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.
Pharmacotherapy and behavioral treatments for alcohol use disorder are limited in their effectiveness, and new treatments with innovative mechanisms would be valuable. In this pilot study, the ...authors tested whether a single subanesthetic infusion of ketamine administered to adults with alcohol dependence and engaged in motivational enhancement therapy affects drinking outcomes.
Participants were randomly assigned to a 52-minute intravenous administration of ketamine (0.71 mg/kg, N=17) or the active control midazolam (0.025 mg/kg, N=23), provided during the second week of a 5-week outpatient regimen of motivational enhancement therapy. Alcohol use following the infusion was assessed with timeline followback method, with abstinence confirmed by urine ethyl glucuronide testing. A longitudinal logistic mixed-effects model was used to model daily abstinence from alcohol over the 21 days after ketamine infusion.
Participants (N=40) were mostly middle-aged (mean age=53 years SD=9.8), predominantly white (70.3%), and largely employed (71.8%) and consumed an average of five drinks per day prior to entering the study. Ketamine significantly increased the likelihood of abstinence, delayed the time to relapse, and reduced the likelihood of heavy drinking days compared with midazolam. Infusions were well tolerated, with no participants removed from the study as a result of adverse events.
A single ketamine infusion was found to improve measures of drinking in persons with alcohol dependence engaged in motivational enhancement therapy. These preliminary data suggest new directions in integrated pharmacotherapy-behavioral treatments for alcohol use disorder. Further research is needed to replicate these promising results in a larger sample.
Amid worsening opioid overdose death rates, the nation continues to face a persistent addiction treatment gap limiting access to quality care for opioid use disorder (OUD). Three FDA-approved ...medications (methadone, buprenorphine, and extended-release naltrexone) have high quality evidence demonstrating reductions in drug use and overdose events, but most individuals with OUD do not receive them. The development of a unified public health framework, such as a Cascade of Care, could improve system level practice and treatment outcomes. In response to feedback from many stakeholders over the past year, we have expanded upon the OUD treatment cascade, first published in 2017, with additional attention to prevention stages and both individual-level and population-based services to better inform efforts at the state and federal level. The proposed cascade framework has attracted considerable interest from federal agencies including the Centers for Disease Control and Prevention (CDC) and National Institute on Drug Abuse (NIDA) along with policy-makers nationwide. We have reviewed recent literature and evidence-based interventions related to prevention, identification, and treatment of individuals with OUD and modeled updated figures from the 2016 National Survey on Drug Use and Health. Many currently employed interventions (prescriber guidelines, prescription monitoring programs, naloxone rescue) address prevention of OUD or downstream complications but not treatment of the underlying disorder itself. An OUD Cascade of Care framework could help structure local and national efforts to combat the opioid epidemic by identifying key targets, interventions, and quality indicators across populations and settings to achieve these ends. Improved data collection and reporting methodology will be imperative.
Background: In clinical trials of behavioral health interventions, outcome variables often take the form of counts, such as days using substances or episodes of unprotected sex. Classically, count ...data follow a Poisson distribution; however, in practice such data often display greater heterogeneity in the form of excess zeros (zero-inflation) or greater spread in the values (overdispersion) or both. Greater sample heterogeneity may be especially common in community-based effectiveness trials, where broad eligibility criteria are implemented to achieve a generalizable sample. Objectives: This article reviews the characteristics of Poisson model and the related models that have been developed to handle overdispersion (negative binomial (NB) model) or zero-inflation (zero-inflated Poisson (ZIP) and Poisson hurdle (PH) models) or both (zero-inflated negative binomial (ZINB) and negative binomial hurdle (NBH) models). Methods: All six models were used to model the effect of an HIV-risk reduction intervention on the count of unprotected sexual occasions (USOs), using data from a previously completed clinical trial among female patients (N = 515) participating in community-based substance abuse treatment (Tross et al. Effectiveness of HIV/AIDS sexual risk reduction groups for women in substance abuse treatment programs: Results of NIDA Clinical Trials Network Trial. J Acquir Immune Defic Syndr 2008; 48(5):581-589). Goodness of fit and the estimates of treatment effect derived from each model were compared. Results: The ZINB model provided the best fit, yielding a medium-sized effect of intervention. Conclusions and Scientific Significance: This article illustrates the consequences of applying models with different distribution assumptions on the data. If a model used does not closely fit the shape of the data distribution, the estimate of the effect of the intervention may be biased, either over- or underestimating the intervention effect.
Overdose risk during a course of treatment with medication for opioid use disorder (MOUD) has not been clearly delineated. The authors sought to address this gap by leveraging a new data set from ...three large pragmatic clinical trials of MOUD.
Adverse event logs, including overdose events, from the three trials (N=2,199) were harmonized, and the overall risk of having an overdose event in the 24 weeks after randomization was compared for each study arm (one methadone, one naltrexone, and three buprenorphine groups), using survival analysis with time-dependent Cox proportional hazard models.
By week 24, 39 participants had ≥1 overdose event. The observed frequency of having an overdose event was 15 (5.30%) among 283 patients assigned to naltrexone, eight (1.51%) among 529 patients assigned to methadone, and 16 (1.15%) among 1,387 patients assigned to buprenorphine. Notably, 27.9% of patients assigned to extended-release naltrexone never initiated the medication, and their overdose rate was 8.9% (7/79), compared with 3.9% (8/204) among those who initiated naltrexone. Controlling for sociodemographic and time-varying medication adherence variables and baseline substance use, a proportional hazard model did not show a significant effect of naltrexone assignment. Significantly higher probabilities of experiencing an overdose event were observed among patients with baseline benzodiazepine use (hazard ratio=3.36, 95% CI=1.76, 6.42) and those who either were never inducted on their assigned study medication (hazard ratio=6.64, 95% CI=2.12, 19.54) or stopped their medication after initial induction (hazard ratio=4.04, 95% CI=1.54, 10.65).
