Attitudes toward extended-release naltrexone treatment for opioid use disorder among African Americans.

BACKGROUND: Extended-release naltrexone (XR-NTX; Vivitrol®) is a long-acting injectable form of naltrexone, which is a medication used to treat opioid use disorder (OUD). In 2010, XR-NTX received Food and Drug Administration approval to treat OUD, becoming the first non-addictive and non-psychoactive medication for this condition. Because uptake of XR-NTX has been relatively low, less is known regarding how persons with OUD view this form of treatment. And because previous studies tend to rely on samples that lack racial diversity or are conducted outside the United States, we know very little about how African Americans view XR-NTX. The objective of this study, therefore, was to identify/explain the most salient attitudes toward XR-NTX as a form of OUD treatment among African Americans. METHODS: In-depth interviews (n = 30) were conducted with a sample of African American adults who used opioids in Southwest Florida between August 2021 and February 2022. Audiotapes of interviews were transcribed, coded, and thematically analyzed. RESULTS: Analyses revealed that participants' attitudes toward XR-NTX were generally positive. Specifically, participants found XR-NTX's monthly injection administration, non-addictive and non-intoxicating properties, and perceived effectiveness (compared to other medications for OUD) most appealing. CONCLUSIONS: Study findings suggest that African Americans who use opioids may have more favorable attitudes toward XR-NTX than other medications for OUD (e.g., methadone), which tend to be highly stigmatized. These data uniquely contribute to the literature by capturing the voices of African Americans who use opioids, a group with high rates of opioid-related deaths.

Association of random and observed urine drug screening with long-term retention in opioid treatment programs.

BACKGROUND: In the US, opioid treatment providers (OTPs) have wide latitude to perform urine drug screening (UDS) and discharge clients for positive results. OTP clients have identified randomized and directly observed UDS as potentially stigmatizing, but little research has examined the association between UDS modality and retention in OTPs. METHODS: This cross-sectional study uses the 2016-2017 NDATSS wave among OTPs that administered methadone. The exposure was a 4-level variable based on whether OTPs had a high percentage (≥ 90% of clients) who experienced randomized, observed, both, or neither modality of UDS. The outcome was the proportion of clients retained in treatment 1 year or longer (long-term retention). Analyses were conducted using fractional logit regression with survey weighting and presented as percentages and 95% confidence intervals. We also present how policies for involuntary clinic discharge modify these effects. RESULTS: 150 OTPs were eligible with a median of 310 clients. 40 (27%) OTPs did not highly utilize either randomized or observed UDS, 22 (15%) only highly utilized observed UDS, 42 (28%) only highly utilized randomized UDS and 46 (31%) utilized both practices on ≥ 90% of clients. Adjusted estimates for long-term retention ranged from 57.7% in OTPs that conducted both randomized and observed UDS on ≥ 90% of clients and 70.4% in OTPs that did not highly utilize these practices. Involuntary discharge may moderate this relationship. CONCLUSION: Findings showed an association between high utilization of randomized and observed UDS and decreased long-term retention, suggesting that UDS modality may impact long-term OTP retention.

Naltrexone Compared With Buprenorphine or Methadone in Pregnancy: A Systematic Review.

