Correspondence

Management of Drug and Alcohol Withdrawal

N Engl J Med 2003; 349:405-407July 24, 2003

Article

To the Editor:

In their informative and practical review of the management of drug and alcohol withdrawal, Kosten and O'Connor (May 1 issue)1 advocate the use of diazepam at a dose of 5 to 10 mg every two to four hours for the management of delirium tremens and withdrawal seizures. They note that longer-acting benzodiazepines have been found to be more effective than placebo in reducing the incidence of seizures and delirium. However, lorazepam may be more effective than diazepam for treating alcohol-withdrawal seizures and status epilepticus. In one study, lorazepam terminated 59.1 percent of episodes of status epilepticus (10 percent caused by alcohol withdrawal), as compared with 42.6 percent for diazepam.2 Intravenous lorazepam treatment is associated with fewer recurrences of seizure than diazepam and with less need for repeated doses, since its efficacy is higher (82 to 100 percent) than that of diazepam (54 to 100 percent).3,4

Although all benzodiazepines enter the cerebral tissue quickly, lorazepam has a longer antiseizure effect (12 to 24 hours) than diazepam (15 to 30 minutes) and a higher affinity for benzodiazepine receptors in the brain.5 However, the systemic half-life of diazepam is nearly 100 hours, as compared with 30 hours for lorazepam. Treatment with diazepam may lead to peripheral accumulation without anticonvulsant efficacy and with an increased likelihood of sedation, making the assessment of mental status difficult.

Gayatri Devi, M.D.
Lenox Hill Hospital, New York, NY 10021
gd@nymemory.org

5 References

1. 1

   Kosten TR, O'Connor PG. Management of drug and alcohol withdrawal. N Engl J Med 2003;348:1786-1795
   Full Text | Web of Science | Medline

2. 2

   Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001;345:631-637[Erratum, N Engl J Med 2001;345:1860.]
   Full Text | Web of Science | Medline

3. 3

   Cock HR, Schapira AH. A comparison of lorazepam and diazepam as initial therapy in convulsive status epilepticus. QJM 2002;95:225-231
   CrossRef | Medline

4. 4

   Rey E, Treluyer JM, Pons G. Pharmacokinetic optimization of benzodiazepine therapy for acute seizures: focus on delivery routes. Clin Pharmacokinet 1999;36:409-424
   CrossRef | Web of Science | Medline

5. 5

   Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med 1998;338:970-976
   Full Text | Web of Science | Medline

To the Editor:

Kosten and O'Connor suggest propanolol as an alternative for severe cocaine-withdrawal symptoms. The use of beta-blockers in patients who have ingested cocaine is not free of hazards. Because of an unopposed alpha effect, the use of beta-blockers may be associated with decreased coronary blood flow and increased coronary vascular resistance, may predispose patients to arrhythmias, and may trigger a hypertensive crisis.1,2 Cocaine is associated with potentially lethal cardiac toxicity. The broad spectrum of adverse events ranges from chronic cardiomyopathy to syncope and sudden cardiac death.3 Delayed toxic effects due to the presence of active metabolites with long half-lives are possible.4 Any use of beta-blockers in this setting requires careful monitoring and caution.

Victor J. Castro, M.D.
McAllen Heart Hospital, McAllen, TX 78503

4 References

1. 1

   Kloner RA, Hale S. Unraveling the complex effects of cocaine on the heart. Circulation 1993;87:1046-1047
   Web of Science | Medline

2. 2

   Fuster V, Alexander RW, O'Rourke RA, eds. Hurst's the heart. 10th ed. Vol. 2. New York: McGraw-Hill, 2001:2051.
   

3. 3

   Castro VJ, Nacht R. Cocaine-induced bradyarrhythmia, an unsuspected cause of syncope. Chest 2000;117:275-277
   CrossRef | Web of Science | Medline

4. 4

   Chokshi SK, Gal D, Isner JM. Vasospasm caused by cocaine metabolite: a possible explanation for delayed onset of cocaine-related cardiovascular toxicity. Circulation 1989;80:Suppl II:II-351 abstract.
   

