At present, only two drugs are currently approved for use in the United States for the treatment of alcohol dependence: the opiate antagonist naltrexone and the alcohol-aversive agent disulfiram. A third medication called acamprosate (calcium acetyl homotaurinate), used in Europe and elsewhere to prevent relapse in alcoholics, is currently under review for use by the U.S. Food and Drug Administration. A "proof-of-concept clinical trial" published in the August issue of Alcoholism: Clinical & Experimental Research examines a potential fourth medication – topiramate – which can act contemporaneously on more than one neuromodulator of dopamine function. Results indicate that topiramate can reduce consumption and craving in alcohol-dependent patients who are not yet abstinent.
"Few medications to treat alcoholism exist," said Bankole A. Johnson, Wurzbach Distinguished Professor in the departments of psychiatry and pharmacology at The University of Texas - Health Science Center at San Antonio, and sole author of the manuscript. "This study is the first demonstration of topiramate's efficacy for treating alcohol dependence … treatment was efficacious at reducing not only drinking and craving for alcohol, but also improving abstinence and lifestyle."
"Alcohol-drinking behavior is complex, involving many neurotransmitter systems," added Raye Z. Litten, co-leader of the Medications Development Team at the National Institute on Alcohol Abuse and Alcoholism. "Dr. Johnson has postulated that targeting several key sites through the use of topiramate could result in a significant decrease in drinking. His results help to show that – unlike disulfiram, which causes an aversive effect – naltrexone, acamprosate, and topiramate can all act to reduce craving or urge to drink. This work is an important step in exploring new types of agents that may have a more potent effect in preventing or reducing drinking."
Brain pathways containing the neurotransmitter dopamine, also referred to as the "feel-good" brain chemical, are believed to mediate alcohol's rewarding effects, including craving. Whereas alcohol consumption facilitates dopamine neurotransmission, topiramate – a sulfamate fructo-pyranose derivative – decreases dopamine release through antagonism of glutamate activity at alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainite receptors and facilitation of the inhibitory neurotransmitter, gamma amino butyric acid (GABA).
Johnson conducted a "proof-of-concept" clinical trial, an experiment designed to test the direct consequences of an idea. Trial participants comprised 150 individuals (107 males, 43 females), 21 to 65 years of age, all of whom were diagnosed with alcohol dependence according to criteria from the Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition. For a 12-week period, 75 patients received topiramate (an escalating dose of 25 mg/day to 300 mg/day), 75 received a placebo, and all received a minimal intervention called Brief Behavioral Compliance Enhancement Treatment. Patients self-reported their alcohol consumption (drinks/day, drinks/drinking day, percent heavy drinking days, percent days abstinent) and craving (using the Obsessive Compulsive Drinking Scale). In addition, serum gamma-glutamyl transferase (GGT) levels – considered a sensitive and reliable biological marker of heavy drinking – were measured at baseline and at three, six, nine, and 12 weeks.
"We found a topiramate-induced improvement in self-reported drinking outcomes," said Johnson, "which was corroborated by corresponding decreases in plasma GGT levels. In addition, topiramate was significantly superior to placebo at reducing craving. Because the dose increased with time, the effects of topiramate were confounded to a certain degree by the dosage amount. However, in my experience, patients need to exceed 200 mg a day of topiramate to have significant benefit in terms of drinking reductions. Of course, there will be exceptional folk who derive benefit at lower levels."
"Results of this study suggest that topiramate has a greater effect on drinking than naltrexone and acamprosate," added Litten. "On the other hand, topiramate appears to have more severe side-effects than naltrexone and acamprosate."
Johnson said the few side effects that were reported in topiramate recipients were mild to moderate in nature, including occasional dizziness, tingling in the skin, psychomotor slowing, word-naming difficulties, and weight loss.
Both Johnson and Litten remarked on topiramate’s apparent ability to reduce consumption in alcohol-dependent patients who were still drinking. Thus, said Litten, "patients were not required to be abstinent before taking the medication."
"Most alcoholics seek help while they are still drinking and wish to quit," added Johnson, "not when they are abstinent. Therefore, topiramate can serve to deliver treatment when it is needed most - at the point of crisis when the patient is still drinking and looking for help to quit. Additionally, topiramate appears to have the potential to reduce alcohol withdrawal symptoms. So it is possible that it can be used for inpatient detoxification and then continued in the outpatient setting to prevent relapse."
"Furthermore," said Litten, "the medication was effective with minimal behavioral intervention, suggesting a potential use in primary-care settings." However, he cautioned, "we must continue to develop and test new types of medications. We also need to test medications in special, understudied populations such as those suffering from psychiatric and/or substance abuse comorbidity, adolescents, and minorities. Because alcoholism is a heterogeneous disease, we most likely need medications that act on multiple sites. A combination of medications and behavioral therapies will most likely product the best outcome. Finally, we know that all patients do not respond to treatment. It is essential to investigate patient characteristics and identify those who do respond to a medication. In particular, the field of pharmacogenetics is most promising, that is, predicting a therapeutic response as well a toxic effect based on one’s genetic profile."
Funding for this Addiction Science Made Easy project is provided by the Addiction Technology Transfer Center National Office, under the cooperative agreement from the Center for Substance Abuse Treatment of SAMHSA.
Articles were written based on the following published research:
Johnson, B.A. Progress in the development of topiramate for treating alcohol dependence: From a hypothesis to a proof-of-concept study. (August 2004). Alcoholism: Clinical & Experimental Research, 28(8):1137-1144.
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