Drug, Alcohol, and Substance Abuse
Role of α2-Agonists in the Treatment of Acute Alcohol Withdrawal
Andrew J Muzyk, Jill A Fowler, Daryn K Norwood, and Allison Chilipko
lcohol dependence represents approx-
A imately 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, hallucina-
tions, and agitation.2 While 86% of pa-
tients with withdrawal will experience
common signs and symptoms including
agitation, tremor, hypertension, and tachy-
cardia, approximately 5% of these patients
may develop more severe symptoms con-
sistent 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 mani-
festations.4-6 The majority of literature on
α2-agonists evaluates the 2 older agents,
lofexidine7-13 and clonidine.14-24 Howev-
er, recent case reports on dexmedeto-
midine, a newer α2-agonist, have gener-
ated interest in this drug class for alcohol
withdrawal management.25-28
Author information provided at end of text.
theannals.com
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.
KEY WORDS: α2-agonist, alcohol withdrawal, clonidine, delirium tremens,
dexmedetomidine, norepinephrine, sympathetic overdrive.
Ann Pharmacother 2011;45:649-57.
Published Online, 26 Apr 2011, theannals.com, DOI 10.1345/aph.1P575
The Annals of Pharmacotherapy n 2011 May, Volume 45 n 649
AJ Muzyk et al.
The purpose of this article is to review the evidence for
α2-agonists in alcohol withdrawal and to examine their
place in therapy.
Data Sources
We performed an extensive English-language MED-
LINE search (1966 to December 2010) to identify articles
evaluating the efficacy and safety of α2-agonists for alco-
hol withdrawal. Search terms included alcohol withdrawal,
delirium tremens, clonidine, dexmedetomidine, α2-agonist,
norepinephrine, noradrenergic, and sympathetic overdrive.
Case reports and clinical studies were evaluated for topic
relevance and clinical applicability. Literature on the use of
lofexidine in alcohol withdrawal was excluded from this
review, as it is not available in the US.
Norepinephrine
Manifestations of alcohol withdrawal include increased
anxiety, agitation, tachycardia, elevated blood pressure,
and insomnia.29,30 These symptoms may evolve into
seizures due to prolonged neurotransmitter imbalance pre-
cipitated by increased neurotoxins. Drug therapy is target-
ed to correct the imbalance between γ-aminobutyric acid
(GABA) and glutamate receptors.29 While the use of ben-
zodiazepines has been well documented in the treatment of
alcohol withdrawal, adjunctive use of drug therapy target-
ing other neurotransmitters remains to be established.29-36
Further understanding of alcohol withdrawal requires
examination of the kindling process and neurochemical
adaptation. Large consumption of alcohol over short peri-
ods can be problematic, as the process is often followed by
abrupt periods of alcohol cessation. Each period of cessa-
tion is associated with an intense excitatory process in the
central nervous system called kindling.30-33 The kindling
hypothesis states that withdrawal symptoms gradually be-
come more severe with repeated occurrences of alcohol
withdrawal due to altered transmission of various neuro-
transmitters, including GABA, glutamate, and norepineph-
rine. Ultimately, these gradual and continual physiological
changes alter the transmission of these neurotransmitters,
increasing the risk for seizures and DTs.30,37 Targeting these
neurotransmitters may ameliorate symptoms associated
with alcohol withdrawal and has the potential to minimize
some of the resulting neurotoxic effects observed in alco-
hol withdrawal.30
While GABA is the primary target of benzodiazepines,
the noradrenergic system is another pathway shown to play
an important role in the alcohol withdrawal syndrome.29,36
Animal models revealed a decrease in brain epinephrine
concentrations during alcohol consumption, which is sus-
pected to be associated with the reward process. Further-
more, these animal studies have illustrated an endocrine
650 n The Annals of Pharmacotherapy n 2011 May, Volume 45
pathway by discovering a depletion of epinephrine in the
hypothalamus during alcohol consumption. However,
when alcohol was removed, epinephrine concentrations
were shown to increase beyond pre-alcohol exposure lev-
els.35,37 This neurochemical imbalance of elevated noradre-
nergic activity in alcohol withdrawal was later validated in
humans.38
Similar to the animal models, specific areas of the brain
were assessed for noradrenergic activity in humans. The
locus coeruleus portion of the brain contains the cells for
brain noradrenergic activity. The sedative effects of alcohol
are potentially explained by a decrease in noradrenergic ac-
tivity noted in the locus coeruleus during alcohol consump-
tion. Alcohol consumption also has an effect on norepi-
