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Home , Alcoholism, Alcohol abuse, Alcohol dependence, Alcohol detoxification, Carbamazepine, Delirium tremens

Introduction to Withdrawal

Richard Saitz, M.D., M.P.H.

Heavy drinkers who suddenly decrease their alcohol consumption or abstain completely may experience alcohol withdrawal (AW). of AW can include, among others, mild to moderate , , , or agitation. The most severe manifestations of withdrawal include tremens, , and . These manifestations result from alcohol-induced imbalances in the brain chemistry that cause excessive neuronal activity if the alcohol is withheld. Management of AW includes thorough assessment of the severity of the patient’s symptoms and of any complicating conditions as well as treatment of the withdrawal symptoms with pharmacological and nonpharmacological approaches. Treatment can occur in both inpatient and outpatient settings. Recognition and treatment of withdrawal can represent a first step in the patient’s recovery process. KEY WORDS: AOD withdrawal syndrome; biochemical mechanism; neurotransmission; receptors; ; symptom; ; anxiety state; ; AODR (alcohol and other drug related) hallucinosis; AODR ; AOD abstinence; disease severity; patient assessment; treatment method; alcohol withdrawal agents; drug therapy; ; care; literature review

very year more than one-and- clinical syndrome that affects people a-half million people in the accustomed to regular alcohol intake RICHARD SAITZ, M.D., M.P.H., is an EUnited States either enter alco- who either decrease their alcohol assistant professor of medicine in the holism treatment or are admitted to consumption or stop com- Clinical Addiction Research and a general hospital because of medical pletely. In these people, the central Education Unit, Section of General consequences resulting from alcohol nervous system (CNS) has adjusted to Internal Medicine, Department of dependence. These patients, as well as the constant presence of alcohol in the Medicine, at Boston Medical Center a substantial number of other people body and compensates for alcohol’s and Boston University School of Medicine; who stop drinking without seeking depressive effects on both brain func- a faculty fellow in the Center for professional treatment, experience tion and the communication among Substance Prevention Faculty alcohol withdrawal (AW). AW is a nerve cells (i.e., ). Consequently, Development Program; and a generalist when the alcohol level is suddenly physician faculty scholar of the Robert 1Clinicians generally distinguish between signs and lowered, the brain remains in a hyper- Wood Johnson Foundation. symptoms of a disorder or syndrome. “Signs” are changes in the patient’s condition that can be active, or hyperexcited, state, causing objectively observed by an examiner (e.g., temperature, withdrawal syndrome. Support for this work was provided a rash, or high blood pressure). Conversely, symp- AW syndrome varies significantly by National Institute on Alcohol toms are changes that are subjectively perceived by among alcoholics in both its clinical Abuse and grant the patient (e.g., irritability or for alcohol). manifestations and its severity. These 5RO1–AA–10870 and by Center The term “manifestations of alcohol withdrawal,” 1 which is used in this article, can refer to either signs manifestations can range from mild for Prevention grant or symptoms. to severe consequences, 1T15–SPO7773.