OBJECTIVE: Although naltrexone is an evidence-based medication for opioid use disorder (MOUD), few data are available with use in pregnancy. Our objective was to assess outcomes of pregnant individuals with opioid use disorder (OUD) taking naltrexone compared with those taking methadone or buprenorphine. DATA SOURCES: We undertook a systematic review using electronic database search (PubMed, CINAHL, EMBASE, PsycInfo), conference proceedings, and trial registries including ClinicalTrials.gov . METHODS OF STUDY SELECTION: We conducted an electronic search of research articles through May 2023 for randomized controlled trials, prospective cohort, and retrospective cohort studies of naltrexone (oral, implant, or extended release) compared with methadone or buprenorphine (sublingual or extended release) among pregnant individuals with OUD. After double review of all articles, we abstracted obstetric (primary outcome: gestational age at delivery), neonatal (primary outcome: neonatal abstinence syndrome [NAS]), and substance use outcomes. TABULATION, INTEGRATION, AND RESULTS: Five studies met eligibility criteria; four were retrospective cohort studies, and one was a prospective cohort study. Four studies included data on gestational age at delivery (weeks) with no difference detected between the two groups in any study (mean difference ranging -0.20, 95% CI, -1.49-1.09 to 0.8, 95% CI, -0.15 to 1.75). Three studies included data on NAS with all studies detecting a lower risk in the naltrexone group compared with methadone or buprenorphine (relative risk ranging from 0.08, 95% CI, 0.01-1.16 to 0.15, 95% CI, 0.06-0.36). Most studies (four of five) had a moderate or high potential for selection bias primarily driven by small sample size and lack of controlling for confounders. CONCLUSION: Although the evidence base is limited, available data suggest that naltrexone use in pregnancy is a reasonable MOUD option with reassuring perinatal outcomes. To enhance confidence in this conclusion and to assess substance use outcomes, further comparative studies of pregnant people with OUD taking naltrexone and other MOUD types are needed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, 42017074249.

The Association Between Self-Reported Anxiety and Retention in Opioid Agonist Therapy: Findings From a Canadian Pragmatic Trial.

BACKGROUND: Prescription-type opioid use disorder (POUD) is often accompanied by comorbid anxiety, yet the impact of anxiety on retention in opioid agonist therapy (OAT) is unclear. Therefore, this study investigated whether baseline anxiety severity affects retention in OAT and whether this effect differs by OAT type (methadone maintenance therapy (MMT) vs. buprenorphine/naloxone (BNX)). METHODS: This secondary analysis used data from a pan-Canadian randomized trial comparing flexible take-home dosing BNX and standard supervised MMT for 24 weeks. The study included 268 adults with POUD. Baseline anxiety was assessed using the Beck Anxiety Inventory (BAI), with BAI ≥ 16 indicating moderate-to-severe anxiety. The primary outcomes were retention in assigned and any OAT at week 24. In addition, the impact of anxiety severity on retention was examined, and assigned OAT was considered an effect modifier. RESULTS: Of the participants, 176 (65%) reported moderate-to-severe baseline anxiety. In adjusted analyses, there was no significant difference in retention between those with BAI ≥ 16 and those with BAI < 16 assigned (29% vs. 28%; odds ratio (OR) = 2.03, 95% confidence interval (CI) = 0.94-4.40; P = 0.07) or any OAT (35% vs. 34%; OR = 1.57, 95% CI = 0.77-3.21; P = 0.21). In addition, there was no significant effect modification by OAT type for retention in assigned (P = 0.41) or any OAT (P = 0.71). In adjusted analyses, greater retention in treatment was associated with BNX (vs. MMT), male gender identity (vs. female, transgender, or other), enrolment in the Quebec study site (vs. other sites), and absence of a positive urine drug screen for stimulants at baseline. CONCLUSIONS: Baseline anxiety severity did not significantly impact retention in OAT for adults with POUD, and there was no significant effect modification by OAT type. However, the overall retention rates were low, highlighting the need to develop new strategies to minimize the risk of attrition from treatment. CLINICAL TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov (NCT03033732).

Wiidookaage'Win: A Community-Based Qualitative Approach to Developing a Facebook Group Intervention for Native Women to Support Recovery From Opioid Use.

