alpha2-Agonists for Acute Alcohol Withdrawal

Abstract and Introduction

Abstract

Objective: To evaluate literature reporting on the role of norepinephrine in alcohol withdrawal and to determine the safety and efficacy of α₂-agonists in reducing symptoms of this severe condition.
Data Sources: Articles evaluating the efficacy and safety of the α₂-agonists clonidine and dexmedetomidine were identified from an English-language MEDLINE search (1966-December 2010). Key words included alcohol withdrawal, delirium tremens, clonidine, dexmedetomidine, α₂-agonist, norepinephrine, and sympathetic overdrive.
Study Selection and Data Extraction: Studies that focused on the safety and efficacy of clonidine and dexmedetomidine in both animals and humans were selected.
Data Synthesis: The noradrenergic system, specifically sympathetic overdrive during alcohol withdrawal, may play an important role in withdrawal symptom development. Symptoms of sympathetic overdrive include anxiety, agitation, elevated blood pressure, tachycardia, and tremor. Therefore, α₂-agonists, which decrease norepinephine release, may have a role in reducing alcohol withdrawal symptoms. The majority of controlled animal and human studies evaluated clonidine, but the most recent literature is from case reports on dexmedetomidine. The literature reviewed here demonstrate that these 2 α₂-agonists safely and effectively reduce symptoms of sympathetic overdrive and concomitant medication use. Dexmedetomidine may offer an advantage over current sedative medications used in the intensive care unit, such as not requiring intubation with its use, and therefore further study is needed to fully elicit its benefit in alcohol withdrawal.
Conclusion: Clonidine and dexmedetomidine may provide additional benefit in managing alcohol withdrawal by offering a different mechanism of action for targeting withdrawal symptoms. Based on literature reviewed here, the primary role for clonidine and dexmedetomidine is as adjunctive treatment to benzodiazepines, the standard of care in alcohol withdrawal.

Introduction

Alcohol dependence represents approximately 20% of hospital admissions and acute alcohol withdrawal constitutes a serious medical emergency requiring prompt recognition to prevent withdrawal complications.^[1] Acute alcohol withdrawal may progress to a medical emergency through the development of seizures and delirium tremens: cloudy consciousness, severe autonomic instability, hallucinations, and agitation.^[2] While 86% of patients with withdrawal will experience common signs and symptoms including agitation, tremor, hypertension, and tachycardia, approximately 5% of these patients may develop more severe symptoms consistent with delirium tremens (DTs).^[3]

Benzodiazepines remain the standard of treatment for withdrawal seizures and DTs, although α₂-agonists may have an adjunctive role in reducing sympathetic overdrive and associated symptom manifestations.^[4–6] The majority of literature on α₂-agonists evaluates the 2 older agents, lofexidine^[7–13] and clonidine.^[14–24] However, recent case reports on dexmedetomidine, a newer α₂-agonist, have generated interest in this drug class for alcohol withdrawal management.^[25–28]

The purpose of this article is to review the evidence for α₂-agonists in alcohol withdrawal and to examine their place in therapy.