Vol. 22, No. 1, 1998 5 such as delirium tremens (DT’s) and toms. Moreover, the symptoms of AW Of these , scientists even death. Substantial variability also were dose dependent: The men who best understand the roles of GABA exists in the incidence with which had consumed the largest amounts of and glutamate. For example, researchers symptoms occur in various drinkers. alcohol developed the most severe have demonstrated that alcohol Some people who regularly consume manifestations of withdrawal, such as enhances (i.e., potentiates) GABA’s alcohol never experience any withdrawal hallucinations, seizures, and DT’s. inhibitory effects on signal-receiving symptoms. Conversely, in some alco- These findings support the association neurons, thereby suppressing neuronal holics withdrawal symptoms can occur between alcohol intake and the clinical activity. With chronic alcohol exposure, at blood alcohol concentrations (BAC’s) manifestations of withdrawal syndrome. however, GABA receptors become less that would be intoxicating in non- responsive to the neurotransmitter, alcohol-dependent people but which and higher alcohol concentrations are for the dependent patients represent required to achieve the same level of a decline from their usual BAC’s. Most manifestations suppression. This clinically observed This article briefly reviews the mech- of withdrawal adaptation is referred to as tolerance. anisms, clinical features, and man- When alcohol is removed from this agement of AW. The article also discusses will resolve after adapted system, the GABA receptors how the treatment of AW can be linked several hours to remain less responsive, leading to an to the treatment of imbalance in favor of excitatory neu- and any co-occurring or underlying dis- several days. rotransmission. This imbalance is orders. For more in-depth discussions of enhanced further by an alcohol- some of these issues, the reader is referred induced increase in the number of to subsequent articles in this issue. one type of receptor for the excitatory To better understand the mecha- neurotransmitter, glutamate. Even nisms underlying withdrawal, one when alcohol is removed, the number Mechanisms of Alcohol must briefly review some of the prin- of these receptors remains elevated, Withdrawal ciples of neuronal communication in leading to enhanced excitatory neuro- the CNS. The transmission of nerve transmission. Both of these mechanisms Historically, several mechanisms have signals from one to the next is contribute to the neuronal hyperex- been suggested to play a role in the achieved, in general, through small citability that is characteristic of AW. development (i.e., etiology) of AW. For molecules called neurotransmitters, (For more information on the neuro- example, researchers initially thought which are secreted by the signal- chemical mechanisms underlying with- that withdrawal might be caused by emitting neuron. The neurotransmitter drawal, see the article by Littleton, nutritional deficiencies (Isbell et al. 1955; molecules traverse the small gap (i.e., pp. 13–24.) Victor and Adams 1953) and that some the ) between adjacent neurons complications of withdrawal (e.g., seizures) and interact with docking molecules might result directly from alcohol use (i.e., receptors) on the signal-receiving Clinical Features of or intoxication (Ng et al. 1988). Although neuron. The interaction between a Alcohol Withdrawal alcoholic patients exhibit many metabolic neurotransmitter and its receptor and nutritional disturbances, overwhelm- initiates a cascade of chemical and Despite this current understanding of ing laboratory and clinical evidence electrical reactions in the signal- the mechanisms underlying AW syn- now indicates that the constellation of receiving cell that depending on the drome, some controversies still exist signs and symptoms known as AW are neurotransmitter involved, results in regarding the risk, complications, and caused by interrupting the constant the activation or inhibition of that cell. clinical management of withdrawal. exposure of the CNS to alcohol. Thus, excitatory neurotransmitters These controversies likely arise from The hypothesis that withdrawal (e.g., glutamate) stimulate the signal- the varied clinical manifestations of occurs as a result of “insufficient” alco- receiving neuron, whereas inhibitory the syndrome in alcoholic patients hol intake or abstinence in dependent neurotransmitters (e.g., gamma- and from the diverse settings in which patients rather than because of nutri- aminobutyric acid [GABA]) inhibit these patients are encountered. For tional deficiencies was supported by an the neuron. Under normal conditions, example, some alcoholic patients who early study of men who received large a tight balance is maintained between cut down or stop drinking may expe- daily doses of alcohol (Isbell et al. excitatory and inhibitory influences. rience no withdrawal symptoms, 1955). The study participants, who Regular alcohol intake affects whereas others experience severe man- also were well fed, each consumed up numerous excitatory and inhibitory ifestations. In fact, even in clinical to almost 30 standard drinks per day neurotransmitter systems in the brain studies of patients presenting for for up to 3 months. Upon abstaining (Begleiter and Kissin 1996). Similarly, , the proportion from this alcohol intake, these men many neurotransmitters and mecha- of patients who developed significant invariably developed withdrawal symp- nisms probably are involved in AW. symptoms ranged from 13 to 71