nephrine turnover in the brain; low levels of consumption
result in increased turnover, while higher levels result in
decreased turnover.31,33
One of the primary receptors for noradrenergic trans-
mission is the α2-receptor. Under normal circumstances the
α2-receptor inhibits the firing of the presynaptic norepi-
nephrine neuron. However, evidence suggests that during
alcohol withdrawal, signaling at the α2-receptor may be
less sensitive, resulting in an inability of the noradrenergic
system to regulate its firing.31,33 Therefore, a potent α2-ago-
nist, such as clonidine, is capable of reversing abnormal
neuronal firing and elevated norepinephrine levels.31,33
Thus, α2-agonists may provide benefit in managing alco-
hol withdrawal, as these agents offer an additional mecha-
nism for minimizing the kindling process.
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 rec-
ognized 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, cloni-
dine still has not become a first-line treatment option for al-
cohol withdrawal.
CLINICAL STUDIES
The earliest studies of clonidine in the treatment of alco-
hol 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 in-
cluded 60 male alcoholic inpatients.14 Self-rated and nurse
observer–rated symptoms of alcohol withdrawal were sig-
nificantly reduced with clonidine as compared to placebo
on day 2 of treatment (p < 0.025 and p < 0.01, respective-
theannals.com

ly), with no hypotension. Unfortunately, the only finding
that can be inferred from this study is the benefit of cloni-
dine as an adjunctive therapy; all patients received diphen-
hydramine 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 al-
coholic 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 clini-
cian ratings of alcohol withdrawal symptoms on the Com-
prehensive Psychopathological Rating Scale. The applica-
bility of this study’s findings is further limited due to pa-
tients on clonidine having a significantly higher daily
alcohol intake prior to admission and the allowance of
low-dose benzodiazepine administration at night for all pa-
tients. There was 1 report of hypotension and 1 report of
dizziness in the clonidine group.
More recent studies provide a clearer picture of cloni-
dine’s role in the treatment of acute alcohol withdrawal by
comparing this agent to other standards of treatment. Man-
hem 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 medica-
tion has been widely used in Europe for management of al-
cohol withdrawal. In data reported for 17 patients who
completed the study, treatment with clonidine was shown
to significantly lower blood pressure and pulse as com-
pared 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 withdraw-
al in male patients with alcohol dependence.18,19 Their first
study compared tapered doses of clonidine 0.2-0.6 mg dai-
ly 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
theannals.com The Annals of Pharmacotherapy
α2-Agonists in Acute Alcohol Withdrawal
heart rate (p < 0.001) were significantly lower with cloni-
dine compared to chlordiazepoxide although no significant
differences in respiratory rate, diaphoresis, restlessness, or
tremor, or subjective reports of alcohol withdrawal symp-
toms, 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 Pa-
tients randomized to clonidine received a 0.2-mg oral load-
ing dose plus application of two 0.2 mg/24-hour transder-
mal patches at bedtime on day 1. One patch was removed
on day 3 and the other on day 4. In data reported for 43 pa-
tients who completed the study, there was no significant
difference in patient-reported subjective symptoms of alco-
hol withdrawal. Mean systolic and diastolic blood pressure
and pulse were significantly lower for patients in the cloni-
dine group (p < 0.001 for all). Mean scores on the Hamil-
ton 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 withdraw-
al. Robinson et al. randomized 32 alcohol inpatients to cloni-
dine 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 chlormethia-
zole. Patients in the clonidine group withdrew due either to
adverse effects, with 3 patients developing symptomatic or-
thostatic hypotension, or lack of efficacy, with 2 patients ex-
periencing 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 experi-
enced seizures or hallucinations had a history of severe alco-
hol 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 reflec-
tion 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 Cloni-
dine 0.1 mg, alprazolam 1 mg, diazepam 10 mg, or place-
bo was given orally every hour until alcohol withdrawal
symptom ratings on the revised Clinical Institute With-
drawal 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 effec-
n 2011 May, Volume 45 n 651
AJ Muzyk et al.
