Exploring Alcohol Withdrawal Syndrome DEBORAH A. FINN, PH.D., AND JOHN C. CRABBE, PH.D. Alcohol withdrawal syndrome is characterized by hyperactivity of the nervous system. This hyperactivity represents the brain’s attempt to function normally despite the inhibitory effect of chronic alcohol consumption. The syndrome manifests when alcohol consumption ceases. Experimental, clinical, and genetic research have linked the development of withdrawal to alterations in the sensitivity of neuronal communication systems. Early treatment of the syndrome is advised, because the symptom severity may increase with each subsequent episode. KEY WORDS: AOD withdrawal syndrome; chronic AODE (alcohol and other drug effects); symptom; biological inhibition; neurotransmission; neurochemistry; neurotransmitters; neurotransmitter receptors; animal model; animal strains; membrane channel; genetic mapping; biochemical mechanism; literature review lcohol withdrawal syndrome teins, which bind to neurotransmitters, animal models to study the mecha- consists of unpleasant physical and ion channels through which ions1 nisms and genetics of withdrawal; and Aand mental symptoms follow- (e.g., sodium or calcium) enter the the involvement of neurotransmitters, ing the cessation of alcohol consump- cell. Following repeated administra- receptors, and ion channels in the tion. These symptoms may range from tion of alcohol, the brain attempts to syndrome. For a discussion on the role mild tremor to hallucinations and restore normal functioning through convulsions. Repeated withdrawal adaptations (i.e., tolerance) that re- DEBORAH A. FINN, PH.D., is an episodes may contribute to the devel- duce alcohol’s initial perturbing ef- assistant professor in the Department opment of alcohol dependence and to fects (figure 1). Long-term exposure of Behavioral Neuroscience, Oregon the negative health consequences of to alcohol can lead to physical depen- Health Sciences University, and a drinking. An increased understanding dence, in which neuronal adaptations research pharmacologist at the Dept. of Veterans Affairs Medical Center, of the genetic and biochemical corre- to alcohol become sufficiently pro- Portland, Oregon. lates of the syndrome may lead to nounced that the brain requires the improved treatments for withdrawal continued presence of alcohol to func- JOHN C. CRABBE, PH.D., is a professor as well as for other aspects of alcohol tion normally. When a person termi- in the Department of Behavioral dependence. nates a prolonged drinking session, Neuroscience, Oregon Health The symptoms of withdrawal rep- the adaptations that developed to Sciences University, director of the resent a phase in the alcohol-induced offset alcohol’s initial inhibitory ac- Portland Alcohol Research Center, cycle of neuronal inhibition and exci- tions are unopposed, resulting in a and a research career scientist at the tation. Research has demonstrated that rebound hyperexcitability, or with- Dept. of Veterans Affairs Medical short-term (i.e., acute) administration drawal syndrome. Center, Portland, Oregon. of alcohol can alter the release of This article describes the symp- toms of alcohol withdrawal; the use of Support for this work was provided by chemical messengers (i.e., neurotrans- grants from the National Institute on mitters) from neurons and can disrupt 1For a definition of this and other technical Alcohol Abuse and Alcoholism the function of proteins in neuronal terms used in this article, see central glossary, (AA10760 and AA08621) and the membranes, including receptor pro- pp. 177–179. Department of Veterans Affairs. VOL. 21, NO. 2, 1997 149 Severe alcohol withdrawal is fre- quently complicated in its later stages Drug-free by the presence of delirium tremens + (DT). Patients with DT are agitated, confused, and disoriented, with delu- sions and vivid hallucinations. DT may Acute Chronic Withdrawal persist until 96 hours after cessation of drinking (Victor and Adams 1953). 0 THE KINDLING MODEL OF ALCOHOL WITHDRAWAL Tolerance Last Sedation SEVERITY dose Central Nervous System Activity Several factors are associated with Time increased withdrawal severity, includ- ing increased alcohol consumption, a greater number of prior withdrawal episodes, the occurrence of medical Figure 1 Alcohol’s effect during exposure and withdrawal. The zero line represents problems, and the use of other drugs a hypothetical measure of overall brain excitability. For most physiological in addition to alcohol (Schuckit et al. or behavioral measures, acute alcohol administration produces short-term stimulation (i.e., points above the zero line), followed by depression or 1995). According to one hypothesis sedation (i.e., points below the zero line). Continued alcohol adminis- (Ballenger