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Home , Alcoholism, Alcohol abuse, Alcohol dependence, Alcohol detoxification

Applied Evidence

N EW R ESEARCH F INDINGS T HAT A RE C HANGING C LINICAL P RACTICE

3 Regimens for withdrawal and

Chad A. Asplund, MD, Jacob W. Aaronson, DO, and Hadassah E. Aaronson, DO Department of Family Practice, DeWitt Army Community Hospital, Fort Belvoir, Va

Practice recommendations withdrawal symptoms and no serious psychiatric or medical can be safely treated in ■ Patients with mild to moderate alcohol with- the outpatient setting. Patients with history of drawal symptoms and no serious psychi- severe withdrawal symptoms, or deliri- atric or medical comorbidities can be safely um tremens, comorbid serious psychiatric or med- treated in the outpatient setting (SOR: A). ical illnesses, or lack of reliable support network should be considered for detoxification in the ■ Patients with moderate withdrawal should inpatient setting. receive pharmacotherapy to treat their symptoms and reduce their risk of seizures ■ THE PROBLEM OF ALCOHOL and tremens during outpatient WITHDRAWAL detoxification (SOR: A). Up to 71% of individuals presenting for alcohol ■ are the treatment of detoxification manifest significant symptoms of choice for alcohol withdrawal (SOR: A). alcohol withdrawal.4 Alcohol withdrawal is a clinical syndrome that affects people accus- ■ ln healthy individuals with mild-to-moderate tomed to regular alcohol intake who either alcohol withdrawal, has decrease their alcohol consumption or stop many advantages making it a first-line completely. treatment for properly selected patients (SOR: A). Physiology Alcohol enhances gamma-aminobutyric acid’s n our small community hospital—with limited (GABA) inhibitory effects on signal-receiving financial and medical resources—we have , thereby lowering neuronal activity, Idesigned and implemented an outpatient alco- leading to an increase in excitatory glutamate hol detoxification clinical practice guideline to pro- receptors. Over time, tolerance occurs as GABA vide cost-effective, evidence-based medical care to receptors become less responsive to neurotrans- our patients, in support of their alcohol treatment. mitters, and more alcohol is required to produce Those patients with mild-to-moderate alcohol the same inhibitory effect. When alcohol is removed acutely, the number of excitatory glu- tamate receptors remains, but without the sup- Corresponding author: Chad Asplund, MD, 5663 5 Marshall Road, Fort Belvoir, VA 22060. E-mail: pressive GABA effect. This situation leads to [email protected]. the of alcohol withdrawal.

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Symptoms medical condition. This evaluation should include Noticeable alcohol withdrawal symptoms may an assessment of coexisting medical and psychi- appear within hours of cessation or decreasing atric conditions, the severity of previous with- alcohol intake. The most common symptoms drawal symptoms, and the risk factors for with- include , for alcohol, , drawal complications. The initial symptoms of vivid dreams, , hypervigilance, agitation, alcohol withdrawal are not specific and may , loss of appetite, , , mimic other serious disease conditions; therefore, headache, and sweating.5 Even without treat- the initial assessment should exclude potentially ment, most of these relatively benign symptoms serious medical and psychiatric comorbidities. resolve within hours to days. Initially, assessment of common alcohol-relat- More concerning are , delirium ed medical problems should be conducted. These tremens (DTs), and seizures. Transient auditory complications include , gastrointestinal or visual hallucinations may occur within the first bleeding, disease, cardiomyopathy, pancre- 2 days of decreasing or discontinuing alcohol con- atitis, neurological impairment, imbal- sumption, and can be separate from DTs. DTs, ances, and nutritional deficiencies. A physical which present within 2 to 4 days of the last drink examination should be performed to assess for (and can last up to 3 to 4 days), are characterized , congestive , hepatic or by disorientation, persistent visual and auditory , infectious conditions, bleed- hallucinations, agitation and tremulousness, and ing, and nervous system impairment. autonomic signs resulting from the activation of Initial alcohol level and urine drug screen -related . These signs include should be assessed, as recent high levels of alco- tachycardia, , and . hol intake and substance place the patient DTs are much more serious than the “alcohol at higher risk for complications. Unstable mood shakes”—5% of patients who experience DTs die disorders—delirium, , severe depres- from metabolic complications.6 The occurrence of sion, suicidal or homicidal ideation—while poten- DTs is 5.3 times higher in men than in women;7 tially difficult to assess during intoxication, need however, women may exhibit fewer autonomic to be considered and ruled out. symptoms, making DTs in women more difficult to diagnose.6 Stabilize the patient Grand mal seizures can occur in up to 25% of After initial assessment, vital signs (eg, heart alcoholics undergoing withdrawal.4 If alcohol- rate, blood pressure, and temperature) should be related seizures do occur, they generally do so stabilized while fluid, electrolyte, and nutritional within 1 day of cessation of alcohol intake, but disturbances are corrected. Some patients under- can occur up to 5 days later. going alcohol withdrawal may require intravenous Risk factors for prolonged or complicated fluids to correct severe resulting from alcohol withdrawal include duration of alcohol vomiting, diarrhea, sweating, and . consumption, the number of lifetime prior detoxi- Alcoholics are often deficient in or fications, prior seizures, prior episodes of DTs, minerals, including , folate, and magne- and current intense craving for alcohol.6–10 sium (although replacing makes no difference in clinically meaningful outcomes) ■ BEFORE TREATMENT: (level of evidence [LOE]: 1, double-blind random- ASSESS AND STABILIZE ized controlled trial).11 All patients being treated Initial assessment of the patient for alcohol withdrawal should be given 100 mg of Before initiating treatment for alcohol withdraw- thiamine immediately and daily (LOE: 3; insuffi- al, perform a thorough assessment of the patient’s cient evidence from randomized controlled trials

