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

Andrew J Muzyk PharmD; Jill A Fowler PharmD; Daryn K Norwood PharmD; Allison Chilipko PharmD

Disclosures

The Annals of Pharmacotherapy. 2011;45(5):649-657. 

In This Article

Clonidine

Clonidine, the oldest α2-agonist, was developed in the 1960s and received Food and Drug Administration (FDA) approval in 1974 for the treatment of hypertension. This remains its only FDA-approved indication; however, the potential utility of clonidine in alcohol withdrawal was recognized in the 1970s.[14] Since that time, a number of studies have evaluated clonidine's efficacy for controlling alcohol withdrawal symptoms. Despite decades of research, clonidine still has not become a first-line treatment option for alcohol withdrawal.

Clinical Studies

The earliest studies of clonidine in the treatment of alcohol withdrawal were limited by the use of concomitant medications. Bjorkqvist et al. evaluated the efficacy of a clonidine taper, 0.15 mg up to 3 times daily, in a 4-day, randomized, double-blind, placebo-controlled trial that included 60 male alcoholic inpatients.[14] Self-rated and nurse observer–rated symptoms of alcohol withdrawal were significantly reduced with clonidine as compared to placebo on day 2 of treatment (p < 0.025 and p < 0.01, respectively), with no hypotension. Unfortunately, the only finding that can be inferred from this study is the benefit of clonidine as an adjunctive therapy; all patients received diphenhydramine 25 mg and metaqualone 250 mg at night for sleep and half of the patients in each group received at least 1 dose of chlorpromazine 50 mg. Additionally, all patients with a history of seizures received diphenylhydantoin 150 mg twice daily.

In a 7-day, randomized, open-label study of 26 male alcoholic inpatients, Walinder et al. compared clonidine 4 μg/kg twice daily with the standard care, carbamazepine 200 mg 3–4 times daily combined with a neuroleptic agent, chlorprothixene or dixyrazine, dosed 3 times daily.[15] Results were reported for 19 of the 26 patients. The study showed no significant differences between groups in clinician ratings of alcohol withdrawal symptoms on the Comprehensive Psychopathological Rating Scale. The applicability of this study's findings is further limited due to patients on clonidine having a significantly higher daily alcohol intake prior to admission and the allowance of low-dose benzodiazepine administration at night for all patients. There was 1 report of hypotension and 1 report of dizziness in the clonidine group.

More recent studies provide a clearer picture of clonidine's role in the treatment of acute alcohol withdrawal by comparing this agent to other standards of treatment. Manhem et al. compared clonidine 0.15–0.3 mg every 6 hours to chlormethiazole 500–1000 mg every 6 hours over 4 days in 20 male alcoholic inpatients.[16] All patients received carbamazepine 200 mg twice daily. Chlormethiazole is a nonbenzodiazepine sedative/hypnotic that potentiates the effects of GABA at the GABAA receptor.[17] This medication has been widely used in Europe for management of alcohol withdrawal. In data reported for 17 patients who completed the study, treatment with clonidine was shown to significantly lower blood pressure and pulse as compared with chlormethiazole (p < 0.05 for both), although no significant difference was found between the groups on nurse observer–rated assessments of alcohol withdrawal symptoms. Plasma norepinephrine and epinephrine levels, assessed twice daily, were significantly lower in patients treated with clonidine starting on day 1 of treatment (p < 0.01). No specific adverse effects with clonidine, including seizures, were reported, although 1 patient in each group developed alcohol withdrawal delirium.

Two studies by Baumgartner et al. compared clonidine to chlordiazepoxide for management of alcohol withdrawal in male patients with alcohol dependence.[18,19] Their first study compared tapered doses of clonidine 0.2–0.6 mg daily to chlordiazepoxide 50–150 mg daily in 61 patients.[18] The only adjunctive medication allowed in this 4-day study was acetaminophen. Patients with a history of seizures were excluded. For the 47 patients who completed the study, mean systolic blood pressure (p < 0.02) and heart rate (p < 0.001) were significantly lower with clonidine compared to chlordiazepoxide although no significant differences in respiratory rate, diaphoresis, restlessness, or tremor, or subjective reports of alcohol withdrawal symptoms, were observed between treatments. In their second study, the authors evaluated the efficacy of transdermal clonidine compared to oral chlordiazepoxide 50–150 mg daily in 50 patients experiencing alcohol withdrawal.[19] Patients randomized to clonidine received a 0.2-mg oral loading dose plus application of two 0.2 mg/24-hour transdermal patches at bedtime on day 1. One patch was removed on day 3 and the other on day 4. In data reported for 43 patients who completed the study, there was no significant difference in patient-reported subjective symptoms of alcohol withdrawal. Mean systolic and diastolic blood pressure and pulse were significantly lower for patients in the clonidine group (p < 0.001 for all). Mean scores on the Hamilton Anxiety Rating Scale were also significantly lower for the clonidine group (p < 0.02). No patients in either study experienced clinically significant hypotension or alcohol withdrawal seizures. The results from both studies show that clonidine was as efficacious as chlordiazepoxide in the management of mild-to-moderate alcohol withdrawal, with advantages in controlling sympathetic symptoms.

