Psychometric properties of the Treatment Effectiveness Assessment in methamphetamine use disorder.

INTRODUCTION: The ability for people living with stimulant use disorder to live meaningful lives requires not only abstinence from addictive substances, but also healthy engagement with their community, lifestyle practices, and overall health. The Treatment Effectiveness Assessment (TEA) assesses components of recovery consisting of four functional domains: substance use, health, lifestyle, and community. This secondary data analysis of 403 participants with severe methamphetamine use disorder tested the reliability and validity of the TEA. METHODS: Participants were enrolled in the Accelerated Development of Additive Pharmacotherapy Treatment (ADAPT-2) for methamphetamine use disorder. The study used total TEA and domain scores at baseline to assess factor structure and internal consistency, as well as construct validity related to substance cravings (visual analog scale [VAS]), quality of life (quality-of-life assessment [QoL]), mental health (Patient Health Questionnaire-9 [PHQ-9], Concise Health Risk Tracking Scale Self-Report [CHRT-SR16]), and social support (CHRT-SR16). RESULTS: Individual TEA items showed moderate to large correlations with each other (r = 0.27-0.51; p < .001), and strong correlations to the total score (r = 0.69-0.78; p < .001). Internal consistency was strong (coefficient α = 0.73 [0.68-0.77]; coefficient ω = 0.73 [0.69-0.78]). Construct validity was acceptable, with the strongest correlation between the TEA Health item and the general health status item on the QoL (r = 0.53, p < .001). CONCLUSIONS: TEA has acceptable levels of reliability and validity supporting prior similar findings in a sample of participants with moderate to severe methamphetamine use disorder. Results from this study provide support for its use in assessing clinically meaningful changes beyond simply reduced substance use.

Continued Posttrial Benefits of Buprenorphine Extended Release: RECOVER Study Findings.

BACKGROUND: This analysis describes participants' opioid use disorder (OUD) outcomes for 18 months after discontinuing extended-release buprenorphine injection (BUP-XR, SUBLOCADE). METHODS: The RECOVER (Remission From Chronic Opioid Use: Studying Environmental and Socioeconomic Factors on Recovery) study recruited participants from BUP-XR clinical trials (NCT02357901, NCT025100142, and NCT02896296) to assess whether there were sustained benefits after leaving the trial. Abstinence from opioids and from all illicit substances (excluding medical cannabis), health-related quality of life, depression, and employment were measured after BUP-XR discontinuation and change in outcomes assessed at 6, 12, and 18 months. Results were analyzed within the full cohort and by duration of BUP-XR treatment (0-2 months, 3-5 months, 6-11 months, 12 months, or 13-18 months) with and without inverse probability weights adjusting for differences in baseline characteristics. RESULTS: Of 533 participants, 529 were assessed over the 18-month study period. Further posttrial pharmacotherapy was reported by 33% of participants. At RECOVER baseline, longer BUP-XR was associated with higher abstinence (0-2 months BUP-XR [n = 116]: 38.8%; 3-5 months BUP-XR [n = 61]: 41.0%; 6-11 months BUP-XR [n = 86]: 68.6%; 12 months BUP-XR [n = 135]: 71.9%; 18 months BUP-XR [n = 131]: 88.2%) and greater 12-Item Short Form Health Survey mental component scores. Over 60% of participants had stable or improved outcomes at 6, 12, and 18 months assessments. Overall 47% of participants self-reported sustained opioid abstinence for the full 18-month follow-up, with greater sustained abstinence associated with longer BUP-XR treatment duration. A sensitivity analysis, removing patients receiving medications for OUD, yielded similar results. CONCLUSIONS: Participants from BUP-XR clinical trials who continued into RECOVER maintained or improved on numerous outcomes over 18 months, demonstrating the long-term positive impact of OUD pharmacotherapy.

Moderation of buprenorphine therapy for cocaine dependence efficacy by variation of the Prodynorphin gene.

