Dexmedetomidine infusion as adjunctive therapy to benzodiazepines for acute alcohol withdrawal.
ABSTRACT To report a case of alcohol withdrawal and delirium tremens successfully treated with adjunctive dexmedetomidine.
A 30-year-old man with a history of alcohol abuse was admitted to the general medical unit because of altered mental status and agitation. He was initially treated for alcohol withdrawal with benzodiazepines; his condition then deteriorated and he was transferred to the intensive care unit. Because of the patient's poor response to benzodiazepines (oxazepam and lorazepam, with midazolam the last one used), intravenous dexmedetomidine was started at an initial dose of 0.2 microg/kg/h and titrated to 0.7 microg/kg/h to the patient's comfort. Midazolam was subsequently tapered to discontinuation due to excessive sedation. In the intensive care unit, the patient's symptoms remained controlled with use of dexmedetomidine alone. He remained in the intensive care unit for 40 hours; dexmedetomidine was then tapered to discontinuation and the patient was transferred back to the general medical unit on oral oxazepam and thiamine, which had been started in the emergency department. He was discharged after 5 days.
A review of the PubMed database (1989-2007) failed to identify any other instances of dexmedetomidine having been used as the principal agent to treat alcohol withdrawal. The use of sedative to treat delirium tremens is well documented, with benzodiazepines being the agents of choice. The clinical utility of benzodiazepines is limited by their stimulation of the gamma-aminobutyric acid receptors, an effect not shared by dexmedetomidine, a central alpha(2)-receptor agonist that induces a state of cooperative sedation and does not suppress respiratory drive.
In patients with delirium tremens, dexmedetomidine should be considered as an option for primary treatment. This case illustrates the need for further studies to investigate other potential uses for dexmedetomidine.
- [Show abstract] [Hide abstract]
ABSTRACT: Adjunctive medications to manage alcohol withdrawal syndrome (AWS) in patients not adequately responding to escalating doses of benzodiazepines (BZDs) are limited. The use of the N-methyl-d-aspartate antagonist ketamine, may serve as an effective adjunct agent; however, no published data currently exist for this practice.Annals of Pharmacotherapy 10/2014; 49(3). · 2.92 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: This study evaluated the impact of dexmedetomidine (DEX) administration on benzodiazepine (BZD) requirements in intensive care unit (ICU) patients experiencing alcohol withdrawal syndrome (AWS).Journal of Intensive Care Medicine 10/2014;
- [Show abstract] [Hide abstract]
ABSTRACT: In severe alcohol withdrawal (AW), benzodiazepines may be inadequate to control symptoms. In many situations, benzodiazepine dosing escalates despite no additional efficacy and introduces potential toxicities. Severe cases of AW may require additional agents to control symptoms. Case reports and studies have shown benefits with dexmedetomidine and propofol in severe AW, but these agents have not been compared with one another. This study compares the effects of dexmedetomidine and propofol on benzodiazepine and haloperidol utilization in patients with AW.Clinical Pharmacology: Advances and Applications 01/2014; 6:171-7.
mains a common problem for the medi-
cal community. The extreme form of al-
cohol withdrawal is delirium tremens,
which historically has had mortality
rates greater than 30%; however, today,
with prompt diagnosis and refined med-
ical treatment, the mortality rate for
delirium tremens is approximately 5%.1
The primary pharmacologic agents used
to treat delirium tremens are benzodi-
azepines, but other drugs have been used.
We report a case of delirium tremens in
which intravenous dexmedetomidine was
used successfully as adjunctive treatment
for withdrawal symptoms; we also de-
scribe the pharmacologic basis for its
lcohol withdrawal, with its signifi-
cant morbidity and mortality, re-
A 30-year-old male with a history of
chronic alcohol abuse was admitted to
the general medical unit with a diagnosis
of altered mental status and agitation.
