Alcohol withdrawal syndrome in medical patients

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,¹ states 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.

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

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

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

Which benzodiazepine to use?

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 chlordiazepox-ide 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 ben-zodiazepines 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 cloni-dine 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