Varenicline for the Treatment of Cocaine Dependence.

OBJECTIVES: Varenicline is a partial agonist at the α2ß4 and α6ß2 nAChR receptors and a full agonist at α7 receptors. Both α7 and α6ß2 receptors are implicated in the neural reward circuitry activated by cocaine use. A preliminary clinical trial suggested that varenicline treatment reduced cocaine use. This trial was intended to replicate and extend the findings of the previous trial. METHODS: This was a 12-week, double-blind, placebo-controlled clinical trial involving 156 subjects with DSM IV cocaine dependence. Subjects received up to 2 mg of varenicline or identical placebo daily along with weekly relapse prevention psychotherapy. The primary outcome measure was cocaine use measured by thrice-weekly urine drug screens. Additional outcome measures included end of study cocaine abstinence, cocaine craving, cocaine withdrawal symptom severity, cigarette use, and global improvement measure by the Clinical Global Improvement Scale. RESULTS: End of study cocaine abstinence, measured by urine drug screens during the last 3 weeks of the trial, was not different between groups (8% in the varenicline treated subjects and versus 9% in placebo-treated subjects). Generalized estimating equations analysis of urine drug screen results showed no significant difference between groups in cocaine abstinence over the 12 weeks of the trial. There were no significant differences between the 2 groups in cocaine craving or cocaine withdrawal symptom severity. Varenicline was well-tolerated. There were no medication-associated serious adverse events. CONCLUSIONS: Varenicline plus cognitive-behavioral therapy does not seem to be an efficacious treatment for cocaine dependence.

Biomarkers for the development of new medications for cocaine dependence.

There has been significant progress in personalized drug development. In large part, this has taken place in the oncology field and been due to the ability of researchers/clinicians to discover and develop novel drug development tools (DDTs), such as biomarkers. In cancer treatment research, biomarkers have permitted a more accurate pathophysiological characterization of an individual patient, and have enabled practitioners to target mechanistically the right drug, to the right patient, at the right time. Similar to cancer, patients with substance use disorders (SUDs) present clinically with heterogeneous symptomatology and respond variably to therapeutic interventions. If comparable biomarkers could be identified and developed for SUDs, significant diagnostic and therapeutic advances could be made. In this review, we highlight current opportunities and difficulties pertaining to the identification and development of biomarkers for SUDs. We focus on cocaine dependence as an example. Putative diagnostic, pharmacodynamic (PD), and predictive biomarkers for cocaine dependence are discussed across a range of methodological approaches. A possible cocaine-dependent clinical outcome assessment (COA)--another type of defined DDT--is also discussed. At present, biomarkers for cocaine dependence are in their infancy. Much additional research will be needed to identify, validate, and qualify these putative tools prior to their potential use for medications development and/or application to clinical practice. However, with a large unmet medical need and an estimated market size of several hundred million dollars per year, if developed, biomarkers for cocaine dependence will hold tremendous value to both industry and public health.

Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence.

BACKGROUND: Alcohol use, abuse and dependence remain a pressing public health problem. Based on its mechanism of action, varenicline seemed to be a likely candidate for treating alcohol dependence. METHODS: Alcohol dependent subjects (n=40) were enrolled in a 13-week double-blind placebo controlled clinical trial. Subject visits were once per week. At each visit, subjects were tested for breath alcohol levels, provided self-report data on alcohol and nicotine use, and on mood and craving. In addition, subjects received once a week medical management (MM). RESULTS: There was no difference between varenicline and placebo treated groups on any of the drinking outcomes. Compared to placebo-treated subjects, varenicline treated subjects had decreased rates of alcohol craving and cigarette smoking, as well as greater mood improvements during the later part of the study (weeks 6-13). In addition, among subjects who were cigarette smokers, those treated with varenicline were significantly less likely to report heavy drinking during the trial. CONCLUSIONS: Although varenicline was not significantly more effective than placebo at reducing drinking during the trial, its effects on alcohol craving and mood suggest that future investigation of the mechanism of action of varenicline, as well as additional clinical studies may be warranted. In particular, the findings regarding the influence of smoking status on heavy drinking among varenicline-treated subjects should be investigated in future studies.

Low frequency genetic variants in the µ-opioid receptor (OPRM1) affect risk for addiction to heroin and cocaine.

