Medications and Alcohol Craving Robert M. Swift, M.D., Ph.D. The use of medications as an adjunct to alcoholism treatment is based on the premise that craving and other manifestations of alcoholism are mediated by neurobiological mechanisms. Three of the four medications approved in the United States or Europe for treating alcoholism are reported to reduce craving; these include naltrexone (ReVia™), acamprosate, and tiapride. The remaining medication, disulfiram (Antabuse®), may also possess some anticraving activity. Additional medications that have been investigated include ritanserin, which has not been shown to decrease craving or drinking levels in humans, and ondansetron, which shows promise for treating early onset alcoholics, who generally respond poorly to psychosocial treatment alone. Use of anticraving medications in combination (e.g., naltrexone plus acamprosate) may enhance their effectiveness. Future studies should address such issues as optimal dosing regimens and the development of strategies to enhance patient compliance. KEY WORDS: AOD (alcohol and other drug) craving; anti alcohol craving agents; alcohol withdrawal agents; drug therapy; neurobiological theory; alcohol cue; disulfiram; naltrexone; calcium acetylhomotaurinate; dopamine; serotonin uptake inhibitors; buspirone; treatment outcome; reinforcement; neurotransmitters; patient assessment; literature review riteria for defining alcoholism Results of craving research are often tions (i.e., pharmacotherapy) to improve vary widely. Most definitions difficult to interpret, because the subjec- the effectiveness of psychosocial alco- Cof alcohol dependence include tive nature of craving makes it difficult holism treatment (Litten et al. 1996; the following descriptors: a compulsion to assess and quantify. Also, the quality Swift 1999). Alcoholism pharma- to seek and consume alcohol, a loss of and intensity of craving may vary cotherapy is based on the premise that control over consumption after begin- according to personal characteristics as alcohol use is mediated through spe- ning a drinking session, and a strong well as environmental circumstances or likelihood of relapse during or after experimental conditions. Nevertheless, withdrawal.1 These manifestations may phenomena associated with craving ROBERT M. SWIFT, M.D., PH.D., is an be accompanied by a conscious desire may have important implications for associate professor in the Department of or urge to consume alcohol (i.e., crav- preventing and treating alcoholism. Psychiatry and Human Behavior at Brown ing). Craving can occur spontaneously, For example, high levels of craving are University and associate chief of staff for or it can be elicited by internal or exter- associated with increased probability research and education at the Providence nal stimuli, known as cues (see sidebar of relapse, particularly during the early Veterans Administration Medical Center by Tiffany on p. 216 ). Internal cues stages of the posttreatment period (Anton in Providence, Rhode Island. may include emotional states (e.g., anx- et al. 1996). In addition, treatments iety) or symptoms of acute alcohol that reduce craving have been shown to 1Symptoms of acute withdrawal (e.g., tremors, agi- withdrawal. External cues may include reduce subsequent alcohol use (Monti tation, and seizures) may occur following cessation exposure to alcohol-related environ- et al. 1993).2 or reduction of heavy drinking. ments or objects (e.g., bottles of alco- In the past decade there has been 2Craving alone is neither necessary nor sufficient holic beverages or advertisements). increasing interest in the use of medica- for relapse. Vol. 23, No. 3, 1999 207 cific neurobiological and behavioral mechanisms that initiate and maintain The Role of Neurons and Neurotransmitters drinking. Several medications have The ends of adjacent nerve cells, or neurons, are generally separated from demonstrated their ability to reduce one another by microscopic gaps called synapses. Most neurons communi- alcohol consumption in humans, and cate with one another by releasing chemicals called neurotransmitters, several of these drugs are reported to which cross the synapse and attach to a receptor protein on the receiving reduce alcohol craving. Researchers can neuron. Each neurotransmitter binds preferentially to a single family of reasonably conclude that medications receptor subtypes, each of which may then stimulate, inhibit, or modulate a which reduce craving may be effective specific physiological function. A single neuron generally releases only one in alcoholism treatment. or a few types of neurotransmitters but may contain several types of recep- tors. A neurotransmitter released into a synapse is usually quickly removed Assessing and Measuring