His last alcohol intake was approximately
24 hours before admission. His past
medical history was significant only for
an old basal ganglia stroke complicated
by seizures, in addition to multiple ad-
missions for alcohol withdrawal syndrome. His most re-
cent previous hospital admission was 4 months before the
current one. He received a 20-mg/kg loading dose of
phenytoin due to low serum concentrations on admission
and was subsequently given a dosage of 4 mg/kg daily as a
continuation of his previously established outpatient regi-
men. He was also started on oral oxazepam 30 mg twice
daily and intravenous thiamine 100 mg once daily. Labora-
tory tests performed in the emergency department showed
a negative urine drug screen and serum ethanol level less
than 10 mg/dL.
Dexmedetomidine Infusion as Adjunctive Therapy to
Benzodiazepines for Acute Alcohol Withdrawal
Jamil Darrouj, Nitin Puri, Erin Prince, Anthony Lomonaco, Antoinette Spevetz, and David R Gerber
Author information provided at the end of the text.
The Annals of Pharmacotherapy I
2008 November, Volume 42 I
OBJECTIVE: To report a case of alcohol withdrawal and delirium tremens
successfully treated with adjunctive dexmedetomidine.
CASE SUMMARY: A 30-year-old man with a history of alcohol abuse was admitted
to the general medical unit because of altered mental status and agitation. He
was initially treated for alcohol withdrawal with benzodiazepines; his condition
then deteriorated and he was transferred to the intensive care unit. Because of
the patient’s poor response to benzodiazepines (oxazepam and lorazepam, with
midazolam the last one used), intravenous dexmedetomidine was started at an
initial dose of 0.2 µg/kg/h and titrated to 0.7 µg/kg/h to the patient’s comfort.
Midazolam was subsequently tapered to discontinuation due to excessive
sedation. In the intensive care unit, the patient’s symptoms remained controlled
with use of dexmedetomidine alone. He remained in the intensive care unit for 40
hours; dexmedetomidine was then tapered to discontinuation and the patient was
transferred back to the general medical unit on oral oxazepam and thiamine,
which had been started in the emergency department. He was discharged after 5
DISCUSSION: A review of the PubMed database (1989–2007) failed to identify any
other instances of dexmedetomidine having been used as the principal agent to
treat alcohol withdrawal. The use of sedative to treat delirium tremens is well
documented, with benzodiazepines being the agents of choice. The clinical utility
of benzodiazepines is limited by their stimulation of the γ-aminobutyric acid
receptors, an effect not shared by dexmedetomidine, a central α2-receptor
agonist that induces a state of cooperative sedation and does not suppress
CONCLUSIONS: In patients with delirium tremens, dexmedetomidine should be
considered as an option for primary treatment. This case illustrates the need for
further studies to investigate other potential uses for dexmedetomidine.
KEY WORDS: alcohol withdrawal, delirium tremens, dexmedetomidine.
Ann Pharmacother 2008;42:1703-5.
Published Online, 9 Sept 2008, www.theannals.com, DOI 10.1345/aph.1K678
On hospital day 2, the patient became significantly agi-
tated, disoriented, and combative, with severe tremors and
tachycardia. Because of concerns regarding the develop-
ment of alcohol withdrawal and delirium tremens, he was
transferred to the intensive care unit (ICU) for monitoring
and possible intervention. An alcohol withdrawal score
was not calculated, as this is not routine practice in our in-
stitution. His vital signs upon transfer to the ICU were:
blood pressure 130/80 mmHg, heart rate 180 beats/min,
temperature 37.2˚C, respiratory rate 28 breaths/min, and ar-
terial oxygen saturation 100% on room air. In the ICU, he
was given a total of 10 mg of lorazepam intramuscularly pri-
or to the placement of an intravenous catheter; he subse-
quently received a total of 35 mg of midazolam as bolus
doses in addition to 0.16 mg/kg/h as an intravenous infusion
for approximately 3 hours. The patient demonstrated a mod-
est response to this regimen, but less severe tremors contin-
ued, along with episodes of severe agitation that would sub-
side spontaneously, followed by incoherent speech. He re-
mained able to protect his airway during that time.
