Alcohol is currently the second most abused drug

CME EARN CATEGORY I CME CREDIT by reading this article and the article beginning on page 40 and successfully completing the posttest on page 4. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of September 007. LEARNING OBJECTIVES Describe the supposed mechanism of action of alcohol withdrawal List the signs and symptoms associated with alcohol withdrawal Discuss the steps in evaluating the hospitalized patient with suspected alcohol withdrawal Outline treatment goals related to supportive care, pharmacologic choices, and posthospital therapy Managing alcohol withdrawal in hospitalized patients Therapy includes benzodiazepines to reduce withdrawal symptoms and prevent delirium. Symptom-driven protocols may be more beneficial than scheduled-dosing plans. Zachary Hartsell, MPAS, PA-C; Jennifer Drost, MMSc, PA-C; James A. Wilkens, MD; Adriane I. Budavari, MD Alcohol is currently the second most abused drug in the United States and is abused by up to 9% of the population. 1, Approximately 11 to 1 million people report heavy alcohol intake, and the costs of medical complications related to alcohol abuse in the United States are estimated to be almost $100 billion per year. Although many definitions of alcoholism exist, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) classifies women who consume more than 7 drinks per week and men who consume more than 14 drinks per week as being at high-risk of progressing to alcoholism. More than 4 drinks a day is considered heavy alcohol use for women, more than drinks a day for men. Heavy alcohol users are at risk for withdrawal symptoms, with hospitalized patients who abuse alcohol at greatest risk. Some reports suggest that at least % of general medical inpatients have alcohol use disorders. 4 In trauma patients, the rate is much higher, with alcohol dependence or abuse present in % to 47% of these patients. In a study of 4 trauma patients admitted to a suburban US hospital, 4% were found to have elevated blood alcohol levels and % were legally intoxicated. The incidence of patients with alcohol withdrawal syndrome is projected to be nearly million per year, with more than 00,000 per year having withdrawal symptoms severe enough to require pharmacologic treatment. Even though alcohol withdrawal is a common inpatient disorder, studies suggest that many hospitalized patients are not receiving appropriate diagnosis or treatment. Bostwick and colleagues found that in an urban Level I trauma center, approximately 7% of alcohol abusers were identified. 7 Despite this, only 4% of these patients had withdrawal pro- Ken Sherman / Graphistock / Jupiterimages 0 JAAPA SEPTEMBER 007 0(9) www.jaapa.com

phylaxis ordered, and only 8% were monitored for alcohol withdrawal signs and symptoms. 7 This article reviews the pathophysiology of alcohol withdrawal, describes how to evaluate and monitor patients potentially suffering from this condition, and suggests treatment strategies. PATHOPHYSIOLOGY Although the exact mechanism of action for alcohol withdrawal is unknown, the GABA inhibition theory is the most widely accepted. Alcohol enhances the inhibitory chloride influx mediated by gamma-aminobutyric acid alpha (GABA- A), resulting in clinical sedation. With chronic alcohol use, tolerance develops and GABA receptor function is downregulated. Alcohol also inhibits the excitatory N-methyl-Daspartate (NMDA) receptor, thus diminishing the excitatory effects of glutamate and, over time, increasing neuroexcitatory tone. Finally, alcohol causes alpha-receptors to inhibit norepinephrine release. As a result, when alcohol is abruptly withdrawn, the unopposed hyperexcitable neurons cause the symptoms of withdrawal. 8 Another key pathophysiologic concept in alcohol withdrawal is the phenomenon of kindling. Kindling begins as a single electrical stimulus initially causing no overt clinical manifestations but eventually results in the appearance of abnormal behavior (such as seizures) when the stimulus is administered repeatedly. Applied to alcoholism, kindling explains why each episode of alcohol withdrawal appears to increase patients risk of withdrawal symptoms. Chronic alcoholics typically experience progressively shorter intervals between their last drink and onset of symptoms, as well as progressive worsening of symptoms during each subsequent episode of alcohol withdrawal. CLINICAL PRESENTATION The signs and symptoms of alcohol withdrawal fall along a spectrum, ranging from mild and