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FIGURE 1 The Clinical Institute Withdrawal Assessment for Alcohol—Revised

Addiction Research Foundation Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) Patient ______Date |—|—|—| Time ____:____ Y m d (24-hour clock, midnight=00:00)

Pulse or heart rate, taken for one minute: ______Blood pressure: ______/ ______

NAUSEA AND VOMITING—Ask “Do you feel sick to your TACTILE DISTURBANCES—Ask “Have you any itching, stomach? Have you vomited?” Observation. pins and needles sensations, any burning, any numbness, 0 no nausea and no vomiting or do you feel bugs crawling on or under your skin?” 1 mild nausea with no vomiting Observation. 2 0 none 1 very mild itching, pins and needles, burning or numbness 3 2 mild itching, pins and needles, burning or numbness 4 intermittent nausea with dry heaves 3 moderate itching, pins and needles, burning or numbness 5 4 moderately severe hallucinations 6 5 severe hallucinations 7 constant nausea, frequent dry heaves and vomiting 6 extremely severe hallucinations 7 continuous hallucinations TREMOR—Arms extended and fingers spread apart. Observation. AUDITORY DISTURBANCES—Ask “Are you more aware of 0 no tremor sounds around you? Are they harsh? Do they frighten you? Are you hearing anything that is disturbing to you? Are 1 not visible, but can be felt fingertip to fingertip you hearing things you know are not there?” Observation. 2 0 not present 3 1 very mild harshness or ability to frighten 4 moderate, with patient’s arm extended 2 mild harshness or ability to frighten 5 3 moderate harshness or ability to frighten 6 4 moderately severe hallucinations 7 severe, even with arms not extended 5 severe hallucinations 6 extremely severe hallucinations PAROXYSMAL SWEATS—Observation. 7 continuous hallucinations 0 no sweat visible VISUAL DISTURBANCES—Ask “Does the light appear to be 1 barely perceptible sweating, palms moist too bright? Is its color different? Does it hurt your eyes? 2 Are you seeing anything that is disturbing to you? Are you 3 seeing things you know are not there?” Observation. 4 beads of sweat obvious on forehead 0 not present 5 1 very mild sensitivity 6 2 mild sensitivity 7 drenching sweats 3 moderate sensitivity 4 moderately severe hallucinations ANXIETY—Ask “Do you feel nervous?” Observation. 5 severe hallucinations 0 no anxiety, at ease 6 extremely severe hallucinations 1 mildly anxious 7 continuous hallucinations 2 HEADACHE, FULLNESS IN HEAD—Ask “Does your head 3 feel different? Does it feel like there is a band around your 4 moderately anxious, or guarded, so anxiety is inferred head?” Do not rate for dizziness or lightheadedness. 5 Otherwise, rate severity. 6 0 not present 7 equivalent to acute panic states as seen in severe delirium 1 very mild or acute schizophrenic reactions 2 mild 3 moderate AGITATION—Observation. 4 moderately severe 0 normal scarcity 5 severe 1 somewhat more than normal activity 6 very severe 7 extremely severe 2 3 ORIENTATION AND CLOUDING OF SENSORIUM— 4 moderately fidgety and restless Ask “What day is this? Where are you? Who am I?” 5 0 oriented and can do serial additions 6 1 cannot do serial additions or is uncertain about date 7 paces back and forth during most of the interview, 2 disoriented for date by no more than 2 calendar days or constantly thrashes about 3 disoriented for date by more than 2 calendar days 4 disoriented for place and/or person

