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Although opioids have known antidepressant activity, their use in major depressive disorder (MDD) has been greatly limited by risk of abuse and addiction. Our aim was to determine whether opioid modulation achieved through a combination of a μ-opioid partial agonist, buprenorphine (BUP), and a potent μ-opioid antagonist, samidorphan (SAM), would demonstrate antidepressant activity without addictive potential. A placebo-controlled crossover study assessed the opioid pharmacodynamic profile following escalating doses of SAM co-administered with BUP in opioid-experienced adults. A subsequent 1-week, placebo-controlled, parallel-group study was conducted in subjects with MDD and an inadequate response to standard antidepressant therapy. This second study evaluated safety and efficacy of ratios of BUP/SAM that were associated with partial and with maximal blockade of opioid responses in the initial study. Pupillometry, visual analog scale assessments, and self-reported questionnaires demonstrated that increasing amounts of SAM added to a fixed dose of BUP resulted in dose-dependent reductions in objective and subjective opioid effects, including euphoria and drug liking, in opioid-experienced adults. Following 7 days of treatment in subjects with MDD, a 1 : 1 ratio of BUP and SAM, the ratio associated with maximal antagonism of opioid effects, exhibited statistically significant improvement vs placebo in HAM-D17 total score (p=0.032) and nearly significant improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) total score (p=0.054). Overall, BUP/SAM therapy was well tolerated. A combination of BUP and SAM showed antidepressant activity in subjects with MDD. Balanced agonist-antagonist opioid modulation represents a novel and potentially clinically important approach to the treatment of MDD and other psychiatric disorders.

In a randomized trial involving participants with methamphetamine use disorder, the response among those who received bupropion and naltrexone was 11 percentage points higher than that among participants who received placebo. Adverse events included gastrointestinal disorders.

This study investigated the safety and efficacy of subcutaneous methylnaltrexone, a μ-opioid–receptor antagonist, for treating opioid-induced constipation in patients with advanced illness. Methylnaltrexone rapidly induced laxation without affecting central analgesia or precipitating withdrawal. This study investigated the safety and efficacy of subcutaneous methylnaltrexone for treating opioid-induced constipation in patients with advanced illness. Methylnaltrexone rapidly induced laxation without affecting central analgesia or precipitating withdrawal. Clinicians often use opioids to treat moderate-to-severe pain; however, opioids frequently induce or aggravate constipation. Empirically, laxative therapy may be burdensome and ineffective and result in temporally unpredictable responses. In addition, severe opioid-induced constipation may limit opioid therapy, worsening analgesia. These drawbacks can substantially compromise the quality of life, especially in patients with advanced illness. Opioid-induced constipation is predominantly mediated by gastrointestinal μ-opioid receptors. 1 , 2 Selective blockade of these peripheral receptors might relieve constipation without compromising centrally mediated effects of opioid analgesia or precipitating withdrawal. N-methylation of the uncharged systemic opioid antagonist, naltrexone, 3 results in a charged derivative, methylnaltrexone, which . . .

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 . . .

RationaleAlcohol use disorder is a common and devastating mental illness for which satisfactory treatments are still lacking. Nalmefene, as an opioid receptor modulator, could pharmacologically support the reduction of drinking by reducing the (anticipated) rewarding effects of alcohol and expanding the range of treatment options. It has been hypothesized that nalmefene acts via an indirect modulation of the mesolimbic reward system. So far, only a few imaging findings on the neuronal response to nalmefene are available.ObjectivesWe tested the effect of a single dose of 18 mg nalmefene on neuronal cue-reactivity in the ventral and dorsal striatum and subjective craving.MethodsEighteen non-treatment-seeking participants with alcohol use disorder (67% male, M = 50.3 ± 13.9 years) with a current high-risk drinking level (M = 76.9 ± 52 g of pure alcohol per day) were investigated using a cue-reactivity task during functional magnetic resonance imaging (fMRI) in a double-blind, placebo-controlled, cross-over study/design. In addition, self-reported craving was assessed before and after exposure to alcohol cues.ResultsAn a priori defined region of interest (ROI) analysis of fMRI data from 15 participants revealed that nalmefene reduced alcohol cue-reactivity in the ventral, but not the dorsal striatum. Additionally, the subjective craving was significantly reduced after the cue-reactivity task under nalmefene compared to placebo.ConclusionIn the present study, reduced craving and cue-reactivity to alcohol stimuli in the ventral striatum by nalmefene indicates a potential anti-craving effect of this drug via attenuation of neural alcohol cue-reactivity.

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. 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. 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. 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. Alkermes.

Samidorphan (3-carboxamido-4-hydroxy naltrexone) is a novel opioid receptor antagonist that is currently in clinical development. The oral dose pharmacokinetics, safety, and tolerability of samidorphan were evaluated in 2 double-blind, placebo-controlled, randomized studies in healthy adults. The first study investigated single, ascending doses of 3.7 to 55.7 mg of samidorphan in 16 healthy adults; the second study evaluated multiple ascending doses of 10 or 20 mg of samidorphan administered for 7 days in 30 healthy adults. Across the two studies, 39 of 46 subjects were male; 32 were white, 11 were black, and 3 were hispanic. Mean age was 34.9 years and mean weight was 84.2 kg. In both studies, samidorphan was rapidly absorbed, with a Tmax of 1 hour, and AUC increased with increasing dose. Samidorphan plasma levels declined in a monoexponential manner, with a half-life of ~7 to 9 hours. After multiple doses, steady state was approached by day 6 and achieved by day 7 after the 10-mg dose, but steady state was not reached for the 20-mg dose. Accumulation was low, with accumulation ratios <1.65. In both studies, samidorphan was generally well tolerated, with somnolence reported as the most common adverse event. In these single- and multiple-dose studies in healthy volunteers, samidorphan exhibited a pharmacokinetic profile consistent with once-daily dosing. ClinicalTrials.gov identifier: NCT00800319.

