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In this trial involving adult ex-prisoners who had a history of opioid dependence, extended-release naltrexone resulted in a lower rate of opioid relapse than did usual treatment (brief counseling and referrals). The drug did not reduce rates of reincarceration or unsafe sex. Opioid-use disorder is a chronic relapsing condition that has serious public health consequences. Opioid dependence disproportionately affects U.S. criminal justice system populations, and relapse and overdose deaths occur at high rates after release from incarceration. 1 Evidence-based opioid-agonist maintenance therapies for opioid dependence (methadone and buprenorphine) are effective in prison, jail, and community reentry (i.e., parole) settings 2 – 5 but have historically been unavailable or discouraged among criminal justice clients. 6 – 8 Extended-release naltrexone (Vivitrol, Alkermes), a sustained-release monthly injectable formulation of the full mu-opioid receptor antagonist, was approved by the Food and Drug Administration in 2010 for the prevention of relapse to . . .

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. 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. 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). 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. NIDA Clinical Trials Network.

BackgroundEmergency department (ED)-initiated buprenorphine/naloxone with continuation in primary care was found to increase engagement in addiction treatment and reduce illicit opioid use at 30 days compared to referral only or a brief intervention with referral.ObjectiveTo evaluate the long-term outcomes at 2, 6 and 12 months following ED interventions.DesignEvaluation of treatment engagement, drug use, and HIV risk among a cohort of patients from a randomized trial who completed at least one long-term follow-up assessment.ParticipantsA total of 290/329 patients (88% of the randomized sample) were included. The followed cohort did not differ significantly from the randomized sample.InterventionsED-initiated buprenorphine with 10-week continuation in primary care, referral, or brief intervention were provided in the ED at study entry.Main MeasuresSelf-reported engagement in formal addiction treatment, days of illicit opioid use, and HIV risk (2, 6, 12 months); urine toxicology (2, 6 months).Key ResultsA greater number of patients in the buprenorphine group were engaged in addiction treatment at 2 months [68/92 (74%), 95% CI 65–83] compared with referral [42/79 (53%), 95% CI 42–64] and brief intervention [39/83 (47%), 95% CI 37–58; p < 0.001]. The differences were not significant at 6 months [51/92 (55%), 95% CI 45–65; 46/70 (66%) 95% CI 54–76; 43/76 (57%) 95% CI 45–67; p = 0.37] or 12 months [42/86 (49%) 95% CI 39–59; 37/73 (51%) 95% CI 39–62; 49/78 (63%) 95% CI 52–73; p = 0.16]. At 2 months, the buprenorphine group reported fewer days of illicit opioid use [1.1 (95% CI 0.6–1.6)] versus referral [1.8 (95% CI 1.2–2.3)] and brief intervention [2.0 (95% CI 1.5–2.6), p = 0.04]. No significant differences in illicit opioid use were observed at 6 or 12 months. There were no significant differences in HIV risk or rates of opioid-negative urine results at any time.ConclusionsED-initiated buprenorphine was associated with increased engagement in addiction treatment and reduced illicit opioid use during the 2-month interval when buprenorphine was continued in primary care. Outcomes at 6 and 12 months were comparable across all groups.

Background The concomitant presence of major depressive disorder (MDD) and opioid use disorder (OUD) poses a formidable clinical challenge, warranting effective interventions that address both psychiatric and addictive components. Aims This study sought to compare the efficacy of adjunctive ketamine and buprenorphine in mitigating anxiety symptom severity and craving intensity in individuals with co-occurring MDD and OUD. Methods A randomized, double-blind clinical trial was conducted, involving individuals meeting diagnostic criteria for both MDD and OUD. Participants were randomly assigned to receive adjunctive ketamine or buprenorphine, in conjunction with standard psychiatric and addiction treatments. Anxiety symptom severity and craving intensity were assessed using Hamilton Anxiety Rating Scale (HAM-A), and the Opioid Craving Scale after 2 h, 24 h, and 7 days. Results The findings revealed distinct treatment trajectories, with ketamine demonstrating rapid and substantial reduction in anxiety symptom severity within hours of administration, accompanied by a pronounced decline in opioid craving intensity. In contrast, buprenorphine was associated with a more gradual but sustained improvement in anxiety symptoms over several days, paralleled by a modest initial reduction in opioid craving, followed by persistent attenuation. Conclusions In conclusion, this randomized clinical trial provides evidence supporting the efficacy of adjunctive Ketamine and Buprenorphine in reducing anxiety symptoms and craving intensity in patients with co-occurring MDD and OUD. Trial registration IRCT20211214053411N1.