Total CIWA-Ar Score____ This scale is not copyrighted and may be used freely. Rater’s Initials____ Maximum Possible Score 67

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TABLE 1

Pharmacologic treatment of alcohol withdrawal

Medication Comments LOE

Benzodiazepines Remain drug of choice for acute alcohol withdrawal14 A Highly significant decrease in seizures and delirium Risk reduction 7.72 seizures/100 patients, 4.9 DTs/100 patients20 Some abuse potential

Carbamazepine Well-documented anticonvulsant activity; prevents seizures A from alcohol Withdrawal No abuse potential Especially good for those with multiple previously treated withdrawals22 Relative risk of first drink after withdrawal in group over 3 times higher than carbamazepine22 If carbamazepine-treated patients , they drink less than benzodiazepine-treated patients [absolute risk reduction=4]22

Valproic acid Significantly affects the course of acute alcohol withdrawal and A reduces need for treatment with a benzodiazepine [absolute risk reduction=4] 24 Use limited by side effects which mimic alcohol withdrawal Wide therapeutic range makes unintentional overdose uncommon to guide clinicians in the dose, frequency, route, or monitor response to treatment. It offers an duration of thiamine treatment for prophylaxis increase in efficiency over the original CIWA-A against or treatment of WKS due to alcohol scale, while retaining clinical usefulness, validity, abuse).4 Thiamine should be given before glucose and reliability. It can be incorporated into the usual containing fluids, to avoid the risk of precipitating clinical care of patients undergoing alcohol with- Wernicke syndrome (LOE: 3).12 drawal and into clinical drug trials of alcohol with- drawal (strength of recommendation [SOR]=A].5,13 Assess the severity of the withdrawal Once a diagnosis of alcohol withdrawal is made, ■ PHARMACOTHERAPY complete an assessment of the severity of with- Patients experiencing more serious withdrawal drawal and the risk of complications. The best (with CIWA-Ar scores >8) should receive pharma- validated tool is the Clinical Institute Withdrawal cotherapy to treat their symptoms and reduce Assessment for Alcohol–Revised (CIWA-Ar) their risk of seizures and DTs (SOR=A).14 symptom scale (Figure 1).10 This instrument rates 10 withdrawal features; it takes only a few Benzodiazepines minutes to administer and may be repeated when Benzodiazepines are the mainstay of treatment re-evaluation is necessary. CIWA-Ar scores of ≤8 in alcohol withdrawal (number needed to treat are suggestive of mild withdrawal symptoms, [NNT]=17; data from large meta-analysis while those ≥15 confer an increased risk for con- of 6 prospective, placebo-controlled trials) fusion and seizures. (SOR=A).10,14–16 Like alcohol, these agents mag- CIWA-Ar is reliable, brief, uncomplicated, and nify GABA’s effect on the brain. Benzodiazepines clinically useful scale that can also be used to are cross-tolerant with alcohol; during

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Alcohol detoxification in a community hospital

The problem. In our small community hospi- uncomplicated alcohol withdrawal patients. Many tal, prior to the development of a clinical practice of our patients are at low risk for serious compli- guideline, admissions for “inpatient alcohol detoxi- cations, and we hoped to triage such individuals fication” were among our top 5, with a select few to an outpatient treatment setting. To organize the patients making multiple, repeat visits. Additionally, thought process, a flowchart was developed and we had no standardized, consistent strategy for refined. By incorporating current evidence, a clin- initial emergency room evaluation; frequent early ical practice guideline was developed. discharges against medical advice; multiple read- Evidence-based algorithm. We developed missions; infrequent and inconsistent entry into an evidence-based algorithm, Outpatient our outpatient Alcohol and Treatment for (Figure 2), Program; and no existing process for primary care which uses a gradually tapering regimen, and outpatient follow-up. We found ourselves in a situ- allows providers to prescribe the medication they ation where we were essentially our feel most appropriate given the clinical situation. patients in a destructive behavior. With no formal Results. In the 12 months since implementa- policy or guidelines, physicians tended to follow tion of our clinical practice guideline, total alcohol- the path of least resistance: repeated short-stay related admission decreased from 4 to 5 per admissions with limited therapeutic benefit. month to only 1 during the entire period; further- The process. Our initial goal was to develop more, no patients treated with our guidelines were a standardized policy in an attempt to minimize subsequently hospitalized for complications of the number of admissions of mild-to-moderate, alcohol withdrawal.