self-limiting to life-threatening (see Figure 1, page ). Importantly, these signs and symptoms should be attributed to alcohol withdrawal only after other medical conditions are considered and ruled out. Minor withdrawal The manifestations of mild alcohol withdrawal typically start between and 10 hours after the last drink. This early stage of alcohol withdrawal is characterized by mild autonomic hyperactivity, manifesting as tremulousness, mild anxiety, tachycardia, hypertension, GI upset, insomnia, and vivid dreams. Since the signs and symptoms of alcohol withdrawal are quite nonspecific at this stage, the diagnosis can often be missed. Symptoms of minor withdrawal typically resolve spontaneously in 4 to 48 hours, with or without treatment. Major withdrawal Major withdrawal syndromes tend to occur approximately 48 to 7 hours after the last drink. They include alcoholic hallucinosis, alcohol seizures, and delirium tremens (DTs). First characterized in 1989, alcoholic hallucinosis occurs in an estimated 10% to % of hospitalized alcoholics. 9-11 Hallucinations can be tactile, visual, or auditory, but patients with alcoholic hallucinosis unlike those with DTs maintain a clear sensorium. Although definite risk factors for alcoholic hallucinosis have not been identified, a study of 4 patients in a Veterans Affairs drug and alcohol treatment center found that those who developed alcoholic hallucinosis were younger at the onset of their alcoholism and tended to be heavier drinkers than alcohol abusers who did not. 11 Alcoholic seizures occur in up to 10% of patients suffering alcohol withdrawal. They tend to occur 4 hours after the last drink but can occur even while alcohol is still measurable in the blood. Alcoholic seizures are single, short, generalized tonic-clonic seizures that can recur successively but rarely progress to status epilepticus. 9 Status epilepticus, focal seizures or seizures associated with fever or known head trauma, and seizures starting after the patient becomes delirious are not typical of alcohol withdrawal and require further workup. DTs is considered the end point of the alcohol withdrawal spectrum and represents a medical emergency. DTs occurs in approximately % of patients with alcohol withdrawal. Symptoms typically start 48 to 7 hours after the last drink and include confusion, disorientation, impaired attention, severe autonomic activity, and hallucinations. A history of DTs, a long history of sustained drinking, age greater than years, concurrent medical comorbidities, and seizure activity during the present admission are risk factors. Earlier studies found mortality in patients with DTs to be as high as 0% even with treatment, but more recently mortality is cited at about 1%, with death generally occurring from KEY POINTS Early identification of patients who are experiencing an alcohol withdrawal syndrome includes recognizing the spectrum of withdrawal indicators and monitoring carefully for signs and symptoms. With appropriate treatment, the risk of complications from alcohol withdrawal is significantly lessened. Benzodiazepines are the drug of choice for the treatment of most patients who have alcohol withdrawal syndrome. Studies suggest that use of a symptom-triggered dosing protocol may reduce treatment times for patients with alcohol withdrawal syndrome. In addition to recognizing alcohol withdrawal, clinicians should take the time to screen patients for alcohol abuse. Proper identification can ensure appropriate outpatient follow-up. COMPETENCIES Medical knowledge Interpersonal & communication skills Patient care Professionalism Practice-based learning and improvement Systems-based practice SEPTEMBER 007 0(9) www.jaapa.com JAAPA 1

CME Alcohol withdrawal arrhythmias or concomitant illnesses. When DTs is unrecognized and untreated, mortality can exceed %. 