Thirty-one hours after emergency department admis-
sion, intravenous dexmedetomidine 0.2 µg/kg/h was start-
ed and titrated to 0.7 µg/kg/h to patient comfort. A signifi-
cant improvement in tremor and confusion, with fewer and
less severe episodes of agitation, was noticed immediately
after dexmedetomidine was started. Midazolam was ta-
pered to 1 mg/h over the next 3 hours secondary to deep
sedation. Within 5 hours after the midazolam dosage was
decreased, the patient showed significant improvement in
mental status and became more appropriate in his behav-
ior. Midazolam was ultimately stopped, leaving dexmede-
tomidine 0.7 µg/kg/h as the only sedation. Dexmedetomi-
dine was titrated down slowly and was stopped 24 hours
later (total dexmedetomidine infusion time 39 hours; the
first 14 hours overlapped with the midazolam infusion).
The patient was started on a regular diet the following
morning and was transferred back to the general medical
floor on oral oxazepam and thiamine on ICU day 3. He
was discharged home on hospital day 5.
Dexmedetomidine, a selective central α2-receptor ago-
nist used for sedation in initially intubated and mechanical-
ly ventilated patients, is approved by the Food and Drug
Administration for use for no more than 24 hours. Unlike
benzodiazepines, which act on the γ-aminobutyric acid
(GABA) system and can cause respiratory depression,
dexmedetomidine does not inhibit respiratory drive or de-
press neurologic status, resulting in a state of cooperative
sedation. Alcohol is a central nervous system depressant,
and patients who are undergoing withdrawal have de-
pressed levels of GABA and elevated levels of epi-
nephrine, which may lead to a hyperadrenergic state and
induce hemodynamic lability.
Dexmedetomidine decreases the hyperarousal state
commonly associated with alcohol withdrawal through its
central α2-agonist activity and not by stimulating GABA
as benzodiazepines do, which can make patients more
prone to bouts of delirium. Healthy individuals treated
with dexmedetomidine at low concentrations have been
demonstrated to have decreased norepinephrine levels and
decreased heart rates.2
The initial therapeutic goal when treating a patient with
alcohol withdrawal syndrome focuses on control of agita-
tion. Long-acting benzodiazepines (eg, chlordiazepoxide,
diazepam, oxazepam, lorazepam) are the therapy of choice
for reduction of both mortality and duration of symptoms.
Long-acting benzodiazepines have also been shown in
controlled trials and meta-analyses to be associated with a
decrease in the incidence of seizures and fewer adverse re-
actions compared with both placebo and neuroleptic agents
such as haloperidol.3-5Reversal of common vitamin abnor-
malities, including treatment with thiamine prior to glu-
cose administration to prevent development of Wernicke
syndrome, as well as initiation of a multivitamin contain-
ing folic acid, is also part of the initial management of any
patient with alcohol dependency.
Other drug classes have been used in the management
of acute alcohol withdrawal with varying degrees of effica-
cy. Carbamazepine is used extensively in Europe as an al-
ternative to benzodiazepines for treatment of mild-to-mod-
erate alcohol withdrawal syndrome. Carbamazepine has a
lower potential for abuse and produces less sedation than
benzodiazepines do, but its use has been limited by lack of
sufficient evidence that it reduces seizure rates or prevents
delirium.2,6Propofol has also been discussed in several
case reports as adjuvant therapy for patients who have not
achieved adequate delirium control despite maximum ben-
zodiazepine therapy. It is hypothesized that this may be
due to propofol’s activation of a different set of receptors
than those activated by benzodiazepines and, therefore,
propofol may be useful when benzodiazepine receptors
have become saturated.2,7Centrally acting α2-agonist
agents such as clonidine have been shown to reduce auto-
nomic symptoms of alcohol withdrawal syndrome such as
tachycardia, hypertension, and tremors via reduction of
neurotransmitter release.4,6Clonidine also has been shown
to decrease the activity of the sympathetic nervous system
response in alcohol withdrawal syndrome and may be use-
ful in decreasing the dosage of sedative–hypnotics that
need to be given to achieve symptom control.8Clonidine,
however, has not been shown to reduce the incidence of
seizures or delirium and thus is indicated for use only in
conjunction with a sedative–hypnotic agent.9β-Adrenergic
antagonists have been used in the treatment of alcohol
withdrawal syndrome in conjunction with benzodiazepines
for control of persistent signs of adrenergic hyperactivity
such as tachycardia and hypertension.2No evidence indi-
The Annals of Pharmacotherapy I
2008 November, Volume 42
J Darrouj et al.