tive than placebo in the management of alcohol withdraw-
al. Alprazolam, but not diazepam, was superior to cloni-
dine based on number of doses required to control alcohol
withdrawal symptoms (p < 0.04). The authors did not re-
port the occurrence of any seizures during the study.
Lastly, cases of successful use of an intravenous cloni-
dine 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 fluni-
trazepam combined with clonidine, chlormethiazole com-
bined 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 in-
travenous 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 hallucina-
tions. Cardiac complications, including bradycardia, first-de-
gree 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 me-
chanical ventilation (p = 0.04). Lower median benzodi-
azepine doses were required when flunitrazepam was com-
bined with clonidine than when flunitrazepam was combined
with haloperidol (171 mg vs 284 mg, respectively). The au-
thors concluded that a benzodiazepine combined with cloni-
dine 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 with-
drawal.
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 pa-
tients 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 eval-
uation 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
652 n The Annals of Pharmacotherapy n 2011 May, Volume 45
Dexmedetomidine
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 Addi-
tionally, the recent FDA approval of dexmedetomidine for
sedation without intubation now provides clinicians with an
additional medication to treat patients with alcohol withdraw-
al who require ICU placement. These patients represent 9-
39% of ICU admissions who would otherwise receive seda-
tives requiring intubation, such as intravenous benzodi-
azepines, intravenous barbiturates, and propofol.42
Dexmedetomidine is the S-enantiomer of medetomi-
dine, a sedative and analgesic for veterinary use, and has
structural similarity to clonidine.43 However, dexmedeto-
midine is 8 times more selective for the α2-receptor than
clonidine. Dexmedetomidine produces sedation, anxioly-
sis, and sympatholysis through agonism of central presy-
naptic α2-autoreceptors with no activity at GABA or opi-
oid receptors, conferring sedation without respiratory com-
promise.
ANIMAL STUDIES
Results from animal studies with dexmedetomidine re-
ported an amelioration of symptoms of sympathetic over-
drive as well as neuroprotection from excessive cate-
cholamine 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 supe-
rior cervical sympathetic ganglion.44 A study comparing
dexmedetomidine to placebo, diazepam, and propranolol
showed significant reduction in tremor, rigidity, and irri-
tability within the first 12 hours of ethanol cessation.45 Dur-
ing the entire treatment period, both dexmedetomidine and
diazepam produced significant reductions in withdrawal
symptoms. Interestingly, dexmedetomidine was superior to
propranolol in reducing withdrawal symptoms, strengthen-
ing the theory that dexmedetomidine may have a benefit in
alcohol withdrawal outside of just decreasing elevated nor-
adrenergic 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 dexmedetomi-
dine described a 49-year-old woman admitted to the ICU
theannals.com

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
α2-Agonists in Acute Alcohol Withdrawal
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.

Table 1. Summary of Prospective, Randomized Clinical Trials of Clonidine for Treatment of Alcohol Withdrawal
Patients
Randomized
Study (N)/Patients
Design/ Included in Primary Efficacy
Reference Duration Analyses (n) Treatment Arms Measures Results

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

BP = blood pressure; CIWA-Ar = revised Clinical Institute Withdrawal Assessment for Alcohol scale; DB = double-blind; OL = open-label; PC = place-
bo-controlled; PG = parallel group; R = randomized; RB = rater-blinded.