by chemical degradation or by transporter molecules that carry the neuro- Craving transmitter back into the neuron that released it. The function of a neuro- transmitter can be increased or mimicked by drugs, medications, or other chemical agents (i.e., agonists) or decreased, inhibited, or reversed by other Because craving is a subjective phe- agents (i.e., antagonists). nomenon, researchers commonly assess its intensity based on the self-reports of study participants.3 The simplest craving The Neurobiology 1996). Reinforcement of AOD use is assessments are single-item questionnaires. of Craving associated with release of the neuro- In the most basic approach, the subject transmitter dopamine in a brain region responds to a question (such as, “How Research during the past decade has called the nucleus accumbens (Roberts much do you desire alcohol right now?”) expanded our knowledge of the brain and Koob 1997) (see textbox above). by selecting one of three to five statements mechanisms that mediate the use of Long-term exposure to alcohol can lead that indicate increasing levels of intensity alcohol and other drugs (AODs). Alcohol to compulsive use that characterizes (e.g., from “not at all” to “very much”). may be consumed for its rewarding dependence (Roberts and Koob 1997). In some studies the patient rates his or effects, which are sometimes consciously Following repeated administration her craving on a visual analog scale (VAS). perceived as a pleasurable state (e.g., of alcohol, the brain attempts to restore In this approach, the patient places a mark the effects of mild alcohol intoxica- normal function through physiological on a line that is approximately 4 inches tion), or as relief from a painful or adjustments (i.e., counteradaptations) long and divided into arbitrary units uncomfortable state (e.g., amelioration that tend to reduce alcohol’s initial beginning with zero. The reliability of of withdrawal symptoms). Repeated sedating effects (Roberts and Koob 1997). single-item craving assessments is variable. exposure to a rewarding stimulus increases When a person terminates a prolonged Multi-item questionnaires include the the probability that a person will con- drinking session, these counteradapta- Obsessive Compulsive Drinking Scale tinue to seek, approach, and maintain tions are unopposed, resulting in signs (Anton et al. 1995), which contains 14 contact with the particular stimulus. and symptoms of acute withdrawal. questions, each rated on a scale from 0 to Stated simply, a person who finds alco- During this period, craving may represent 4, and the Alcohol Urge Questionnaire, hol use rewarding may subsequently a desire to self-medicate the anxiety which contains 8 statements rated from drink more often and in larger quanti- and hyperexcitability that accompany 1 to 7 (Bohn et al. 1995). ties. This process is referred to as posi- this state. Craving is sometimes assessed by tive reinforcement when its goal is to Certain manifestations of counter- measuring certain physiological changes attain a pleasurable state and is referred adaptation, presumably involving per- thought to accompany craving, such as to as negative reinforcement when its sistent dopamine dysregulation in the changes in heart rate, blood pressure, goal is to ameliorate an unpleasant state nucleus accumbens, can prolong vul- salivation, and sweat gland activity. Finally, (Roberts and Koob 1997).4 nerability to craving long after the acute craving can be assessed by directly AODs may activate the same neuro- symptoms of withdrawal have subsided. observing a subject’s drinking behavior. biological mechanisms that respond to This mechanism may account for the Behavioral measurements may include conventional reinforcers, such as food ability of cues, such as the sight, sound, number of drinks consumed, time and sexual activity (Di Chiara et al. or smell of alcohol, to trigger relapse elapsed between cue exposure and initia- years after an alcoholic has stopped tion of drinking (i.e., latency), and time drinking (Roberts and Koob 1997). elapsed between commencement and 4Research suggests that in some alcoholics an aver- The processes involved in addiction completion of drinking. sive state may result from inherited deficiencies in include complex interactions among serotonin or other neurotransmitters; this state may several neurotransmitters in addition to 3This section presents a brief overview. For more detail, initially be alleviated by self-medication with alco- see the article in this issue by Drobes and Thomas, hol but will actually worsen from long-term, con- dopamine (see table, p. 209). For exam- pp. 179–186. tinued consumption (Roberts and Koob 1997). ple, opioid peptides may mediate some 208 Alcohol Research & Health