Mae Hannawa, PharmD

Article Type

Article

Changed

Tue, 08/15/2017 - 14:43

Display Headline

Alcohol withdrawal syndrome in medical patients

Author(s)

Justine S. Gortney, PharmD, BCPS

Joshua N. Raub, PharmD, BCPS

Pragnesh Patel, MD

Lianne Kokoska, PharmD

Mae Hannawa, PharmD

Amy Argyris, PharmD, BCPS

Deprived of alcohol while in the hospital, up to 80% of patients who are alcohol-dependent risk developing alcohol withdrawal syndrome,¹ a potentially life-threatening condition. Clinicians should anticipate the syndrome and be ready to treat and prevent its complications.

Because alcoholism is common, nearly every provider will encounter its complications and withdrawal symptoms. Each year, an estimated 1.2 million hospital admissions are related to alcohol abuse, and about 500,000 episodes of withdrawal symptoms are severe enough to require clinical attention.^1–3 Nearly 50% of patients with alcohol withdrawal syndrome are middle-class, highly functional individuals, making withdrawal difficult to recognize.¹

While acute trauma patients or those with alcohol withdrawal delirium are often admitted directly to an intensive care unit (ICU), many others are at risk for or develop alcohol withdrawal syndrome and are managed initially or wholly on the acute medical unit. While specific statistics have not been published on non-ICU patients with alcohol withdrawal syndrome, they are an important group of patients who need to be well managed to prevent the progression of alcohol withdrawal syndrome to alcohol withdrawal delirium, alcohol withdrawal-induced seizure, and other complications.

This article reviews how to identify and manage alcohol withdrawal symptoms in noncritical, acutely ill medical patients, with practical recommendations for diagnosis and management.

CAN LEAD TO DELIRIUM TREMENS

In people who are physiologically dependent on alcohol, symptoms of withdrawal usually occur after abrupt cessation.⁴ If not addressed early in the hospitalization, alcohol withdrawal syndrome can progress to alcohol withdrawal delirium (also known as delirium tremens or DTs), in which the mortality rate is 5% to 10%.^5,6 Potential mechanisms of DTs include increased dopamine release and dopamine receptor activity, hypersensitivity to N-methyl-d-aspartate, and reduced levels of gamma-aminobutyric acid (GABA).⁷

Long-term changes are thought to occur in neurons after repeated detoxification from alcohol, a phenomenon called “kindling.” After each detoxification, alcohol craving and obsessive thoughts increase,⁸ and subsequent episodes of alcohol withdrawal tend to be progressively worse.

Withdrawal symptoms

Alcohol withdrawal syndrome encompasses a spectrum of symptoms and conditions, from minor (eg, insomnia, tremulousness) to severe (seizures, DTs).² The symptoms typically depend on the amount of alcohol consumed, the time since the last drink, and the number of previous detoxifications.⁹

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,¹states that to establish a diagnosis of alcohol withdrawal syndrome, a patient must meet four criteria:

The patient must have ceased or reduced alcohol intake after heavy or prolonged use.
Two or more of the following must develop within a few hours to a few days: autonomic hyperactivity (sweating or pulse greater than 100 beats per minute); increased hand tremor; insomnia; nausea or vomiting; transient visual, tactile, or auditory hallucinations or illusions; psychomotor agitation; anxiety; grand mal seizure.
The above symptoms must cause significant distress or functional impairment.
The symptoms must not be related to another medical condition.

Some of the symptoms described in the second criterion above can occur while the patient still has a measurable blood alcohol level, usually within 6 hours of cessation of drinking.¹⁰ Table 1 describes the timetable of onset of symptoms and their severity.²

The elderly may be affected more severely

While the progression of the symptoms described above is commonly used for medical inpatients, the timeline may be different in an elderly patient. Compared with younger patients, elderly patients may have higher blood alcohol concentrations owing to lower total body water, so small amounts of alcohol can produce significant effects.^11,12 Brower et al¹² found that elderly patients experienced more withdrawal symptoms, especially cognitive impairment, weakness, and high blood pressure, and for 3 days longer.

In the elderly, alcohol may have a greater impact on the central nervous system because of increased permeability of the blood-brain barrier. And importantly, elderly patients tend to have more concomitant diseases and take more medications, all of which can affect alcohol metabolism.

ASSESSMENT SCALES FOR ALCOHOL WITHDRAWAL SYNDROME

A number of clinical scales for evaluating alcohol withdrawal have been developed. Early ones such as the 30-item Total Severity Assessment (TSA) scale and the 11-item Selected Severity Assessment (SSA) scale were limited because they were extremely detailed, burdensome to nursing staff to administer, and contained items such as daily “sleep disturbances” that were not acute enough to meet specific monitoring needs or to guide drug therapy.^13,14

The Clinical Institute Withdrawal Assessment for alcohol (CIWA-A) scale, with 15 items, was derived from the SSA scale and includes acute items for assessment as often as every half-hour.¹⁵

The CIWA-Ar scale for assessing alcohol withdrawal syndrome

The CIWA-Ar scale (Table 2) was developed from the CIWA-A scale by Sullivan et al.¹⁵ Using both observation and interview, it focuses on 10 areas: nausea and vomiting, tremor, paroxysmal sweats, anxiety, agitation, headache, disorientation, tactile disturbances, auditory disturbances, and visual disturbances. Scores can range from 0 to 67; a higher score indicates worse withdrawal symptoms and outcomes and therefore necessitates escalation of treatment.

