Efficacy and Safety of Esmethadone (REL-1017) in Patients With Major Depressive Disorder and Inadequate Response to Standard Antidepressants: A Phase 3 Randomized Controlled Trial.

To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants. In this phase 3, double-blind, placebo-controlled trial, outpatients with MDD () were randomized to daily oral esmethadone (75 mg on day 1, followed by 25 mg daily on days 2 through 28) or placebo between December 2020 and December 2022. The primary efficacy measure was change from baseline (CFB) to day 28 in the Montgomery-Asberg Depression Rating Scale (MADRS) score.

The novel uncompetitive NMDA receptor antagonist esmethadone (REL-1017) has no meaningful abuse potential in recreational drug users.

Esmethadone (REL-1017) is the opioid-inactive dextro-isomer of methadone and a low-affinity, low-potency uncompetitive NMDA receptor antagonist. In a Phase 2, randomized, double-blind, placebo-controlled trial, esmethadone showed rapid, robust, and sustained antidepressant effects. Two studies were conducted to evaluate the abuse potential of esmethadone.

Safety and Efficacy of Lofexidine for Medically Managed Opioid Withdrawal: A Randomized Controlled Clinical Trial.

Objectives: To investigate the safety and efficacy of lofexidine for treating opioid withdrawal syndrome (OWS) and facilitating completion of opioid withdrawal.

Methods: A multicenter, double-blind, placebo-controlled study was conducted at 18 US centers from June 2013 to December 2014. Participants (n = 603) aged ≥18 years, dependent on short-acting opioids, and seeking withdrawal treatment, randomized 3:3:2 to receive lofexidine 2.

A phase III, randomized, multi-center, double blind, placebo controlled study of safety and efficacy of lofexidine for relief of symptoms in individuals undergoing inpatient opioid withdrawal.

Background: Lofexidine is an alpha-2-adrenergic receptor agonist approved in the United Kingdom (UK) for the treatment of opioid withdrawal symptoms. Lofexidine has demonstrated better efficacy than placebo for reducing opioid withdrawal symptoms in patients undergoing opioid withdrawal with less reported hypotension than clonidine.

Methods: Designed as an FDA registration trial, this 8-day, randomized, double-blind, placebo-controlled, parallel-group study in 264 patients dependent on short-acting opioids evaluated the efficacy of lofexidine hydrochloride in reducing withdrawal symptoms in patients undergoing opioid withdrawal.

Psychometric evaluation of the 10-item Short Opiate Withdrawal Scale-Gossop (SOWS-Gossop) in patients undergoing opioid detoxification.

Introduction: The Short Opiate Withdrawal Scale (SOWS)-Gossop is a 10-item questionnaire developed to evaluate opioid withdrawal symptom severity. The scale was derived from the original 32-item Opiate Withdrawal Scale in order to reduce redundancy while providing an equally sensitive measure of opioid withdrawal symptom severity appropriate for research and clinical practice. The objective of this study was to examine the psychometric properties and provide score interpretation guidelines for the SOWS-Gossop 10-item version.

A multisite, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of vigabatrin for treating cocaine dependence.

Importance: Cocaine dependence is a significant public health problem, yet no validated pharmacological treatment exists. The potent γ-aminobutyric acid (GABA)ergic medication vigabatrin has previously been shown to be effective in a double-blind single-site study conducted in Mexico.

Objective: To evaluate the safety and efficacy of vigabatrin for the treatment of cocaine dependence in a U.

Fine-grain analysis of the treatment effect of topiramate on methamphetamine addiction with latent variable analysis.

Background: As reported previously, 140 methamphetamine-dependent participants at eight medical centers in the U.S. were assigned randomly to receive topiramate (N=69) or placebo (N=71) in a 13-week clinical trial.

Topiramate for the treatment of methamphetamine addiction: a multi-center placebo-controlled trial.

Aims:   Topiramate has shown efficacy at facilitating abstinence from alcohol and cocaine abuse. This double-blind, placebo-controlled out-patient trial tested topiramate for treating methamphetamine addiction.

Design:   Participants (n = 140) were randomized to receive topiramate or placebo (13 weeks) in escalating doses from 25 mg/day [DOSAGE ERROR CORRECTED] to the target maintenance of 200 mg/day in weeks 6-12 (tapered in week 13).

Risk management and post-marketing surveillance for the abuse of medications acting on the central nervous system: expert panel report.

The abuse and diversion of medications is a significant public health problem. This paper is part of a supplemental issue of Drug and Alcohol Dependence focused on the development of risk management plans and post-marketing surveillance related to minimizing this problem. The issue is based on a conference that was held in October 2008.

Bupropion for the treatment of methamphetamine dependence.

Bupropion was tested for efficacy in increasing weeks of abstinence in methamphetamine-dependent patients, compared to placebo. This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 30-day follow-up. Five outpatient substance abuse treatment clinics located west of the Mississippi participated in the study.

The NIDA Methamphetamine Clinical Trials Group: a strategy to increase clinical trials research capacity.

Aims: In order to increase the number of investigative teams and sites conducting research on pharmacological treatments for methamphetamine use disorders, the National Institute on Drug Abuse (NIDA) established an infrastructure of clinical sites in areas where methamphetamine addiction is prevalent. This multi-site infrastructure would serve to run multiple Phases II and III protocols effectively and expeditiously.

Methods: NIDA collaborated with investigators from the University of California at Los Angeles (UCLA) to set up the Methamphetamine Clinical Trials Group (MCTG).

Impact of formulation on the abuse liability, safety and regulation of medications: the expert panel report.