PURPOSE: The aim of this secondary analysis was to identify prodynorphin (PDYN) genetic markers moderating the therapeutic response to treatment of cocaine dependence with buprenorphine/naloxone (Suboxone®; BUP). METHODS: Cocaine-dependent participants (N = 302) were randomly assigned to a platform of injectable, extended-release naltrexone (XR-NTX) and one of three daily medication arms: 4 mg BUP (BUP4), 16 mg BUP (BUP16), or placebo (PLB) for 8 weeks (Parent Trial Registration: Protocol ID: NIDA-CTN-0048, Clinical Trials.gov ID: NCT01402492). DNA was obtained from 277 participants. Treatment response was determined from weeks 3 to 7 over each 1-week period by the number of cocaine-positive urines per total possible urines. RESULTS: In the cross-ancestry group, the PLB group had more cocaine-positive urines than the BUP16 group (P = 0.0021). The interactions of genetic variant × treatment were observed in the rs1022563 A-allele carrier group where the BUP16 group (N = 35) had fewer cocaine-positive urines (P = 0.0006) than did the PLB group (N = 26) and in the rs1997794 A-allele carrier group where the BUP16 group (N = 49) had fewer cocaine-positive urines (P = 0.0003) than did the PLB group (N = 58). No difference was observed in the rs1022563 GG or rs1997794 GG genotype groups between the BUP16 and PLB groups. In the African American-ancestry subgroup, only the rs1022563 A-allele carrier group was associated with treatment response. CONCLUSION: These results suggest that PDYN variants may identify patients who are best suited to treatment with XR-NTX plus buprenorphine for cocaine use disorder pharmacotherapy.

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.).

Recovery From Opioid Use Disorder (OUD) After Monthly Long-acting Buprenorphine Treatment: 12-Month Longitudinal Outcomes From RECOVER, an Observational Study.

OBJECTIVES: While evidence has mounted regarding the short-term effectiveness of pharmacotherapy for opioid use disorder (OUD), little is known about longer-term psychosocial, economic, and health outcomes. We report herein 12-month outcomes for an observational study enrolling participants who had previously taken part in a long-acting buprenorphine subcutaneous injection (BUP-XR) trial for moderate to severe OUD. METHODS: The RECOVER (Remission from Chronic Opioid Use: Studying Environmental and SocioEconomic Factors on Recovery; NCT03604861) study enrolled participants from 35 US community-based sites. Self-reported sustained opioid abstinence over 12 months and self-reported past-week abstinence at 3-, 6-, 9-, and 12-month visits were assessed. Multiple regression models assessed the association of BUP-XR duration with abstinence, controlling for potential confounders. Withdrawal, pain, health-related quality of life, depression, and employment at RECOVER baseline and 12-month visits were also compared to values collected before treatment in the BUP-XR trial. RESULTS: Of 533 RECOVER participants, 425 completed the 12-month visit (average age 42 years; 66% male); 50.8% self-reported sustained 12-month and 68.0% past-week opioid abstinence. In multiple regressions, participants receiving 12-month versus ≤2-month BUP-XR treatment duration had significantly higher likelihood of sustained opioid abstinence (75.3% vs 24.1%; P = 0.001), with similar results for past-week self-reported abstinence over time. During RECOVER, participants had fewer withdrawal symptoms, lower pain, positive health-related quality of life, minimal depression, and higher employment versus pre-trial visit. CONCLUSIONS: RECOVER participants reported positive outcomes over the 12-month observational period, including high opioid abstinence and stable or improved humanistic outcomes. These findings provide insights into the long-term impact of pharmacotherapy in OUD recovery.

Effects of monthly buprenorphine extended-release injections on patient-centered outcomes: A long-term study.