6 Alcohol & Research World Introduction to Alcohol Withdrawal

percent (Victor and Adams 1953; the first seizure (Victor and Brausch • Abnormal function Saitz et al. 1994). What is the reason 1967). Although multiple seizures are for this variability? Likely, individual not common, AW is one of the most • Prior detoxification patients differ in their underlying common causes in the risks for withdrawal symptoms. These of —a medical emer- • Past experience of seizures or DT’s differences result from factors such as gency characterized by continuous, the patient’s pattern of alcohol use, the unrelenting seizures. • Intense craving for alcohol presence of coexisting illnesses, varia- DT’s, which last up to 3 or 4 days, tions in genetic influences and CNS are characterized by disorientation and • Concomitant acute illness mechanisms, as well as the neuro- are usually accompanied by autonomic chemical mechanisms described in signs resulting from the activation of • Older age the previous section. the nerves responsible for the body’s Despite the variability in the type response to ). Those signs include • Use of other drugs in addition to and severity of symptoms that a person severe agitation, rapid heartbeat (i.e., alcohol can experience, the clinical syndrome ), high blood pressure, and of AW has been well defined. Its symp- . (Thus, DT’s are a much more • More severe withdrawal symptoms toms generally appear within hours of serious condition than the “shakes,” when presenting for treatment. stopping or even just lowering alco- which often are also colloquially referred hol intake and, thus, BAC. The most to as DT’s.) DT’s can develop between common symptoms include tremor, 1 and 4 days after the onset of with- craving for alcohol, insomnia, vivid drawal and are generally preceded by Management of Alcohol dreams, anxiety, hypervigilance,2 additional autonomic signs, such as Withdrawal agitation, irritability, loss of appetite sweating and tremors. About five percent (i.e., anorexia), , , of the patients who experience DT’s die headache, and sweating. Even without from metabolic or cardiovascular com- Assessment treatment, most of these manifesta- plications, trauma, or infections (Victor tions will usually resolve several hours and Adams 1953; Cutshall 1964). Before initiating any interventions, to several days after their appearance. the first step in managing a patient’s withdrawal is to assess thoroughly the The most severe manifestations of Risk Factors for DT’s and Seizures AW include hallucinosis, seizures, and patient’s condition. This assessment DT’s (see also the figure on pp. 63, Given the wide range of potential mani- should include an evaluation of the from Victor and Adams’ classic paper). festations associated with withdrawal, presence of coexisting medical and Hallucinosis, which may occur within is it possible to predict their develop- psychiatric conditions, the severity of 1 or 2 days of decreasing or abstaining ment in individual patients? Currently, the withdrawal symptoms, and the from alcohol intake, is a the answer is “no.” To date, most studies risk of withdrawal complications. distinct from DT’s. Patients with alcohol of predictors of severe or complicated Moreover, reassessment of the with- hallucinosis see, hear, or feel things that withdrawal have been too limited method- drawal symptoms at regular intervals are not there even though they are fully ologically to allow clinically accurate until they have resolved can help conscious and aware of their surround- prognoses for individual patients. Based guide treatment as well as encourage ings. Moreover, hallucinosis is not on current understanding of the with- the clinician to monitor the patient necessarily preceded by various physio- drawal syndrome, as well as on some for the development of complications logical changes (i.e., autonomic signs). clinical research results, however, clini- that might require more intensive AW seizures also can occur within 1 cians have identified some patient charac- observation or treatment. or 2 days of decreased alcohol intake, teristics that likely confer a risk of more The symptoms of withdrawal are even in the absence of other withdrawal severe withdrawal symptoms; prolonged not specific and easily can be con- signs and symptoms. The patient usu- symptoms; or withdrawal-specific com- fused with other medical conditions. ally experiences only one generalized plications, such as DT’s or seizures. Consequently, the clinician’s initial convulsion, which involves shaking of These factors include the following: assessment also serves to exclude other the arms and legs and loss of conscious- conditions with symptoms similar to ness. If a second convulsion occurs, it • More severe alcohol dependence, those of AW. Examples of such condi- generally happens within 6 hours of including prior development of tions include (i.e., withdrawal symptoms the collection of blood in the space 2The term “hypervigilance” refers to a state of between the membranes surrounding being overly concerned with everything (e.g., • Higher levels of alcohol intake, the CNS), , meningitis, one’s surroundings), of being “on edge.” This resulting in higher BAC’s and other infections. Similarly, seizures state manifests itself, for example, by continually looking around and moving one’s head in abrupt, and DT’s may be confused with other jerky movements. • Longer duration of alcoholism conditions that should be excluded

Vol. 22, No. 1, 1998 7 Figure 1 The Clinical Institute Withdrawal Assessment for Alcohol, revised (CIWAÐAr) (Sullivan et al. 1989; Foy et al. 1988). This instrument rates 10 withdrawal features, takes only a few minutes to administer, and can be repeated easily when necessary. A total score of 15 or more points indicates that the patient is at increased risk for severe withdrawal effects, such as and seizures.