1 EVALUATING THE PATIENT The first step in evaluating the hospitalized patient with suspected alcohol withdrawal is ruling out other medical conditions that could be causing the signs and symptoms. When alcohol withdrawal remains likely, key historical information includes total duration of alcohol use, daily quantity of alcohol ingestion, elapsed time since last drink, history of alcohol withdrawal syndromes, abuse of other substances, and history of major medical and/or psychiatric conditions. The physical examination should not only focus on identifying the signs and symptoms of alcohol withdrawal but should also attempt to uncover any signs of complicating medical conditions including (but not limited to) arrhythmias, heart failure, liver disease, pancreatitis, or infections. Once alcohol withdrawal syndrome has been diagnosed, the severity of the episode should be determined since severity will guide further therapy. Although most patients undergoing alcohol withdrawal need close observation, some warrant admission to an ICU. These include patients with advanced age; hemodynamic instability; hyperthermia (persistent temperature higher than 9 C/10 F); a severe electrolyte disturbance or acid-base disorder; moderate to severe cardiac, pulmonary, or renal disease; active infection; rhabdomyolysis (as evidenced by an elevated creatine kinase [CK] level combined with a normal CKMB/troponin level); or prior DTs or withdrawal seizures. 1 Prevention that is, trying to identify which patients are at high risk for alcohol withdrawal before they become symptomatic is considered the best practice. Although patients may be reluctant to discuss their drinking, the interview remains the most reliable and accurate means of assessing alcohol intake and determining who is at risk for withdrawal. Although validated only in the outpatient setting, the CAGE questionnaire can also be a useful interview tool for assessing inpatients suspected of alcohol abuse. It is comprised of the following four questions: Have you ever felt the need to Cut down on drinking? Have you ever felt Annoyed by criticism of your drinking? Have you ever felt Guilty about your drinking? Have you ever taken a morning Eye opener? The CAGE questionnaire has an overall sensitivity of 8% and a specificity of 89%; with three positive answers, its sensitivity is 100%. 14 The main disadvantage of the CAGE is that it does not distinguish between past and present alcohol use, and it therefore does not provide any information about the current status of the patient with respect to alcohol withdrawal syndrome. The CAGE questions are designed to elicit information about alcohol abuse in hopes of identifying patients most at risk for withdrawal; therefore it is most appropriate to use during the admission interview, before the withdrawal symptoms begin. Laboratory results that may indicate alcohol abuse include elevations in mean corpuscular volume (MCV), gammaglutamyl transpeptidase (GGT), and liver transaminases. Elevated liver transaminases with the pattern of AST being more than times higher than ALT is the most common laboratory finding in patients who abuse alcohol. One study noted this finding in 8% of patients admitted with alcoholic hepatitis. 1 Additionally, this pattern is generally not seen in other forms of liver disease. 1 GGT is commonly measured to determine chronic alcohol use but has a sensitivity of only 0% to 40%. 1 GGT can be elevated in patients with nonalcoholic forms of liver disease or in those taking certain medications. An elevated MCV is an index of RBC size. MCV increases with excessive alcohol intake after 4 to 8 weeks. The mechanism of the elevation in chronic alcoholism is unknown, but the elevation is found in 90% of alcoholics. Patients who binge drink or who have started drinking heavily only recently (within 90 days) may have normal-size RBCs. 1 In more recent studies, elevations in carbohydratedeficient transferrin level was shown to be a more sensitive and specific biologic marker for detecting alcohol abuse, but testing for this is impractical in the hospital setting. 17 DETERMINING SYMPTOM SEVERITY In patients with suspected active alcohol withdrawal, the Clinical Institute Withdrawal Assessment for Alcohol scale, revised (CIWA-Ar), is the best tool to determine severity and to guide therapeutic intervention (see Figure, page 4). The CIWA-Ar is well-validated and has high reproducibility and reliability. 18 The CIWA-Ar was created to assess and guide treatment of acute alcohol withdrawal. It also has utility in triage. For example, patients with a CIWA-Ar score of less than 10 can be observed and in some cases may be treated as outpatients, as long as they have a stable living situation with close followup and no history of relapses or major comorbid mental or medical illness. 19 Patients with a CIWA-Ar score greater than 10 should be admitted for inpatient treatment and close observation. Patients with a CIWA-Ar score greater than 1 will need initiation of treatment with benzodiazepines. After being used as a triaging tool, the CIWA-Ar can be used to guide therapy and monitor for worsening of the withdrawal. 18 FIGURE 1. The spectrum of alcohol withdrawal syndrome Classification Minor Major Clinical features Tremulousness Hallucinosis Seizures Delirium tremens (-8 h) (10-0 h) (-48 h) (- d) 4 stages of alcohol withdrawal 1. Autonomic hyperactivity. Hallucination. Neuronal excitation 4. Delirium tremens JAAPA SEPTEMBER 007 0(9) www.jaapa.com