INTRODUCTION: The physical, social, psychological, and economic burden of opioid use disorder (OUD) is substantial. As of the year 2019, the predominant focus of OUD research was outcomes such as retention and abstinence. We report herein the effects of extended-release buprenorphine (BUP-XR), the first FDA-approved subcutaneously injected, monthly treatment for OUD, on patient-centered outcomes. MATERIALS AND METHODS: Patient-centered outcomes were collected during an open-label safety study of participants with OUD (NCT# 02510014) evaluating BUP-XR. Measures collected during the study included the EQ-5D-5L, SF-36v2, Treatment Effectiveness Assessment (TEA), Addiction Severity Index-Lite (ASI-Lite), employment/insurance status questionnaire, and Medication Satisfaction Questionnaire (MSQ). Changes from baseline to end of study week 49 were analyzed using mixed models for repeated measures. "Baseline" was defined as the value collected prior to the first BUP-XR injection. Results presented are for those participants who initiated treatment on BUP-XR during the open-label study and were eligible to receive up to 12 injections. RESULTS: Four hundred twelve participants were included in analyses; 206 participants discontinued BUP-XR prematurely. Mean EQ-5D-5L scores remained stable from baseline to end of study. Statistically significant improvements from baseline to end of study were noted for the SF-36v2 mental component summary score (difference = 5.0, 95%CI: 3.5-6.5) and 7 of 8 domain scores (P < .05 for all comparisons); the SF-36v2 physical component summary remained stable from baseline to end of study. The TEA total score (difference = 9.3 points, 95%CI: 8.0-10.5) and 4 of 4 domain scores (difference = 2-3 points per domain) significantly improved from baseline to end of study. Significant improvements (P < .05 for all comparisons) on the ASI-Lite were seen for all problem areas except alcohol use from baseline to end of study. Employment rate increased 7% whereas health insurance status remained stable from baseline to end of study. Medication satisfaction measured using the MSQ was >88% at end of study. CONCLUSIONS: Treatment with BUP-XR monthly injections for up to 12 months in this cohort of treatment-seeking individuals with OUD led to positive PCOs and high treatment satisfaction, which correspond to personal recovery.

Depot Buprenorphine Injection In The Management Of Opioid Use Disorder: From Development To Implementation.

Buprenorphine has pharmacologic advantages over methadone, especially buprenorphine's better safety profile. The true significance of buprenorphine's introduction lies in returning the care of those suffering from opioid use disorder (OUD) to the hands of the physician. The clinical success of buprenorphine has been meager, in part because most physicians have not been exposed to treating these patients. For physicians inclined to treat OUD, the barriers to buprenorphine's implementation have been onerous and largely counter to the norms of medical practice. Some notable concerns pertain to buprenorphine's clinical pharmacology like street diversion, unintended use and accidental poisoning. Recently, injectable buprenorphine preparations have been introduced to mitigate these latter shortcomings. Yet, the injectable preparations' clinical and commercial success has fallen far short of expectation. Here, we review the clinical pharmacology of these products and their expected clinical advantages for the manufacturers, clinicians, policy makers and patients, and offer our perspective, as clinicians and researchers, on how things can improve. Questions remain whether clinicians are willing to overcome barriers to treat OUD using these medications.

Measuring recovery in opioid use disorder: clinical utility and psychometric properties of the Treatment Effectiveness Assessment.

Purpose: The Treatment Effectiveness Assessment (TEA) is a patient-centered instrument for evaluating treatment progress and recovery from substance use disorders, including opioid use disorder (OUD). We assessed the TEA's reliability and validity and determined minimal clinically important differences (MIDs) in participants with moderate to severe OUD. Patients and methods: The TEA measures change in four single-item domains (substance use, health, lifestyle, community involvement) from treatment initiation across the duration of a treatment program. Self-reported responses range from 1 ("none or not much") to 10 ("much better") with items summed to a total score ranging from 4-40. We assessed floor and ceiling effects, internal consistency, test-retest reliability, known-groups validity (ANOVA stratified by current health status [36-Item Short Form Health Survey item 1]), convergent/divergent validity, and MIDs using data from a phase 3, open-label clinical trial of buprenorphine extended-release monthly injection for subcutaneous use (BUP-XR). Participants with OUD completed the TEA at screening and before monthly injections for up to 12 months. Results: Among 410 participants (mean age 38 years; 64% male), the mean baseline (pre-injection 1) TEA total score was 25.4 (SD 9.7), with <10% of participants at the measure floor and 10%-20% at the ceiling across domains. Internal consistency was high (Cronbach's α=0.90), with marginal test-retest reliability (intraclass correlation coefficient =0.69). Mean TEA total score consistently increased from baseline (n=410; mean 25.4 [SD 9.7]) to end of study (n=337; 35.0 [6.7]) and differentiated between current health status groups (P<0.001); it was weakly correlated with other measures of health-related quality of life/severity. MIDs ranged from 5-8 for the TEA total score across anchor- and distribution-based approaches. Conclusion: The TEA exhibited acceptable reliability and validity in a cohort of participants with moderate to severe OUD treated with BUP-XR. Given its brevity and psychometric properties, the TEA is a promising tool for use in clinical practice and research.

