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 case reports described in this review article demonstrate the benefit that patients have derived from the adjunctive use of dexmedetomidine to their current treatment regimen for alcohol withdrawal. Dexmedetomidine successfully controlled psychomimetic and sympathetic symptoms of withdrawal, an effect that was seen almost immediately following initiation of this medication. This immediate benefit with dexmedetomidine is expected due to its rapid onset of action (~15 minutes).[43]

Dexmedetomidine produced a "cooperative sedation" in which patients remained calm but were easily roused and cooperative with commands. This cooperative sedation allowed clinicians to adequately sedate a patient without having to stop the infusion in order to perform routine patient assessments. Given its receptor profile, dexmedetomidine does not increase the risk for respiratory compromise when combined with benzodiazepines. Additionally, the use of dexmedetomidine may allow for a reduction in benzodiazepine doses, as well as reduce the need for other adjunctive medications, such as anticonvulsants and antipsychotics; these findings were seen in the case reports by Rovasalo et al.[26] and Darrouj et al.[27]

Despite the beneficial effects seen in these case reports, a number of issues with dexmedetomidine still remain unresolved, including loading dose utility, maximum dosage, and duration of therapy greater than 24 hours.

The FDA-approved labeling recommends a loading dose of 1 μg/kg over 10 minutes followed by a continuous infusion of 0.2 μg/kg to 0.7 μg/kg for no longer than 24 hours.[43] These parameters were derived from 2 initial studies with dexmedetomidine, but recent clinical trials veered from this dosing regimen without loss of benefit or adverse effects.[47] The case reports mentioned in this review were also unconventional in the dosing of dexmedetomidine and provide examples of how this medication may be effectively and safely used in this specific patient population, in which no clinical trials currently exist to guide therapy.

Recent literature has also questioned the benefit of initiating dexmedetomidine therapy with a loading dose as well as the precise dose needed to effectively and safely load a patient given the concerns for hypertension and the debatable incremental benefit of immediate symptom control.[48] While the case reports do not discuss this issue, 2 patients were loaded with bolus doses: 1 patient received 0.5 μg/kg, while the other received 1 μg/kg. Both of the patients received symptom benefit following the loading dose and neither experienced any adverse effects.

The maximum dosage restriction for dexmedetomidine remains a subject of deliberation when compared to the conventional infusion dose range, from 0.2 μg/kg/h to 0.7 μg/kg/h.[48] The case reports described here effectively implemented this standard regimen for withdrawal management. In contrast, 3 other studies have revealed that dosages up to 1.5 μg/kg/h did not confer excessive sedation as assessed by the targeted Richmond Agitation Sedation Scale score.[48]

Finally, additional research has challenged the current labeling on duration of therapy, which limits use of dexmedetomidine to 24 hours.[48] Although rebound hypertension or tachycardia has been reported with sudden clonidine discontinuation, comparable effects have not been seen with dexmedetomidine, despite the pharmacologic similarity. Both the MENDS and SEDCOM trials reported that prolonged use of dexmedetomidine was not significantly associated with a greater incidence of adverse effects.[39,40]

In reflection of its structural association to clonidine, dexmedetomidine's adverse effect profile comprises mainly cardiovascular adverse effects, including changes in blood pressure and heart rate.[49] Following the initial loading dose, bradycardia and hypertension are commonly experienced due to dexmedetomidine's effect on peripheral α2b-receptors in vascular smooth muscle and are the main reason a loading dose is used less commonly.[43,49] Clinical trials have also documented that the continued use of dexmedetomidine increases the risk for hypotension, but no patients in the case reports with dexmedetomidine experienced this adverse effect, despite treatment with dexmedetomidine for over 24 hours. All 3 patients had reductions in blood pressure and heart rate, but not to unacceptable levels, according to the authors. This may represent a benefit of dexmedetomidine for a patient population whose blood pressure and heart rates are often dangerously elevated during alcohol withdrawal.

The adverse effect profile of dexmedetomidine compares well with that of other intravenous sedatives used in these patients: drug accumulation resulting in difficult awakenings with midazolam; narrow therapeutic index and respiratory depression with intravenous barbiturates; propylene glycol toxicity and metabolic acidosis with lorazepam infusions; and hypertriglyceridemia, pancreatitis, and propofol infusion syndrome with propofol.[49,50] In the above-cited clinical trials and case reports, dexmedetomidine has been used without additive toxicity in combination with a variety of different medications, including benzodiazepines, propofol, fentanyl, and morphine.

The total costs associated with dexmedetomidine use in alcohol withdrawal treatment are difficult to calculate. However, a cost-minimization analysis of dexmedetomidine used for ICU sedation may provide some insight into cost savings with this agent versus other ICU sedatives.[48] Dexmedetomidine was reported to have a median per-patient adjusted total ICU cost savings of $9679 compared with midazolam. Driving these savings were a reduction in costs associated with mechanical ventilation and length of ICU stay. Lastly, this difference in cost savings occurred despite dexmedetomidine having a higher acquisition cost compared to midazolam.


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