Unfortunately, few clinicians report routinely using the CAGE questionnaire or the CIWA-Ar with patients. According to Friedmann and colleagues, although most clinicians ask patients if they consume alcohol, only 1% report using a validated screening tool such as the CAGE. 0 In addition, the CIWA-Ar is rather labor-intensive, requiring high levels of nursing care to administer effectively. However, without validated tools, diagnoses of alcoholism and alcohol withdrawal are delayed, as are necessary treatments. TREATMENT Treatment goals for alcohol withdrawal syndrome include alleviating symptoms, preventing progression to DTs, controlling underlying comorbidities, and initiating rehabilitation. 9 Supportive care Treating a patient in alcohol withdrawal includes providing a quiet environment with supervision and precautions against falls. Electrolyte abnormalities should be corrected, but routine administration of magnesium has not proved effective. 1 Similarly, IV fluids should be reserved for patients with signs of excess fluid loss. Finally, a daily multivitamin (orally if possible) and thiamine (100 mg by convention) are generally recommended, though formal evidence to support these interventions is lacking. A recent Cochrane systematic review found insufficient evidence from randomized controlled trials to guide clinicians in the optimal dose, route, frequency, or duration of thiamine for prophylaxis against or treatment of Wernicke-Korsakoff syndrome. Pharmacologic therapy Pharmacologic treatment of alcohol withdrawal centers upon using medications that are crosstolerant with alcohol. Benzodiazepines are considered first-line therapy. Their mechanism of action is to enhance the depressant neurotransmitter GABA and replace the effects of alcohol. A review of 7 trials with a total of 4,01 patients found that the risk of alcohol withdrawal seizure was reduced with the use of benzodiazepines compared with placebo. Although no specific benzodiazepine has been shown to be superior to another, certain agents are recommended, based largely on their pharmacokinetics. For example, long-acting agents such as diazepam and chlordiazepoxide effectively prevent rebound symptoms. In patients who are elderly, have hepatic disease, or are critically ill, intermediate-acting agents like lorazepam or oxazepam are preferred to prevent oversedation. Lorazepam and diazepam are available for oral, IV, and IM administration, whereas chlordiazepoxide and oxazepam have only oral formulations. 4 Clonazepam, temazepam, and alprazolam are not recommended. Fixed-dose versus symptom-triggered regimens An influential randomized controlled trial by Daeppen and colleagues inspired a major change in how benzodiazepines are administered to hospitalized patients experiencing alcohol withdrawal syndrome. This study compared symptom-triggered benzodiazepine therapy (administering a dose in response to symptoms) versus fixed-dose (administering a fixed dose at standard intervals regardless of symptoms) therapy. The CIWA-Ar was used to measure the severity of the withdrawal, and an appropriate dose of benzodiazepine was given based on the score. In the 117 patients studied, symptomtriggered dosing showed no difference in comfort levels. However, the mean duration of treatment was shorter in the group treated in response to symptoms (0 hours vs hours), and there was a marked decrease in the mean quantity of medication administered (7 mg vs 1 mg). There was no difference in complications between the two groups. IV ethanol (IVE) historically was used for the treatment and prevention of alcohol withdrawal. Discussion of its use was confined to case reports, whose authors felt IVE to be less sedating than benzodiazepines. A 004 review of anecdotal reports of IVE in critically ill patients with alcohol withdrawal similarly found no evidence to support its use. 7 This conclusion is a result of IVE s inconsistent pharmacokinetic profile, relatively narrow therapeutic index, and enhancement of drug interactions secondary to hepatic metabolism. 