Patient-centered Outcomes in Participants of a Buprenorphine Monthly Depot (BUP-XR) Double-blind, Placebo-controlled, Multicenter, Phase 3 Study.

OBJECTIVE: Opioid use disorder (OUD) is associated with physical, social, psychological, and economic burden. This analysis assessed the effects of RBP-6000, referred to as BUP-XR (extended-release buprenorphine), a subcutaneously injected, monthly buprenorphine treatment for OUD compared with placebo on patient-centered outcomes measuring meaningful life changes. METHODS: Patient-centered outcomes were collected in a 24-week, phase 3, placebo-controlled study assessing the efficacy, safety, and tolerability of BUP-XR 300/300 mg (6 × 300 mg) and 300/100 mg (2 × 300 mg followed by 4 × 100 mg) injections in treatment-seeking participants with moderate-to-severe OUD. Measures included the EQ-5D-5L, SF-36v2, Medication Satisfaction Questionnaire, employment/insurance status, and healthcare resource utilization (HCRU). Changes from baseline to end of study were compared across treatment arms, using mixed models for repeated measures. RESULTS: Participants receiving BUP-XR (n = 389) versus placebo (n = 98) had significantly greater changes from baseline on the EQ-5D-5L index (300/300 mg: difference = 0.0636, P = 0.003), EQ-5D-5L visual analog scale (300/300 mg: difference = 5.9, P = 0.017; 300/100 mg: difference = 7.7, P = 0.002), and SF-36v2 physical component summary score (300/300 mg: difference = 3.8, P < 0.001; 300/100 mg: difference = 3.2, P = 0.002). Satisfaction was significantly higher for participants receiving BUP-XR 300/300 mg (88%, P < 0.001) and 300/100 mg (88%, P < 0.001) than placebo (46%). Employment and percentage of insured participants increased by 10.8% and 4.1% with BUP-XR 300/300 mg and 10.0% and 4.7% with 300/100 mg but decreased by 12.6% and 8.4% with placebo. Participants receiving BUP-XR compared with placebo had significantly fewer hospital days per person-year observed. CONCLUSIONS: These results show the feasibility of measuring patient-centered life changes in substance use disorder clinical studies. Participants receiving up to 6 monthly injections of BUP-XR, compared with placebo, reported better health, increased medication satisfaction, increased employment, and decreased healthcare utilization.