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AJ Muzyk et al.
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 inter-
mittent 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 al-
cohol withdrawal that is unmitigated by benzodiazepines.
These cases described patients who had alcohol withdraw-
al 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 convul-
sions who was admitted for seizures with brief loss of con-
sciousness 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 ini-
tiation 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 dis-
continued without incident.
Darrouj et al. described a 30-year-old male admitted
due to altered mental status and agitation secondary to al-
cohol 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 disorient-
ed and developed tachycardia (heart rate 180 beats/min),
warranting ICU admission. After bolus doses of lorazepam
and midazolam were administered, a midazolam continu-
ous infusion was initiated, without significant improve-
ment. Dexmedetomidine was initiated at a dose of 0.2-0.7
µg/kg/h, and significant improvement was noticed imme-
diately, allowing midazolam to be tapered and eventually
discontinued. Follow-up vital sign data were not collected
at the time of α2-agonist commencement. Dexmedetomi-
dine 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 laparo-
scopic surgical procedures.28 Unfortunately, the author did
not report on blood alcohol levels or alcohol withdrawal
654 n The Annals of Pharmacotherapy n 2011 May, Volume 45
symptoms and did not provide a detailed description of the
use of dexmedetomidine.
Discussion
The case reports described in this review article demon-
strate the benefit that patients have derived from the ad-
junctive use of dexmedetomidine to their current treatment
regimen for alcohol withdrawal. Dexmedetomidine suc-
cessfully 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 al-
lowed clinicians to adequately sedate a patient without hav-
ing 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 benzodi-
azepine doses, as well as reduce the need for other adjunc-
tive 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 un-
resolved, 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 re-
view were also unconventional in the dosing of
dexmedetomidine and provide examples of how this med-
ication may be effectively and safely used in this specific
patient population, in which no clinical trials currently ex-
ist to guide therapy.
Recent literature has also questioned the benefit of initi-
ating 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 con-
trol.48 While the case reports do not discuss this issue, 2 pa-
tients were loaded with bolus doses: 1 patient received 0.5
µg/kg, while the other received 1 µg/kg. Both of the pa-
tients received symptom benefit following the loading dose
and neither experienced any adverse effects.
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The maximum dosage restriction for dexmedetomidine
remains a subject of deliberation when compared to the con-
ventional infusion dose range, from 0.2 µg/kg/h to 0.7
µg/kg/h.48 The case reports described here effectively imple-
mented 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 dex-
medetomidine to 24 hours.48 Although rebound hypertension
or tachycardia has been reported with sudden clonidine dis-
continuation, comparable effects have not been seen with
dexmedetomidine, despite the pharmacologic similarity.
Both the MENDS and SEDCOM trials reported that pro-
longed use of dexmedetomidine was not significantly asso-
ciated with a greater incidence of adverse effects.39,40
In reflection of its structural association to clonidine,
dexmedetomidine’s adverse effect profile comprises main-
ly cardiovascular adverse effects, including changes in
blood pressure and heart rate.49 Following the initial load-
ing dose, bradycardia and hypertension are commonly ex-
perienced 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 ex-
perienced this adverse effect, despite treatment with
dexmedetomidine for over 24 hours. All 3 patients had re-
ductions in blood pressure and heart rate, but not to unac-
ceptable levels, according to the authors. This may repre-
sent 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 com-
pares 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 lo-
razepam infusions; and hypertriglyceridemia, pancreatitis,
and propofol infusion syndrome with propofol.49,50 In the
above-cited clinical trials and case reports, dexmedetomi-
dine has been used without additive toxicity in combina-
tion with a variety of different medications, including ben-
zodiazepines, 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 dexmedetomi-
dine 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-pa-
tient adjusted total ICU cost savings of $9679 compared
theannals.com The Annals of Pharmacotherapy
α2-Agonists in Acute Alcohol Withdrawal
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.