Opioid-induced respiratory depression driven by ligand binding to mu-opioid receptors is a leading cause of opioid-related fatalities. Buprenorphine, a partial agonist, binds with high affinity to mu-opioid receptors but displays partial respiratory depression effects. The authors examined whether sustained buprenorphine plasma concentrations similar to those achieved with some extended-release injections used to treat opioid use disorder could reduce the frequency and magnitude of fentanyl-induced respiratory depression. In this two-period crossover, single-centre study, 14 healthy volunteers (single-blind, randomized) and eight opioid-tolerant patients taking daily opioid doses ≥90 mg oral morphine equivalents (open-label) received continuous intravenous buprenorphine or placebo for 360 minutes, targeting buprenorphine plasma concentrations of 0.2 or 0.5 ng/mL in healthy volunteers and 1.0, 2.0 or 5.0 ng/mL in opioid-tolerant patients. Upon reaching target concentrations, participants received up to four escalating intravenous doses of fentanyl. The primary endpoint was change in isohypercapnic minute ventilation (VE). Additionally, occurrence of apnea was recorded. Fentanyl-induced changes in VE were smaller at higher buprenorphine plasma concentrations. In healthy volunteers, at target buprenorphine concentration of 0.5 ng/mL, the first and second fentanyl boluses reduced VE by [LSmean (95% CI)] 26% (13-40%) and 47% (37-59%) compared to 51% (38-64%) and 79% (69-89%) during placebo infusion (p = 0.001 and < .001, respectively). Discontinuations for apnea limited treatment comparisons beyond the second fentanyl injection. In opioid-tolerant patients, fentanyl reduced VE up to 49% (21-76%) during buprenorphine infusion (all concentration groups combined) versus up to 100% (68-132%) during placebo infusion (p = 0.006). In opioid-tolerant patients, the risk of experiencing apnea requiring verbal stimulation following fentanyl boluses was lower with buprenorphine than with placebo (odds ratio: 0.07; 95% CI: 0.0 to 0.3; p = 0.001). Results from this proof-of-principle study provide the first clinical evidence that high sustained plasma concentrations of buprenorphine may protect against respiratory depression induced by potent opioids like fentanyl.

Neuropsychopharmacologic effects of long-term opioid therapy (LTOT) in the context of chronic pain may result in subjective anhedonia coupled with decreased attention to natural rewards. Yet, there are no known efficacious treatments for anhedonia and reward deficits associated with chronic opioid use. Mindfulness-Oriented Recovery Enhancement (MORE), a novel behavioral intervention combining training in mindfulness with savoring of natural rewards, may hold promise for treating anhedonia in LTOT. Veterans receiving LTOT ( = 63) for chronic pain were randomized to 8 weeks of MORE or a supportive group (SG) psychotherapy control. Before and after the 8-week treatment groups, we assessed the effects of MORE on the late positive potential (LPP) of the electroencephalogram and skin conductance level (SCL) during viewing and up-regulating responses (i.e. savoring) to natural reward cues. We then examined whether these neurophysiological effects were associated with reductions in subjective anhedonia by 4-month follow-up. Patients treated with MORE demonstrated significantly increased LPP and SCL to natural reward cues and greater decreases in subjective anhedonia relative to those in the SG. The effect of MORE on reducing anhedonia was statistically mediated by increases in LPP response during savoring. MORE enhances motivated attention to natural reward cues among chronic pain patients on LTOT, as evidenced by increased electrocortical and sympathetic nervous system responses. Given neurophysiological evidence of clinical target engagement, MORE may be an efficacious treatment for anhedonia among chronic opioid users, people with chronic pain, and those at risk for opioid use disorder.

BackgroundIdentifying effective strategies to improve access to medication treatments for opioid use disorder (MOUD) is imperative. Within the Veterans Health Administration (VHA), provision of MOUD varies significantly, requiring development and testing of implementation strategies that target facilities with low provision of MOUD.ObjectiveDetermine the effectiveness of external facilitation in increasing the provision of MOUD among VHA facilities with low baseline provision of MOUD compared to matched controls.DesignPre-post, block randomized study designed to compare facility-level outcomes in a stratified sample of eligible facilities. Four blocks (two intervention facilities in each) were defined by median splits of both the ratio of patients with OUD receiving MOUD and number of patients with OUD not currently receiving MOUD (i.e., number of actionable patients). Intervention facilities participated in a 12-month implementation intervention.ParticipantsVHA facilities in the lowest quartile of MOUD provision (35 facilities), eight of which were randomly assigned to participate in the intervention (two per block) with twenty-seven serving as matched controls by block.InterventionExternal facilitation included assessment of local barriers/facilitators, formation of a local implementation team, a site visit for action planning and training/education, cross-facility quarterly calls, monthly coaching calls, and consultation.Main MeasuresPre- to post-change in the facility-level ratio of patients with an OUD diagnosis receiving MOUD compared to control facilities.Key ResultsIntervention facilities significantly increased the ratio of patients with OUD receiving MOUD from an average of 18% at baseline to 30% 1 year later, with an absolute difference of 12% (95% confidence interval [CI]: 6.6%, 17.0%). The difference in differences between intervention and control facilities was 3.0% (95% CI: − 0.2%. 6.7%). The impact of the intervention varied by block, with smaller, less complex facilities more likely to outperform matched controls.ConclusionsIntensive external facilitation improved the adoption of MOUD in most low-performing facilities and may enhance adoption beyond other interventions less tailored to individual facility contexts.