A scientific meeting was held in April 2005 to consider how the formulation of medications might impact on their potential for abuse. The background papers prepared for this meeting, as well as abstracts of volunteered presentations, are published in this supplemental issue of Drug and Alcohol Dependence. This paper is the Expert Panel Report summarizing the discussions held following the formal presentations and including the suggested recommendations for additional research that emerged from these discussions.

Involving the pharmaceutical and biotech communities in medication development for substance abuse.

Pharmacotherapy as adjunctive treatment is an integral part of the strategy for treating substance abuse. Although there are several approved drugs for the treatment of opioid, alcohol, and nicotine dependence, the pharmaceutical industry, for a variety of reasons, has been reluctant to enter this area to develop medications for substance abuse indications. Therefore, in 1990, a Medication Development Program was established by NIDA to carry out and assist in stimulating development of new pharmacotherapies.

Efficacy of over-the-counter nicotine patch.

This study aimed to assess the efficacy of the nicotine patch for smoking cessation, under simulated conditions of over-the-counter sale, absent any direct instruction or behavioral treatment. In a randomized, double-blind, placebo-controlled, multicenter study, 567 smokers were randomized to an active nicotine patch (n = 283) or placebo (n = 284). Treatment followed a three-step program of 21 mg/day for 6 weeks, 14 mg/day for 2 weeks and 7 mg/day for 2 weeks.

Real-world efficacy of prescription and over-the-counter nicotine replacement therapy.

Aims: To assess smoking cessation rates achieved with nicotine gum and patch in simulated over-the-counter (OTC) and actual prescription (Rx) settings.

Design: Separate open-label studies with gum and patch in OTC and Rx settings.

Participants: There were multiple samples: OTC gum: 2981 smokers; OTC patch: 2367; Rx gum: 324; Rx patch: 669.

Diazepam and methadone blood levels following concurrent administration of diazepam and methadone.

Results of a previous study indicated that the opioid effects of methadone were enhanced by the concurrent administration of diazepam in methadone-maintained subjects. To determine whether a pharmacokinetic interaction might account for this methadone-diazepam interaction, the plasma levels of methadone, diazepam and diazepam metabolites were determined in blood samples collected during that study. Five adult male patients on methadone maintenance (50-60 mg/day) were administrated single doses of placebo, diazepam (20 and 40 mg), methadone (100%, 150% and 200% of the maintenance dose), and four diazepam-methadone dose combinations (20 and 40 mg diazepam in combination with 100% and 150% of the maintenance dose).

The pharmacokinetics of pentazocine and tripelennamine.

The pharmacokinetics of single and combined doses of pentazocine HCl (40 and 80 mg) and tripelennamine HCl (50 and 100 mg) were studied in six healthy drug abusers. After intramuscular administration of 40 or 80 mg pentazocine alone, mean peak plasma concentrations at 15 minutes were 102 and 227 ng/ml, respectively, and mean plasma t1/2 values were 4.6 and 5.

Oesophageal cancer studies in the Caspian littoral of Iran: some residual results, including opium use as a risk factor.

A study was conducted in northern Iran in areas of very high, high and moderately low incidence of oesophageal cancer. Morphine metabolites in urine as an indicator of opium use, and a variety of nutritional and biochemical measures, including salivary antipyrine half-life, were determined in households with a case of oesophageal cancer and in control households. Results on 1,590 individuals showed that the prevalence of appreciable levels (greater than or equal to 1 microgram/ml) of urinary morphine metabolites was much higher in areas of high and very high incidence of oesophageal cancer than in low-incidence areas, particularly for those under age 50 years in both sexes, where a 6-fold difference was seen.

63Ni electron-capture gas chromatographic assay for buprenorphine and metabolites in human urine and feces.

A 63Ni electron-capture gas chromatographic assay is described for buprenorphine, a potent narcotic agonist--antagonist. In addition, the assay is useful for the measurement of the metabolite norbuprenorphine and demethoxybuprenorphine, a rearrangement product resulting when buprenorphine is exposed to acid and heat. An extraction procedure was developed which optimized recovery of buprenorphine from biological samples and produced minimal background interferences and emulsion problems.

The metabolism and excretion of buprenorphine in humans.

Buprenorphine, a powerful mixed agonist-antagonist analgesic which shows promise of providing maintenance pharmacotherapy for heroin addicts, is metabolized in male human subjects to norbuprenorphine and to conjugated buprenorphine and norbuprenorphine. Following subcutaneous, sublingual, and oral buprenorphine administration to a single subject, total metabolite excretion in urine was 2, 13.4, and 12.

Morphine-like discriminative stimulus effects of buprenorphine and demethoxybuprenorphine in rats: quantitative antagonism by naloxone.

The interactions between the opioid antagonist naloxone and the opioids morphine, buprenorphine and demethoxybuprenorphine ( DMB ), an acid-catalyzed rearrangement product of buprenorphine, were evaluated quantitatively in rats trained to discriminate between saline and 3.0 mg/kg of morphine using a two-choice, shock avoidance procedure. Dose-effect curves for each of the three agonists were determined alone and in the presence of varying doses of naloxone (0.

Stability of the 6,14-endo-ethanotetrahydrooripavine analgesics: acid-catalyzed rearrangement of buprenorphine.

Buprenorphine (I), a member of the 6,14-endo-ethanotetrahydrooripavine series of analgesics, undergoes an acid-catalyzed rearrangement reaction when exposed to acid and heat. The product was shown by 1H-NMR and GC-MS to have undergone overall elimination of a molecule of methanol with concurrent formation of a tetrahydrofuran ring at C(6)-C(7) of I. Short-term stability studies across a wide range of pH and temperature conditions indicate that I is stable in aqueous solution at pH greater than 3 for 24 h at 36-38 degrees C.