The CIWA-Ar scale is now the one most commonly used in clinical trials^16–20 and, we believe, in practice. Other scales, including the CIWA-AD and the Alcohol Withdrawal Scale have been validated but are not widely used in practice.^14,21

BASELINE ASSESSMENT AND EARLY SUPPORTIVE CARE

A thorough history and physical examination should be performed on admission in patients known to be or suspected of being alcohol-dependent to assess the patient’s affected body systems. The time elapsed since the patient’s last alcohol drink helps predict the onset of withdrawal complications.

Baseline laboratory tests for most patients with suspected alcohol withdrawal syndrome should include a basic blood chemistry panel, complete blood cell count, and possibly an alcohol and toxicology screen, depending on the patient’s history and presentation.

Hydration and nutritional support are important in patients presenting with alcohol withdrawal syndrome. Severe disturbances in electrolytes can lead to serious complications, including cardiac arrhythmia. Close monitoring and electrolyte replacement as needed are recommended for hospitalized alcoholic patients and should follow hospital protocols.²²

Thiamine and folic acid status deserve special attention, since long-standing malnutrition is common in alcoholic patients. Thiamine deficiency can result in Wernicke encephalopathy and Korsakoff syndrome, characterized by delirium, ataxia, vision changes, and amnesia. Alcohol withdrawal guidelines recommend giving thiamine intravenously for the first 2 to 5 days after admission.²³ In addition, thiamine must be given before any intravenous glucose product, as thiamine is a cofactor in carbohydrate metabolism.²³ Folic acid should also be supplemented, as chronic deficiencies may lead to megaloblastic or macrocytic anemia.

Most patients with a CIWA-Ar score ≥ 8 benefit from benzodiazepine therapy

CIWA-Ar scale. To provide consistent monitoring and ongoing treatment, clinicians and institutions are encouraged to use a simple assessment scale that detects and quantifies alcohol withdrawal syndrome and that can be used for reassessment after an intervention.²¹ The CIWA-Ar scale should be used to facilitate “symptom-triggered therapy” in which, depending on the score, the patient receives pharmacologic treatment followed by a scheduled reevaluation.^23,24 Most patients with a CIWA-Ar score of 8 or higher benefit from benzodiazepine therapy.^16,18,19

PRIMARY DRUG THERAPIES FOR MEDICAL INPATIENTS

Benzodiazepines are the first-line agents

Benzodiazepines are the first-line agents recommended for preventing and treating alcohol withdrawal syndrome.²³ Their various pharmacokinetic profiles, wide therapeutic indices, and safety compared with older sedative hypnotics make them the preferred class.^23,25 No single benzodiazepine is preferred over the others for treating alcohol withdrawal syndrome: studies have shown benefits using short-acting, intermediate-acting, and long-acting agents. The choice of drug is variable and patient-specific.^16,18,26

Benzodiazepines promote and enhance binding of the inhibitory neurotransmitter GABA to GABA_A receptors in the central nervous system.²⁷ As a class, benzodiazepines are all structurally related and produce the same effects—namely, sedation, hypnosis, decreased anxiety, muscle relaxation, anterograde amnesia, and anticonvulsant activity.²⁷

The most studied benzodiazepines for treating and preventing alcohol withdrawal syndrome are chlordiazepoxide, oxazepam, and lorazepam,^16–20 whereas diazepam was used in older studies.²³

Diazepam and chlordiazepoxide are metabolized by oxidation, each sharing the long-acting active metabolite desmethyldiazepam (half-life 72 hours), and short-acting metabolite oxazepam (half-life 8 hours).²⁷ In addition, the parent drugs also have varying pharmacokinetic profiles: diazepam has a half-life of more than 30 hours and chlordiazepoxide a half-life of about 8 hours. Chlordiazepoxide and diazepam’s combination of both long- and short-acting benzodiazepine activity provides long-term efficacy in attenuating withdrawal symptoms, but chlordiazepoxide’s shorter parent half-life allows more frequent dosing.

Lorazepam (half-life 10–20 hours) and oxazepam (half-life 5–20 hours) undergo glucuronide conjugation and do not have metabolites.^27,28 Table 3 provides a pharmacokinetic summary.^27,28

Various dosage regimens are used in giving benzodiazepines, the most common being symptom-triggered therapy, governed by assessment scales, and scheduled around-the-clock therapy.²⁹ Current evidence supports symptom-triggered therapy in most inpatients who are not critically ill, as it can reduce both benzodiazepine use and adverse drug events and can reduce the length of stay.^16,19

Trials of symptom-triggered benzodiazepine therapy

Most inpatient trials of symptom-triggered therapy (Table 4)^3,16–20 used the CIWA-Ar scale for monitoring. In some of the studies, benzodiazepines were given if the score was 8 or higher, but others used cut points as high as 15 or higher. Doses:

Chlordiazepoxide (first dose 25–100 mg)
Lorazepam (first dose 0.5–2 mg)
Oxazepam (30 mg).

After each dose, patients were reevaluated at intervals of 30 minutes to 8 hours.