8 Alcohol Health & Research World Introduction to Alcohol Withdrawal

during initial assessment. For example, Once a diagnosis of AW has been riencing severe withdrawal symptoms, DT’s, which represent an acute confu- made, the clinician must assess the proven benefits of treatment include sional state, can mimic delirium from severity of withdrawal and the risk amelioration of symptoms, preven- other medical causes, such as encephali- for associated complications. The tion of both seizures and DT’s, and tis, meningitis, adverse effects of some best validated tool for such an assess- treatment of DT’s. Treatment also , or Wernicke’s encephalopa- ment is the Clinical Institute may prevent increasing severity of thy.3 Likewise, AW seizures must be dis- Withdrawal Assessment for Alcohol, withdrawal during subsequent with- tinguished from seizures resulting from revised (CIWA–Ar) (Sullivan et al. drawal episodes and encourage the other causes, such as mineral or 1989; Foy et al. 1988) (see figure 1). patient to enter alcoholism treatment abnormalities, , brain tumors, This instrument, which rates 10 for prevention. , or subdural hematoma. Thus, a withdrawal features, can be adminis- Patients with mild withdrawal symp- tered in only a few minutes and toms (i.e., CIWA–Ar scores of 8 or diagnosis of DT’s and AW seizures repeated when necessary. A total less) and no increased risk for seizures should be made only after other reason- score of 15 or more points indicates can be managed without specific phar- able causes for these complications have that the patient is at an increased risk macotherapy (Mayo-Smith 1997; been excluded. for confusion and seizures. Saitz and O’Malley 1997). Successful A thorough assessment also should nonpharmacological treatments include anticipate health problems that fre- Treatment of Alcohol Withdrawal frequent reassurance and monitoring quently occur in patients withdrawing by treatment staff in a quiet, calm from alcohol. These complications Based on the patient’s score on the environment. Most patients with mild may include the following: CIWA–Ar, the physician determines withdrawal symptoms, whether they the appropriate treatment (see table). are treated or not, do not develop • (i.e., an inflammation For all patients, especially those expe- complications. of the stomach lining, which often is associated with bleeding)

• Gastrointestinal bleeding (e.g., from Examples of Specific Regimens Used in the Treatment of Alcohol Withdrawal the esophagus, stomach, or intestines)

• Treatment Approach Treatment Component • Cardiomyopathy (i.e., any disorder of the heart muscle) Monitoring ¥ Monitor the patient by administering the CIWAÐAr1 test every 4 to 8 hours until the score has been • (i.e., an inflammation lower than 8 to 10 points for 24 hours of the ) ¥ Use additional assessments as needed • Disturbances in the electrolyte balance (e.g., alcohol — Symptom-triggered regimens ¥ Perform the CIWAÐAr every hour to assess the patient’s need for a metabolic derangement that results in too much acid in the ¥ Administer one of the following medications every hour when the CIWAÐAr score is at least 8 to 10 bloodstream—and abnormally low points: levels of in the blood) — (50Ð100 milligrams [mg]) • Deficiency of the vitamin folate, — (10Ð20 mg) which can cause lower-than-normal — (2Ð4 mg) numbers of blood cells Fixed-schedule regimens ¥ Administer one of the following medications every • Deficiency of the vitamin , 6 hours: which can lead to serious neurological —Chlordiazepoxide (4 doses of 50 mg, then 8 doses of 25 mg) problems, such as Wernicke’s enceph- —Diazepam (4 doses of 10 mg, then 8 doses of 5 mg) alopathy (accordingly, thiamine should —Lorazepam (4 doses of 2 mg, then 8 doses of 1 mg) be administered to all patients under- ¥ Provide additional medication if these regimens do going AW to prevent the development not control the symptoms (i.e., the CIWAÐAr score of this syndrome). remains at least 8 to 10 points)

3Wernicke’s encephalopathy is an acute condition 1CIWAÐAr = Clinical Institute Withdrawal Assessment for Alcohol, revised. For further information see figure 1. characterized by general confusion, abnormal eye SOURCE: Mayo-Smith 1997. movements, and difficulty walking or keeping one’s balance.