PURPOSE: To develop a culturally-tailored American Indian/Alaska Native (AI/AN) women's Facebook group supporting opioid recovery as an adjunct to medication. DESIGN: Community-based, qualitative approach. SETTING: Minnesota, U.S. PARTICIPANTS: AI/AN women in opioid recovery, interested parties, and a Community Advisory Committee (CAC) of AI/AN women with lived experience, health care providers, and community members. INTERVENTION: We developed evidence-based content focusing on stress/trauma and substance use, mindfulness, responding to triggers, and supportive community resources. Additional content centered on AI/AN culture was also selected. METHOD: Interviews were conducted by two women, then transcribed and coded using content analysis with NVivo software. Results were presented to CAC for further content refinement. RESULTS: CAC members (n = 10) guided study methods, intervention development, and dissemination activities. 14 AI/AN women (mean age 36.4 years; mean 6.7 months opioid abstinence) and 12 interested parties (7 men, 5 women) were receptive to an AI/AN gender-specific Facebook group, preferring content with AI/AN people and/or text resonating with AI/AN culture (e.g., Native traditions, family, personal stories, historical trauma). Recommendations included (1) protect confidentiality, (2) retain positivity, (3) incorporate resources and exercises to build coping skills, and (4) moderators should be authentic and relatable to build trust. CONCLUSIONS: Our approach provides a model for developing culturally tailored, appealing and effective social media interventions to support AI/AN women in recovery from opioid use disorder.

Repeated measures analysis of opioid use disorder treatment on clinical opiate withdrawal scale in a randomized clinical trial: sex differences.

PURPOSE: Sex differences may exist in opioid use disorder (OUD) treatment. This study examined the treatment effects of buprenorphine/naloxone (BUP/NX) and methadone (MET) on the Clinical Opiate Withdrawal Scale (COWS) score in individuals with OUD and tested whether the associations differ by sex. METHOD: We performed a secondary analysis of the data from the National Drug Abuse Treatment Clinical Trials Network (CTN) protocol-0027. A total of 1269 participants (861 males and 408 females) being aged 18 or older with OUD were randomly assigned to receive BUP/NX (n = 740) or MET (n = 529). The paired t test was initially used to compare the COWS scores between pre-dose and post-dose for BUP/NX and MET treatments, separately. The linear mixed model was used to examine the changes in COWS score adjusted for baseline demographic, substance use, and mental health disorders. The interaction of sex and treatment was detected and stratified analysis by sex was conducted. RESULTS: The paired t test showed that both BUP/NX and MET treatments significantly reduced the COWS scores (p values <0.0001). BUP/NX revealed higher COWS scores than MET (p = 0.0008) and females demonstrated significantly higher COWS scores than males (p = 0.0169). Stratified by sex, BUP/NX compared with MET revealed higher COWS scores only in males (p = 0.0043), whereas baseline amphetamines use disorder and major depressive disorder were significantly associated with COWS scores in females (p = 0.0158 and 0.0422, respectively). CONCLUSIONS: Both BUP/NX and MET are effective in decreasing opioid withdrawal symptoms via COWS scores, however, treatment plans for OUD by clinical providers should consider sex differences.

Who receives heroin-assisted treatment? A comparison of patients receiving opioid maintenance treatment in Denmark.

BACKGROUND: Since 2010, heroin-assisted treatment (HAT) has been one of the treatment options available to people with opioid use disorder (OUD) in Denmark. This study aimed to characterize HAT patients at treatment start and compare their individual characteristics to those of patients entering traditional opioid maintenance treatment (OMT) with methadone or buprenorphine during the same period. METHODS: Patients who initiated HAT or OMT with methadone or buprenorphine in Denmark from 2010 to 2018 were included (n=6798). Multiple national registers were linked to compare treatment groups in terms of socio-demographic variables, previous OUD treatment episodes, hospital-based care, and criminal conviction history. RESULTS: Nearly all HAT patients had a history of methadone treatment (91%) and half had residential treatment experience (48%). In the year previous to admission, HAT patients recorded the highest percentages of non-fatal overdoses (12%) and chronic hepatitis C diagnoses (16%), and the lowest percentages of psychiatric disorders (11%) compared to traditional OMT patients. Criminal convictions were also common: 39% of the HAT group had committed a property crime and 18% a drug-related crime the year before HAT entry. During the study period, an overall reduction in OMT enrollments for each year was recorded. The HAT proportion to the total remained fairly stable (4%-10%), while the buprenorphine proportion increased. CONCLUSIONS: In Denmark, OMT patients exhibited numerous vulnerabilities at treatment start, and among the patient groups, HAT patients were the most burdened. HAT seems to reach the target group and adhere to formulated eligibility criteria.