Efficacy and safety of a monthly buprenorphine depot injection for opioid use disorder: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: RBP-6000, referred to as BUP-XR (extended-release buprenorphine), is a subcutaneously injected, monthly buprenorphine treatment for opioid use disorder. BUP-XR provides sustained buprenorphine plasma concentrations to block drug-liking of abused opioids over the entire monthly dosing period, while controlling withdrawal and craving symptoms. Administration of BUP-XR in a health-care setting also mitigates abuse, misuse, diversion, and unintentional exposure. We aimed to investigate the efficacy of different BUP-XR dosing regimens in participants with opioid use disorder. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial was done at 36 treatment centres in the USA. Treatment-seeking adults aged 18-65 years who had moderate or severe opioid use disorder (as defined by the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders) entered an open-label run-in phase of up to 2 weeks' treatment with buprenorphine-naloxone sublingual film. Eligible participants were then randomly assigned (4:4:1:1) with an interactive voice/web-response system to receive BUP-XR 300 mg/300 mg (six injections of 300 mg), BUP-XR 300 mg/100 mg (two injections of 300 mg plus four injections of 100 mg), or volume-matched placebo every 28 days, and received weekly individual drug counselling. No supplemental buprenorphine was allowed. The primary efficacy endpoint was participants' percentage abstinence from opioid use, defined as the percentage of each participant's negative urine samples and self-reports of illicit opioid use from week 5 to week 24, analysed in the full analysis set. Safety was assessed in all participants who received at least one dose of BUP-XR or placebo. This study is registered with ClinicalTrials.gov, number NCT02357901. FINDINGS: From Jan 28, 2015, to Nov 12, 2015, 1187 potential participants were screened, 665 entered run-in, and 504 received BUP-XR 300 mg/300 mg (n=201), BUP-XR 300 mg/100 mg (n=203), or placebo (n=100). Mean participants' percentage abstinence was 41·3% (SD 39·7) for BUP-XR 300 mg/300 mg and 42·7% (38·5) for 300 mg/100 mg, compared with 5·0% (17·0) for placebo (p<0·0001 for both BUP-XR regimens). No compensatory non-opioid drug use was observed during BUP-XR treatment. The most common adverse events were headache (17 [8%] participants in the BUP-XR 300 mg/300 mg group vs 19 [9%] participants in the BUP-XR 300 mg/100 mg group vs six [6%] participants in the placebo group), constipation (16 [8%] vs 19 [9%] vs 0), nausea (16 [8%] vs 18 [9%] vs five [5%]), and injection-site pruritis (19 [9%] vs 13 [6%] vs four [4%]). The BUP-XR safety profile was consistent with other buprenorphine products for treatment of opioid use disorder, except for injection-site reactions, which were reported in more than 5% of all participants who received BUP-XR, but were mostly mild and not treatment-limiting. INTERPRETATION: Participants' percentage abstinence was significantly higher in both BUP-XR groups than in the placebo group. Treatment with BUP-XR was also well tolerated. The availability of this monthly formulation, delivered by health-care providers, represents an advance in treatment for opioid use disorder that enhances the benefits of buprenorphine by delivering sustained, optimal exposure, while reducing risks of current buprenorphine products. FUNDING: Indivior.

Medication Adherence Monitoring Using Smartphone Video Dosing in an Open-label Pilot Study of Monthly Naltrexone Plus Once-daily Bupropion for Methamphetamine Use Disorder: Feasibility and Acceptability.

OBJECTIVES: This article describes how smartphones were used to monitor and encourage medication adherence in a pilot study evaluating the potential efficacy of a combination pharmacotherapy for methamphetamine use disorder. We examine the feasibility, utility, and acceptability of using smartphones to capture dosing videos from the perspectives of participants and staff. METHODS: The study was an 8-week, open-label evaluation of extended-release injectable naltrexone combined with once-daily oral extended-release bupropion (BRP, Welbutrin XL, 450 mg/day). Participants attended visits twice-weekly for observed BRP dosing, assessments, and medical management. BRP was dispensed once weekly for dosing on nonclinic days. Medication adherence was assessed objectively (by observation in the clinic and smartphone videos for dosing at home) and subjectively (self-reports of dosing). Surveys assessing the smartphone component were completed by participants and study staff. RESULTS: Participants (N = 49) reported taking 93.6% of the dispensed BRP doses while 86.6% of dispensed doses were confirmed via dosing video and in-person observations. Most participants who completed the survey agreed that the smartphone was easy to use (92.6%) and that taking the dosing videos helped to remember to take the study medication (80.5%). Staff agreed that the smartphone helped collect accurate dosing data for most (77.5%) participants. CONCLUSIONS: The use of smartphones for video-based oral medication dosing in this study provided a feasible and acceptable mechanism to encourage, monitor, and confirm medication adherence. Video-confirmed dosing adherence provides an objective numerical indicator of the lowest medication adherence rate participants achieve, allowing investigators to more confidently interpret results.

Buprenorphine Maintenance Subjects Are Hyperalgesic and Have No Antinociceptive Response to a Very High Morphine Dose.