and Post 1978), repeated tration causes neuronal adaptations that reduce alcohol’s initial perturbing withdrawal episodes increase the effects and result in tolerance. Physical dependence indicates that alcohol severity of subsequent withdrawal is needed to balance the neuronal adaptations and maintain normal brain syndromes as a result of “kindling.” function. Removal of alcohol from the body induces a rebound stimulatory In kindling, a convulsion-promoting effect, resulting in hyperexcitability of the nervous system (i.e., withdrawal drug or electric shock administered syndrome). repeatedly at doses below the effec- SOURCE: Adapted from Metten and Crabbe 1996. tive level for a single administration eventually elicits a convulsion after a single administration. Thus, the neu- rochemical changes that occur during of withdrawal in the development of may occur within the first 2 days of alcohol withdrawal (i.e., reduced addiction, see the article by Roberts abstinence in 5 to 10 percent of pa- function of inhibitory neurotransmis- and Koob, pp. 101–106. tients (Victor and Adams 1953; sion and increased activity of excitatory Schuckit et al. 1995; Yost 1996). neurotransmission) not only contribute SYMPTOMS OF ALCOHOL According to clinical studies, ap- to the withdrawal syndrome, but also WITHDRAWAL proximately 10 percent of alcoholics may cause long-term changes in brain may develop an additional set of with- excitability by a kindlinglike process Alcohol withdrawal is characterized by drawal symptoms. These symptoms (Glue and Nutt 1990). Consistent with symptoms of hyperactivity of the auto- represent a combination of marked the kindling hypothesis, the severity nomic nervous system, a division of autonomic nervous system hyperactiv- of withdrawal in mice, measured by the nervous system that helps manage ity, including large increases in blood handling-induced convulsions the body’s response to stress (Schuckit pressure, pulse, breathing rate, and (HIC’s), increases with repeated expo- et al. 1995; Yost 1996). Alcoholics heart rate, as well as elevated body sure to alcohol vapor and subsequent often continue to consume alcohol to temperature. Drenching sweats can withdrawal episodes compared with relieve or avoid withdrawal symptoms. cause severe dehydration, and tremor mice that received an equivalent dose The initial symptoms usually are can become sufficiently pronounced of alcohol vapor in a single adminis- relatively mild and include anxiety, to prevent the patient from performing tration (Becker and Hale 1993). insomnia, and tremors. These symp- such simple activities as manipulating Therefore, both animal and human toms may begin within 3 to 6 hours an eating utensil. Typically, these studies indicate a greater likelihood of following cessation of drinking and more severe symptoms peak in inten- severe withdrawal symptoms in pa- often before the blood alcohol concen- sity between the third and fourth days tients who have experienced a greater tration (BAC) has returned to zero. of abstinence and generally improve number of past withdrawal episodes. The symptoms usually abate within by the fifth day (Schuckit et al. 1995) These data suggest that early treat- 1 to 3 days. Severe convulsions also (figure 2). ment for alcohol withdrawal convul- 150 ALCOHOL HEALTH & RESEARCH WORLD Alcohol WithdrawalRunning Syndrome Heads sions may minimize increased with- and provide an overview of the main drawal severity in subsequent findings with each animal model. 70 episodes by preventing this kindling- 60 like process. Research is needed to Inbred Strains confirm this possibility. 50 An inbred strain is derived from 20 40 generations of brother-sister matings, 30 ANIMAL MODELS OF ALCOHOL resulting in a population of animals 20 WITHDRAWAL that is essentially genetically identical. 10 Thus, trait variation within an inbred Percentage of patients 0 Researchers have used various meth- strain can be attributed to environ- 123456714 ods to induce physical dependence in mental causes, whereas variation Days After Cessation of Drinking animals in order to define and quanti- between inbred strains can be attribut- fy the withdrawal syndrome. The ed to genetic causes. Studies docu- Convulsions (68 patients) most common paradigms utilize a Transient hallucinations menting differences in alcohol (50 patients) nutritionally balanced liquid diet con- withdrawal severity among inbred Tremors (50 patients) taining alcohol, inhalation of alcohol strains show clear evidence of genetic Motor and autonomic vapor, or multiple daily doses of alco- overactivity, confusion, and influence (Kakihana 1979; Crabbe et disordered sense perception hol administered either by injection or al. 1983). (44 patients) by a tube inserted into the esophagus One