Initiation and rapid titration of methadone and slow-release oral morphine (SROM) in an acute care, inpatient setting: a case series.

BACKGROUND: Methadone titration in an outpatient setting typically involves initiation with subtherapeutic doses with slow titration to mitigate the risks of respiratory depression and overdose. In pregnancy, and generally, subtherapeutic doses of methadone and slow titrations are associated with poorer outcomes in terms of treatment retention and ongoing illicit opioid use. We aim to describe rapid titration of OAT in an inpatient setting for pregnant injection opioid users with high opioid tolerance secondary to a fentanyl-based illicit drug supply. METHODS: Retrospective case series of patients admitted to a tertiary center with a primary indication of opioid withdrawal and treatment for severe opioid use disorder in pregnancy. RESULTS: Twelve women received rapid methadone titrations with or without slow-release oral morphine for opioid use disorder during a total of fifteen hospital admissions. All women included in the study were active fentanyl users (12/12). Methadone dosing was increased rapidly with no adverse events with a median dose at day 7 of 65 mg (IQR 60-70 mg) and median discharge dose of 85 mg (IQR 70-92.5 mg) during their admission for titration. Slow-release oral morphine was used in half of the titration admissions (8/15) with a median dose of 340 mg (IQR 187.5-425 mg) at discharge. The median length of admission was 12 days (IQR 9.5-15). CONCLUSIONS: A rapid titration of methadone was completed in an inpatient setting with or without slow-release oral morphine, without adverse events showing feasibility of this protocol for a pregnant population in an inpatient setting. Patients achieved therapeutic doses of methadone (and/or SROM) faster than outpatient counterparts with no known adverse events.

A genome-wide association, polygenic risk score and sex study on opioid use disorder treatment outcomes.

Opioid use disorder continues to be a health concern with a high rate of opioid related deaths occurring worldwide. Medication Assisted Treatments (MAT) have been shown to reduce opioid withdrawal, cravings and opioid use, however variability exists in individual's treatment outcomes. Sex-specific differences have been reported in opioid use patterns, polysubstance use and health and social functioning. Candidate gene studies investigating methadone dose as an outcome have identified several candidate genes and only five genome-wide associations studies have been conducted for MAT outcomes. This study aimed to identify genetic variants associated with MAT outcomes through genome-wide association study (GWAS) and test the association between genetic variants previously associated with methadone dose through a polygenic risk score (PRS). Study outcomes include: continued opioid use, relapse, methadone dose and opioid overdose. No genome-wide significance SNPs or sex-specific results were identified. The PRS identified statistically significant results (p < 0.05) for the outcome of methadone dose (R2 = 3.45 × 10-3). No other PRS was statistically significant. This study provides evidence for association between a PRS and methadone dose. More research on the PRS to increase the variance explained is needed before it can be used as a tool to help identify a suitable methadone dose within this population.

Impact of COVID-19-related methadone regulatory flexibilities: views of state opioid treatment authorities and program staff.

BACKGROUND: During the COVID-19 pandemic, federal regulations in the USA for methadone treatment of opioid use disorder (OUD) were temporarily revised to reduce clinic crowding and promote access to treatment. METHODS: As part of a study seeking to implement interim methadone without routine counseling to hasten treatment access in Opioid Treatment Programs with admission delays, semi-structured qualitative interviews were conducted via Zoom with participating staff (N = 11) in six OTPs and their State Opioid Treatment Authorities (SOTAs; N = 5) responsible for overseeing the OTPs' federal regulatory compliance. Participants discussed their views on the response of OTPs in their states to the pandemic and the impact of the COVID-related regulatory flexibilities on staff, established patients, and new program applicants. Interviews were audio recorded, transcribed, and a content analysis was conducted using ATLAS.ti. RESULTS: All SOTAs requested the blanket take-home exemption and supported the use of telehealth for counseling. Participants noted that these changes were more beneficial for established patients than program applicants. Established patients were able to obtain a greater number of take-homes and attend individual counseling remotely. Patients with limited resources had greater difficulty or were unable to access remote counseling. The convenience of intake through telehealth did not extend to new program applicants because the admission physical exam requirement was not waived. CONCLUSIONS: The experienced reflections of SOTAs and OTP providers on methadone practice changes during the COVID-19 pandemic offer insights on SAMHSA's proposed revisions to its OTP regulations. Trial registration Clinicaltrials.gov # NCT04188977.