withdrawal from 1 agent, the other may serve as Anticonvulsants a substitute. Benzodiazepines also reduce the Attractive alternatives to benzodiazepines include incidence of DTs and seizures (Table 1).5,14 the anticonvulsants carbamazepine (Tegretol) and The most commonly used benzodiazepines valproic acid (Depakote). are (Valium), Carbamazepine. Carbamazepine has been (Librium), and (Ativan). All appear used successfully for many years in Europe,21 but to be equally efficacious in treating alcohol has not been used widely in the US due to the withdrawal symptoms (LOE: 1; randomized safety, efficacy, and familiarity of benzodiazepines controlled trial). (Table 1). The use of anticonvulsants, however, Longer-acting agents, such as chlordiazepox- has several advantages. They are not as sedating ide or diazepam, contribute to an overall as benzodiazepines and do not have the abuse smoother withdrawal course with lessened potential, making them particularly useful in the breakthrough or rebound symptoms, but they outpatient setting. may also lead to excess sedation for patients The use of anticonvulsant medication decreas- with hepatic dysfunction.17–20 Shorter-acting ben- es the possibility of seizures, one of the more seri- zodiazepines, such as (Serax), may ous complications of alcohol withdrawal result in greater discomfort and more dis- (NNT=36) (LOE: 1, 2 double-blind randomized charges against medical advice, because alcohol controlled trials). The brain cell kindling-like phe- withdrawal symptoms tend to recur when serum nomenon—in which repeated episodes of alcohol benzodiazepine levels drop. withdrawal is associated with increasing severity

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FIGURE 2 Guiding a patient through alcohol detoxification

A patient requests detoxification from alcohol. Present your facility’s

policy. ▲ Consider transfer to YES

Does the patient have an ▲ inpatient treatment unstable ? facility if patient is medically stable.

NO ▲

YES Does the patient have a ▲ Admit for comorbid condition? detoxification.

NO ▲

Is there a history of YES Admit or transfer ▲ delerium tremens or for inpatient withdrawal symptoms? detoxification.

NO Medical history

▲ NO Has the patient had NO follow-up; follow up ▲ ▲ Is the patient intoxicated? a drink in the last with primary care 5 days? manager if lab

YES results clinically ▲ significant. YES Normalize blood alcohol concentration. ▲

▲ YES ▲ NO ▲ Is the CIWA* result <8? Is the CIWA result >15? Admit or transfer for inpatient detoxification.

YES NO

▲ ▲ Medical history follow-up;

follow-up with primary care ▲ Follow outpatient manager if lab results detox protocol. clinically significant.

*CIWA, Clinical Institute Withdrawal Assessment (see Figure 1).