cates that these medications have any positive effect on
seizure activity or delirium.10,11Neuroleptics (eg, haloperi-
dol, phenothiazines) can be used in conjunction with seda-
tive–hypnotics to improve control of agitation, but they have
been associated with prolonged duration of delirium and in-
creased complication rates when used as monotherapy.2,12
Several studies performed in rats have demonstrated the
efficacy of dexmedetomidine in the treatment of alcohol
withdrawal. Riihioja et al.10demonstrated a decrease in with-
drawal symptoms (ie, rigidity, tremor, irritability) in rats treat-
ed with subcutaneous injections of dexmedetomidine.10This
group subsequently compared dexmedetomidine with diaze-
pam and propranolol in the treatment of alcohol withdrawal
and demonstrated that both dexmedetomidine and diazepam
were effective at controlling a wide range of symptoms, but
propranolol was effective only at reducing tremors.13These
investigators also demonstrated a diminution of alcohol-in-
duced neuronal loss in the locus ceruleus of rats treated for
alcohol withdrawal with dexmedetomidine.14
Despite its increasing use as a sedative in the critical
care setting, there are scant data on the use of dexmedeto-
midine in the management of acute alcohol withdrawal in
humans. Rovasalo et al.15reported on the successful use of
dexmedetomidine in a patient experiencing delirium
tremens in a psychiatric hospital.15In that case, dexmede-
tomidine was added to a standard regimen that included
haloperidol and diazepam. Baddigam et al.16reported on
the use of dexmedetomidine in treating withdrawal in 3
postoperative cardiothoracic surgical patients, but these pa-
tients differed significantly from our patient and from the
patient in the case reported by Rovasalo et al. The patients
reported by Baddigam et al. were a 17-year-old polysub-
stance abuser and 2 infants (1 aged 4 mo; 1 aged 55 days),
both of whom were thought to have become dependent on
sedation with narcotics and/or benzodiazepines as a conse-
quence of their postoperative management.16
Our patient represents only the second case of which we
are aware in which a patient has been treated with dexmed-
etomidine for acute delirium tremens. Although our patient
was initially treated with benzodiazepines, this regimen
was ultimately discontinued in favor of dexmedetomidine,
suggesting a possible role for this drug as monotherapy in
this situation. Whether dexmedetomidine served as true
monotherapy at any point or simply as adjunctive therapy
to more traditional benzodiazepine treatment remains spec-
To our knowledge, this is the only case report of a patient
treated successfully with dexmedetomidine for acute deliri-
um tremens. The patient demonstrated a significant decrease
in agitation, improvement of mental status, and return of ap-
propriateness of response after initiation of dexmedetomi-
dine therapy. While the use of dexmedetomidine in the treat-
ment of acute delirium tremens has not been extensively
studied thus far, the success in this case suggests that further
research on the topic may be warranted.