Sublingual/Buccal buprenorphine and dental problems: a pharmacovigilance study.

BACKGROUND: The association between dental problems and sublingual/buccal buprenorphine is unclear. We conducted an analysis of dental adverse drug reactions reported with sublingual/buccal buprenorphine in VigiBase®, the pharmacovigilance database of the World Health Organization. RESEARCH DESIGN AND METHODS: We performed disproportionality analyses to compare the reporting rates of dental problems with sublingual/buccal buprenorphine, compared to other buprenorphine formulations and methadone. Significant signals were considered if the lower boundary of the 95% confidence interval of the Reporting Odds Ratio (ROR) was > 1; cases were ≥ 3 and p-value <0.05. We conducted sensitivity analyses by calculating the ROR according to the reporter's qualification and the reporting continent (United States of America and Europe). RESULTS: We included 30,769 reports with all buprenorphine forms. We found 20 cases of dental problems with sublingual/buccal buprenorphine. Sublingual/buccal buprenorphine was associated with an overreporting of dental problems compared to other buprenorphine formulations (ROR = 15.10; 95% CI [7.50-30.39]; p < 0.005) and compared to methadone (ROR = 6.02; 95% CI [3.21-11.30]; p < 0.005). Overreporting of dental problems was consistent in sensitivity analyses, except in Europe compared with other buprenorphine formulations and with methadone. CONCLUSIONS: Sublingual/buccal buprenorphine might increase the risk of reporting dental problems. However, these results do not modify the benefits of sublingual/buccal buprenorphine in the treatment of opioid use disorders.

Feasibility and preliminary efficacy of a community support intervention for people with opioid use disorder.

BACKGROUND AND OBJECTIVES: People receiving agonist treatment for opioid use disorder often have family or friends who do not use illicit substances and could be mobilized to support recovery efforts. The present study evaluates the feasibility and preliminary efficacy of a community support intervention (CSI) designed to increase drug-free social support and expand drug-free network support. METHODS: Participants receiving methadone treatment and using illicit drugs (n = 33) were randomly assigned to a weekly CSI or education group for 12 weeks. CSI participants attended the group with a drug-free family member or friend, and were scheduled to engage together in two community activities per week designed to meet drug-free people. Education participants attended a weekly education group and were given two weekly written homework sessions. RESULTS: CSI groups were well attended. CSI participation was associated with reduced conflict with the family member or friend, and with increased engagement in self-help groups. No condition differences were observed in social network variables or urinalysis results, though four CSI participants (24%) compared to 0 education participants met criteria for substantial (>75%) reductions in drug use. Many eligible patients chose not to participate. DISCUSSION AND CONCLUSIONS: These findings suggest good implementation feasibility and acceptability, and low demand feasibility. Broader clinical implementation requires strategies to improve patient willingness to enlist available social support. SCIENTIFIC SIGNIFICANCE: Mobilizing family and friends to provide social support for people engaged in active drug use is possible. More work is needed on how to leverage support to change existing networks.

Opioid use and COVID-19: a secondary analysis of the impact of relaxation of methadone take-home dosing guidelines on use of illicit opioids.