Objective: Acute pain management in opioid-dependent persons is complicated because of tolerance and opioid-induced hyperalgesia. Very high doses of morphine are ineffective in overcoming opioid-induced hyperalgesia and providing antinociception to methadone-maintained patients in an experimental setting. Whether the same occurs in buprenorphine-maintained subjects is unknown. Design: Randomized double-blind placebo-controlled. Subjects were tested on two occasions, at least five days apart, once with intravenous morphine and once with intravenous saline. Subjects were tested at about the time of putative trough plasma buprenorphine concentrations. Setting: Ambulatory. Subjects: Twelve buprenorphine-maintained subjects: once daily sublingual dose (range = 2-22 mg); no dose change for 1.5-12 months. Ten healthy controls. Methods: Intravenous morphine bolus and infusions administered over two hours to achieve two separate pseudo-steady-state plasma concentrations one hour apart. Pain tolerance was assessed by application of nociceptive stimuli (cold pressor [seconds] and electrical stimulation [volts]). Ten blood samples were collected for assay of plasma morphine, buprenorphine, and norbuprenorphine concentrations until three hours after the end of the last infusion; pain tolerance and respiration rate were measured to coincide with blood sampling times. Results: Cold pressor responses (seconds): baseline: control 34 ± 6 vs buprenorphine 17 ± 2 (P = 0.009); morphine infusion-end: control 52 ± 11(P = 0.04), buprenorphine 17 ± 2 (P > 0.5); electrical stimulation responses (volts): baseline: control 65 ± 6 vs buprenorphine 53 ± 5 (P = 0.13); infusion-end: control 74 ± 5 (P = 0.007), buprenorphine 53 ± 5 (P > 0.98). Respiratory rate (breaths per minute): baseline: control 17 vs buprenorphine 14 (P = 0.03); infusion-end: control 15 (P = 0.09), buprenorphine 12 (P < 0.01). Infusion-end plasma morphine concentrations (ng/mL): control 23 ± 1, buprenorphine 136 ± 10. Conclusions: Buprenorphine subjects, compared with controls, were hyperalgesic (cold pressor test), did not experience antinociception, despite high plasma morphine concentrations, and experienced respiratory depression. Clinical implications are discussed.

Treatment of opioid dependence with buprenorphine/naloxone sublingual tablets: A phase 3 randomized, double-blind, placebo-controlled trial.

INTRODUCTION: The purpose of the study is to evaluate the efficacy and safety of buprenorphine/naloxone sublingual tablets for the treatment of opioid dependence in Chinese adults. METHODS: This multicenter, double-blind, placebo-controlled study included four periods: induction (3-5 days), stabilization (7-21 days), randomization/treatment (6 weeks), and postmedication follow-up (1 week). A total of 442 participants with opioid dependence were enrolled; 260 were randomized to buprenorphine/naloxone or placebo. The primary outcome was retention in treatment, defined as the time from randomization to treatment completion or treatment failure. Secondary outcomes included maximum consecutive days of abstinence from opioids, self-reported craving and opioid withdrawal symptoms, and urine drug screen results. Safety assessments included adverse event reporting, electrocardiograms, clinical laboratory tests, vital signs, and prior/concomitant medications. RESULTS: The median treatment retention time (95% confidence internal) with buprenorphine/naloxone was 32 days (26-38) versus 6 days (5-8) for placebo, with a Cox hazard ratio of 0.28 (95% confidence interval, 0.21-0.38; P < 0.0001). The median maximum consecutive days of abstinence (95% confidence interval) was: buprenorphine/naloxone, 21 days (26-38); placebo, 5 days (5-8) with a Cox hazard ratio of 0.38 (95% confidence interval, 0.25-0.60; P < 0.0001). Withdrawal and craving symptoms were significantly milder with buprenorphine/naloxone versus placebo (P < 0.001). Urine drug screen results indicated significantly lower opioid usage in the buprenorphine/naloxone group compared with placebo (P < 0.001). The most commonly reported adverse events in the buprenorphine/naloxone group during treatment were aspartate aminotransferase increased and nasopharyngitis. DISCUSSION: Efficacy and safety results from this clinical trial support a positive benefit-risk ratio for buprenorphine/naloxone sublingual tablet use in the treatment of an opioid-dependent Chinese population.