7 Every patient should be offered counseling services either as an inpatient or as an outpatient. Adjunct medications Benzodiazepines are considered firstline therapy for alcohol withdrawal syndrome, and adjunct medication should be used only in conjunction with benzodiazepines. Beta-blockers and alpha-blockers have been traditionally used in the management of alcohol withdrawal, particularly to treat hypertension. The purpose of beta-blockade in alcohol withdrawal is to reduce the result of increased cardiac autonomicity, including arrhythmias and increased cardiac output. Adjunctive therapy with beta-blockers should be considered in patients with known coronary artery disease. Alpha-blockers, such as clonidine, work similarly to decrease sympathetic tone and affect mainly the alpha-receptors. 4 Historically, anticonvulsants have been widely used to control alcohol withdrawal symptoms (particularly seizures). Carbamazepine is used widely throughout Europe for outpatient treatment of alcohol withdrawal. It appears to suppress the kindling effect and to decrease the craving for alcohol after withdrawal. 9 A 00 review of 48 studies found the use of anticonvulsants controversial. Because of the heterogeneity of agents available and the limited studies performed, no recommendation could be made on their use for alcohol withdrawal. When compared to benzodiazepines, anticonvulsants had equal efficacy in preventing seizures but a worse side effect profile. 8 Additionally, studies have shown no effect on arresting the progression to DTs. 9 Neuroleptics are often used to treat agitation and hallucinations in alcohol withdrawal syndrome. In 004, Mayo-Smith and colleagues published a meta-analysis of nine prospective controlled trials which culminated in the formation of an evidence-based practice guideline for the management of alcohol withdrawal delirium. 9 They suggested that sedativehypnotics are more effective than neuroleptic agents in reduc- SEPTEMBER 007 0(9) www.jaapa.com JAAPA

CME Alcohol withdrawal FIGURE. Clinical Institute Withdrawal Assessment for Alcohol Scale ASSESSMENT OF ALCOHOL WITHDRAWAL Patient Date Time Pulse or heart rate, taken for 1 min Blood pressure NAUSEA AND VOMITING Ask: Do you feel sick to your stomach? Have you vomited? 0 No nausea and no vomiting 1 4 Intermittent nausea with dry heaves 7 Constant nausea, frequent dry heaves and vomiting TREMOR Ask patient to extend arms and spread fingers apart. 0 No tremor 1 Tremor not visible but can be felt, fingertip to fingertip 4 Moderate tremor with arms extended 7 Severe tremor, even with arms not extended PAROXYSMAL SWEATS 0 No sweat visible 1 Barely perceptible sweating, palms moist 4 Beads of sweat obvious on forehead 7 Drenching sweats ANXIETY Ask: Do you feel nervous? 0 No anxiety (at ease) 1 Mildly anxious 4 Moderately anxious or guarded, so anxiety is inferred 7 Equivalent to acute panic states as occur in severe delirium or acute schizophrenic reactions AGITATION 0 Normal activity 1 Somewhat more than normal activity 4 Moderately fidgety and restless 7 Paces back and forth during most of the interview or constantly thrashes about TACTILE DISTURBANCES Ask: Do you have any itching, pinsand-needles sensations, burning or numbness, or do you feel like bugs are crawling on or under your skin? 0 none 1 Very mild itching, pins-and-needles sensation, burning or numbness Mild itching, pins-and-needles sensation, burning or numbness Moderate itching, pins-and-needles sensation, burning or numbness 4 Moderately severe hallucinations Severe hallucinations Extreme severe hallucinations 7 Continuous hallucinations AUDITORY DISTURBANCES Ask: Are you more aware of sounds around you? Are they harsh? Do they frighten you? Are you hearing anything that is disturbing to you? Are you hearing things you know are not there? 0 not present 1 Very mild harshness or ability to frighten Mild harshness or ability to frighten Moderate harshness or ability to frighten 4 Moderately severe hallucinations Severe hallucinations Extremely severe hallucinations 7 Continuous hallucinations VISUAL DISTURBANCES Ask: Does the light appear to be too bright? Is its color different? Does it hurt your eyes? Are you seeing anything that is disturbing to you? Are you seeing things you know are not there? 0 Not present 1 Very mild sensitivity Mild sensitivity Moderate sensitivity 4 Moderately severe hallucinations Severe hallucinations Extremely severe hallucinations 7 Continuous hallucinations HEADACHE, FULLNESS IN HEAD Ask: Does your head feel different? Does it feel like there is a band around your head? Do not rate for dizziness or lightheadedness. Otherwise, rate severity. 