Background: An exemption to existing U.S. regulation of methadone maintenance therapy after the onset of the COVID-19 pandemic permitted increased take-home doses beginning March 2020.Objectives: We assessed the impact of this exemption on opioid use.Methods: A pre/post study of 187 clients recruited from an OTP who completed a survey and consented to share their urine drug testing (UDT) data. Use of fentanyl, morphine, hydromorphone, codeine, and heroin was assessed via UDT. Receipt of take-home methadone doses was assessed from clinic records for 142 working days pre- and post-COVID exemption. Analysis was conducted using a linear regression model to assess the association between increased take-home doses and use of illicit opioids.Results: In the pre- vs. post-COVID-19 SAMHSA exemption periods, 26.2% vs. 36.3% of UDTs were positive for 6-acetylmorphine respectively, 32.6% vs. 40.6% positive for codeine, 34.2% vs 44.2% positive for hydromorphone, 39.5% vs. 48.1% positive for morphine, 8.0% vs. 14.4% positive for fentanyl (p-value < .001). However, in the unadjusted descriptive data, when grouped by change in substance use, those clients who experienced a decrease in the use of morphine, codeine, and heroin post-COVID-19 were given significantly more take-home doses than the groups that had no change or an increase in the use of these substances. In the adjusted model, there was no significant relationship between change in opioid use and increased receipt of take-home methadone doses.Conclusions: Although take-home doses post-COVID-19 nearly doubled, this increase was not associated with a significant change in use of illicit opioids.

Efficacy and safety of tramadol in the treatment of opioid withdrawal: A meta-analysis of randomized controlled trials.

BACKGROUND: Pharmacotherapeutic options for the treatment of opioid withdrawal are limited by abuse potential, adverse effects, and lack of availability of existing drugs. The results from previous clinical trials on tramadol are contradictory and non-conclusive; hence the present meta-analysis was conducted to evaluate the efficacy and safety of tramadol in the treatment of opioid withdrawal. METHODS: Reviewers extracted data from eight relevant clinical trials after a literature search on MEDLINE/PubMed, Cochrane databases, and clinical trial registries. Quality assessment was done using the risk-of-bias assessment tool, and the random-effects model was used to estimate effect size in frequentist and Bayesian approaches. Subgroup analysis, meta-regression, and sensitivity analysis were done as applicable. PRISMA guidelines were followed in reporting findings. RESULTS: Tramadol significantly reduced opioid withdrawal scale score (SMD: -0.44; 95%CI: -0.76 to -0.13; PI: -1.54 to 0.71; p = 0.006) when all comparators were considered together in the frequentist approach but the reduction was non-significant in Bayesian approach. However, the subgroup analysis revealed no significant difference between tramadol and comparators like placebo (SMD: -1.12; 95%CI: -2.69 to 0.45) buprenorphine (SMD: -0.21; 95%CI: -0.43 to 0.01), clonidine (SMD: -0.26; 95%CI: -0.55 to 0.02) and methadone (SMD: -0.84; 95%CI: -1.78 to 0.10). Meta-regression showed non-significant associations between the SMD in opioid withdrawal score with the duration and dose of tramadol therapy. There were no significant differences in treatment retention at the end of studies between tramadol and comparators. Safety data in the individual studies were inadequate to analyze. CONCLUSION: Authors conclude that the efficacy of tramadol in reducing opioid withdrawal symptoms is not significantly different from comparators with low certainty of evidence against placebo, moderate against methadone, whereas with high certainty of evidence against buprenorphine and clonidine.

Attitudes toward methadone treatment among Black/African Americans: Implications for engagement and retention.

Despite its ability to lower the risk of opioid misuse, methadone is viewed by patients with a certain degree of ambivalence. Research has documented a variety of patient attitudes toward methadone, but the majority of these studies have relied on samples with little Black/African American representation. The primary goal of this study, therefore, was to identify and explain the attitudes of Black/African Americans toward methadone treatment. Surveys were used to identify which attitudes were most prevalent while interview data are presented to help explain and provide context to these attitudes. Data were drawn from the Florida Minority Health Survey, a mixed-methods project that included online surveys (n = 303) and in-depth interviews (n = 30). Only persons 18 years old or over who identified as Black/African American and reported past 90-day opioid misuse were eligible to participate. Analyses revealed that negative attitudes largely revolved around methadone's perceived helpfulness and side effects. The most strongly held attitudes were (a) methadone in a treatment program gets you high just like heroin, (b) the sooner a person stops taking methadone, the better, and (c) methadone is a "crutch." These findings contribute to the literature by improving our understanding of why some Black/African Americans may be ambivalent about methadone. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Methadone Induction for a Patient With Precipitated Withdrawal in the Emergency Department: A Case Report.