Vol. 22, No. 1, 1998 9 Many patients who experience not only improve Two primary approaches can be mild withdrawal symptoms do not the symptoms of AW but also reduce used to administer benzodiazepines seek treatment at all. Nevertheless, the incidence of DT’s and seizures. In during AW treatment: (1) the tradi- even those patients may benefit from addition, they generally are safe and tional, fixed-schedule approach and treatment in the long term, because can be administered repeatedly over (2) the symptom-triggered approach. repeated withdrawal episodes may several hours. The best-studied ben- In the fixed-schedule dosing regimen, enhance the brain’s susceptibility to zodiazepines for AW treatment are the patient receives a specific dose of the hyperexcitability that occurs diazepam, chlordiazepoxide, and lora- the medication every 6 hours for 2 to during AW. This process is known as zepam. These agents all are relatively 3 days, regardless of the presence or kindling. (For more information on long acting (i.e., for up to several severity of symptoms. For the symp- kindling, see the article by Becker, days) and therefore can provide a tom-triggered approach, the patient’s pp. 25–33.) Clinical studies have smooth course of treatment without CIWA–Ar score is determined hourly, found that patients with a history of the risk of rebound symptoms (e.g., and the medication is administered multiple withdrawal episodes have a seizures) that occur late during with- only when the score is elevated. Patients higher risk of seizures than do drawal. Lorazepam should be used in with no symptoms receive no medica- patients experiencing their first with- patients with severe liver dysfunction tion. This approach is an efficient drawal episode (Lechtenberg and and in patients who are at high risk of way to dose benzodiazepines during Worner 1991). The results of these experiencing serious medical conse- AW, because it allows the physician clinical studies are confounded by quences following sedation, such as to administer the correct amount of differences among the subjects in the people with severe lung disease or medication for the patient’s symp- severity of dependence, duration of elderly patients. Short-acting (i.e., for toms. Moreover, when compared dependence, and quantity of alcohol several hours) benzodiazepines proba- with fixed-schedule dosing, symptom- consumed. The findings are consis- bly are efficacious as well but are triggered dosing delivers less med- tent, however, with information ob- associated with a greater risk of re- ication over a shorter period of time tained using animal research. Thus, bound symptoms. To prevent recur- (e.g., the first 8 hours of withdrawal) prompt appropriate treatment of rence of withdrawal symptoms, these (see figure 2). This approach has not withdrawal, even in patients with agents must be given in increasingly been tested, however, in patients who mild symptoms, may conceivably smaller doses (i.e., require tapering) exhibit no or only mild symptoms prevent the development of compli- before they can be discontinued. but who are at high risk for seizures cated, more severe withdrawal during subsequent episodes.

Pharmacotherapy of Alcohol 120 Symptom-triggered Withdrawal Symptoms 100 100 Patients who experience more severe Fixed schedule withdrawal (i.e., who have CIWA- 80 75 Ar scores of 8 to 15 or greater) 60 should receive pharmacotherapy to 50 treat their symptoms and reduce their risk of seizures and DT’s. The Administered 40 medications with the best efficacy 25 25 25 25 25 25 25 and safety are the benzodiazepines. 20 Like alcohol, these agents enhance 000 0 0 0 0 0 Median Amount of Chlordiazepoxide 0 the effect of the neurotransmitter 0Ð89Ð16 17 Ð24 25Ð32 33Ð40 41Ð48 49Ð56 57Ð64 65Ð72 GABA on the brain. Because of their Hours of Withdrawal similar effects, benzodiazepines and alcohol are cross-tolerant—in other words, a person who is tolerant to Figure 2 Administration period and median amount of the alcohol also is tolerant to benzodi- chlordiazepoxide administered over the course of alcohol withdrawal to patients undergoing a symptom-triggered or fixed-schedule dosing azepines. Cross-tolerance also implies regimen. The results demonstrate that compared with patients on a fixed- that when a person experiences a schedule regimen, patients on a symptom-triggered regimen required deficiency of one agent (e.g., alcohol much less medication for a shorter period of time and were therefore at during withdrawal), the other agent lower risk for unwanted side effects from the medication. (e.g., a benzodiazepine) can serve as a substitute, thereby easing the with- SOURCE: Saitz et al. 1994. drawal symptoms.

