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Home , Alcoholism, Alcohol abuse, Alcohol detoxification, Alcohol intoxication, Ataxia, Delirium tremens

Complications of Withdrawal

Pathophysiological Insights

Louis A. Trevisan, M.D., Nashaat Boutros, M.D., Ismene L. Petrakis, M.D., and John H. Krystal, M.D.

Disease processes or events that accompany acute alcohol withdrawal (AW) can cause significant illness and . Some patients experience , which may increase in severity with subsequent AW episodes. Another potential AW is tremens, characterized by , mental , and disorientation. Cognitive impairment and delirium may lead to a chronic disorder (i.e., Wernicke-). Psychiatric problems associated with withdrawal include , , and disturbance. In addition, alterations in physiology, mood, and behavior may persist after acute withdrawal has subsided, motivating to heavy . Recent advances in neurobiology may support the development of improved medications to decrease the risk of AW complications and support long-term . KEY WORDS: AOD withdrawal syndrome; severity; disease complication; AODR (alcohol and other related) ; ; Wernicke Korsakoff ; anxiety state; emotional and psychiatric depression; ; mood and affect disturbance; heart disorder; acute AODE (alcohol and other drug effects); AODD (alcohol and other drug dependence) relapse; GABA receptors; glutamate receptors; sex ; drug therapy; AOD abstinence; literature review

brupt reduction or total cessa- associated with protracted withdrawal syndromes and their implications for tion of long-term alcohol may motivate the patient to relapse to the treatment of withdrawal. A consumption produces a heavy drinking. This article describes well-defined cluster of symptoms the acute withdrawal syndrome and called acute alcohol withdrawal (AW). its complications, including seizures, Although some patients experience delirium tremens, Wernicke-Korsa- LOUIS A. TREVISAN, M.D., is an relatively mild withdrawal symptoms, assistant clinical professor, NASHAAT koff syndrome, neuropsychiatric disease processes or events that BOUTROS, M.D., is an associate disturbances, and cardiovascular com- accompany AW can cause significant professor, ISMENE L. PETRAKIS, M.D., illness and death. After acute with- plications as well as the protracted is an assistant professor, and drawal has subsided, a poorly defined withdrawal syndrome. Recent find- JOHN H. KRYSTAL, M.D., is an syndrome of protracted withdrawal ings are discussed regarding the associate professor in at may ensue. The persistent alterations alcohol-induced alterations of nervous the Department of Psychiatry, Yale in physiology, mood, and behavior system function that underlie these University, New Haven, Connecticut.

Vol. 22, No. 1, 1998 61 Acute Alcohol alcohol detoxifications and the develop- section for a discussion on Wernicke’s Withdrawal Syndrome ment of alcohol withdrawal compli- syndrome) (Saitz 1995). Death may cations, including seizures, has been occur in up to 5 percent of patients Alcohol withdrawal is a distinctive ascribed to cumulative long-term with DT’s. The risk of death is reduced, clinical syndrome with potentially changes in excitability (i.e., the however, in patients receiving adequate serious consequences (see table) “kindling” hypothesis) (Ballenger and medication and medical support. (American Psychiatric Association Post 1978; Brown et al. 1988). (For Alcoholics who are awaiting surgical 1994). Symptoms begin as early as further discussion on kindling, see the or medical treatment often exhibit 6 hours after the initial decline from article by Becker, pp. 25–33.) DT’s when their alcohol consumption peak intoxication. Initial symptoms is abruptly interrupted by hospitaliza- include , anxiety, , tion. Therefore, hospital staff must restlessness, and . Particularly Delirium Tremens remain vigilant for in mildly alcohol-dependent persons, of alcohol withdrawal, even in patients these symptoms may comprise the DT’s are a serious manifestation of alco- not known to be alcoholic. In addition, entire syndrome and may subside with- hol dependence that develops 1 to 4 clinicians must learn to differentiate out treatment after a few days. More days after the onset of acute alcohol DT’s from other possible causes of serious withdrawal symptoms occur withdrawal in persons who have been delirium (Alvi and Gonzalez 1995). in approximately 10 percent of patients. drinking excessively for years. Signs of The prediction of complicated alco- These symptoms include a low-grade DT’s include extreme hyperactivity of hol withdrawal is an important part of fever, rapid breathing, tremor, and the autonomic ,1 along treatment to ensure that profuse sweating. The time course of with hallucinations. Women experienc- appropriate therapies may be planned withdrawal is outlined in the figure on ing DT’s appear to exhibit autonomic in advance. Risk factors for prolonged p. 63. Seizures may occur in more than symptoms less frequently than men. or complicated alcohol withdrawal 5 percent of untreated patients in acute Co-occurring medical problems may include lifetime or current long dura- alcohol withdrawal. Another severe com- obscure the diagnosis and treatment tion of alcohol consumption, lifetime plication is delirium tremens (DT’s), of DT’s or worsen the outcome. Such prior detoxifications, prior seizures, which is characterized by hallucinations, medical problems include altered blood prior episodes of DT’s, and current mental confusion, and disorientation. chemistry, certain infections, and intense for alcohol (Saitz 1995). The mortality rate among patients Wernicke’s syndrome (see the following Certain clinical and biochemical findings exhibiting DT’s is 5 to 25 percent.