Table 1. Summary of Prospective, Randomized Clinical Trials of Clonidine for Treatment of Alcohol Withdrawal
Reference	Study Design/Duration	Patients Randomized (N)/Patients Included in Analyses (n)	Treatment Arms	Primary Efficacy Measures	Results
Bjorkqvist (1975)¹⁴	R, DB, PC 4 days	60/60	Clonidine 0.15 mg up to 3 times daily vs placebo Adjunctive diphenhydramine, metaqualone, chlorproma-zine, and diphenylhydantoin allowed	Self-rated and nurse observer–rated symptoms of alcohol withdrawal	Self-rated and nurse observer–rated symptoms of alcohol withdrawal both significantly reduced with clonidine vs placebo on day 2 of treatment (p < 0.025 and p < 0.01, respectively)
Walinder (1981)¹⁵	R, OL, PG 7 days	26/19	Clonidine 4 μg/kg twice daily vs standard care (carbamazepine 200 mg 3–4 times daily plus chlorprothixene or dixyrazine 50 mg 3 times daily) Adjunctive low-dose benzodiazepines allowed	Clinician ratings of alcohol withdrawal symptoms on the Comprehensive Psychopathological Rating Scale	No significant difference in clinician ratings of alcohol withdrawal between clonidine and standard care (p value not reported)
Manhem (1985)¹⁶	R, DB, PG 4 days	20/17	Clonidine 0.15–0.3 mg every 6 h vs chlormethiazole 500–1000 mg every 6 h All pts. received carbamazepine 200 mg twice daily	BP; pulse; nurse observer–rated symptoms of alcohol withdrawal	BP and pulse lower with clonidine vs chlormethiazole (p < 0.05 for both); no significant difference in nurse observer ratings of alcohol withdrawal between clonidine and chlormethiazole (overall p value not reported)
Baumgartner (1987)¹⁸	R, DB, PG 4 days	61/47	Clonidine 0.2–0.6 mg daily vs chlordiazepoxide 50–150 mg daily	Clinician-rated symptoms of alcohol withdrawal	Lower overall clinician-rated symptoms of alcohol withdrawal with clonidine vs chlordiazepoxide (overall p value not reported), driven by differences in BP and pulse between groups
Baumgartner (1991)¹⁹	R, DB, PG 4 days	50/43	Clonidine 0.2 mg oral load plus two 0.2 mg/24 h transdermal patches (1 patch removed on day 3 and the other on day 4) vs chlordiazepoxide 50–150 mg daily	Clinician ratings of alcohol withdrawal symptoms on the Alcohol Withdrawal Assessment Scale	Lower mean clinician-rated symptoms of alcohol withdrawal with clonidine vs chlordiazepoxide (p < 0.03), driven by differences in BP, pulse, and anxiety ratings between groups
Robinson (1989)²⁰	R, DB, PG 4 days	32/32	Clonidine 0.3–0.9 mg vs chlormethiazole 1000–3000 mg	Alcohol withdrawal to an asymptomatic stage or symptomatic/physical deterioration requiring study withdrawal	50% of pts. in the clonidine group were withdrawn from the trial due to clinical deterioration vs none in the chlormethiazole group (p = 0.002)
Adinoff (1994)²¹	R, DB, PC, PG 4 days	25/25	Repeated doses of clonidine 0.1 mg, alprazolam 1 mg, diazepam 10 mg, or placebo	Number of doses required to achieve a CIWA-Ar score of ≤5	Fewer doses of alprazolam were required to achieve CIWA-Ar ≤5 vs clonidine (p < 0.04) and placebo (p < 0.03); clonidine did not separate from placebo (p value not reported)
Spies (1996)²³	R, RB, PG Unspecified duration, up to 17 days	180/159	Flunitrazepam/clonidine, chlormethiazole/haloperidol, or flunitrazepam/haloperidol (iv bolus followed by continuous iv infusion at varying doses to achieve a CIWA-Ar score <10)	Duration of controlled or assisted mechanical ventilation and frequency of major complications	Longer duration of mechanical ventilation with chlormethiazole/haloperidol (p = 0.03), cardiac complications more frequent with with flunitrazepam/clonidine (p = 0.005), and pneumonia less frequent with flunitrazepam/clonidine (p = 0.04) vs other drugs

Table 1. Summary of Prospective, Randomized Clinical Trials of Clonidine for Treatment of Alcohol Withdrawal

Reference

Study Design/Duration

Patients Randomized (N)/Patients Included in Analyses (n)

Treatment Arms

Primary Efficacy Measures

Results

Bjorkqvist (1975)¹⁴

R, DB, PC 4 days

60/60

Clonidine 0.15 mg up to 3 times daily vs placebo
Adjunctive diphenhydramine, metaqualone, chlorproma-zine, and diphenylhydantoin allowed