The µ-opioid receptor (MOR) binds exogenous and endogenous opioids and is known to mediate the rewarding effects of drugs of abuse. Numerous genetic studies have sought to identify common genetic variation in the gene encoding MOR (OPRM1) that affects risk for drug addiction. The purpose of this study was to examine the contribution of rare coding variants in OPRM1 to the risk for addiction. Rare and low frequency variants were selected using the National Heart Lung and Blood Institute - Exome Sequencing Project (NHLBI-ESP) database, which has screened the exomes of over 6500 individuals. Two SNPs (rs62638690 and rs17174794) were selected for genotyping in 1377 European American individuals addicted to heroin and/or cocaine. Two different SNPs (rs1799971 and rs17174801) were genotyped in 1238 African American individuals addicted to heroin and/or cocaine. Using the minor allele frequencies from the NHLBI-ESP dataset as a comparison group, case-control association analyses were performed. Results revealed an association between rs62638690 and cocaine and heroin addiction in European Americans (p=0.02; 95% C.I. 0.47 [0.24-0.92]). This study suggests a potential role for rare OPRM1 variants in addiction disorders and highlights an area worthy of future study.

Deep brain stimulation compared with methadone maintenance for the treatment of heroin dependence: a threshold and cost-effectiveness analysis.

AIMS: To determine the success threshold at which a theoretical course of deep brain stimulation (DBS) would provide the same quality of life (QoL) and cost-effectiveness for heroin dependence as methadone maintenance treatment (MMT). DESIGN: We constructed a decision analysis model to calculate QoL after 6 months of MMT and compared it to a theoretical course of DBS. We also performed a cost-effectiveness analysis using societal costs of heroin dependence, MMT and DBS. SETTING: Systematic literature review and meta-analysis. PARTICIPANTS: Patients (n = 1191) from 15 trials administering 6 months of MMT and patients (n = 2937) from 45 trials of DBS for movement disorders. MEASUREMENTS: Data on QoL before and after MMT, retention in MMT at 6 months, as well as complications of DBS and their impact on QoL in movement disorders. FINDINGS: We found a QoL of 0.633 (perfect health = 1) in heroin addicts initiating MMT. Sixty-six per cent of patients completed MMT, but only 47% of them had opiate-free urine samples, resulting in an average QoL of 0.7148 (0.3574 quality-adjusted life years (QALYs) over 6 months). A trial of DBS is less expensive ($81,000) than untreated (or relapsed) heroin dependence ($100,000), but more expensive than MMT ($58,000). A theoretical course of DBS would need a success rate of 36.5% to match MMT, but a success rate of 49% to be cost-effective. CONCLUSIONS: The success rate, defined as the percentage of patients remaining heroin-free after 6 months of treatment, at which deep brain stimulation would be similarly cost-effective in treating opiate addiction to methadone maintenance treatment, is estimated at 49%.

Early abstinence in cocaine pharmacotherapy trials predicts successful treatment outcomes.

There is a robust relationship between early and later abstinence in smoking cessation, but that relationship has not been explored among other substances of abuse. To assess whether early abstinence during treatment, as opposed to baseline abstinence, predicted later abstinence among cocaine-dependent patients, data from two randomized double-blind controlled clinical pharmacotherapy trials were analyzed. Similar to the findings in the smoking cessation literature, results indicate that abstinence in the first 2 weeks of pharmacotherapy predicted later in-trial abstinence. This finding has implications both for treatment research and for clinical practice, suggesting that patients who do not respond early in treatment may need a more intensive intervention.

The search for medications to treat stimulant dependence.

Progress in understanding the neurobiology of stimulant dependence has enabled researchers to identify medications whose pharmacological effects suggest that they might help patients initiate abstinence or avoid relapse. Several of these medications and a vaccine have shown encouraging results in controlled clinical trials with cocaine-dependent patients. The search for a medical treatment for methamphetamine dependence started more recently, due to the later emergence of this epidemic, but at least one candidate medication has shown promise in early clinical testing. Treatment approaches that combine efficacious medications and empirically proven behavioral interventions, such as voucher-based reinforcement therapy, will almost certainly produce the best results.

Why do those who request smoking treatment fail to attend the first appointment?

As part of a larger trial of pharmacological and counseling interventions for light smokers, we performed a telephone-screening interview followed by a scheduled time for an in-person eligibility appointment. Of the 407 who screened positive and expressed interest in participation, 202 failed to attend the first scheduled appointment. This article examines person, study, and study-site characteristics that differentiated those who did follow through from those who did not. The study also examined the self-reported quit rates of both groups 12 weeks later, the time of the study termination. Analyses suggested that nonattendees were more likely to be younger, unemployed, and African American. The most frequently cited reasons for missing the eligibility appointment were work/family obligations, inconvenient appointment times, and personal schedule problems. Those who kept the initial appointment were more likely to report smoking abstinence at 12 weeks. The study has implications for increasing the utilization of potentially effective treatments for smokers.