0 Not present 1 Very mild Mild Moderate 4 Moderately severe Severe Very severe 7 Extremely severe ORIENTATION AND CLOUDING OF SENSORIUM Ask: What day is this? Where are you? Who am I? 0 Oriented and can do serial additions 1 Cannot do serial additions or is uncertain about date Date disorientation by no more than calendar days Date disorientation by more than calendar days 4 Disoriented for place/or person Total score: (maximum = 7) Rater s initials Adapted from Sullivan JT, Sykora K, Schneiderman J, et al. Assessment of alcohol withdrawal: the revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar). Br J Addict. 1989;84:1-17. 4 JAAPA SEPTEMBER 007 0(9) www.jaapa.com

ing duration of delirium and mortality, with a relative risk of death when using neuroleptics of., though the confidence interval was very wide (9% CI, 1.-4.7). Importantly, the nine trials cited were decades old (199-1978), occurring when diagnostic criteria were less clear and older neuroleptics were used. In contrast, other practice guidelines have recommended haloperidol as first-line therapy for delirium including alcohol withdrawal delirium. 0 In the absence of clear research evidence demonstrating their efficacy and safety in treating alcohol withdrawal, antipsychotics such as haloperidol should be used with caution. In low doses, haloperidol can treat agitation and hallucinations, but it has no effect on autonomic dysfunction. Additionally, antipsychotics theoretically can lower the seizure threshold, as well as place hypomagnesemic withdrawal patients at risk for torsades de pointes. Finally, baclofen appears to be a promising new therapy for alcohol withdrawal. Baclofen is a GABA-B receptor agonist. In several small studies, it reduced moderate and severe symptoms in alcohol withdrawal syndrome, and it had a more favorable side effect profile than benzodiazepines. Furthermore, baclofen exhibits less addictive properties and may be more effective than benzodiazepines at helping to maintain abstinence in alcoholics. 1, Before widespread use of baclofen can be recommended, however, larger studies comparing it directly to benzodiazepines are needed. Treatment after hospitalization Ensuring proper follow-up is one of the key steps in effectively managing patients with alcohol-related disorders. Long-term abstinence should be the goal, and the process can start with a brief intervention from the provider. For example, a brief bedside intervention may play a major role in helping patients achieve the long-term goal of total abstinence. A large meta-analysis of controlled studies looking at the impact of brief interventions on drinking behaviors found that brief intervention was superior to no intervention, and some studies found brief intervention was as effective as extensive therapy. Although inpatient psychiatry consultation is not mandatory for every patient, it should be considered for those with withdrawal symptoms resistant to treatment, those with comorbidities or multiple substance intoxications, and those with a co-existing psychiatric disorder. Every patient should be offered counseling services either as an inpatient or as an outpatient. Additionally, the intervention of social workers and a case manager is essential to ensuring proper follow-up of the patient. JAAPA The authors practice in the Department of Hospital Internal Medicine, Mayo Clinic Hospital, Phoenix, Arizona. They have indicated no relationships to disclose relating to the content of this article. DRUGS MENTIONED Alprazolam (Alprazolam Intensol, Xanax) Baclofen (Lioresal Intrathecal) Carbamazepine Chlordiazepoxide (Librium, Limbitrol) Clonazepam (Klonopin) Clonidine (Catapres, Clorpres, Duraclon) Diazepam (Diazepam Intensol, Valium) Haloperidol (Haldol, Haloperidol Intensol) Lorazepam (Ativan, Lorazepam Intensol) Oxazepam (Serax) Temazepam (Restoril) REFERENCES 1. US Preventive Services Task Force. Screening and behavioral counseling interventions in primary care to reduce alcohol misuse: recommendation and statement. Ann Intern Med. 004; 140(7):4-.. Grant BF. Alcohol consumption, alcohol abuse and alcohol dependence. The United States as an example. Addiction. 1994;89:17-1.. NIAAA: Social work education for the prevention and treatment of alcohol use disorders. Module 1: epidemiology of alcohol use disorders in the United States. 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Brief interventions for alcohol problems: a review. Addiction. 199;88():1. SEPTEMBER 007 0(9) www.jaapa.com JAAPA