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


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

In This Article


The positive results from dexmedetomidine clinical trials on measures of sedation, analgesia, delirium, intubation days, concomitant medications, and ICU length of stay provide a groundwork for a growing body of literature demonstrating benefit of dexmedetomidine in alcohol withdrawal.[39–41] Additionally, the recent FDA approval of dexmedetomidine for sedation without intubation now provides clinicians with an additional medication to treat patients with alcohol withdrawal who require ICU placement. These patients represent 9–39% of ICU admissions who would otherwise receive sedatives requiring intubation, such as intravenous benzodiazepines, intravenous barbiturates, and propofol.[42]

Dexmedetomidine is the S-enantiomer of medetomidine, a sedative and analgesic for veterinary use, and has structural similarity to clonidine.[43] However, dexmedetomidine is 8 times more selective for the α2-receptor than clonidine. Dexmedetomidine produces sedation, anxiolysis, and sympatholysis through agonism of central presynaptic α2-autoreceptors with no activity at GABA or opioid receptors, conferring sedation without respiratory compromise.

Animal Studies

Results from animal studies with dexmedetomidine reported an amelioration of symptoms of sympathetic overdrive as well as neuroprotection from excessive catecholamine release.[44–46] Initial studies in rats demonstrated a significant decrease in tremor, rigidity, and irritability through reduction of morphofunctional alterations and 3-methoxy-4-hydroxyphenethyleneglycol levels in the superior cervical sympathetic ganglion.[44] A study comparing dexmedetomidine to placebo, diazepam, and propranolol showed significant reduction in tremor, rigidity, and irritability within the first 12 hours of ethanol cessation.[45] During the entire treatment period, both dexmedetomidine and diazepam produced significant reductions in withdrawal symptoms. Interestingly, dexmedetomidine was superior to propranolol in reducing withdrawal symptoms, strengthening the theory that dexmedetomidine may have a benefit in alcohol withdrawal outside of just decreasing elevated noradrenergic tone.

Case Reports

There are 4 case reports suggesting clinical efficacy with dexmedetomidine in patients admitted for acute alcohol withdrawal uncontrolled by benzodiazepines. These case reports demonstrate control of agitation within hours of dexmedetomidine initiation.

The first case report on this novel use of dexmedetomidine described a 49-year-old woman admitted to the ICU with uncontrolled agitation, hypertension, and tachycardia secondary to presumed cocaine and alcohol withdrawal.[25] Dexmedetomidine was initially administered as a loading dose of 1 μg/kg infused over 20 minutes. The dosage was then titrated to a maintenance dose ranging from 0.2 to 0.7 μg/kg/h to maintain a Motor Activity Assessment Scale score of 3 (ie, calm and cooperative without need for an external stimulus to induce movement). Following the loading dose, the patient's acute agitation resolved and she remained compliant with care throughout her hospital stay. Over the 3-day treatment course, her blood pressure ranged from 110/60 to 130/70 mm Hg, with a heart rate from 80 to 100 beats/min. The patient also received intermittent lorazepam doses of 1–2 mg for seizure prophylaxis.

Two more recent case reports by Rovasalo et al.[26] and Darrouj et al.[27] provide a detailed description for using dexmedetomidine in patients experiencing complicated alcohol withdrawal that is unmitigated by benzodiazepines. These cases described patients who had alcohol withdrawal with severe agitation and tachycardia uncontrolled by a combination of medications, including benzodiazepines, who gained immediate symptom relief with the addition of dexmedetomidine.

Rovasalo et al. described a 50-year-old male with past hospitalizations for withdrawal hallucinations and convulsions who was admitted for seizures with brief loss of consciousness and severe delirium after 3 days of abstinence.[26] On admission, his blood pressure was 117/89 mm Hg and heart rate was 130 beats/min. During the next 2 days, he received a cumulative dose of 360 mg of diazepam and 12.5 mg of haloperidol, without symptom resolution. Dexmedetomidine was given as a 0.5-μg/kg loading dose over 10 minutes, followed by a stepwise infusion taper: 0.175 μg/kg/h for 90 minutes, 0.1 μg/kg/h for 6 hours, and 0.05 μg/kg/h for 8 hours. Diazepam 15 mg/day and haloperidol 5 mg/day were continued. One hour after the initiation of dexmedetomidine the patient became calm; after 2 hours he was sleeping but arousable, with a blood pressure of 110/55 mm Hg and a heart rate of 55 beats/min. The next day his restraints were removed and the infusion was discontinued without incident.

Darrouj et al. described a 30-year-old male admitted due to altered mental status and agitation secondary to alcohol withdrawal.[27] His last alcohol drink was 24 hours prior to admission, and his serum ethanol level was less than 10 mg/dL. He had multiple previous admissions for alcohol withdrawal. Despite receiving oxazepam 30 mg twice daily, phenytoin, and thiamine, he became disoriented and developed tachycardia (heart rate 180 beats/min), warranting ICU admission. After bolus doses of lorazepam and midazolam were administered, a midazolam continuous infusion was initiated, without significant improvement. Dexmedetomidine was initiated at a dose of 0.2–0.7 μg/kg/h, and significant improvement was noticed immediately, allowing midazolam to be tapered and eventually discontinued. Follow-up vital sign data were not collected at the time of α2-agonist commencement. Dexmedetomidine was stopped after 39 hours, an oxazepam tapering regimen was initiated, and the patient was transferred out of ICU.

Two additional cases have been reported. Both patients had a history of alcohol abuse and were undergoing laparoscopic surgical procedures.[28] Unfortunately, the author did not report on blood alcohol levels or alcohol withdrawal symptoms and did not provide a detailed description of the use of dexmedetomidine.


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