Most of these trials showed no difference in rates of adverse drug events such as seizures, hallucinations, and lethargy with symptom-triggered therapy compared with scheduled therapy.^16,18,20 They also found either no difference in the incidence of delirium tremens, or a lower incidence of delirium tremens with symptom-triggered therapy than with scheduled therapy.^16–18,20

Weaver et al¹⁹ found no difference in length of stay between scheduled therapy and symptom-triggered therapy, but Saitz et al¹⁶ reported a median benzodiazepine treatment duration of 9 hours with symptom-triggered therapy vs 68 hours with fixed dosing. Thus, the study by Saitz et al suggests that hospitalization might be shorter with symptom-triggered therapy.

Many of the trials had notable limitations related to the diversity of patients enrolled and the protocols for both symptom-triggered therapy and fixed dosing. Some trials enrolled only inpatients in detoxification programs; others focused on inpatients with acute medical illness. The inpatient alcohol treatment trials^16,18 excluded medically ill patients and those with concurrent psychiatric illness,^16,18 and one excluded patients with seizures.¹⁶ One of the inpatient alcohol treatment program trials¹⁶ excluded patients on beta-blockers or clonidine because of concern that these drugs could mask withdrawal symptoms, whereas trials in medically ill patients allowed these same drugs.^17,19,20

Most of the patients were men (approximately 75%, but ranging from 74% to 100%), and therefore the study results may not be as applicable to women.^16–20 Most participants were middle-aged, with average ages in all studies between 46 and 55. Finally, the studies used a wide range of medications and dosing, with patient monitoring intervals ranging from every 30 minutes to every 8 hours.^16–20

In a 2010 Cochrane analysis, Amato et al²⁹ concluded that the limited evidence available favors symptom-triggered regimens over fixed-dosing regimens, but that differences in isolated trials should be interpreted very cautiously.

Therapeutic ethanol

Aside from the lack of evidence to support its use in alcohol withdrawal syndrome, prescribing oral ethanol to alcoholic patients clearly poses an ethical dilemma. However, giving ethanol intravenously has been studied, mostly in surgical trauma patients.³⁰

Early reports described giving intravenous ethanol on a gram-to-gram basis to match the patient’s consumption before admission to prevent alcohol withdrawal syndrome. But later studies reported prevention of alcohol withdrawal syndrome with very small amounts of intravenous ethanol.^30,31 While clinical trials have been limited to ICU patients, ethanol infusion at an initial rate of 2.5 to 5 g per hour and titrated up to 10 g per hour has appeared to be safe and effective for preventing alcohol withdrawal syndrome.^30,31 The initial infusion rate of 2.5 to 5 g per hour is equivalent to 4 to 10 alcoholic beverages per 24 hours.

Nevertheless, ethanol infusion carries the potential for toxicities (eg, gastric irritation, precipitation of acute hepatic failure, hypoglycemia, pancreatitis, bone marrow suppression, prolonged wound healing) and drug interactions (eg, with anticoagulants and anticonvulsants). Thus, ethanol is neither widely used nor recommended.^25,31

ADJUNCTIVE THERAPIES

Many medications are used adjunctively in the acute setting, both for symptoms of alcohol withdrawal syndrome and for agitation.

Haloperidol

No clinical trial has yet examined haloperidol monotherapy in patients with alcohol withdrawal syndrome in either general medical units or intensive care units. Yet haloperidol remains important and is recommended as an adjunct therapy for agitation.^23,32 Dosing of haloperidol in protocols for surgical patients ranged from 2 to 5 mg intravenously every 0.5 to 2 hours, with a maximum dosage of 0.5 mg per kg per 24 hours.^7,33

Alpha-2 agonists

Alpha-2 agonists are thought to reduce sympathetic overdrive and the autonomic symptoms associated with alcohol withdrawal syndrome, and these agents (primarily clonidine) have been studied in the treatment of alcohol withdrawal syndrome.^34,35

Clonidine. In a Swedish study,³⁴ 26 men ages 20 to 55 who presented with the tremor, sweating, dysphoria, tension, anxiety, and tachycardia associated with alcohol withdrawal syndrome received clonidine 4 µg per kg twice daily or carbamazepine 200 mg three to four times daily in addition to an antiepileptic. Adjunctive use of a benzodiazepine was allowed at night in both groups. No statistically significant difference in symptom reduction was noted between the two groups, and there was no difference in total benzodiazepine use.

Dexmedetomidine, given intravenously, has been tested as an adjunct to benzodiazepine treatment in severe alcohol withdrawal syndrome. It has been shown to decrease the amount of total benzodiazepine needed compared with benzodiazepine therapy alone, but no differences have been seen in length of hospital stay.^36–39 However, research on this drug so far is limited to ICU patients.

Beta-blockers

Beta-blockers have been used in inpatients with alcohol withdrawal syndrome to reduce heart rate and potentially reduce alcohol craving. However, the data are limited and conflicting.

Atenolol 50 to 100 mg daily, in a study in 120 patients, reduced length of stay (4 vs 5 days), reduced benzodiazepine use, and improved vital signs and behavior compared with placebo.⁴⁰

Propranolol 40 mg every 6 hours reduced arrhythmias but increased hallucinations when used alone in a study in 47 patients.⁴¹ When used in combination with chlordiazepoxide, no benefit was seen in arrhythmia reduction.⁴¹

Barbiturates and other antiepileptics

Data continue to emerge on antiepileptics as both monotherapy and adjunctive therapy for alcohol withdrawal syndrome. Barbiturates as monotherapy were largely replaced by benzodiazepines in view of the narrow therapeutic index of barbiturates and their full agonist effect on the GABA receptor complex. However, phenobarbital has been evaluated in patients presenting with severe alcohol withdrawal syndrome or resistant alcohol withdrawal (ie, symptoms despite large or repeated doses of benzodiazepines) as an adjunct to benzodiazepines.^42,43

In addition, a newer trial⁴⁴ involved giving a single dose of phenobarbital in the emergency department in combination with a CIWA-Ar–based benzodiazepine protocol, compared with the benzodiazepine protocol alone. The group that received phenobarbital had fewer ICU admissions; its evaluation is ongoing.