Among patients with opioid use disorder seeking medication treatment, the risk of overdose events over the next 24 weeks is elevated among those who fail to initiate or discontinue medication and those who report benzodiazepine use at baseline.
Aims
To assess the long‐term safety of subcutaneous buprenorphine (CAM2038) weekly and monthly depots.
Design
Phase 3, open‐label, observational, multi‐centre 48‐week trial (ClinicalTrials.gov ...NCT02672111).
Setting
Twenty‐six out‐patient sites (United States, United Kingdom, Hungary, Denmark, Sweden, Germany, Australia) between 14 December 2015 and 12 April 2017.
Participants
Two hundred and twenty‐eight adults with opioid use disorder; 227 received CAM2038 (37 initiated onto CAM2038 and 190 converted from sublingual buprenorphine).
Interventions
CAM2038 weekly (8, 16, 24 or 32 mg) or monthly (64, 96, 128 or 160 mg) with flexible dosing and individualized titration utilizing multiple CAM2038 weekly and monthly doses.
Measurements
Safety variables, urine toxicology samples and self‐reported illicit opioid use were collected at each visit. Participants were administered a patient satisfaction survey at months 6 and 12, completed by 162 of 227 (71.4%) participants.
Findings
The study treatment period was completed by 167 of 227 (73.6%) participants. At least one treatment‐emergent adverse event (TEAE) was reported by 143 of 227 (63.0%) participants, of whom 60 of 227 (26.4%) reported as being drug‐related. Most of the TEAEs, reported by 128 of 227 (56.4%) of participants, were mild or moderate in intensity. Injection‐site reactions were reported by 46 of 227 (20.3%) participants, with most 45 of 46 (97.8%) reported as mild to moderate. Five participants (2.2%) discontinued the study drug due to a TEAE, two cases (0.9%) of which were injection‐site‐related. No serious adverse events were attributed to the study drug. Among those remaining in the study, the percentage of opioid‐negative urine tests combined with self‐reports was 63.0% (17 of 27) in new‐to‐treatment participants and 82.8% (111 of 134) for those converted from sublingual buprenorphine. Participants reported high levels of satisfaction with CAM2038.
Conclusions
Subcutaneous buprenorphine delivered weekly or monthly (CAM2038) was well tolerated, with a systemic safety profile consistent with the known profile of sublingual buprenorphine. CAM2038 weekly and monthly was associated with high retention rates and low levels of illicit opioid use throughout this study.
Summary Background Opioid dependence is associated with low rates of treatment-seeking, poor adherence to treatment, frequent relapse, and major societal consequences. We aimed to assess the ...efficacy, safety, and patient-reported outcomes of an injectable, once monthly extended-release formulation of the opioid antagonist naltrexone (XR-NTX) for treatment of patients with opioid dependence after detoxification. Methods We did a double-blind, placebo-controlled, randomised, 24-week trial of patients with opioid dependence disorder. Patients aged 18 years or over who had 30 days or less of inpatient detoxification and 7 days or more off all opioids were enrolled at 13 clinical sites in Russia. We randomly assigned patients (1:1) to either 380 mg XR-NTX or placebo by an interactive voice response system, stratified by site and gender in a centralised, permuted-block method. Participants also received 12 biweekly counselling sessions. Participants, investigators, staff, and the sponsor were masked to treatment allocation. The primary endpoint was the response profile for confirmed abstinence during weeks 5–24, assessed by urine drug tests and self report of non-use. Secondary endpoints were self-reported opioid-free days, opioid craving scores, number of days of retention, and relapse to physiological opioid dependence. Analyses were by intention to treat. This trial is registered at ClinicalTrials.gov , NCT00678418. Findings Between July 3, 2008, and Oct 5, 2009, 250 patients were randomly assigned to XR-NTX (n=126) or placebo (n=124). The median proportion of weeks of confirmed abstinence was 90·0% (95% CI 69·9–92·4) in the XR-NTX group compared with 35·0% (11·4–63·8) in the placebo group (p=0·0002). Patients in the XR-NTX group self-reported a median of 99·2% (range 89·1–99·4) opioid-free days compared with 60·4% (46·2–94·0) for the placebo group (p=0·0004). The mean change in craving was −10·1 (95% CI −12·3 to −7·8) in the XR-NTX group compared with 0·7 (−3·1 to 4·4) in the placebo group (p<0·0001). Median retention was over 168 days in the XR-NTX group compared with 96 days (95% CI 63–165) in the placebo group (p=0·0042). Naloxone challenge confirmed relapse to physiological opioid dependence in 17 patients in the placebo group compared with one in the XR-NTX group (p<0·0001). XR-NTX was well tolerated. Two patients in each group discontinued owing to adverse events. No XR-NTX-treated patients died, overdosed, or discontinued owing to severe adverse events. Interpretation XR-NTX represents a new treatment option that is distinct from opioid agonist maintenance treatment. XR-NTX in conjunction with psychosocial treatment might improve acceptance of opioid dependence pharmacotherapy and provide a useful treatment option for many patients. Funding Alkermes.
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