, there were no overdose events in the extended-release naltrexone group and seven in the usual-treatment group (P=0.02). CONCLUSIONS: In this trial involving criminal justice offenders, extended-release naltrexone was associated with a rate of opioid relapse that was lower than that with usual treatment. Opioid-use prevention effects waned after treatment discontinuation. (Funded by the National Institute on Drug Abuse; ClinicalTrials.gov number, NCT00781898.).

Differential Posttreatment Outcomes of Methylphenidate for Smoking Cessation for Individuals With ADHD.

BACKGROUND AND OBJECTIVES: In a multisite, randomized study (CTN-0029), a 3-month course of Osmotic-Release Oral System Methylphenidate (OROS-MPH) improved smoking cessation in a group of patients with higher baseline severity in Attention-Deficit/Hyperactivity Disorder (ADHD). This treatment, however, worsened smoking cessation outcome in the group with lower baseline ADHD severity. We want to examine whether this differential treatment effect persisted after OROS-MPH was discontinued. METHODS: We conducted a secondary analysis of the 1-month follow-up data from CTN-0029 after the discontinuation of OROS-MPH (N = 134). Nicotine patch was tapered during this month. We tested whether OROS-MPH had an effect on self-reported 7-day abstinence by week, as well as possible treatment by baseline ADHD severity interactions. RESULTS: Abstinence diminished overall in time after the end of the treatment. In the high baseline severity group, patients who received OROS-MPH had an advantage in 7-day abstinence at week 15 (40% for OROS-MPH vs 20% for placebo, odds ratio = 2.63, P = .028). In the lower severity group (n = 121), no difference was detected (29% for OROS-MPH vs 32% for placebo, P = 1.00) between the two treatment groups. There was also a significant treatment by baseline ADHD severity interaction (P = .03). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: OROS-MPH promotes abstinence beyond the course of treatment for patients with more severe ADHD, while the paradoxical effects in the lower baseline severity group is not persistent after medication discontinuation. Targeting ADHD in smoking cessation as a comorbidity therefore can have broader impact with more precise patient selection. (Am J Addict).