Seizures Diagnostic Criteria for Alcohol Withdrawal1 1. Cessation of or reduction in alcohol use that has been heavy or Withdrawal seizures usually consist of prolonged. generalized convulsions alternating 2. Two or more of the following symptoms have developed within with spasmodic muscular contractions hours to a few days after criterion 1: (i.e., tonic-clonic seizures). Seizures that begin locally (e.g., with twitching • Autonomic hyperactivity (for example, sweating or pulse of a limb) suggest the presence of a greater than 100 beats per minute) co-occurring disorder, which should • Increased hand tremor be fully investigated. • Insomnia More than 90 percent of alcohol • Transient visual, tactile, auditory hallucinations or illusions withdrawal seizures occur within 48 • Nausea or hours after the patient stops drinking. • Excessive, purposeless physical activity (i.e, psychomotor agitation) Fewer than 3 percent of such seizures • Anxiety may occur 5 to 20 days after the last • Grand mal seizures. drink (Victor and Brausch 1967). Clinical data suggest that the likelihood 3. The symptoms in criterion 2 cause clinically significant distress of having withdrawal seizures, as well or impairment in social, occupational, or other important areas as the severity of those seizures, increases of functioning. with the number of past withdrawals. 4. The symptoms are not attributable to a general medical condition The correlation between the number of and are not better accounted for by another .

1As defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (American Psychiatric 1The autonomic nervous system is a division of Association 1994). the nervous system that helps manage the body’s response to .