Summary
To our knowledge, this is the first comprehensive review
to examine the role of α2-agonists, including dexmedetomi-
dine, in the treatment of alcohol withdrawal. The influence of
noradrenergic neurotransmission in alcohol withdrawal has
been established; however, the benefits of solely targeting this
neurotransmitter or neuronal pathway are limited. Clinical tri-
als with clonidine and case reports with dexmedetomidine
have reported benefit with this drug class in ameliorating the
symptoms of sympathetic overdrive that are part of the alco-
hol withdrawal symptom constellation. Although α2-agonists
provide an additional pharmacologic agent in the clinician’s
armamentarium, they offer no benefit in the prevention or
treatment of alcohol withdrawal seizures or delirium tremens.
Therefore, we believe that the only role for α2-agonists is as
adjunctive medication to benzodiazepines.
Positive findings from case reports on use of dexmede-
tomidine, coupled with its ease of use, safety profile, and
lack of intubation requirements, make this medication a
valuable choice for alcohol withdrawal in the ICU. Lastly,
because dexmedetomidine offers advantages over medica-
tions currently used in the ICU, further study is merited to
fully elicit its place in the alcohol withdrawal treatment al-
gorithm.
Andrew J Muzyk PharmD, Assistant Professor, Campbell Univer-
sity School of Pharmacy and Health Sciences, Durham, NC
Jill A Fowler PharmD, Clinical Pharmacy Specialist, Psychiatry,
University of Iowa Hospitals and Clinics, Iowa City, IA; Assistant Pro-
fessor (Clinical), College of Pharmacy, University of Iowa
Daryn K Norwood PharmD, Clinical Specialist, Internal Medicine,
Department of Pharmacy, Union Memorial Hospital, Baltimore, MD
Allison Chilipko PharmD, PGY-2 Pharmacy Resident in Internal
Medicine, Department of Pharmacy, Union Memorial Hospital
Correspondence: Dr. Muzyk, Andrew.Muzyk@duke.edu
Reprints/Online Access: www.theannals.com/cgi/reprint/aph.1P575
Conflict of interest: Authors reported none
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El Papel de los Agonistas α2 en el Tratamiento de la Abstinencia
Aguda de Alcohol
AJ Muzyk, JA Fowler, DK Norwood, y A Chilipko
Ann Pharmacother 2011;45:649-57.
EXTRACTO
OBJETIVO: Evaluar la literatura disponible sobre el papel de la
norepinefrina en el desarrollo de la abstinencia de alcohol y determinar
la seguridad y eficacia de los agonistas α2 en la mejora de los síntomas
de este severo problema.
FUENTES DE DATOS: Se identificaron los artículos que evaluaban la
eficacia y seguridad de los agonistas α2 –clonidina, dexmedetomidina,
publicados en inglés, mediante una búsqueda en MEDLINE desde 1966
hasta diciembre de 2010. Las palabras clave incluyeron: alcohol
withdrawal, delirium tremens, clonidine, dexmedetomidine, α2 agonist,
norepinephrine, y sympathetic overdrive.
SELECCIÓN DE ESTUDIOS Y EXTRACCIÓN DE DATOS: Se seleccionaron los
estudios enfocados a la seguridad y eficacia de los agonistas
α2–clonidina, dexmedetomidina tanto en animales como en humanos.
SÍNTESIS DE DATOS: El sistema noradrenérgico, específicamente la
hiperactividad simpática durante la retirada del alcohol, puede jugar un
importante papel en el desarrollo del síndrome de abstinencia. Los
síntomas de hiperactividad simpática incluyen ansiedad, agitación,
presión arterial elevada, taquicardia y temblor. Por tanto, los agonistas α2
pueden tener un papel adyuvante en disminuir la liberación de
norepinefrina y en consecuencia reducir las manifestaciones del
síndrome. La mayoría de los estudios controlados, tanto en animales
como en humanos, se han realizado con clonidina, pero la literatura más
recientes son comunicaciones de casos con dexmedetomidina. La
literatura con estos 2 agonistas α2 demuestran que estos medicamentos
reducen segura y efectivamente los síntomas de la hiperactividad
simpática y el uso de medicación concomitante.
