Asli Memisoglu

Injectable extended-release naltrexone (XR-NTX) for opioid dependence: long-term safety and effectiveness

AIMS To describe drug use and safety with intramuscular injectable extended-release naltrexone (XR-NTX) in opioid dependence during a 1-year open-label extension phase. DESIGN Following 6 months of randomized, double-blind, placebo (PBO)-controlled injections given every 28 days, patients receiving XR-NTX 380 mg continued and PBO patients were switched to open-label XR-NTX, with monthly individual drug counseling, for a further year. SETTING Thirteen clinical sites in Russia. PARTICIPANTS Adult opioid-dependent outpatients. MEASUREMENTS Monthly urine samples; reports of craving and functioning; adverse events. FINDINGS For the open-label extension (n = 114), 67 continued on XR-NTX and 47 switched from PBO during the double-blind phase to XR-NTX during the open-label phase. Overall, 62.3% (95% CI: 52.7%, 71.2%) completed the extension. Discontinuation occurred most commonly because of withdrawal of consent (18.4%) and loss to follow-up (11.4%); two patients discontinued as a result of lack of efficacy and one because of adverse events. Urine testing revealed that 50.9% (41.5%, 60.4%) were abstinent from opioids at all assessments during the 1-year open-label phase. Adverse events reported by 21.1% of patients were judged to be study drug-related. Injection site reactions were infrequent (6.1%) and the majority were mild. Elevations in liver function tests occurred for 16.7% of patients, but none of these elevations was judged to be clinically significant. No patients died, overdosed or discontinued as a result of severe adverse events. CONCLUSIONS During a 1-year open-label extension phase of injectable XR-NTX for the prevention of relapse in opioid dependence, 62.3% of patients completed the phase and 50.9% were abstinent from opioids. No new safety concerns were evident.

Opioid Modulation With Buprenorphine/Samidorphan as Adjunctive Treatment for Inadequate Response to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial

OBJECTIVE Major depressive disorder has been associated with dysregulation of the endogenous opioid system. The authors sought to determine whether opioid modulation achieved through administration of ALKS 5461, a combination of a μ- and κ-opioid partial agonist, buprenorphine, and a μ-opioid antagonist, samidorphan, would exhibit antidepressant activity in patients with major depression. METHOD A multicenter, randomized, double-blind, placebo-controlled, two-stage sequential parallel comparison design study was conducted in adults with major depression who had an inadequate response to one or two courses of antidepressant treatment. Participants were randomly assigned to receive adjunctive treatment with 2 mg/2 mg of buprenorphine/samidorphan (the 2/2 dosage group), 8 mg/8 mg of buprenorphine/samidorphan (the 8/8 dosage group), or placebo. Antidepressant effect was measured based on change from baseline to the end of 4 weeks of treatment on the 17-item Hamilton Depression Rating Scale (HAM-D), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Clinical Global Impressions severity scale (CGI-S). RESULTS Compared with the placebo group, there were significantly greater improvements in the 2/2 dosage group across the three depression outcome measures (HAM-D: -2.8, 95% CI=-5.1, -0.6; MADRS: -4.9, 95% CI=-8.2, -1.6; CGI-S: -0.5, 95% CI=-0.9, -0.1). There was also evidence of improvement in the 8/8 dosage group, although it did not achieve statistical significance. Overall, the buprenorphine/samidorphan combinations were well tolerated, and there was no evidence of opioid withdrawal on treatment discontinuation. CONCLUSIONS The buprenorphine/samidorphan combination is a novel and promising candidate for treatment of major depressive disorder in patients who have an inadequate response to standard antidepressants.

A placebo-controlled pilot study of the novel opioid receptor antagonist ALKS-33 in binge eating disorder.

OBJECTIVE To assess preliminarily the effectiveness of a novel opioid antagonist, ALKS-33, in binge eating disorder (BED). METHOD In this randomized, placebo-controlled, flexible dose, proof-of-concept trial, 62 outpatients with BED and obesity received ALKS-33 (N = 26) or placebo (N = 36) for 6 weeks. Outcome measures of binge eating, body weight, and eating pathology were assessed. RESULTS A large decrease in binge eating episode frequency was observed following both ALKS-33 and placebo treatment. There was no significant difference between treatment groups in binge eating episode frequency or any other measure of binge eating, body weight, or eating pathology. DISCUSSION In this preliminary proof-of-concept study in BED, ALKS-33 did not separate from placebo. Although a failed trial cannot be excluded, the finding is consistent with earlier observations in bulimia nervosa with other opioid antagonists and suggests ALKS-33, at least when administered daily for 6 weeks, may not be efficacious for BED.