To the Editor:

Kosten and O'Connor describe the treatment of alcohol-withdrawal symptoms with symptom-triggered therapy, rather than with medication given on a fixed scale. However, our clinical experience with patients who have head and neck cancer, among whom the prevalence of alcohol abuse is greater than 60 percent, is that the prevention of alcohol-withdrawal symptoms is even more important. This idea is supported by the literature.1 All of our patients who have a history of alcohol abuse receive 150 μg of clonidine before surgery and 300 μg per day, intravenously or orally, for the next five days in combination with benzodiazepines. We advise not waiting to provide treatment until withdrawal symptoms start. The symptoms may mimic cardiovascular, neurologic, or infectious problems. By the time those major complications have been ruled out, most patients have had full-blown withdrawal symptoms, and their treatment has become much more difficult.

Johannes Huitink, M.D., Ph.D.
Dirk Buitelaar, M.D.
Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
j.huitink@nki.nl

1 References

1. 1

   Spies CD, Rommelspacher H. Alcohol withdrawal in the surgical patient: prevention and treatment. Anesth Analg 1999;88:946-954
   CrossRef | Web of Science | Medline

Author/Editor Response

The correspondents emphasize the complexity of withdrawal treatments. As Dr. Devi indicates, in a study of lorazepam and diazepam, either of these medications was better than placebo in terminating seizures.1 However, the two medications did not differ (relative hazard for the persistence of status epilepticus, 0.65; 95 percent confidence interval, 0.36 to 1.17) when adjusted for covariates, such as the 15 percent higher rate of previous seizures in the diazepam group than in the lorazepam group. One limitation of lorazepam, but not diazepam, is the need for refrigeration. In addition, the brain levels of diazepam rise more quickly because it is more lipid-soluble than lorazepam. Dr. Devi mentions that the antiseizure effects of lorazepam last 50 times as long as those of diazepam, but this appears to have been an inaccuracy in the original 1993 report2 that was then carried over into the cited 1998 review.3 It is correct, however, that the duration of activity of diazepam is three times that of lorazepam; it is for this reason that diazepam is used, because a very-long-acting agent is better than a short-acting agent for minimizing withdrawal symptoms.

Drs. Huitink and Buitelaar suggest that because some patients undergoing surgery are at high risk for alcohol withdrawal, preemptive treatment, rather than symptom-triggered use of medication, may be appropriate. We caution that benzodiazepines given after anesthesia can lead to acute respiratory arrest because of intensified sensitivity of the γ-aminobutyric acid neurotransmitter receptors. Furthermore, their use of clonidine seems poorly considered. Clonidine will not stop seizures, which constitute the most severe complication, and will simply add to the hypotension and potential respiratory suppression induced by the benzodiazepines. We caution against the combined use of these medications in patients who may have respiratory complications due to preemptive use of benzodiazepines. If benzodiazepines are used, we suggest short-acting agents, rather than diazepam, to minimize the duration of any respiratory compromise.

Dr. Castro wisely cautions about the use of propranolol in cocaine withdrawal because of the potential for outpatients to use cocaine while taking propranolol. The medical safety and potential efficacy of carvedilol, an alpha- and beta-blocker, for reducing cocaine reinforcement has recently been shown in laboratory studies in humans, and we agree that it would be a better medication to relieve withdrawal symptoms in outpatients.4 However, the clinical efficacy of carvedilol has not yet been tested in outpatients in a placebo-controlled trial.

Thomas Kosten, M.D.
Patrick O'Connor, M.D., M.P.H.
Yale University School of Medicine, New Haven, CT 06516
thomas.kosten@yale.edu

4 References

1. 1

   Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001;345:631-637[Erratum, N Engl J Med 2001;345:1860.]
   Full Text | Web of Science | Medline

2. 2

   Treatment of convulsive status epilepticus: recommendations of the Epilepsy Foundation of America's Working Group on Status Epilepticus. JAMA 1993;270:854-859
   CrossRef | Web of Science

3. 3

   Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med 1998;338:970-976
   Full Text | Web of Science | Medline

4. 4

   Sofuoglu M, Brown S, Babb DA, Pentel PR, Hatsukami DK. Carvedilol affects the physiological and behavioral response to smoked cocaine in humans. Drug Alcohol Depend 2000;60:69-76
   CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   Dirk R. Buitelaar, Alfons J. M. Balm, Ninja Antonini, Harm van Tinteren, Johannes M. Huitink. (2006) Cardiovascular and respiratory complications after major head and neck surgery. Head & Neck 28:7, 595-602
   CrossRef

2. 2

   Paolo Calabresi, Letizia Maria Cupini. (2005) Medication-overuse headache: similarities with drug addiction. Trends in Pharmacological Sciences 26:2, 62-68
   CrossRef