Journal Article Annotations
2017, 4th Quarter

Substance Use & Addictive Disorders

Annotations by S. Alex Sidelnik, MD, and Diana Robinson, MD
January 2018

Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial
Effectiveness of injectable extended-release naltrexone vs daily buprenorphine-naloxone for opioid dependence: a randomized clinical noninferiority trial

PUBLICATION #1 — Substance Use & Addictive Disorders

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

Lee JD, Nunes EV Jr, Novo P, et al

Abstract: Lancet 2017 Nov 14 (Epub ahead of print)

Background: Extended-release naltrexone (XR-NTX), an opioid antagonist, and sublingual buprenorphine-naloxone (BUP-NX), a partial opioid agonist, are pharmacologically and conceptually distinct interventions to prevent opioid relapse. We aimed to estimate the difference in opioid relapse-free survival between XR-NTX and BUP-NX.

Methods: We initiated this 24 week, open-label, randomised controlled, comparative effectiveness trial at eight US community-based inpatient services and followed up participants as outpatients. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 opioid use disorder, and had used non-prescribed opioids in the past 30 days. We stratified participants by treatment site and opioid use severity and used a web-based permuted block design with random equally weighted block sizes of four and six for randomisation (1:1) to receive XR-NTX or BUP-NX. XR-NTX was monthly intramuscular injections (Vivitrol; Alkermes) and BUP-NX was daily self-administered buprenorphine-naloxone sublingual film (Suboxone; Indivior). The primary outcome was opioid relapse-free survival during 24 weeks of outpatient treatment. Relapse was 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use. This trial is registered with ClinicalTrials.gov, NCT02032433.

Findings: Between Jan 30, 2014, and May 25, 2016, we randomly assigned 570 participants to receive XR-NTX (n=283) or BUP-NX (n=287). The last follow-up visit was Jan 31, 2017. As expected, XR-NTX had a substantial induction hurdle: fewer participants successfully initiated XR-NTX (204 [72%] of 283) than BUP-NX (270 [94%] of 287; p<0·0001). Among all participants who were randomly assigned (intention-to-treat population, n=570) 24 week relapse events were greater for XR-NTX (185 [65%] of 283) than for BUP-NX (163 [57%] of 287; hazard ratio [HR] 1·36, 95% CI 1·10-1·68), most or all of this difference accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures. Among participants successfully inducted (per-protocol population, n=474), 24 week relapse events were similar across study groups (p=0·44). Opioid-negative urine samples (p<0·0001) and opioid-abstinent days (p<0·0001) favoured BUP-NX compared with XR-NTX among the intention-to-treat population, but were similar across study groups among the per-protocol population. Self-reported opioid craving was initially less with XR-NTX than with BUP-NX (p=0·0012), then converged by week 24 (p=0·20). With the exception of mild-to-moderate XR-NTX injection site reactions, treatment-emergent adverse events including overdose did not differ between treatment groups. Five fatal overdoses occurred (two in the XR-NTX group and three in the BUP-NX group).

Interpretation: In this population it is more difficult to initiate patients to XR-NTX than BUP-NX, and this negatively affected overall relapse. However, once initiated, both medications were equally safe and effective. Future work should focus on facilitating induction to XR-NTX and on improving treatment retention for both medications.

On PubMed: Lancet 2017 Nov 14 (Epub ahead of print)

Annotation (Alex Sidelnik)

Type of study: Randomized controlled trial

The finding: The study found that extended-release naltrexone (XR-NTX) was more difficult to initiate compared to buprenorphine-naloxone (BUP-NX), which negatively affected overall relapse rates. However, after successful initiation of XR-NTX, it was found to be equally effective as BUP-NX with regards to relapse rates and adverse events.

Strength and weaknesses: The study was a multicentre, open-label, randomized controlled trial of 24 weeks comparing XR-NTX with BUP-NX initiated during an acute inpatient detoxification admission. The primary outcome was time to relapse with secondary outcomes including proportion of patients successfully inducted, adverse events, and opioid craving. Among the intention-to-treat population, BUP-NX had a lower overall relapse rate compared to XR-NTX, which was related to initiation failures with XR-NTX. The study had a number of strengths including a relatively large sample size, long study duration, and good generalizability as the study was performed in typical community-based treatment settings. Despite a number of strengths, limitations included heterogeneity across treatment sites with regards to management of detoxification (opioid based versus non-opioid based), varied induction protocols among sites, which may have created variance in successful induction to XR-NTX, and applicability of the study in non-detoxification settings.

Relevance: The study demonstrated that although XR-NTX is more difficult to initiate, it was equally effective and safe compared to BUP-NX after successful initiation. In clinical practice, the study supports that among patients that are good candidates for XR-NTX, XR-NTX may be as effective as BUP-NX after successful initiation.

PUBLICATION #2 — Substance Use & Addictive Disorders

Effectiveness of injectable extended-release naltrexone vs daily buprenorphine-naloxone for opioid dependence: a randomized clinical noninferiority trial

Tanum L, Solli KK, Latif ZE, et al

Abstract: JAMA Psychiatry 2017; 74(12):1197-1205

Importance: To date, extended-release naltrexone hydrochloride has not previously been compared directly with opioid medication treatment (OMT), currently the most commonly prescribed treatment for opioid dependence.