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have been associated with high risk for are left with an abnormal gaze, persis- of alcohol is an impor- the development of DT’s, including spe- tent , and a potentially disabling tant contributing factor in the memory cific alterations of blood chemistry; ele- memory disorder known as Korsakoff’s disorders of alcoholics (Charness 1993). vated ; and certain nervous syndrome. Although fewer than 5 system disturbances, including muscular percent of patients initially exhibit a incoordination (Wetterling et al. 1994). depressed level of consciousness, the Disturbances of Mood, course in untreated patients may progress Thought, and Perception through , , and death. Wernicke-Korsakoff Nutritional status should be closely Withdrawing alcoholics exhibit psy- Syndrome monitored during treatment of acute chiatric difficulties that may be related AW to prevent Wernicke-Korsakoff to the process of withdrawal itself or to The combination of Wernicke’s and syndrome (for more details, see the co-occurring conditions. The major Korsakoff’s syndromes is not a com- article by Myrick and Anton, pp. 38–43). psychiatric problems associated with plication of AW but rather of a nutri- Approximately 80 percent of alco- acute and protracted withdrawal are tional deficiency. Nevertheless, the holic patients recovering from Wernicke’s anxiety, depression, and sleep dis- syndromes usually occur during AW. syndrome exhibit the selective memory turbance. Less frequently, psychotic Wernicke’s syndrome is a disorder of disturbance of Korsakoff’s syndrome symptoms, including delusions and the nervous system caused by (Victor et al. 1989). Symptoms of hallucinations, may be associated with deficiency, and alcoholics account for Korsakoff’s syndrome include severe withdrawal (Smith 1995). most cases in the (Victor for past events, along with et al. 1989). The syndrome is charac- impaired ability to commit current Anxiety terized by severe cognitive impairment experience to memory. The patient and delirium, abnormal gait (i.e., ataxia), often recites imaginary experiences Anxiety disorders are manifested by and of certain eye muscles to fill gaps in his or her memory. extreme fear and anxiety, accompanied (reviewed in Charness 1993). A Although the patient may be apathetic, by heart ; shallow, rapid majority of patients are profoundly intellectual abilities other than memory breathing (i.e., hyperventilation); disoriented, indifferent, and inatten- are relatively preserved (Charness 1993). sweating; and dizziness. Alcohol has tive; some exhibit an agitated delirium Korsakoff’s syndrome can occur in antianxiety properties that promote its related to alcohol withdrawal. Ocular the absence of alcohol use; however, use to self-medicate anxiety (George signs improve within hours to days; the disease rarely follows Wernicke’s et al. 1990a,b). However, prolonged ataxia and confusion improve within syndrome in nonalcoholics. This obser- alcohol use—and especially acute AW days to weeks. A majority of patients vation has lead to speculation that the states—can increase anxiety levels. Marked signs of anxiety commonly appear between 12 and 48 hours after cessation of alcohol consumption

70 Seizures (Peyser 1982). Transient hallucinations Hyperventilation may occur during 60 acute withdrawal, leading to disturbed Motor and autonomic overactivity, confusion, blood chemistry and resulting in symp- and disordered 50 perception toms that may be indistinguishable from those that occur in anxiety dis- 40 orders (Kushner et al. 1990). Some researchers have hypothesized that 30 repeated AW may predispose alcoholics to certain anxiety disorders through 20 the process of kindling (see the article by Becker, p. 25–33) (Lepola 1994).

Specific Withdrawal Symptoms 10 Percentage of Subjects Experiencing

0 Depression Days After Cessation of Drinking Depressive symptoms often are observed in patients who are intoxicated or under- going alcohol . As many The relationship between cessation of drinking and the onset of tremors, as 15 percent of alcoholics are at risk hallucinations, seizures, and delirium tremens. for death by , and recent con- SOURCE: Adapted from Victor and Adams 1953. sumption of alcohol appears to increase the danger of a fatal outcome from