CONCLUSIONES: La clonidina y la dexmedetomidina pueden aportar un
beneficio adicional en el manejo de la abstinencia de alcohol ofreciendo
un mecanismo de acción diferente frente al síndrome de abstinencia.
Basándose en la literatura revisada, el principal papel de la clonidina y la
dexmedetomidina es el de terapia coadyuvante del tratamiento estándar
de la abstinencia de alcohol, las benzodiazepinas. Dado que la
dexmedetomidina ofrece ventajas con respecto a los medicamentos
utilizados actualmente en las unidades de cuidados intensivos (ICU) para
la tratar la abstinencia de alcohol, merece la pena realizar más estudios
para determinar claramente su papel en este entorno.
Traducido por Juan del Arco
theannals.com The Annals of Pharmacotherapy
α2-Agonists in Acute Alcohol Withdrawal
Le Rôle des Agonistes α-Adrénergiques dans le Traitement du
Sevrage Alcoolique
AJ Muzyk, JA Fowler, DK Norwood, et A Chilipko
Ann Pharmacother 2011;45:649-57.
RÉSUMÉ
OBJECTIF: Revoir le rôle de la norépinéphrine dans le développement du
sevrage alcoolique et déterminer l’innocuité et l’efficacité des agonistes
des récepteurs adrénergiques α2 dans le traitement de ce syndrome.
SOURCES D’INFORMATION: Une recherche a été effectuée dans la banque
de données MEDLINE (de 1966 au mois de décembre 2010) en utilisant
les mots-clés suivants: clonidine, dexmédétomidine, sevrage alcoolique,
délirium tremens, agoniste α-adrénergique, norépinéphrine,
hyperactivité sympathique.
SÉLECTION DE L’INFORMATION: Toutes les études animales et les essais
cliniques publiés en langue anglaise et ayant évalué l’innocuité et
l’efficacité des agonistes α-adrénergiques (clonidine et
dexmédétomidine) ont été considérés pour cette revue.
RÉSUMÉ: Le système noradrénergique, et plus particulièrement
l’hyperactivité sympathique observée durant le sevrage alcoolique,
semble jouer un rôle prépondérant lors du développement des
symptômes de sevrage. Ces symptômes incluent de l’anxiété, de
l’agitation, une élévation de la pression artérielle, des épisodes de
tachycardie et des tremblements. Les agonistes des récepteurs
adrénergiques α2 peuvent jouer un rôle d’appoint afin de diminuer la
libération de la norépinéphrine et par conséquent, l’apparition des
symptômes. La majorité des études animales et des essais cliniques
disponibles ont évalué la clonidine bien que certains rapports de cas
faisant état de l’utilisation de la dexmédétomidine ont récemment été
publiés. Les littérature suggèrent que ces 2 agents peuvent diminuer de
façon efficace les symptômes de l’hyperactivité sympathique et
l’utilisation de médicaments pour contrôler ces symptômes.
CONCLUSIONS: Les effets bénéfiques de la clonidine et de la
dexmédétomidine peuvent être mis à profit lors de la prise en charge du
syndrome de sevrage alcoolique. Ces agents semblent représenter une
thérapie d’appoint efficace aux benzodiazépines qui demeurent la pierre
angulaire de traitement. L’administration de la dexmédétomidine par la
voie parentérale peut offrir plusieurs avantages dans un contexte
d’utilisation aux soins intensifs. Des essais cliniques additionnels sont
toutefois nécessaires avant de mieux préciser le rôle d’appoint des
agonistes adrénergiques α2 dans le traitement du sevrage alcoolique.
Traduit par Sylvie Robert
n 2011 May, Volume 45 n 657