The three other medications with the most data are carbamazepine, valproic acid, and gabapentin.^45,46 However, the studies were small and the benefit was modest. Although these agents are possible alternatives in protracted alcohol withdrawal syndrome, no definite conclusion can be made regarding their place in therapy.⁴⁶

RECOMMENDATIONS FOR DRUG THERAPY AND SUPPORTIVE CARE

Which benzodiazepine to use?

No specific benzodiazepine is recommended, but studies best support the long-acting drug chlordiazepoxide

No specific benzodiazepine is recommended over the others for managing alcohol withdrawal syndrome, but studies best support the long-acting agent chlordiazepoxide.^16,17,20 Other benzodiazepines such as lorazepam and oxazepam have proved to be beneficial, but drugs should be selected on the basis of patient characteristics and drug metabolism.^18,19,27

Patients with severe liver dysfunction and the elderly may have slower oxidative metabolism, so the effects of medications that are primarily oxidized, such as chlordiazepoxide and diazepam, may be prolonged. Therefore, lorazepam and oxazepam would be preferred in these groups.⁴⁷ While most patients with alcohol withdrawal syndrome and liver dysfunction do not have advanced cirrhosis, we recommend liver function testing (serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels) and screening for liver disease, given the drug metabolism and package insert caution for use in those with impaired hepatic function.⁴⁸

Patients with end-stage renal disease (stage 5 chronic kidney disease) or acute kidney injury should not receive parenteral diazepam or lorazepam. The rationale is the potential accumulation of propylene glycol, the solvent used in these formulations.

In the elderly, the Beers list of drugs to avoid in older adults includes benzodiazepines, not differentiating individual benzodiazepines in terms of risk.⁴⁹ However, chlordiazepoxide may be preferable to diazepam due to its shorter parent half-life and lower lipophilicity.²⁷ Few studies have been done using benzodiazepines in elderly patients with alcohol withdrawal syndrome, but those published have shown either equivalent dosing required compared with younger patients or more severe withdrawal for which they received greater amounts of chlordiazepoxide.^9,12 Lorazepam and oxazepam have less potential to accumulate in the elderly compared with the nonelderly due to the drugs’ metabolic profiles; lorazepam is the preferred agent because of its faster onset of action.⁴⁷ Ultimately, the choice of benzodiazepine in elderly patients with alcohol withdrawal syndrome should be based on patient-specific characteristics.

How should benzodiazepines be dosed?

While the CIWA-Ar thresholds and subsequent dosing of benzodiazepines varied in different studies, we recommend starting benzodiazepine therapy at a CIWA-Ar score of 8 or higher, with subsequent dosing based on score reassessment. Starting doses of benzodiazepines should be chlordiazepoxide 25 to 50 mg, lorazepam 1 to 2 mg, or oxazepam 15 mg.^16–20

Subsequent doses should be titrated upward, increasing by 1.5 to 2 times the previous dose and monitored at least every 1 to 2 hours after dose adjustments. Once a patient is stable and the CIWA-Ar score is less than 8, monitoring intervals can be extended to every 4 to 8 hours. If the CIWA-Ar score is more than 20, studies suggest the need for patient reevaluation for transfer to the ICU; however, some health systems have a lower threshold for this intervention.^7,14,50

Dosing algorithms and CIWA-Ar goals may vary slightly from institution to institution, but it has been shown that symptom-triggered therapy works best when hospitals have a protocol for it and staff are adequately trained to assess patients with alcohol withdrawal syndrome.^7,50,51 Suggestions for dose ranges and symptom-triggered therapy are shown in Table 5.

In case of benzodiazepine overdose or potential benzodiazepine-induced delirium, flumazenil could be considered.⁵²

Patients who should not receive symptom-triggered therapy include immediate postoperative patients in whom clinicians cannot properly assess withdrawal symptoms and patients with a history of DTs.⁵¹ While controversy exists regarding the use of symptom-triggered therapy in patients with complicated medical comorbidities, there are data to support symptom-triggered therapy in some ICU patients, as it has resulted in less benzodiazepine use and reduced mechanical ventilation.^53,54

There are limited data to support phenobarbital in treating resistant alcohol withdrawal syndrome, either alone or concurrently with benzodiazepines, in escalating doses ranging from 65 to 260 mg, with a maximum daily dose of 520 mg.^42,55,56

Haloperidol

For patients exhibiting agitation despite benzodiazepine therapy, giving haloperidol adjunctively can be beneficial.

Haloperidol can be used in medical patients as an adjunctive therapy for agitation, but caution is advised because of the potential for a lowering of the seizure threshold, extrapyramidal effects, and risk of QTc prolongation leading to arrhythmias. Patients considered at highest risk for torsades de pointes may have a QTc of 500 msec or greater.⁵⁷

Patients should also be screened for factors that have been shown to be independent predictors of QTc prolongation (female sex, diagnosis of myocardial infarction, septic shock or left ventricular dysfunction, other QT-prolonging drugs, age > 68, baseline QTc ≥ 450 msec, and hypokalemia).⁵⁸ If combined predictors have been identified, it is recommended that haloperidol be avoided.