Vol. 22, No. 1, 1998 63 self-harm (Madden 1993). This finding Cardiovascular altered function of specific receptors may be attributable to the release of Complications in the brain. Receptors are specialized behavioral inhibition associated with proteins on the surface of nerve cells or with the depres- The heart is a major site of alcohol- that receive chemical signals from other sive feeling states that accompany the induced organ damage, including distur- cells. These signals are generally con- decline from peak intoxication. Depres- bances of heartbeat rhythm (Smith veyed by chemical messengers released sive disorders commonly emerge during 1995). For example, the “holiday heart by nearby nerve cells (i.e., neurotrans- AW (Madden 1993); in addition to syndrome” consists of episodes of abnor- mitters). With long-term alcohol con- the depressive feeling states associated mal cardiac rhythms following a bout of sumption, receptors affected by alcohol with alcohol consumption and with- drinking (Smith 1995). Because arrhyth- undergo adaptive changes in an attempt drawal, the social, psychological, and mia generally occurs after a binge, rather to maintain normal function. When physical problems associated with alco- than during intoxication, AW may be a alcohol consumption ceases, these holism may contribute to the devel- contributing factor to the occurrence of changes are no longer adaptive and may opment of depressive disorders. alcohol-related (Smith 1995). contribute to the phenomena associ- Further study is required to elucidate ated with AW. Two important brain Sleep Disturbances the possible connection between AW communication systems affected by and increased sudden cardiac death. alcohol involve the Sleep disturbances—including frequent gamma-aminobutyric acid (GABA) awakening, restless sleep, insomnia, and glutamate. and night terrors—are among the most Protracted Withdrawal Syndrome common complaints of alcoholics The GABA System (Smith 1995). Sleep problems persist into AW, with pronounced insomnia Data appear to indicate that a protracted GABA is an inhibitory and marked sleep fragmentation (Le withdrawal syndrome (PWS) may that helps to regulate brain function Bon et al. 1997). In addition, alco- develop following AW and may persist by rendering nerve cells less sensitive holics show increased incidence of for at least 1 year. Some manifestations to further signaling. Single doses of interrupted breathing during sleep of PWS include symptoms associated alcohol facilitate the inhibitory function compared with the general popula- with AW that persist beyond their typical of the GABAA receptor, contributing tion. These sleep disturbances can time course. These symptoms include to alcohol’s intoxicating effects (Suzdak cause daytime drowsiness, reducing tremor; sleep disruption; anxiety; et al. 1986). During withdrawal, brain the efficiency of performance of day- depressive symptoms; and increased GABA levels fall below normal and time tasks and increasing the risk of breathing rate, body temperature, blood GABA activity declines (Petty et al. car crashes (Aldrich in press). pressure, and pulse (Alling et al. 1982; 1993). In addition, the sensitivity of Schuckit et al. 1991). Other symptoms GABAA receptors to chemical signals Hallucinations and Perceptual of PWS appear to oppose symptoms of also may be reduced in recently detox- Disturbance AW. These symptoms of PWS include ified alcoholic patients (Gilman et al. decreased energy, lassitude, and 1996). The combination of reduced Visual, auditory, and tactile hallucina- decreased overall (Satel brain GABA levels and GABAA-receptor tions are frequently experienced in acute, et al. 1993). sensitivity may be considered an adap- complicated AW or DT’s. Halluci- The significance of this cluster of tation to the presence of alcohol. In nations that are not connected with symptoms has been debated (Satel et the absence of alcohol, the resulting DT’s occur in 3 to 10 percent of al. 1993). For example, PWS could decrease in inhibitory function may patients during severe AW from 12 reflect the brain’s slow recovery from contribute to symptoms of nervous hours to 7 days after cessation or the reversible nerve cell damage common system hyperactivity associated with reduction of alcohol consumption in alcoholism. Clinically, the symptoms both acute and protracted AW. (Platz et al. 1995). of PWS are important, because they In one study, 10 percent of 532 may predispose abstinent alcoholics to The Glutamate System male patients admitted to a relapse in an attempt to alleviate the Affairs Hospital for AW developed symptoms (Satel et al. 1993). The major excitatory neurotransmitter hallucinations (Tsuang et al. 1994). in the brain is glutamate, which com- Patients who hallucinated tended to municates with three major subtypes be younger at the onset of their alcohol Neurobiology of Alcohol of glutamate receptors. Among these, problems, consumed more alcohol per Withdrawal the N-methyl-D-aspartate (NMDA) drinking occasion, developed more receptor plays a role in memory, learn- alcohol-related life problems, and had Alcohol affects the way in which ing, and the generation of seizures higher rates of other drug use than nerve cells communicate. For example, (Finn and Crabbe 1997). Alcohol patients who did not hallucinate. alcohol’s sedating effect is related to inhibits the excitatory function of the