Remission from chronic opioid use-Studying environmental and socio-economic factors on recovery (RECOVER): Study design and participant characteristics.

Few opioid use disorder (OUD) treatment studies measure meaningful life changes during long-term recovery, focusing instead on retention and abstinence. Here, we report on the design and participant characteristics of the RECOVER study, a study exploring life changes in persons with OUD for up to 24 months following participation in a Phase III trial evaluating buprenorphine extended-release monthly injection for subcutaneous use (known as RBP-6000 during development). This multisite, observational, cohort study tracks clinical, environmental, and socio-economic changes using self-administered assessments, urine drug screens (UDS), and public databases. Outcomes include demographics (e.g., patient characteristics, employment history, criminal history), lifetime and recent OUD drug use and treatment, and current health and resource use. Demographic and psychosocial characteristics are compared to a national, population-based study. RECOVER participants (N = 533) tend to be single, white, males aged 26 years or older. Mean age at first opioid use was 21.7 years; lifetime substance-related overdose was 24.2%. At first assessment, 334 (62.7%) participants reported past 7-day and 296 (55.5%) reported past 28-day opioid abstinence. Five hundred UDS were collected at the first assessment; buprenorphine (90.6%), marijuana (45.2%), and opiates (34.4%) were most commonly identified. Two hundred forty-nine (47.2%) participants reported full- or part-time employment. Participants were like a national sample with differences found for age, race/ethnicity, employment, education, and health-related quality of life. We hope that further research using this approach can provide data supporting the patient-centered development of OUD treatments and be adopted by substance use disorder studies to incorporate recovery-related, life-activity outcomes.

Sex differences in opioid use and medical issues during buprenorphine/naloxone treatment.

BACKGROUND: There are sex differences in buprenorphine/naloxone clinical trials for opioid use. While women have fewer opioid-positive urine samples, relative to men, a significant decrease in opioid-positive samples was found during treatment for men, but not women. In order to inform sex-based approaches to improve treatment outcomes, research is needed to determine if opioid use, and predictors of opioid use, differs between men and women during treatment. OBJECTIVES: To test for sex differences in opioid use during a buprenorphine/naloxone clinical trial and determine if sex differences exist in the associations between addiction-related problem areas and opioid use over the course of the trial. METHOD: This secondary data analysis of the National Drug Abuse Treatment Clinical Trials Network (CTN) 0003 examined sex differences (men = 347, women = 169) in opioid-positive samples in a randomized clinical trial comparing 7-day vs. 28-day buprenorphine/naloxone tapering strategies. Addiction-related problem areas were defined by Addiction Severity-Lite (ASI-L) domain composite scores. RESULTS: Women were more likely than men to use opioids during the course of the buprenorphine/naloxone clinical trial (B = .33, p = .01) and medical issues were positively related to submitting an opioid-positive sample during treatment for women (B = 1.67, p = .01). No ASI-L domain composite score was associated with opioid-positive samples during treatment for men. CONCLUSION: Women were more likely than men to use opioids during the course of the buprenorphine/naloxone clinical trial, and medical issues predicted opioid use during treatment for women but not men. Complementary treatment for medical problems during opioid replacement therapy may benefit women.

Testing and linkage to HIV care in China: a cluster-randomised trial.

