ADAM Bisaga - US grants

The prevalence of heroin use has been increasing. However, the availability of efficacious treatments is limited, and relapse rates remain high. The development of more effective pharmacotherapies that reverse the physiologic effects of opioid dependence and prevent relapse to heroin use remains a priority. This application for a mentored research career award aims to enhance the research skills of Adam Bisaga, MD, by focusing on a systematic laboratory and clinical evaluation of memantine, an NMDA antagonist, for the treatment of opioid dependence. Dr. Bisaga, a Board Certified psychiatrist, is a research fellow in the Division on Substance Abuse at Columbia University. As a psychiatric resident and fellow, Dr. Bisaga has been exploring the theoretical basis for the clinical use of NMDA antagonists in the treatment of addictions and has collected pilot data using memantine to treat the opioid abstinence syndrome. In the next several years, he plans to carry out studies that would systematically evaluate the efficacy of memantine for opioid dependence. Two aspects of pharmacotherapy will be addressed: detoxification and relapse prevention. This novel approach to treatment will be initially evaluated using a laboratory model, and will be followed by a controlled clinical trial. Unique expertise and resources available at the Division on Substance Abuse make possible comprehensive training in such translational research. Under the sponsorship and guidance of Dr. Marian Fischman, together with the resources available at Columbia University, Dr. Bisaga will be able to achieve his long-term career goal of becoming a clinical research scientist with expertise in multiple approaches in addiction research and medication development. His training plan includes an extensive program of individualized instruction by major experts in the field, both at Columbia and elsewhere, in addition to formal course work. Training is planned specifically in the following areas: methods of new medications development for opioid dependence, including methodology and logistics of conducting clinical treatment trials; methodology and ethics of conducting research with opioids in the human laboratory; psychology of learning and conditioned responses; psychotherapy with substance abusers; integration of psychosocial interventions into medication treatment trials, and biostatistics. The research plan specifically includes the following: a laboratory study examining the effect of memantine on naloxone-precipitated opiate withdrawal, followed by a controlled clinical opioid detoxification trial comparing memantine with clonidine; a laboratory study of the effects of memantine pretreatment on cue-induced opioid craving in opioid-dependent subjects maintained on naltrexone; and a placebo-controlled trial of adjunctive memantine in the population of patients receiving naltrexone and cognitive behavioral therapy for opioid addiction. Taken together, the proposed plans will provide Dr. Bisaga with the opportunity to receive state-of-the-art training and research experience that will enable him to become an independent researcher in the field of addiction psychiatry.

DESCRIPTION (provided by applicant): Opioid abuse and dependence continues to be a significant problem in the US;in particular, rates of non-medical use of prescription opioids have increased in the past several years. The main treatment approaches include detoxification followed by psychosocial treatment or agonist maintenance. Unfortunately, rates of relapse are high with detoxification only approaches, and agonist-based treatments have several limitations and remain controversial. The alternative pharmacological strategy, naltrexone maintenance, has clear advantages. However, its use has been limited due to difficulties in initiating treatment and poor tolerability during the first weeks of treatment. Pharmacological strategies targeting aversive symptoms associated with opioid withdrawal and naltrexone induction could significantly improve its early tolerability, permit expansion of clinical use, and improve long-term outcome of opioid dependence treatment. There is strong support, from preclinical and preliminary clinical studies suggesting that dronabinol, a cannabinoid receptor agonist, may be effective in improving tolerability of naltrexone induction. Dronabinol may diminish signs and symptoms associated with naltrexone induction consistent with acute and residual opioid withdrawal, such as insomnia, anergia, hyperalgesia, GI distress, lack of appetite, anxiety, irritability, heightened stress reactivity, dysphoria, and anhedonia. Our uncontrolled observations suggest that among naltrexone-treated opioid dependent patients, moderate use of cannabis was associated with improved treatment retention. The goal of this three-year study is to test the efficacy of dronabinol as an adjunct to maintenance treatment with naltrexone in opioid-dependent individuals. We are proposing a randomized, double-blind, placebo controlled, parallel-groups, 8-week study of relapse prevention in opioid-dependent individuals. Participants will be randomized into one of two conditions: (1) Naltrexone + Placebo and (2) Naltrexone + dronabinol 20 mg bid (N=40 per group). Treatment will be delivered in an outpatient setting except for the initial phase of inpatient detoxification, lasting 8 days. A long-acting, injectable form of naltrexone 380 mg (Vivitrol) will be administered once per month (the total of two injections), while dronabinol or placebo will be taken daily. In addition, patients will receive a psychosocial intervention that will include elements of motivational interviewing and cognitive-behavioral relapse prevention therapy. Primary outcome measure will be retention in treatment by the end of the study. The primary aim is to test the efficacy of dronabinol in reducing attrition during detoxification and the first two months of naltrexone treatment. PUBLIC HEALTH RELEVANCE: Rates of opioid dependence have increased steadily over the past several years, mostly due to an increase in illicit use of prescription analgesics. The available treatments (agonist-based or therapy-only approaches) are not suitable for all patients and have limited effectiveness. Development of an improved antagonist based approach would open it up as a viable treatment alternative for a larger population of opioid dependent individuals.