10 Alcohol Health & Research World Introduction to Alcohol Withdrawal

or whose withdrawal symptoms that the medication may prevent probably can prevent cannot be adequately assessed. This seizures. Moreover, it does not inter- AW seizures, although insufficient includes patients who receive general fere with mental processes, such as data exist in humans to confirm this or who take medications learning, whereas other agents (e.g., hypothesis. In contrast, phenyotin, that block the sympathetic nervous benzodiazepines) can cause , an medication used system (e.g., beta blockers, which are mental dullness, and sleepiness (i.e., for treating seizures caused by epilepsy used to treat and other ). also and other disorders, is ineffective for cardiovascular disorders). For these does not potentiate alcohol-induced treating AW seizures. Because a diag- patients, the traditional fixed-sched- of the CNS, nor does it nosis of AW-related seizures may ule dosing regimens may be more affect respiratory function. In addi- require further evaluation, however, appropriate. tion, unlike the benzodiazepines, the agent is sometimes administered Many agents other than benzodi- carbamazepine does not have the until other have azepines have been used for managing potential for abuse. Finally, carba- been ruled out. AW. For example, other cross-tolerant mazepine may prevent kindling. This Benzodiazepines also prevent DT’s. medications, such as , agent has not been shown, however, However, no known treatments exist would be expected to relieve with- to prevent withdrawal-specific com- to shorten the course of DT’s once drawal symptoms and prevent with- plications, and it can cause substantial this complication has been established. drawal seizures and DT’s. In fact, a side effects, including nausea and dizzi- Nonetheless, diazepam can improve few studies have demonstrated that ness. (For more information on other outcome by rapidly inducing a calm, long-acting barbiturates can ease medications used in the treatment of awake state, thereby avoiding the withdrawal symptoms. However, withdrawal symptoms, see the article traumatic complications associated controlled studies have not provided by Myrick and Anton, pp. 38–43.) with severe agitation (Thompson et sufficient data to demonstrate that Other medications can serve as al. 1975). Constant monitoring is these agents can prevent seizures or effective adjuncts to care. For exam- essential for patients experiencing this DT’s. Furthermore, barbiturates have ple, beta-blockers (e.g., serious complication. a narrow therapeutic index—that is, and atenolol) can ameliorate some the difference between the minimum manifestations of withdrawal, such as dose required for a therapeutic effect tachycardia, high blood pressure, and Treatment Settings and the dose at which the agents even anxiety, but they increase the become toxic is small. likelihood of delirium when used by Traditionally, patients undergoing Alcohol itself also would be themselves (i.e., as monotherapy). AW have been treated in hospitals expected to improve withdrawal Consequently, these agents should be and inpatient alcohol and other drug symptoms, and alcoholic patients used only in combination with benzo- (AOD) abuse treatment programs. know that alcohol consumption diazepines. In general, the use of General hospitals and even intensive can relieve their symptoms. Alcohol beta-blockers for treating withdrawal care units are appropriate for patients should not be used, however, to treat should be considered primarily for whose withdrawal is severe and/or withdrawal for several reasons. First, patients with coexisting coronary who suffer from comorbid medical, using alcohol as a treatment would artery disease. medica- surgical, or psychiatric conditions promote its acceptability to the alco- tions such as can treat that require hospitalization. For holic. Second, alcohol has known hallucinations and agitation that are patients without severe withdrawal toxic effects (e.g., impairing the unresponsive to adequate doses of or complicating illnesses, inpatient or function of the liver, pancreas, and benzodiazepines. Because antipsy- outpatient AOD treatment settings ) that are not shared chotic medications can increase the are appropriate. Some initial reports by the safer benzodiazepines. Third, risk of seizures, however, these agents even indicate that detoxification can in one clinical study, alcohol was should be used only in combination be completed successfully in the inferior to the benzodiazepine with benzodiazepines. patient’s home (Stockwell et al. 1991). chlordiazepoxide. Withdrawal in settings that offer less —an antihypertensive Management of Withdrawal- intensive monitoring, however, should medication—also may have a role Specific Complications be considered with caution. For exam- in the management of withdrawal ple, as noted previously, the risk fac- symptoms, although it has not been AW seizures generally can be pre- tors for more severe withdrawal still shown to affect the occurrence of vented by medications that are need to be better defined. Further- withdrawal-specific complications. cross-tolerant with alcohol. For more, although numerous studies of Another agent that has shown example, benzodiazepines have been diverse treatment settings have reported promise for managing AW is the shown to prevent both initial and favorable outcomes, many of these anticonvulsant carbamazepine. recurrent seizures. Similarly, carba- studies have included patient groups Animal studies have demonstrated mazepine and the that were referred specifically to the