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NMDA receptor in laboratory studies during detoxification to determine Summary at concentrations associated with mild whether a causal relationship exists. to moderate alcohol intoxication in AW and its complications are among humans (Lovinger et al. 1989; Simson the most visible consequences of alco- et al. 1991). As with the increased Antiseizure Medications holism. Those syndromes arise directly inhibitory function of the GABAA from adaptations made within nerve receptor, the decreased excitatory func- For many years, seizures and other cell communication systems that are tion of the NMDA receptor is consistent symptoms of AW have been treated targets of alcohol in the brain. Among with alcohol’s general effect. with a class of sedating medications its actions, alcohol acutely facilitates Long-term alcohol administration called (e.g., Valium®). the activity of GABAA receptor function produces an adaptive increase in the Several studies have demonstrated and blocks NMDA receptor activity. function of NMDA receptors (Trevisan The adaptations within these systems et al. 1994; Danysz et al. 1992). that the antiseizure medications car- bamezapine (Tegretol®) and valproic contribute to withdrawal-related Acute AW activates glutamate systems symptoms, seizures, and neurotoxicity. acid (Depakene®) are as effective as (Tsai et al. 1995). In turn, AW seizures Repeated AW episodes appear to increase benzodiazepines for this purpose are associated with increased NMDA the risk of future AW seizures. receptor function (Grant et al. 1990). (Stuppaeck et al. 1992; Lambie et al. Acute withdrawal symptoms and Persistent alterations in NMDA receptor 1980; Wilbur and Kulik 1981). More- complications, including seizures, function may potentiate the neuro- over, unlike the benzodiazepines, these hallucinations, and DT’s, represent toxic and seizure-inducing effects of antiseizure medications are not potential medical emergencies. Some complica- increased glutamate release during of . withdrawal (Tsai et al. 1995). tions, including Wernicke-Korsakoff Alcohol withdrawal seizures and syndrome, may be permanently disabling. PWS have been linked to both GABA In addition, the distress associated with Reproductive Hormones and NMDA dysregulation. Although acute and protracted withdrawal pre- and Alcohol Withdrawal the mechanisms of action of carbameza- sents an ongoing motivation to relapse pine and valproic acid are not entirely to alcohol use in recently detoxified Declines in the levels of understood, both medications appear patients. Thus, the early stages of sobriety may contribute to AW. Neurosteroids to increase GABA levels in the brain represent a period of risk at many levels. are substances involved in the metabo- in patients with seizure disorders Available treatments suppress many lism of reproductive hormones that (Petroff et al. 1995). In addition, val- symptoms and complications of AW. also have potent and specific effects on proic acid at therapeutic levels appears Consequently, greater emphasis may various functions of the brain. Certain to be effective at inhibiting seizures now be placed on developing strategies neurosteroids modulate the function induced by the stimulatory effect of to facilitate long-term sobriety. An important step in this direction may be of the GABAA receptor (Paul and Purdy NMDA receptors (Czuczwar et al. 1985). the development of medications that 1992; Devaud et al. 1996); plasma levels Laboratory studies suggest that of these neurosteroids are decreased lack the potential of the benzo- during AW (Romeo et al. 1996). valproic acid may inhibit GABA metab- diazepines. The antiseizure medications Because decreases in neurosteroids may olism and activate GABA synthesis meet these criteria and have the added contribute to AW symptoms, these (Fawcett 1989). In addition, data capacity to suppress kindling. compounds may have potential as med- indicate that carbamezapine decreases AW represents a period of significant ications for alleviating withdrawal the flow of glutamate into slices of clinical risk that requires attentive (Devaud et al. 1996). the , a part of the brain medical management. However, AW Ruusa and Bergman (1996) investi- involved in seizures (Olpe et al. 1985). also provides an opportunity to initiate gated the role of the male reproductive Therefore carbamezapine and valproic treatments that may lead to extended on withdrawal acid prevent alcohol withdrawal sobriety. As such, it is a critical compo- symptoms. Long-term alcohol consump- seizures and kindling. nent of the long-term treatment strategy tion causes failure of the reproductive The antianxiety and mood-stabi- for every patient with alcoholism. ■ system in men. In addition, testos- lizing actions of these terone levels decrease during alcohol may enhance their in treating consumption and increase after with- References drawal. Low levels of testosterone during withdrawal symptoms. These actions AW are associated with psychological also may help relieve the constellation ALDRICH, M.S. Effects of alcohol on sleep. In: symptoms, such as indecision, excessive of symptoms associated with PWS, Gomberg, E.S.L.; Hegedus, A.M.; and Zucker, perhaps resulting in fewer and more R.A. eds. Alcohol Problems and Aging. National worrying, fatigability, and lassitude. Institute on and Alcoholism Ruusa and Bergman (1996) suggest mild during the period fol- Research Monograph No. 33. NIH Pub. No. that testosterone be administered lowing acute withdrawal. 98–4163. Bethesda, MD: the Institute, in press.

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