Given that cannabis use is increasing in the United States, pharmacological treatment options to treat cannabis use disorder are needed. Opioid antagonists modulate cannabinoid effects and may offer a potential approach to reducing cannabis use. In this double-blind, placebo-controlled human laboratory study, we assessed the effects of naltrexone maintenance on the reinforcing, subjective, psychomotor, and cardiovascular effects of active and inactive cannabis. Nontreatment-seeking, daily cannabis smokers were randomized to receive naltrexone (50 mg: n=18 M and 5 F) or placebo (0 mg; n=26 M and 2 F) capsules for 16 days. Before, during, and after medication maintenance, participants completed 10 laboratory sessions over 4-6 weeks, assessing cannabis' behavioral and cardiovascular effects. Medication compliance was verified by observed capsule administration, plasma naltrexone, and urinary riboflavin. Relative to placebo, maintenance on naltrexone significantly reduced both active cannabis self-administration and its positive subjective effects ('good effect'). Participants in the placebo group had 7.6 times (95% CI: 1.1-51.8) the odds of self-administering active cannabis compared with the naltrexone group. This attenuation of reinforcing and positive subjective effects also influenced cannabis use in the natural ecology. Naltrexone had intrinsic effects: decreasing ratings of friendliness, food intake, and systolic blood pressure, and increasing spontaneous reports of stomach upset and headache, yet dropout rates were comparable between groups. In summary, we show for the first time that maintenance on naltrexone decreased cannabis self-administration and ratings of 'good effect' in nontreatment-seeking daily cannabis smokers. Clinical studies in patients motivated to reduce their cannabis use are warranted to evaluate naltrexone's efficacy as a treatment for cannabis use disorder.

The endogenous opioid system is thought to play an important role in the regulation of mood. Buprenorphine/samidorphan (BUP/SAM) combination is an investigational opioid system modulator for adjunctive treatment of major depressive disorder (MDD). To confirm results from early studies, we report the efficacy and safety of BUP/SAM as adjunctive treatment in patients with MDD and an inadequate response to antidepressant therapy (ADT) in FORWARD-4 and FORWARD-5: two phase 3, randomized, double-blind, placebo-controlled studies that utilized the same sequential parallel-comparison design. Efficacy was measured using the Montgomery–Åsberg Depression Rating Scale (MADRS). FORWARD-5 achieved the primary endpoint and demonstrated that adjunctive BUP/SAM 2 mg/2 mg was superior to placebo (average difference change from baseline to week 3 through end of treatment [EOT] in MADRS-6 and −10 versus placebo: −1.5, P = 0.018; −1.9, P = 0.026, respectively). FORWARD-4 did not achieve the primary endpoint (change from baseline in MADRS-10 at week 5 versus placebo: –1.8, P = 0.109), although separate analyses showed significant treatment differences at other timepoints using traditional, regulatory-accepted endpoints such as reduction in MADRS-10 at EOT. The pooled analysis of the two studies demonstrated consistently greater reduction in MADRS-10 scores from baseline for BUP/SAM 2 mg/2 mg versus placebo at multiple timepoints including EOT and average change from baseline to week 3 through EOT (–1.8, P = 0.010; –1.8, P = 0.004, respectively). The overall effect size (Hedges’ g) in the pooled analyses for MADRS-10 change from baseline to EOT was 0.22. Overall, BUP/SAM was generally well tolerated, with most adverse events (AEs) being mild or moderate in severity. The most common AEs, occurring in ≥5% of patients in the BUP/SAM 2 mg/2 mg treatment group, which was more frequently than the placebo group, included nausea, constipation, dizziness, vomiting, somnolence, fatigue, and sedation. There was minimal evidence of abuse, and no evidence of dependence or opioid withdrawal by AEs or objective measures. This report describes adjunctive BUP/SAM 2 mg/2 mg combination, a therapy with a novel opioidergic mechanism of action, as a potential new treatment option for patients with MDD who have an inadequate response to currently available ADT.

BackgroundExtended-release naltrexone/bupropion (NB) is indicated for chronic weight management. Incretin agents are recommended for patients with type 2 diabetes. This analysis looked at the add-on of NB to incretins to see if weight loss could occur in patients already stabilized on incretin agents.MethodsThis was a post-hoc analysis of NB vs. placebo (PL) among subjects with type 2 diabetes stable on an incretin agent prior to randomization in a double-blind, PL-controlled cardiovascular outcome trial (N = 1317).ResultsOver 1 year, mean weight loss was significantly greater among NB patients vs. PL among those taking DPP-4i (mean absolute difference 4.6% [p < 0.0001]) and those taking GLP-1RAs (mean absolute difference 5.2%, p < 0.0001). Proportions of subjects achieving 5% weight loss were significantly greater for NB vs. PL at weeks 26 and 52 among those taking DPP-4is or GLP-1RAs. There were no significant differences in effectiveness observed between NB + DPP-4i and NB + GLP-1RA or between PL + DPP-4i and PL + GLP-1RA in any of the analyses. Serious adverse events were reported by 9.1% and 11.1% for PL + DPP-4i and PL + GLP-1RA, respectively, and 13.3% and 12.4% of NB + DPP-4i and NB + GLP-1RA, respectively.ConclusionNB appears to be effective in reducing weight in patients with T2DM and obesity/overweight who are taking DPP-4ihibitors or GLP-1RA. The SAE rates in all arms of this analysis were lower than have been reported in other cardiovascular outcome trials in type 2 diabetes.