In the era of illicit fentanyl, reports on difficulties with buprenorphine inductions for patients with opioid use disorder are emerging. Methadone is the only other approved medication treatment with efficacy similar to buprenorphine but without risks of precipitated withdrawal. Unfortunately, outpatient methadone inductions can take days to weeks to complete, due in part to regulations that limit administration to opioid treatment programs. We describe a patient with opioid use disorder who presented to the emergency department in precipitated withdrawal who completed a same-day methadone induction with next-day dosing at an opioid treatment program as part of an emergency department methadone protocol. As opioid-related deaths rise, emergency department-initiated methadone is feasible for patients with opioid use disorder.

Buprenorphine versus methadone for the treatment of opioid dependence: a systematic review and meta-analysis of randomised and observational studies.

BACKGROUND: Opioid dependence is associated with substantial health and social burdens, and opioid agonist treatment (OAT) is highly effective in improving multiple outcomes for people who receive this treatment. Methadone and buprenorphine are common medications provided as OAT. We aimed to examine buprenorphine compared with methadone in the treatment of opioid dependence across a wide range of primary and secondary outcomes. METHODS: We did a systematic review and meta-analysis in accordance with GATHER and PRISMA guidelines. We searched Embase, MEDLINE, CENTRAL, and PsycINFO from database inception to Aug 1, 2022; clinical trial registries and previous relevant Cochrane reviews were also reviewed. We included all RCTs and observational studies of adults (aged ≥18 years) with opioid dependence comparing treatment with buprenorphine or methadone. Primary outcomes were retention in treatment at 1, 3, 6, 12, and 24 months, treatment adherence (measured through doses taken as prescribed, dosing visits attended, and biological measures), or extra-medical opioid use (measured by urinalysis and self-report). Secondary outcomes were use of benzodiazepines, cannabis, cocaine, amphetamines, and alcohol; withdrawal; craving; criminal activity and engagement with the criminal justice system; overdose; mental and physical health; sleep; pain; global functioning; suicidality and self-harm; and adverse events. Single-arm cohort studies and RCTs that collected data on buprenorphine retention alone were also reviewed. Data on study, participant, and treatment characteristics were extracted. Study authors were contacted to obtain additional data when required. Comparative estimates were pooled with use of random-effects meta-analyses. The proportion of individuals retained in treatment across multiple timepoints was pooled for each drug. This study is registered with PROSPERO (CRD42020205109). FINDINGS: We identified 32 eligible RCTs (N=5808 participants) and 69 observational studies (N=323 340) comparing buprenorphine and methadone, in addition to 51 RCTs (N=11 644) and 124 observational studies (N=700 035) that reported on treatment retention with buprenorphine. Overall, 61 studies were done in western Europe, 162 in North America, 14 in north Africa and the Middle East, 20 in Australasia, five in southeast Asia, seven in south Asia, two in eastern Europe, three in central Europe, one in east Asia, and one in central Asia. 1 040 827 participants were included in these primary studies; however, gender was only reported for 572 111 participants, of whom 377 991 (66·1%) were male and 194 120 (33·9%) were female. Mean age was 37·1 years (SD 6·0). At timepoints beyond 1 month, retention was better for methadone than for buprenorphine: for example, at 6 months, the pooled effect favoured methadone in RCTs (risk ratio 0·76 [95% CI 0·67-0·85]; I·=74·2%; 16 studies, N=3151) and in observational studies (0·77 [0·68-0·86]; I·=98·5%; 21 studies, N=155 111). Retention was generally higher in RCTs than observational studies. There was no evidence suggesting that adherence to treatment differed with buprenorphine compared with methadone. There was some evidence that extra-medical opioid use was lower in those receiving buprenorphine in RCTs that measured this outcome by urinalysis and reported proportion of positive urine samples (over various time frames; standardised mean difference -0·20 [-0·29 to -0·11]; I·=0·0%; three studies, N=841), but no differences were found when using other measures. Some statistically significant differences were found between buprenorphine and methadone among secondary outcomes. There was evidence of reduced cocaine use, cravings, anxiety, and cardiac dysfunction, as well as increased treatment satisfaction among people receiving buprenorphine compared with methadone; and evidence of reduced hospitalisation and alcohol use in people receiving methadone. These differences in secondary outcomes were based on small numbers of studies (maximum five), and were often not consistent across study types or different measures of the same constructs (eg, cocaine use). INTERPRETATION: Evidence from trials and observational studies suggest that treatment retention is better for methadone than for sublingual buprenorphine. Comparative evidence on other outcomes examined showed few statistically significant differences and was generally based on small numbers of studies. These findings highlight the imperative for interventions to improve retention, consideration of client-centred factors (such as client preference) when selecting between methadone and buprenorphine, and harmonisation of data collection and reporting to strengthen future syntheses. FUNDING: Australian National Health and Medical Research Council.