Jamil Darrouj MD, Fellow, Pulmonary and Critical Care Medicine
Division, Cooper University Hospital, Camden, NJ
Nitin Puri MD, Fellow, Critical Care Medicine, Cooper University
Erin Prince DO, Resident, Emergency Medicine Division, Cooper
Anthony Lomonaco DO, Resident, Anesthesiology Division, Coop-
er University Hospital
Antoinette Spevetz MD FCCM FACP, Associate Professor of
Medicine; Associate Director, Internal Medicine Residency Program,
Section of Critical Care Medicine, Cooper University Hospital
David R Gerber DO FCCP, Associate Professor of Medicine, Uni-
versity of Medicine and Dentistry of New Jersey, Robert Wood John-
son Medical School at Camden; Associate Director, Medical–Surgi-
cal Intensive Care Unit, Cooper University Hospital
Reprints: Dr. Darrouj, 7 MacArthur Blvd., Apt.# 408, Collingswood,
NJ 08108, fax 856/541-3968, email@example.com
1. Yost DA. Alcohol withdrawal syndrome. Am Fam Physician 1996;54:
2. Ebert TJ, Hall JE, Barney JA, Uhrich TD, Colinco MD. The effects of in-
creasing plasma concentrations of dexmedetomidine in humans. Anesthesi-
3. Mayo-Smith MF, Beech LH, Fischer TL, et al. Management of alcohol
withdrawal delirium. Arch Intern Med 2004;164:1405-12.
4. Kosten TR, O’Connor PG. Management of drug and alcohol withdrawal.
N Engl J Med 2003;348:1786-95.
5. Mayo-Smith MF. Pharmacological management of alcohol withdrawal:
a meta-analysis and evidence-based practice guideline: American Soci-
ety of Addiction Medicine Working Group on Pharmacological Manage-
ment of Alcohol Withdrawal. JAMA 1997;278:144-51.
6. Bayard M, McIntyre J, Hill K, Woodside J. Alcohol withdrawal syn-
drome. Am Fam Physician 2004;69:1443-54.
7. McCowan C, Marik P. Refractory delirium tremens treated with propo-
fol: a case series. Crit Care Med 2000;28:1781-4.
8. Wilkins AJ, Jenkins WJ, Steiner JA. Efficacy of clonidine in treatment of
alcohol withdrawal state. Psychopharmacology 1983;81:78-80.
9. Al-Sanouri I, Dikin M, Soubani A. Critical care aspects of alcohol abuse.
South Med J 2005;98:372-81.
10. Riihioja P, Jaatinen P, Oksanen H, Haapalinna A, Heinonen E, Hervonen
A. Dexmedetomidine alleviates ethanol withdrawal symptoms in the rat.
11. Myrick H, Anton RF. Treatment of alcohol withdrawal. Alcohol Health
Res World 1998;22:38-43.
12. Kaim SC, Klett CJ. Treatment of delirium tremens: a comparative evalu-
ation of four drugs. Q J Stud Alcohol 1972;33:1065-72.
13. Riihioja P,Jaatinen P,Oksanen H, Haapalinna A, Heinonen E, Hervonen A.
Dexmedetomidine, diazepam, and propranolol in the treatment of ethanol
withdrawal symptoms in the rat. Alcohol Clin Exp Res 1997;21:804-8.
14. Riihioja P, Jaatinen P, Haapalinna A, Kiianmaa K, Hervonen A. Effects
of dexmedetomidine on rat locus coeruleus and ethanol withdrawal
symptoms during intermittent ethanol exposure. Alcohol Clin Exp Res
15. Rovasalo A, Tohmo H, Aantaa R, Kettunen E, Palojoki R. Dexmedeto-
midine as an adjuvant in the treatment of alcohol withdrawal delirium: a
case report. Gen Hosp Psychiatry 2006;28:362-3.
16. Baddigam K, Russo P, Russo J, Tobias JD. Dexmedetomidine in the
treatment of withdrawal symptoms in cardiothoracic surgery patients. J
Intensive Care Med 2005;20:118-23.
Dexmedetomidine Infusion with Benzodiazepines for Acute Alcohol Withdrawal
The Annals of Pharmacotherapy I
2008 November, Volume 42 I