If haloperidol is to be given, a baseline electrocardiogram and electrolyte panel should be obtained, with daily electrocardiograms thereafter, as well as ongoing review of the patient’s medications to minimize drug interactions that could further increase the risk for QTc prolongation.

Suggested haloperidol dosing is 2 to 5 mg intravenously every 0.5 to 2 hours with a maximum dose of 0.5 mg/kg/24 hours.^8,33 A maximum of 35 mg of intravenous haloperidol should be used in a 24-hour period to avoid QTc prolongation.⁵⁷

Antihypertensive therapy

Many patients receive symptomatic relief of autonomic hyperreactivity with benzodiazepines. However, some may require additional antihypertensive therapy for cardiac adrenergic symptoms (hypertension, tachycardia) if symptoms do not resolve by treating other medical problems commonly seen in patients with alcohol withdrawal syndrome, such as dehydration and electrolyte imbalances.⁷

Published protocols suggest giving clonidine 0.1 mg orally every hour up to three times as needed until systolic blood pressure is less than 140 mm Hg (less than 160 mm Hg if the patient is over age 60) and diastolic pressure is less than 90 mm Hg.⁵¹ Once the patient is stabilized, the dosing can be scheduled to a maximum of 2.4 mg daily.⁵⁹ However, we believe that the use of clonidine should be restricted to patients who have a substantial increase in blood pressure over baseline or are nearing a hypertensive urgency or emergency (pressures > 180/120 mm Hg) and should not be used to treat other general symptoms associated with alcohol withdrawal syndrome.⁴²

In addition, based on limited evidence, we recommend using beta-blockers only in patients with symptomatic tachycardia or as an adjunct in hypertension management.^40,41

Therapies to avoid in acutely ill medical patients

Ethanol is not recommended. Instead, intravenous benzodiazepines should be given in patients presenting with severe alcohol withdrawal syndrome.

Antiepileptics, including valproic acid, carbamazepine, and pregabalin, lack benefit in these patients either as monotherapy or as adjunctive therapy and so are not recommended.^45,60–62

Magnesium supplementation (in patients with normal serum magnesium levels) should not be given, as no clinical benefit has been shown.⁶³