Physical exercise may affect drug use by balancing neurohormonal system mechanisms. Cortisol and β-endorphin, associated with stress, mood, and pleasure feelings, can be affected by exercise and act as regulators of withdrawal symptoms associated with drug use during short-term abstinence. The present study investigated the effect of a supervised, two-month moderate-intensity aerobic exercise program on salivary cortisol and β-endorphin levels in patients with an opioid use disorder (OUD) and on a substitution treatment during a short-term, 24–36 h withdrawal phase from methadone/buprenorphine medication. Ninety opioid users (41 females) in methadone and buprenorphine substitution treatment were randomly divided into four groups: (a) buprenorphine exercise (BEX) (n = 26; age (mean ± SD): 41.9 ± 6.1 yrs), (b) buprenorphine control (BCON) (n = 25; age: 41.9 ± 5.6 yrs), (c) methadone exercise (MEX) (n = 20; age: 46.7 ± 6.6 yrs), and (d) methadone control (MCON) (n = 19; age: 46.1 ± 7.5 yrs). The exercise intervention groups (BEX and MEX) followed a training program on a treadmill for 20 min at 70% HRmax, 3 days/week for 8 weeks. The responses of cortisol and β-endorphin were measured before (t0) and immediately after an exercise session (t20) on different days (i.e., the 1st, 12th, and 24th session) corresponding to the beginning, middle, and end of the training program. A significant increase in β-endorphin levels was observed after the completion of the training intervention (24th exercise session) in both exercise groups (BEX before: 63.8 ± 33; BEX after: 185.6 ± 182.8 pg/mL; MEX before: 115 ± 211; MEX after: 262.3 ± 505.7 pg/mL), whereas β-endorphin was decreased in the control groups (BCON before: 34.7 ± 20.1; BCON after: 24.2 ± 8.8 pg/mL; MCON before: 129.7 ± 185.7; MCON after: 84.9 ± 104.3 pg/mL) (p < 0.05). Inversely, cortisol decreased in both exercise groups post-intervention (BEX before: 9.5 ± 5.9; BEX after: 2.8 ± 1.5 ng/mL; MEX before: 9.3 ± 6.6; MEX after: 3.1 ± 1.5 ng/mL) and increased in control groups (BCON before: 6.3 ± 2.5; BCON after: 10.1 ± 5.4 ng/mL; MCON before: 7.5 ± 3.2; MCON after: 12.5 ± 4.3 ng/mL) (p < 0.05). Moderate-intensity aerobic exercise can beneficially influence β-endorphin and cortisol levels in individuals undergoing treatment for OUD. By increasing endogenous opioid levels and reducing stress hormones, exercise emerges as a promising adjunctive strategy for alleviating withdrawal symptoms, enhancing emotional regulation, and potentially reducing the risk of relapse. The inverse relationship between β-endorphin and cortisol highlights the role of physical activity as a long-term modulator of neuroendocrine function in the context of substance use recovery. Future research should prioritize longitudinal studies extending beyond two months and involving larger, more diverse populations. Additionally, investigating the integration of exercise with non-pharmacological interventions—and its effects on relapse rates, mental health outcomes, and overall quality of life—would provide further insight into its therapeutic value in addiction recovery.

In this trial comparing methadone with buprenorphine in opioid-dependent pregnant women, neonates exposed to buprenorphine required less morphine to treat neonatal abstinence syndrome (NAS) and had a significantly shorter duration of hospitalization and of treatment for NAS. Opioid dependence during pregnancy is compounded by multiple risk factors contributing to adverse maternal, neonatal, and long-term developmental consequences. 1 – 6 Improved treatment options should reduce the public health and medical costs associated with the treatment of neonates exposed to opioids, which in 2009 was estimated at $70.6 million to $112.6 million in the United States alone. 7 Just as the use of methadone in nonpregnant patients with opioid dependence improves patient outcomes, 8 its use as part of a comprehensive approach to the care of pregnant women improves maternal and neonatal outcomes, as compared with no treatment and with medication-assisted withdrawal. 4 , . . .