BACKGROUND: Multistage, stepwise HIV testing and treatment procedures can result in lost opportunities to provide timely antiretroviral therapy (ART). Incomplete engagement of patients along the care cascade translates into high preventable mortality. We aimed to identify whether a structural intervention to streamline testing and linkage to HIV health care would improve testing completeness, ART initiation, and viral suppression and reduce mortality. METHODS: We did a cluster-randomised, controlled trial in 12 hospitals in Guangxi, China. All hospitals were required to be level 2A county general hospitals and ART delivery sites. We selected the 12 most similar hospitals in terms of structural characteristics, past patient caseloads, and testing procedures. Hospitals were randomly assigned (1:1) to either the One4All intervention or standard of care. Hospitals were randomised in a block design and stratified by the historical rate of testing completeness of the individual hospital during the first 6 months of 2013. We enrolled patients aged 18 years or older who were identified as HIV-reactive during screening in study hospitals, who sought inpatient or outpatient care in a study hospital, and who resided in the study catchment area. The One4All strategy incorporated rapid, point-of-care HIV screening and CD4 counts, and in-parallel viral load testing, to promote fast and complete diagnosis and staging and provide immediate ART to eligible patients. Participants in control hospitals received standard care services. All enrolled patients were assessed for the primary outcome, which was testing completeness within 30 days, defined as completion of three required tests and their post-test counselling. Safety assessments were hospital admissions for the first 90 days and deaths up to 12 months after enrolment. This trial is registered with ClinicalTrials.gov, number NCT02084316. FINDINGS: Between Feb 24 and Nov 25, 2014, we enrolled 478 patients (232 in One4All, 246 in standard of care). In the One4All group, 177 (76%) of 232 achieved testing completeness within 30 days versus 63 (26%) of 246 in the standard-of-care group (odds ratio 19·94, 95% CI 3·86-103·04, p=0·0004). Although no difference was observed between study groups in the number of hospital admissions at 90 days, by 12 months there were 65 deaths (28%) in the in the One4All group compared with 115 (47%) in the standard-of-care group (Cox proportional hazard ratio 0·44, 0·19-1·01, p=0·0531). INTERPRETATION: Our study provides strong evidence for the benefits of a patient-centred approach to streamlined HIV testing and treatment that could help China change the trajectory of its HIV epidemic, and help to achieve the goal of an end to AIDS. FUNDING: US National Institute on Drug Abuse Clinical Trials Network and China's National Health and Family Planning Commission.

Care cascade structural intervention versus standard of care in the diagnosis and treatment of HIV in China: a cluster-randomized controlled trial protocol.

BACKGROUND: The high rate of attrition along the care cascade of infection with human immunodeficiency virus (HIV) results in lost opportunities to provide timely antiretroviral therapy (ART) and to prevent unnecessarily high mortality. This study aims to assess the effectiveness of a structural intervention, the one-stop ("One4All") strategy that streamlines China's HIV care cascade with the intent to improve testing completeness, ART initiation, viral suppression, and mortality. METHOD: A two-arm, cluster-randomized controlled trial was implemented in twelve county hospitals in Guangxi China to test the effectiveness of the One4All strategy (intervention arm) compared to the current standard of care (SOC; control arm). The twelve study hospitals were selected for homogeneity and allocated one-to-one to the intervention and control arms. All patients screening HIV positive in study hospitals were enrolled. Target study enrollment was 180 participants per arm, 30 participants per hospital. Basic demographic information was collected as well as HIV risk behavior and route of infection. In intervention hospitals, patients then went on to receive point-of-care CD4 testing and in-parallel viral load (VL) testing whereas patients in control hospitals progressed through the usual SOC cascade. The primary outcome measure was testing completeness within 30 days of positive initial HIV screening result. Testing completeness was defined as receipt of all tests, test results, and post-test counseling. The secondary outcome measure was ART initiation (receipt of first ART prescriptions) within 90 days of positive initial HIV screening result. Tertiary outcome measures were viral suppression (≤200 copies/mL) and all-cause mortality at 12 months. DISCUSSION: We expect that this first-ever, cluster-randomized controlled trial of a bundle of interventions intended to streamline the HIV care cascade in China (the One4All strategy) will provide strong evidence for the benefit of accelerating diagnosis, thorough clinical assessment, and ART initiation via an optimized HIV care cascade. We furthermore anticipate that this evidence will be valuable to policymakers looking to elevate China's overall HIV/AIDS response to meet the UNAIDS 90-90-90 targets and the broader, global goal of eradication of the HIV/AIDS epidemic. TRIAL REGISTRATION: ClinicalTrials.gov # NCT02084316 . (Registered on March 7, 2014).

Prescription opioid addiction and chronic pain: More than a feeling.

A patient, long before becoming the subject of medical scrutiny is, at first simply a storyteller, a narrator of suffering-a traveler who has visited the kingdom of the ill. "To relieve an illness one must begin, then, by understanding the story." The Emperor of All Maladies; Siddhartha Mukherjee.