A study of naltrexone and topiramate combination versus naltrexone alone in craving in alcohol dependence

Alcohol use disorder is chronic psychiatric illness associated with high rates of relapse. For its treatment and relapse prevention multiple pharmacologic agents have been tried including naltrexone, acamprosate, baclofen, topiramate, nalmefene and gabapentin. Naltrexone, an antagonist mainly at the mu-opioid(μ) receptor, with additional antagonistic activity at the kappa(k) and delta(δ) opioid receptors, is US Food and Drug Administration (USFDA approved for the relapse prevention treatment of alcohol use disorder. The opioid receptor blockade prevents increased dopaminergic activity after the consumption of alcohol, thus reducing its rewarding effects. It has been shown that small doses of opioid agonists increase motivation to consume more alcohol and the intake of larger amounts of alcohol to reinstate or increase opioid activity. Since alcohol intake enhances endogenous opioid activity in the central nervous system, it has been proposed that opioid antagonists such as naltrexone may reduce the risk of relapse. While naltrexone targets opioid receptors, many other neurotransmitter systems are targeted by ethanol and, to a greater or lesser extent, contribute to modulating ethanol’s reinforcing effects. On the other hand, topiramate reduces heavy drinking by inhibiting alcohol-induced dopamine release in the reward-related mesolimbic dopamine pathways by enhancing GABA neurotransmission and/or inhibiting glutamatergic neurotransmission. This suppression of alcohol-induced dopamine release could decrease the reinforcing effects of alcohol. Over time, repeated reductions in alcohol-induced reinforcement may devalue the rewarding properties of alcohol cues and attenuate craving for alcohol. However, the relapse rates continue to be high even with the use of either naltrexone or topiramate in people with alcohol use disorder. An approach consisting of using a combination of medications to improve treatment outcomes in alcohol use disorder has also been tried. A study comparing naltrexone, acamprosate, and their combination found the combination of naltrexone and acamprosate to be more effective in lowering relapse rates than placebo and acamprosate . The result with the combination was not significantly different from naltrexone alone. Meanwhile, studies using any other combination of pharmacologic agents aimed at the treatment of alcohol use disorder are lacking. In this study all the patients aged 18-50 years coming to the adult psychiatry OPD and Deaddiction OPD will be screened and diagnosis will be made through ICD-11. Patients with psychiatric comorbidities will be ruled out clinically. Patients will be detoxified and after management of acute withdrawal symptoms with at least 7 days of abstinence, CIWA-Ar score <5, and off benzodiazepines for 3 days will be evaluated for enrollment into the study. Subjects fulfilling the criteria and giving written informed consent will be included into the study. Socioeconomic  Clinical Institute Withdrawal Assessment for Alcohol–Revised (CIWA-Ar) for assessing withdrawal symptoms, Obsessive Compulsive Drinking Scale (OCDS) and Visual Analogue Scale(VAS) for assessing craving and WHO-5 well-being scale will be applied to assess subjective wellbeing. All patients will be started on Naltrexone 50mg to be continued for entire period of the study with rescue medications as required (Trazodone up to 100 mg per day for sleep). Vitamin supplementation and antacid medication will be administered, if needed. Patients will be randomized using computer-generated random table method into 9 blocks with 6 participants each where they will be randomly allotted into 2 groups, intervention and control group. Allocation concealment will be done using the sealed envelope method. Along with naltrexone (50mg/day), the intervention group will receive an additional topiramate (50mg/day) tablet while the Control group will receive an identical placebo tablet. The patients will be assessed at 0, 2, 4, and 6 weeks with a margin of plus minus 2 days. At follow-up assessment, in addition to the application of relevant tools subjects will be asked to report if any alcohol was consumed and the same will be corroborated with the drinking diary and attendants (if present). The patient will be reassessed at weeks 2, 4  and 6. Thus, this research aims to study the efficacy of the combined use of naltrexone and topiramate, medications with different mechanisms of action, in improving the treatment outcomes in patients with alcohol use disorder.