Self-rated and nurse observer–rated symptoms of alcohol withdrawal

Self-rated and nurse observer–rated symptoms of alcohol withdrawal both significantly reduced with clonidine vs placebo on day 2 of treatment (p < 0.025 and p < 0.01, respectively)

Walinder (1981)¹⁵

R, OL, PG 7 days

26/19

Clonidine 4 μg/kg twice daily vs standard care (carbamazepine 200 mg 3–4 times daily plus chlorprothixene or dixyrazine 50 mg 3 times daily)
Adjunctive low-dose benzodiazepines allowed

Clinician ratings of alcohol withdrawal symptoms on the Comprehensive Psychopathological Rating Scale

No significant difference in clinician ratings of alcohol withdrawal between clonidine and standard care (p value not reported)

Manhem (1985)¹⁶

R, DB, PG 4 days

20/17

Clonidine 0.15–0.3 mg every 6 h vs chlormethiazole 500–1000 mg every 6 h
All pts. received carbamazepine 200 mg twice daily

BP; pulse; nurse observer–rated symptoms of alcohol withdrawal

BP and pulse lower with clonidine vs chlormethiazole (p < 0.05 for both); no significant difference in nurse observer ratings of alcohol withdrawal between clonidine and chlormethiazole (overall p value not reported)

Baumgartner (1987)¹⁸

R, DB, PG 4 days

61/47

Clonidine 0.2–0.6 mg daily vs chlordiazepoxide 50–150 mg daily

Clinician-rated symptoms of alcohol withdrawal

Lower overall clinician-rated symptoms of alcohol withdrawal with clonidine vs chlordiazepoxide (overall p value not reported), driven by differences in BP and pulse between groups

Baumgartner (1991)¹⁹

R, DB, PG 4 days

50/43

Clonidine 0.2 mg oral load plus two 0.2 mg/24 h transdermal patches (1 patch removed on day 3 and the other on day 4) vs chlordiazepoxide 50–150 mg daily

Clinician ratings of alcohol withdrawal symptoms on the Alcohol Withdrawal Assessment Scale

Lower mean clinician-rated symptoms of alcohol withdrawal with clonidine vs chlordiazepoxide (p < 0.03), driven by differences in BP, pulse, and anxiety ratings between groups

Robinson (1989)²⁰

R, DB, PG 4 days

32/32

Clonidine 0.3–0.9 mg vs chlormethiazole 1000–3000 mg

Alcohol withdrawal to an asymptomatic stage or symptomatic/physical deterioration requiring study withdrawal

50% of pts. in the clonidine group were withdrawn from the trial due to clinical deterioration vs none in the chlormethiazole group (p = 0.002)

Adinoff (1994)²¹

R, DB, PC, PG 4 days

25/25

Repeated doses of clonidine 0.1 mg, alprazolam 1 mg, diazepam 10 mg, or placebo

Number of doses required to achieve a CIWA-Ar score of ≤5

Fewer doses of alprazolam were required to achieve CIWA-Ar ≤5 vs clonidine (p < 0.04) and placebo (p < 0.03); clonidine did not separate from placebo (p value not reported)

Spies (1996)²³

R, RB, PG Unspecified duration, up to 17 days

180/159

Flunitrazepam/clonidine, chlormethiazole/haloperidol, or flunitrazepam/haloperidol (iv bolus followed by continuous iv infusion at varying doses to achieve a CIWA-Ar score <10)

Duration of controlled or assisted mechanical ventilation and frequency of major complications

Longer duration of mechanical ventilation with chlormethiazole/haloperidol (p = 0.03), cardiac complications more frequent with with flunitrazepam/clonidine (p = 0.005), and pneumonia less frequent with flunitrazepam/clonidine (p = 0.04) vs other drugs

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Role of α2-agonists in the Treatment of Acute Alcohol Withdrawal

Abstract and Introduction

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