Objective: To determine whether treatment with extended-release naltrexone will be as effective as daily buprenorphine hydrochloride with naloxone hydrochloride in maintaining abstinence from heroin and other illicit substances in newly detoxified individuals.

Design, Setting and Participants: A 12-week, multicenter, outpatient, open-label randomized clinical trial was conducted at 5 urban addiction clinics in Norway between November 1, 2012, and December 23, 2015; the last follow-up was performed on October 23, 2015. A total of 232 adult opioid-dependent (per DSM-IV criteria) individuals were recruited from outpatient addiction clinics and detoxification units and assessed for eligibility. Intention-to-treat analyses of efficacy end points were performed with all randomized participants.

Interventions: Randomization to either daily oral flexible dose buprenorphine-naloxone, 4 to 24 mg/d, or extended-release naltrexone hydrochloride, 380 mg, administered intramuscularly every fourth week for 12 weeks.

Main Outcomes and Measures: Primary end points (protocol) were the randomized clinical trial completion rate, the proportion of opioid-negative urine drug tests, and number of days of use of heroin and other illicit opioids. Secondary end points included number of days of use of other illicit substances. Safety was assessed by adverse event reporting.

Results:Of 159 participants, mean (SD) age was 36 (8.6) years and 44 (27.7%) were women. Eighty individuals were randomized to extended-release naltrexone and 79 to buprenorphine-naloxone; 105 (66.0%) completed the trial. Retention in the extended-release naltrexone group was noninferior to the buprenorphine-naloxone group (difference, -0.1; with 95% CI, -0.2 to 0.1; P = .04), with mean (SD) time of 69.3 (25.9) and 63.7 (29.9) days, correspondingly (P = .33, log-rank test). Treatment with extended-release naltrexone showed noninferiority to buprenorphine-naloxone on group proportion of total number of opioid-negative urine drug tests (mean [SD], 0.9 [0.3] and 0.8 [0.4], respectively, difference, 0.1 with 95% CI, -0.04 to 0.2; P < .001) and use of heroin (mean difference, -3.2 with 95% CI, -4.9 to -1.5; P < .001) and other illicit opioids (mean difference, -2.7 with 95% CI, -4.6 to -0.9; P < .001). Superiority analysis showed significantly lower use of heroin and other illicit opioids in the extended-release naltrexone group. No significant differences were found between the treatment groups regarding most other illicit substance use.

Conclusions and Relevance: Extended-release naltrexone was as effective as buprenorphine-naloxone in maintaining short-term abstinence from heroin and other illicit substances and should be considered as a treatment option for opioid-dependent individuals.

On PubMed: JAMA Psychiatry 2017; 74(12):1197-1205

Annotation (Diana Robinson)

Type of study: Randomized controlled trial

The finding: This is a prospective, outpatient, randomized controlled study of treatment with extended-release naltrexone vs. buprenorphine-naloxone in for maintaining abstinence from heroin and other illicit substances in patients who recently underwent detoxification. 159 patients were randomized to treatment with extended-release naltrexone 380mg IM every 4 weeks (n=80pts; 50.3%) or buprenorphine-naloxone 4-24mg/day (n=79pts; 49.7%). The groups showed no significant differences in retention time in the study, total number of opioid-negative urine drug screens, days of use of heroin, and days of use of other illicit opioids. The authors concluded that extended-release naltrexone was as safe and effective as buprenorphine-naloxone at maintaining short term abstinence from heroin.

Strength and weaknesses: Strengths include study design of a prospective, randomized controlled trial of five urban sites from 2012-2015 with 159 randomized patients. To the authors’ knowledge, this is the first study comparing the effectiveness of extended-release naltrexone injections with that of daily oral buprenoprhine-naloxone for opioid medication treatment. Although cross-over data is pending, individuals who completed the 12 week RCT were invited to continue treatment or cross-over to the other treatment for 48 weeks.

Weaknesses include lack of blinding (authors stated they did not blind due to being unethical in the context of increased risk of opioid overdose after detoxification) and exclusion criteria that reduce the study population’s generalizability including excluding other substance use dependence or alcohol dependence, co-morbid psychiatric illness, or serious somatic illness. These are common concurrent diagnoses along with opioid dependence. Also, there was variability in opioid use in the 30 days prior to detoxification at the start of the study with some patients’ last use immediately prior to detoxification and others with sustained abstinence for varying periods of time due to incarceration or inpatient treatment . Additionally, details of the study design information were not included in the main body of the publication and were instead in the supplemental information.

Relevance: CL psychiatrists frequently evaluate patients with opioid dependence in the inpatient and outpatient settings that may benefit from induction or referrals for medication assisted treatment (MAT). It is important to educate ourselves on emerging options for MAT particularly when patients may be from low resource areas were addiction treatment services are difficult to access.