Vol. 22, No. 1, 1998 11 HAYASHIDA, M.; ALTERMAN, A.I.; AND MCLELLAN, particular setting being studied. Other other coexisting medical and psychiatric A.T. Comparative effectiveness and costs of inpatient studies have included only patients disorders (Samet et al. 1996; Saitz et and outpatient detoxification of patients with mild specifically selected for being at low al. 1997). Accordingly, appropriate to moderate alcohol withdrawal syndrome. New risk for severe withdrawal. Thus, these recognition and treatment of AW can England Journal of Medicine 320: 358–365, 1989. studies may have been biased toward represent an important, albeit small, ISBELL, H.; FRASER, H.F.; WIKLER, A.; BELLEVILLE, finding successful outcomes. In the first step toward recovery. R.E.; AND EISENMAN A.J. An experimental study only randomized trial, patients with of the etiology of “rum fits” and delirium tremens. mild to moderate withdrawal received Quarterly Journal of Studies on Alcohol 16:1–33, 1955. pharmacological treatment as either Future Directions LECHTENBERG, R., AND WORNER, T. Relative inpatients or outpatients (Hayashida kindling effect of detoxification and non-detoxifi- et al. 1989). Although outcomes at 6 Many unanswered questions remain cation admissions in alcoholics. Alcohol and months did not differ between inpa- regarding AW and its management. For Alcoholism 26:221–225, 1991. tients and outpatients, fewer outpatients example, researchers still must clarify MAYO-SMITH, M.F., for the American Society of than inpatients completed the treat- the exact molecular and genetic mecha- Working Group on Pharma- cological Management of Alcohol Withdrawal. ment and achieved abstinence 1 month nisms responsible for the varied Pharmacological management of alcohol withdrawal: later. (For more information on inpatient manifestations of withdrawal. Other A meta-analysis and evidence-based practice guide- versus outpatient detoxification, see studies should address the clinical sig- line. Journal of the American Medical Association the article by Hayashida, pp. 44–46.) nificance of kindling and the risk factors 278:144–151, 1997. for more severe withdrawal (Fiellin et NG, S.K.C.; HAUSER, W.A.; BRUST, J.C.M.; AND al. 1998). Additional research also is SUSSER, M. Alcohol consumption and withdrawal Linking Withdrawal to needed to determine the most appro- in new-onset seizures. New England Journal of Alcoholism Treatment priate treatment settings as well as Medicine 319:666–673, 1988. methods of engaging patients in ongoing SAITZ, R., AND O’MALLEY, S.S. Pharmacotherapies AW is often treated, discussed and efforts. Finally, for : Withdrawal and treatment. Medical studied as an entity distinct from alco- research should investigate techniques Clinics of North America 81(4):881–907, 1997. holism treatment. One should to translate knowledge into clinical SAITZ, R.; MAYO-SMITH, M.F.; ROBERTS, M.S.; remember, however, that withdrawal practice (e.g., ways to improve physician REDMOND, H.A.; BERNARD, D.R.; AND CALKINS, and its treatment represent a brief D.R. Individualized treatment for alcohol with- recognition of alcohol dependence) and drawal: A randomized double-blind controlled period of time (i.e., several hours up ways to improve the likelihood that trial. Journal of the American Medical Association to a few days) in the alcoholic’s