References

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association, 2013:501.
Bayard M, McIntyre J, Hill KR, Woodside J Jr. Alcohol withdrawal syndrome. Am Fam Physician 2004; 69:1443–1450.
Kosten TR, O'Connor PG. Management of drug and alcohol withdrawal. N Engl J Med 2003; 348:1786–1795.
Isbell H, Fraser HF, Wilker A, Bellevile RE, Eisenman AJ. An experimental study of the etiology of rum fits and delirium tremens. Q J Stud Alcohol 1955; 16:1–33.
Khan A, Levy P, DeHorn S, Miller W, Compton S. Predictors of mortality in patients with delirium tremens. Acad Emerg Med 2008; 15:788–790.
Monte R, Rabuñal R, Casariego E, López-Agreda H, Mateos A, Pértega S. Analysis of the factors determining survival of alcoholic withdrawal syndrome patients in a general hospital. Alcohol Alcohol 2010; 45:151–158.
Stanley KM, Amabile CM, Simpson KN, Couillard D, Norcross ED, Worrall CL. Impact of an alcohol withdrawal syndrome practice guideline on surgical patient outcomes. Pharmacotherapy 2003; 23:843–854.
Brousse G, Arnaud B, Vorspan F, et al. Alteration of glutamate/GABA balance during acute alcohol withdrawal in emergency department: a prospective analysis. Alcohol Alcohol 2012; 47:501–508.
Liskow BI, Rinck C, Campbell J, DeSouza C. Alcohol withdrawal in the elderly. J Stud Alcohol 1989; 50:414–421.
Etherington JM. Emergency management of acute alcohol problems. Part 1: uncomplicated withdrawal. Can Fam Physician 1996; 42:2186–2190.
Letizia M, Reinbolz M. Identifying and managing acute alcohol withdrawal in the elderly. Geriatr Nurs 2005; 26:176–183.
Brower KJ, Mudd S, Blow FC, Young JP, Hill EM. Severity and treatment of alcohol withdrawal in elderly versus younger patients. Alcohol Clin Exp Res 1994; 18:196–201.
Williams D, Lewis J, McBride A. A comparison of rating scales for the alcohol-withdrawal syndrome. Alcohol Alcohol 2001; 36:104–108.
Reoux JP, Oreskovich MR. A comparison of two versions of the Clinical Institute Withdrawal Assessment for Alcohol: the CIWA-Ar and CIWA-AD. Am J Addict 2006; 15:85–93.
Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of alcohol withdrawal: the revised Clinical Institute Withdrawal Assessment for alcohol scale (CIWA-Ar). Br J Addict 1989; 84:1353–1357.
Saitz R, Mayo-Smith MF, Roberts MS, Redmond HA, Bernard DR, Calkins DR. Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial. JAMA 1994; 272:519–523.
Jaeger TM, Lohr RH, Pankratz VS. Symptom-triggered therapy for alcohol withdrawal syndrome in medical inpatients. Mayo Clin Proc 2001; 76:695–701.
Daeppen JB, Gache P, Landry U, et al. Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial. Arch Intern Med 2002; 162:1117–1121.
Weaver MF, Hoffman HJ, Johnson RE, Mauck K. Alcohol withdrawal pharmacotherapy for inpatients with medical comorbidity. J Addict Dis 2006; 25:17–24.
Reoux JP, Miller K. Routine hospital alcohol detoxification practice compared to symptom triggered management with an Objective Withdrawal Scale (CIWA-Ar). Am J Addict 2000; 9:135–144.
Wetterling T, Kanitz RD, Besters B, et al. A new rating scale for the assessment of the alcohol-withdrawal syndrome (AWS scale). Alcohol Alcohol 1997; 32:753–760.
Myrick H, Anton RF. Treatment of alcohol withdrawal. Alcohol Health Res World 1998; 22:38–43.
Mayo-Smith MF, Beecher LH, Fischer TL, et al; Working Group on the Management of Alcohol Withdrawal Delirium, Practice Guidelines Committee, American Society of Addiction Medicine. Management of alcohol withdrawal delirium. An evidence-based practice guideline. Arch Intern Med 2004; 164:1405–1412.
Sellers EM, Sullivan JT, Somer G, Sykora K. Characterization of DSM-III-R criteria for uncomplicated alcohol withdrawal provides an empirical basis for DSM-IV. Arch Gen Psychiatry 1991; 48:442–447.
Sarff M, Gold JA. Alcohol withdrawal syndromes in the intensive care unit. Crit Care Med 2010; 38(suppl):S494–S501.
Kumar CN, Andrade C, Murthy P. A randomized, double-blind comparison of lorazepam and chlordiazepoxide in patients with uncomplicated alcohol withdrawal. J Stud Alcohol Drugs 2009; 70:467–474.
Bird RD, Makela EH. Alcohol withdrawal: what is the benzodiazepine of choice? Ann Pharmacother 1994; 28:67–71.
Perry EC. Inpatient management of acute alcohol withdrawal syndrome. CNS Drugs 2014; 28:401–410.
Amato L, Minozzi S, Vecchi S, Davoli M. Benzodiazepines for alcohol withdrawal. Cochrane Database Syst Rev 2010; 3:CD005063.
Weinberg JA, Magnotti LJ, Fischer PE, et al. Comparison of intravenous ethanol versus diazepam for alcohol withdrawal prophylaxis in the trauma ICU: results of a randomized trial. J Trauma 2008; 64:99–104.
Craft PP, Foil MB, Cunningham PR, Patselas PC, Long-Snyder BM, Collier MS. Intravenous ethanol for alcohol detoxification in trauma patients. South Med J 1994; 87:47–54.
Ungur LA, Neuner B, John S, Wernecke K, Spies C. Prevention and therapy of alcohol withdrawal on intensive care units: systematic review of controlled trials. Alcohol Clin Exp Res 2013; 37:675–686.
Lansford CD, Guerriero CH, Kocan MJ, et al. Improved outcomes in patients with head and neck cancer using a standardized care protocol for postoperative alcohol withdrawal. Arch Otolaryngol Head Neck Surg 2008; 134:865–872.
Walinder J, Balldin J, Bokstrom K, Karlsson I, Lundstrom B, Svensson TH. Clonidine suppression of the alcohol withdrawal syndrome. Drug Alcohol Depend 1981; 8:345–348.
Muzyk AJ, Fowler JA, Norwood DK, Chilipko A. Role of alpha2-agonists in the treatment of acute alcohol withdrawal. Ann Pharmacother 2011; 45:649–657.
Crispo AL, Daley MJ, Pepin JL, Harford PH, Brown CV. Comparison of clinical outcomes in nonintubated patients with severe alcohol withdrawal syndrome treated with continuous-infusion sedatives: dexmedetomidine versus benzodiazepines. Pharmacotherapy 2014; 34:910–917.
VanderWeide LA, Foster CJ, MacLaren R, Kiser TH, Fish DN, Mueller SW. Evaluation of early dexmedetomidine addition to the standard of care for severe alcohol withdrawal in the ICU: a retrospective controlled cohort study. J Intensive Care Med 2014. [Epub ahead of print October 16, 2014]
Rayner SG, Weinert CR, Peng H, Jepsen S, Broccard AF. Dexmedetomidine as adjunct treatment for severe alcohol withdrawal in the ICU. Ann Intensive Care 2012; 2:12.
Muzyk AJ, Kerns S, Brudney S, Gagliardi JP. Dexmedetomidine for the treatment of alcohol withdrawal syndrome: rationale and current status of research. CNS Drugs 2013; 27:913–920.
Kraus ML, Gottlieb LD, Horwitz RI, Anscher M. Randomized clinical trial of atenolol in patients with alcohol withdrawal. N Engl J Med 1985; 313:905–909.
Zilm DH, Jacob MS, MacLeod SM, Sellers EM, Ti TY. Propranolol and chlordiazepoxide effects on cardiac arrhythmias during alcohol withdrawal. Alcohol Clin Exp Res 1980; 4:400–405.
Hack JB, Hoffmann RS, Nelson LS. Resistant alcohol withdrawal: does an unexpectedly large sedative requirement identify these patients early? J Med Toxicol 2006; 2:55–60.
Hayner CE, Wuestefeld NL, Bolton PJ. Phenobarbital treatment in a patient with resistant alcohol withdrawal syndrome. Pharmacotherapy 2009; 29:875–878.
Rosenson J, Clements C, Simon B, et al. Phenobarbital for acute alcohol withdrawal: a prospective randomized double-blind placebo-controlled study. J Emerg Med 2013; 44:592–598.e2.
Prince V, Turpin KR. Treatment of alcohol withdrawal syndrome with carbamazepine, gabapentin, and nitrous oxide. Am J Health Syst Pharm 2008; 65:1039–1047.
Leggio L, Kenna GA, Swift RM. New developments for the pharmacological treatment of alcohol withdrawal syndrome. A focus on non-benzodiazepine GABAergic medications. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:1106–1117.
Peppers MP. Benzodiazepines for alcohol withdrawal in the elderly and in patients with liver disease. Pharmacotherapy 1996; 16:49–57.
Valeant Pharmaceuticals North America LLC. Librium—chlordiazepoxide hydrochloride capsule, gelatin coated. http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=125207. Accessed November 20, 2015.
American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2012; 60:616–631.
Hecksel KA, Bostwick JM, Jaeger TM, Cha SS. Inappropriate use of symptom-triggered therapy for alcohol withdrawal in the general hospital. Mayo Clin Proc 2008; 83:274–279.
Manasco A, Chang S, Larriviere J, Hamm LL, Glass M. Alcohol withdrawal. South Med J 2012; 105:607–612.
Moore PW, Donovan JW, Burkhart KK, et al. Safety and efficacy of flumazenil for reversal of iatrogenic benzodiazepine-associated delirium toxicity during treatment of alcohol withdrawal, a retrospective review at one center. J Med Toxicol 2014; 10:126–132.
Bostwick JM, Lapid MI. False positives on the clinical institute withdrawal assessment for alcohol-revised: is this scale appropriate for use in the medically ill? Psychosomatics 2004; 45:256–261.
de Wit M, Jones DG, Sessler CN, Zilberberg MD, Weaver MF. Alcohol-use disorders in the critically ill patient. Chest 2010; 138:994–1003.
Young GP, Rores C, Murphy C, Dailey RH. Intravenous phenobarbital for alcohol withdrawal and convulsions. Ann Emerg Med 1987; 16:847–850.
Hendey GW, Dery RA, Barnes RL, Snowden B, Mentler P. A prospective, randomized trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal. Am J Emerg Med 2011; 29:382–385.
Sharma ND, Rosman HS, Padhi ID, Tisdale JE. Torsades de pointes associated with intravenous haloperidol in critically ill patients. Am J Cardiol 1998; 81:238–240.
Tisdale JE, Jaynes HA, Kingery JR, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes 2013; 6:479–487.
Boehringer Ingelheim Pharmaceuticals, Inc. Product Information: Catapres oral tablets, clonidine HCl oral tablets, 2012.
Reoux JP, Saxon AJ, Malte CA, Baer JS, Sloan KL. Divalproex sodium in alcohol withdrawal: a randomized double-blind placebo-controlled clinical trial. Alcohol Clin Exp Res 2001; 25:1324–1329.
Malcolm R, Ballenger JC, Sturgis ET, Anton R. Double-blind controlled trial comparing carbamazepine to oxazepam treatment of alcohol withdrawal. Am J Psychiatry 1989; 146:617–621.
Förg A, Hein J, Volkmar K, et al. Efficacy and safety of pregabalin in the treatment of alcohol withdrawal syndrome: a randomized placebo-controlled trial. Alcohol Alcohol 2012; 47:149–155.
Wilson A, Vulcano B. A double-blind, placebo-controlled trial of magnesium sulfate in the ethanol withdrawal syndrome. Alcohol Clin Exp Res 1984; 8:542–545.