Not all studies have found positive results when clonidine is compared to other medications for acute alcohol withdrawal. Robinson et al. randomized 32 alcohol inpatients to clonidine 0.3–0.9 mg or chlormethiazole 1000–3000 mg over 4 days.[20] Only 8 patients in the clonidine group completed the study compared to all 16 patients assigned to chlormethiazole. Patients in the clonidine group withdrew due either to adverse effects, with 3 patients developing symptomatic orthostatic hypotension, or lack of efficacy, with 2 patients experiencing seizures and 2 patients developing hallucinations. This was despite the fact that patients with major withdrawal symptoms or a history of alcohol withdrawal seizures were excluded from the trial. However, all 4 patients who experienced seizures or hallucinations had a history of severe alcohol withdrawal symptoms, indicating that clonidine alone may be ineffective for management of such patients. The higher incidence of orthostatic hypotension with clonidine in this study as compared to previous studies may be a reflection of the higher doses used.

In another study, Adinoff et al. compared loading doses of clonidine, alprazolam, diazepam, and placebo in 25 male alcoholic patients with no history of seizures.[21] Clonidine 0.1 mg, alprazolam 1 mg, diazepam 10 mg, or placebo was given orally every hour until alcohol withdrawal symptom ratings on the revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar) dropped to 5 or less. The number of clonidine doses required to control alcohol withdrawal symptoms was similar to that with placebo, indicating that clonidine was no more effective than placebo in the management of alcohol withdrawal. Alprazolam, but not diazepam, was superior to clonidine based on number of doses required to control alcohol withdrawal symptoms (p < 0.04). The authors did not report the occurrence of any seizures during the study.

Lastly, cases of successful use of an intravenous clonidine infusion for management of critically ill patients with acute alcohol withdrawal have been reported,[22] although this treatment strategy has not been evaluated in well-controlled clinical trials. Spies et al. investigated the utility of 3 different alcohol withdrawal therapy regimens including flunitrazepam combined with clonidine, chlormethiazole combined with haloperidol, or flunitrazepam combined with haloperidol in 159 trauma patients who developed alcohol withdrawal after admission to an intensive care unit (ICU).[23] Randomly assigned medications were administered as an intravenous bolus dose followed by a continuous intravenous infusion at varying doses to achieve a CIWA-Ar score <10. Four patients in the flunitrazepam/clonidine group were withdrawn from the study because of persistent hallucinations. Cardiac complications, including bradycardia, first-degree atrioventricular node block, and hypotension, were also significantly more frequent in the flunitrazepam/clonidine group (p = 0.005). Patients in this group were significantly less likely to develop pneumonia requiring prolonged mechanical ventilation (p = 0.04). Lower median benzodiazepine doses were required when flunitrazepam was combined with clonidine than when flunitrazepam was combined with haloperidol (171 mg vs 284 mg, respectively). The authors concluded that a benzodiazepine combined with clonidine may be advantageous in patients with pneumonia or those requiring mechanical ventilation.

Table 1 provides a summary of prospective, randomized clinical trials of clonidine for treatment of alcohol withdrawal.

Discussion

Data from randomized, double-blind studies support the efficacy of oral and transdermal clonidine in reducing symptoms of alcohol withdrawal related to sympathetic overdrive, particularly hypertension and tachycardia, in patients with mild-to-moderate alcohol withdrawal. However, the ability of clonidine monotherapy to prevent alcohol withdrawal seizures or alcohol withdrawal delirium has not been demonstrated. Additionally, the use of concomitant anticonvulsant medications or exclusion of patients with a seizure history in many studies further complicates the evaluation of clonidine's effect on severe adverse outcomes of alcohol withdrawal. There is minimal evidence to support the role of intravenous clonidine alone in the management of alcohol withdrawal for patients in critical care settings, and the higher doses needed to control severe symptoms may place patients at a greater risk for adverse effects.[24]

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