Effectiveness of Conditioned Open-label Placebo With Methadone in Treatment of Opioid Use Disorder: A Randomized Clinical Trial.

Importance: Methadone treatment is the most effective evidence-based treatment for opioid use disorder (OUD), but challenges related to dosing and premature treatment dropout argue for adjunct interventions to improve outcomes. One potential behavioral intervention with low risk involves harnessing placebo effects. Objective: To determine the effect of a pharmacologically conditioned open-label placebo (C-OLP) on 90-day methadone dose, retention, drug use, withdrawal, craving, quality of life, and sleep. Design, Setting, and Participants: This 2-arm, open-label, single-blind randomized clinical trial was conducted between December 5, 2017, and August 2, 2019, in an academically affiliated community opioid treatment program. Analyses were conducted between October 1, 2019, and April 30, 2020. A total of 320 newly enrolled adults seeking treatment for moderate to severe OUD were assessed for study eligibility; 131 met eligibility criteria, provided informed consent, and were randomized to either C-OLP or treatment as usual (TAU) in an unequal-block (3:2) manner. Exclusion criteria were pregnancy, hospital/program transfers, and court-ordered treatment. Interventions: Participants randomized to C-OLP received pharmacologic conditioning and a placebo pill and methadone, and participants randomized to TAU were given methadone only. Participants met with the study team 5 times: at baseline (treatment intake) and 2, 4, 8, and 12 weeks postbaseline. Interactions were balanced between the 2 groups. Main Outcomes and Measures: Outcomes included 90-day methadone dose (primary) and treatment retention, drug use, withdrawal, craving, quality of life, and sleep quality (secondary). Analyses were conducted as intention-to-treat. Results: Of the 131 people enrolled in the study, 54 were randomized to TAU and 77 to C-OLP. Mean (SD) age was 45.9 (11.2) years; most of the participants were Black or African American (83 [63.4%]) and male (84 [64.1%]). No significant group differences were observed in the mean (SD) 90-day methadone dose (83.1 [25.1] mg for group TAU, 79.4 [19.6] mg for group C-OLP; t = 0.621991; P = .43), but the groups differed significantly in their retention rates: 33 (61.1%) for TAU and 60 (77.9%) for C-OLP (χ21 = 4.356; P = .04; number needed to treat for the beneficial outcome of 3-month treatment retention, 6; 95% CI, 4-119). C-OLP participants also reported significantly better sleep quality. Conclusions and Relevance: In this randomized clinical trial, C-OLP had no effect on the primary outcome of 90-day methadone dose. However, C-OLP participants were significantly more likely to remain in treatment. These findings support the use of C-OLP as a methadone treatment adjunct, but larger trials are needed to further examine the use of C-OLP. Trial Registration: ClinicalTrials.gov Identifier: NCT02941809.