Click for Credit Link

http://www.clevelandclinicmeded.com/online/journal/01_January-2016/0531408/

Article PDF

Gortney_AlcoholWithdrawalSyndrome.pdf

Author and Disclosure Information

Justine S. Gortney, PharmD, BCPS
Assistant Professor, Director of Assessment, Division of Pharmacy, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI

Joshua N. Raub, PharmD, BCPS
Clinical Pharmacist Specialist in Internal Medicine, Assistant Program Director, Pharmacy Practice, Detroit Receiving Hospital, Detroit, MI

Pragnesh Patel, MD
Assistant Professsor, Wayne State School of Medicine, Division of Geriatrics, University Health Center, Detroit Receiving Hospital, Detroit, MI

Lianne Kokoska, PharmD
United Physicians, Detroit, MI

Mae Hannawa, PharmD
Clinical Pharmacist, Detroit Receiving Hospital, Detroit, MI

Amy Argyris, PharmD, BCPS
Clinical Pharmacist Specialist in Internal Medicine, Harper University Hospital, Detroit, MI

Address: Justine S. Gortney, PharmD, BCPS, Department of Pharmacy Practice, Wayne State College of Pharmacy and Health Sciences, 259 Mack Avenue, Suite 2190, Detroit, MI 48201; e-mail: justine.gortney@wayne.edu

Issue

Cleveland Clinic Journal of Medicine - 83(1)

Publications

Cleveland Clinic Journal of Medicine

Topics

Page Number

67-79

Legacy Keywords

alcohol withdrawal syndrome, delirium tremens, DTs, Clinical Institute Withdrawal Assessment for Alcohol scale, detox, CIWA-Ar, benzodiazepine, chlordiazepoxide, diazepam, lorazepam, oxazepam, haloperidol, clonidine, atenolol, propranolol, barbiturates, Justine Cortney, Joshua Raub, Pragnesh Patel, Lianne Kokoska, Mae Hannawa, Amy Argyris