drinking patients receive state-of-the-art, evidence- 272:519–523, 1994. career. Researchers do not yet know based treatment. Improved insight into SAITZ, R.; MULVEY, K.P.; AND SAMET, J.H. The whether the choice of detoxification these issues will enable clinicians to substance-abusing patient and primary care: method has an impact on long-term improve the efficiency and quality of Linkage via the addiction treatment system? patient outcomes. For example, one may care for patients who are experiencing Substance Abuse 18(4):187–195, 1997. speculate that early treatment may or are at risk for withdrawal. ■ SAMET, J.H.; SAITZ, R.; AND LARSON, M.J. A case prevent more serious symptoms during for enhanced linkage of substance abusers to primary subsequent withdrawal episodes. Further- medical care. Substance Abuse 17(4):181–192, 1996. more, treatments (both pharmacological References STOCKWELL, T.; BOLT, L.; MILNER, I.; RUSSELL, and nonpharmacological) that make G.; BOLDERSTON, H.; AND PUGH, P. Home patients more comfortable may encour- BEGLEITER, H., AND KISSIN, B., EDS. The detoxification from alcohol: Its safety and efficacy age patients to engage in further treat- of Alcohol and Alcohol Dependence. in comparison with inpatient care. Alcohol and ment for their underlying alcohol use New York: Oxford University Press, 1996. Alcoholism 26(5/6):645–650, 1991. disorder and help prevent relapse. Alco- CUTSHALL, B.J. The Saunders-Sutton syndrome: SULLIVAN, J.T.; SYKORA, K.; SCHNEIDERMAN, J.; holic patients are at risk for relapse for An analysis of delirium tremens. Quarterly Journal NARANJO, C.A.; AND SELLERS, E.M. Assessment numerous reasons, including inadequate of Studies on Alcohol 26:423–448, 1964. of alcohol withdrawal: The revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA–Ar). DUPONT, R.L., AND , M.S. Withdrawal and treatment of their withdrawal symptoms, British Journal of Addiction 84:1353–1157, 1989. continued expectations of the reward- reward: Implications for detoxification and relapse ing effects of alcohol, and feelings of prevention. Psychiatric Annals 25(11):663–668, THOMPSON, W.L.; JOHNSON, A.D.; MADDREY, W.L.; 1995. AND Osler Medical Housestaff. Diazepam and distress in the absence of alcohol. for treatment of severe delirium tremens. Effective treatment of withdrawal FIELLIN, D.A.; SAMET, J.H.; AND O’CONNOR, Annals of Internal Medicine 82:175–180, 1975. only addresses the first of these reasons P.G. Reducing bias in observational research on alcohol withdrawal syndrome. Substance Abuse VICTOR, M., AND ADAMS, R.D. The effect of (Dupont and Gold 1995). Nevertheless, 19:23–31, 1998. alcohol on the nervous system. Research Publications for patients who seek assistance with of the Association for Research on Nervous and detoxification, treatment of their with- FOY, A.; MARCH, S.; AND DRINKWATER, V. Use Mental Disorders 32:526–573, 1953. drawal symptoms may present a window of an objective clinical scale in the assessment and management of alcohol withdrawal in a large VICTOR, M., AND BRAUSCH, C. The role of of opportunity for initiating alcoholism general hospital. Alcoholism: Clinical and abstinence in the genesis of alcoholic epilepsy. treatment as well as for attending to Experimental Research 12:360–364, 1988. Epilepsia 8:1–20, 1967.

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