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of withdrawal—is decreased with the anticonvul- TABLE 2 sant carbamazepine.14 Outpatient treatment In a double-blind controlled trial comparing car- for alcohol detoxification bamazepine with oxazepam, carbamazepine was shown to be superior in ameliorating global psy- Thiamine – 100 mg orally per day (for 5 days) chological distress and reducing and anxiety.21 Stuppaeck et al showed that for alcohol Consider folate (1 mg) and multiple vitamin injection withdrawal longer than 5 days, carbamazepine was statistically superior (P<.05) to oxazepam in One of the following regimens: 22,23 reduction of CIWA scores. Carbamazepine is 3-day supply (only) of the following: also superior to benzodiazepines in preventing Chlordiazepoxide rebound withdrawal symptoms and reducing post- 50–100 mg every 6 hours for 4 doses, then treatment drinking, especially in those with a his- 25–50 mg every 6 hours for 8 doses 22 tory of multiple repeated withdrawals (SOR=A). Diazepam It has been shown that patients treated with car- 10–20 mg every 6 hours for 4 doses, then bamazepine were less likely to have a first drink 5–10 mg every 6 hours for 8 doses following detoxification, and if they did drink, they Lorazepam drank less. This difference was especially evident 2–4 mg every 6 hours for 4 doses, then for those patients with a history of multiple with- 1–2 mg every 6 hours for 8 doses (consider drawal attempts.22 this choice if significant hepatic dysfunction) A limitation of carbamazepine use, however, is Carbamazepine (Tegretol) — 5-day supply its interaction with multiple medications that 200 mg 4 times on day 1, undergo hepatic oxidative metabolism, making it 200 mg 3 times on day 2, 200 mg 2 times on day 3, less useful in older patients or those with multiple 200 mg daily for 2 more days (5 days total) medical problems. In summary, in generally healthy individuals with mild-to-moderate alcohol withdrawal, carbamazepine is just as efficacious Other types of medications as benzodiazepines, but has many advantages Alpha-adrenergic agonists,24–30 beta-blockers,31–33 making it the drug of choice for properly selected and calcium channel blockers34,35 have been used patients (SOR=A).21–23 to control symptoms of acute alcohol withdraw- Valproic acid. Another widely used anticon- al, but have demonstrated little efficacy in pre- vulsant, valproic acid, significantly affects the vention of seizures or DTs (LOE: 1).5,36 course of alcohol withdrawal and reduces the need for treatment with a benzodiazepine (LOE: 1).24 ■ TREATMENT REGIMENS Two double-blind, randomized studies showed The acceptable medication regimens for treating that patients treated with valproic acid for 4 to 7 alcohol withdrawal are the gradually tapering days had fewer seizures, dropped out less fre- dose approach, the fixed-schedule approach, and quently, had less severe withdrawal symptoms, the symptom-triggered approach. The first 2 regi- and require less oxazepam than those treated mens are appropriate for the pharmacological with placebo or carbamazepine.24,25 treatment of outpatient alcohol detoxification. Although effective, valproic acid use may be Gradually tapering regimen. With the grad- limited by side effects—somnolence, gastro- ual-dosing plan, patients receive medication intestinal disturbances, , and tremor— according to a predetermined dosing schedule that mimic the symptoms of alcohol withdrawal, for several days as the medication is gradually making it difficult to assess improvement. discontinued (Table 2).

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TABLE 3 Criteria for inpatient alcohol detoxification Consider transfer for inpatient detoxification if the patient:

■ Has current symptoms of moderate to severe alcohol withdrawal (CIWA ≥15)

■ Has a known history of (DTs) or alcohol withdrawal – If the patient has a remote history of seizures or DTs, but has detoxified previously without complications, they may be offered outpatient treatment.

■ Needs and is unable to tolerate oral medication

■ Is in imminent risk of harm to self or others

■ Has had recurrent unsuccessful attempts

■ Has had multiple past detoxifications

■ Has a reasonable likelihood that he will not complete the ambulatory detoxification

■ Has active psychosis or severe cognitive impairment

■ Has concomitant medical or psychological illness

■ Has recent high levels of alcohol consumption

■ Has lack or reliable support network

■ Is pregnant

Fixed-schedule regimen. In the fixed-sched- those patients who require pharmacological ule dosing regimen, the patient receives a fixed treatment during outpatient detoxification dose of medication every 6 hours for 2 to 3 days (CIWA-Ar score 8–15), we prefer the gradually regardless of severity of symptoms. tapering or fixed dosing plan, to provide a mar- Symptom-triggered regimen. For the symp- gin of safety, simplify the dosing schedule, and tom-triggered approach, the patient’s CIWA-Ar maximize compliance (SOR: C, expert opinion).14 score is determined hourly or bihourly and the medication is administered only when the score ■ INPATIENT VS OUTPATIENT is elevated. Typically, benzodiazepines are used TREATMENT in a symptom-triggered regimen, although Most patients undergoing alcohol withdrawal either benzodiazepines or anticonvulsants may may be treated safely in either an inpatient or out- be used in a fixed-schedule plan. patient setting (SOR=A).40 Treatment profession- The main advantage to the symptom-trig- als should assess whether inpatient or outpatient gered approach is that much less medication is treatment would contribute more therapeutically used to achieve the same withdrawal state to an alcoholic’s recovery process.41 (LOE: 1).37–39 The symptom-triggered approach Patients with severe alcohol withdrawal symp- has also shown a possible decrease in DTs and toms (CIWA-Ar ≥15), previous history of DTs or may lead to less oversedation.38,39 seizures, or those with serious psychiatric or med- We favor a symptom-based approach whenev- ical comorbidities should be considered for detoxifi- er adequate periodic assessment of CIWA-Ar can cation in an inpatient setting (SOR=B) (Table 3).10,42 be performed, such as in an inpatient setting. For The main advantage of inpatient detoxification is

CONTINUED

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