Read more about Alcohol withdrawal syndrome in medical patients

Sections

Reviews

Author(s)

Justine S. Gortney, PharmD, BCPS

Joshua N. Raub, PharmD, BCPS

Pragnesh Patel, MD

Lianne Kokoska, PharmD

Mae Hannawa, PharmD

Amy Argyris, PharmD, BCPS

Author(s)

Justine S. Gortney, PharmD, BCPS

Joshua N. Raub, PharmD, BCPS

Pragnesh Patel, MD

Lianne Kokoska, PharmD

Mae Hannawa, PharmD

Amy Argyris, PharmD, BCPS

Click for Credit Link

http://www.clevelandclinicmeded.com/online/journal/01_January-2016/0531408/

Click for Credit Link

http://www.clevelandclinicmeded.com/online/journal/01_January-2016/0531408/

Author and Disclosure Information

Justine S. Gortney, PharmD, BCPS
Assistant Professor, Director of Assessment, Division of Pharmacy, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI

Joshua N. Raub, PharmD, BCPS
Clinical Pharmacist Specialist in Internal Medicine, Assistant Program Director, Pharmacy Practice, Detroit Receiving Hospital, Detroit, MI

Pragnesh Patel, MD
Assistant Professsor, Wayne State School of Medicine, Division of Geriatrics, University Health Center, Detroit Receiving Hospital, Detroit, MI

Lianne Kokoska, PharmD
United Physicians, Detroit, MI

Mae Hannawa, PharmD
Clinical Pharmacist, Detroit Receiving Hospital, Detroit, MI

Amy Argyris, PharmD, BCPS
Clinical Pharmacist Specialist in Internal Medicine, Harper University Hospital, Detroit, MI

Address: Justine S. Gortney, PharmD, BCPS, Department of Pharmacy Practice, Wayne State College of Pharmacy and Health Sciences, 259 Mack Avenue, Suite 2190, Detroit, MI 48201; e-mail: justine.gortney@wayne.edu

Author and Disclosure Information

Justine S. Gortney, PharmD, BCPS
Assistant Professor, Director of Assessment, Division of Pharmacy, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI

Joshua N. Raub, PharmD, BCPS
Clinical Pharmacist Specialist in Internal Medicine, Assistant Program Director, Pharmacy Practice, Detroit Receiving Hospital, Detroit, MI

Pragnesh Patel, MD
Assistant Professsor, Wayne State School of Medicine, Division of Geriatrics, University Health Center, Detroit Receiving Hospital, Detroit, MI

Lianne Kokoska, PharmD
United Physicians, Detroit, MI

Mae Hannawa, PharmD
Clinical Pharmacist, Detroit Receiving Hospital, Detroit, MI

Amy Argyris, PharmD, BCPS
Clinical Pharmacist Specialist in Internal Medicine, Harper University Hospital, Detroit, MI

Address: Justine S. Gortney, PharmD, BCPS, Department of Pharmacy Practice, Wayne State College of Pharmacy and Health Sciences, 259 Mack Avenue, Suite 2190, Detroit, MI 48201; e-mail: justine.gortney@wayne.edu

Article PDF

Gortney_AlcoholWithdrawalSyndrome.pdf

Article PDF

Gortney_AlcoholWithdrawalSyndrome.pdf

Deprived of alcohol while in the hospital, up to 80% of patients who are alcohol-dependent risk developing alcohol withdrawal syndrome,¹ a potentially life-threatening condition. Clinicians should anticipate the syndrome and be ready to treat and prevent its complications.

Because alcoholism is common, nearly every provider will encounter its complications and withdrawal symptoms. Each year, an estimated 1.2 million hospital admissions are related to alcohol abuse, and about 500,000 episodes of withdrawal symptoms are severe enough to require clinical attention.^1–3 Nearly 50% of patients with alcohol withdrawal syndrome are middle-class, highly functional individuals, making withdrawal difficult to recognize.¹

While acute trauma patients or those with alcohol withdrawal delirium are often admitted directly to an intensive care unit (ICU), many others are at risk for or develop alcohol withdrawal syndrome and are managed initially or wholly on the acute medical unit. While specific statistics have not been published on non-ICU patients with alcohol withdrawal syndrome, they are an important group of patients who need to be well managed to prevent the progression of alcohol withdrawal syndrome to alcohol withdrawal delirium, alcohol withdrawal-induced seizure, and other complications.

This article reviews how to identify and manage alcohol withdrawal symptoms in noncritical, acutely ill medical patients, with practical recommendations for diagnosis and management.

CAN LEAD TO DELIRIUM TREMENS

In people who are physiologically dependent on alcohol, symptoms of withdrawal usually occur after abrupt cessation.⁴ If not addressed early in the hospitalization, alcohol withdrawal syndrome can progress to alcohol withdrawal delirium (also known as delirium tremens or DTs), in which the mortality rate is 5% to 10%.^5,6 Potential mechanisms of DTs include increased dopamine release and dopamine receptor activity, hypersensitivity to N-methyl-d-aspartate, and reduced levels of gamma-aminobutyric acid (GABA).⁷

Long-term changes are thought to occur in neurons after repeated detoxification from alcohol, a phenomenon called “kindling.” After each detoxification, alcohol craving and obsessive thoughts increase,⁸ and subsequent episodes of alcohol withdrawal tend to be progressively worse.