Treating Opioid Dependence With Injectable Extended-Release Naltrexone (XR-NTX): Who Will Respond?

Objectives:Once-monthly intramuscular extended-release naltrexone (XR-NTX) has demonstrated efficacy for the prevention of relapse in opioid dependence, providing an alternative to agonist or partial agonist maintenance (ie, methadone and buprenorphine). The question remains, for whom is this unique treatment most efficacious and can patient-treatment matching factors be identified? Methods:A moderator analysis was conducted on a previously reported 24-week, placebo-controlled, multisite, randomized controlled trial of XR-NTX (n = 126) versus placebo (n = 124) among recently detoxified opioid-dependent adults in Russia, which showed XR-NTX superior to placebo in proportion of opioid abstinent weeks. The moderator analysis examined a dichotomous indicator of good clinical response—achieving at least 90% of weeks abstinent over the 24-week trial. A series of logistic regression models were fit for this outcome as functions of treatment (XR-NTX vs placebo), each baseline moderator variable, and their interactions. The 25 baseline variables included demographics, clinical severity (Addiction Severity Index, SF-36, and Clinical Global Impression-Severity), functioning (EQ-5D), craving, and HIV serostatus (HIV+). Results:More XR-NTX patients achieved 90% abstinence (64/126, 51%) versus placebo (39/124, 31%; P = 0.002). There were no significant interactions between baseline variables and treatment. There was a significant main effect of Clinical Global Impression-Severity score (P = 0.02), such that higher severity score was associated with a lower rate of Good Clinical Response. Conclusions:The absence of significant baseline by treatment interactions indicates that no patient-treatment matching variables could be identified. This suggests that XR-NTX was effective in promoting abstinence from opioids across a range of demographic and severity characteristics.

A Phase 4, Pilot, Open-Label Study of VIVITROL® (Extended-Release Naltrexone XR-NTX) for Prisoners

This was a Phase 4, pilot, open-label feasibility study of extended-release injectable naltrexone (XR-NTX) administered to pre-release prisoners having a history of pre-incarceration opioid disorder. We evaluated the relationship between XR-NTX adherence and criminal recidivism (re-arrest and re-incarceration) and opioid and cocaine use. Twenty-seven pre-release male and female prisoners who had opioid disorders during the year prior to index incarceration were recruited and received one XR-NTX injection once each month for 7 months (1 injection pre-release from prison and 6 injections in the community) and of those 27, 10 (37%) were retained in treatment at 7-months post release. Results indicate those completing 6 compared to those completing <6 injections were less likely to test positive for opioids in the community (0% vs. 62.5%, respectively; p=0.003). Although not statistically significant, individuals who did not complete all 6 injections were more likely to be re-arrested compared to those completing all 6 community injections (31.3% vs. 0%, respectively; p=0.123). Contingent upon further study of a randomized controlled trial, XR-NTX may be a feasible option in the prison setting in view of the lack of potential for diversion. Furthermore, these data suggest that completing the entire course of treatment (6 injections) may reduce opioid use and, to a lesser degree, re-arrest and re-incarceration.

A randomized, double-blind, placebo-controlled proof of concept study to evaluate samidorphan in the prevention of olanzapine-induced weight gain in healthy volunteers

Antipsychotic medications are associated with weight gain and adverse metabolic effects that complicate the treatment and management of schizophrenia. Olanzapine (OLZ) in particular is associated with significant weight gain and adverse metabolic effects. The present Phase 1, proof of concept, multicenter, randomized, double-blind, placebo-controlled study investigated the safety and effect on weight of a combination of OLZ (10mg) and the opioid modulator samidorphan (SAM; 5mg) in comparison to OLZ alone in healthy, male normal weight volunteers. Altogether, 106 male subjects with stable body weight and BMI 18-25kg/m2 were randomized to OLZ alone, OLZ+SAM, SAM alone, or placebo in a 2:2:1:1 ratio. The primary efficacy endpoint, mean (SD) body weight change from baseline to last assessment in the 3-week treatment period, was significantly less for OLZ+SAM vs. OLZ alone subjects [+2.2 (1.4) kg vs. +3.1 (1.9) kg; respectively; p=0.02]. In contrast, there was no significant difference in weight from baseline for either SAM or placebo [+0.1 (1.0) kg and +0.8 (1.4) kg, respectively]; p=0.09. Overall, OLZ+SAM compared to OLZ alone had similar safety and tolerability. In addition, less nausea was observed in subjects given OLZ+SAM compared to SAM alone. Thus, OLZ+SAM may offer effective treatment of schizophrenia with less weight gain and metabolic risk. Additional research exploring additional doses over longer durations in psychiatric populations is warranted.