Correspondence

Patients with Alcohol Problems

N Engl J Med 1998; 339:130-131July 9, 1998

Article

To the Editor:

In their excellent review of alcohol problems, O'Connor and Schottenfeld (Feb. 26 issue)1 discuss several ways to treat the alcohol withdrawal syndrome. Although infrequently used therapies such as carbamazepine are considered, the authors do not mention chlormethiazole (clomethiazole), a derivative of vitamin B₁ with sedative and anticonvulsant properties, which is widely used in Europe but not approved for use in the United States.2 Like benzodiazepines, chlormethiazole can cause respiratory depression, which is the main factor limiting its use. It controls agitation and seizures effectively. The availability of solutions containing 4 g of chlormethiazole in 500 ml of water allows for continuous intravenous administration with adjustment of the dose according to the clinical symptoms, resulting in stable plasma levels.

A recent meta-analysis of therapies for alcohol withdrawal concluded that chlormethiazole was superior to placebo, but the inadequacy of the sample size did not allow for definitive conclusions about the prevention of seizures and delirium.3 The authors also concluded that beta-blockers, carbamazepine, and clonidine, all mentioned as possible therapies by O'Connor and Schottenfeld, should not be recommended as monotherapy, since they have not been shown to reduce delirium or seizures.

Furthermore, chlormethiazole has been shown to inhibit the activity of cytochrome P-450 2E1 in humans. This activity is increased in patients with alcoholism and has detrimental effects on the liver through free-radical formation.4

Although data supporting the use of this drug in Europe are admittedly scanty, there may be some advantages to using chlormethiazole that justify a comparison with benzodiazepines.

Juan C. Garcia-Monco, M.D.
Marian Gomez Beldarrain, M.D.
Hospital de Galdacano, 48960 Galdacano, Vizcaya, Spain

4 References

1
O'Connor PG, Schottenfeld RS. Patients with alcohol problems. N Engl J Med 1998;338:592-602
Full Text | Web of Science | Medline

2
Herran A, Vazquez-Barquero JL. Treating alcohol dependence: chlormethiazole is widely used in Europe. BMJ 1997;315:1466-1466
CrossRef | Web of Science | Medline

3
Mayo-Smith MJ. Pharmacological management of alcohol withdrawal: a meta-analysis and evidence-based practice guideline. JAMA 1997;278:144-151
CrossRef | Web of Science | Medline

4
Gebhardt AC, Lucas D, Menez JF, Seitz HK. Chlormethiazole inhibition of cytochrome P450 2E1 as assessed by chlorzoxazone hydroxylation in humans. Hepatology 1997;26:957-961
CrossRef | Web of Science | Medline

To the Editor:

The excellent review of alcohol problems by O'Connor and Schottenfeld does not mention γ-hydroxybutyric acid (GHB) either in the management of the alcohol withdrawal syndrome or in the prevention of relapse. GHB has been shown to be effective in suppressing the alcohol withdrawal syndrome,1 reducing the craving for alcohol,2,3 and maintaining abstinence.4

In particular, a placebo-controlled trial involving 23 subjects showed that GHB (50 mg per kilogram of body weight) was very effective in suppressing withdrawal symptoms during a seven-hour observation period and was well tolerated.1 A further randomized, placebo-controlled trial in 82 subjects showed that the same dose of GHB fractionated into three daily doses for three months was more effective than placebo in increasing the number of days of abstinence and reducing the number of daily drinks and the craving for alcohol in patients with alcoholism.2 Recently, the same dosage was used for six months in 179 patients with alcoholism.3 Of the 109 subjects who completed the study, 78 percent remained abstinent throughout the six-month period of drug administration. More recently, we showed that greater fractionation (into six doses) of the same dose of GHB increases the abstinence rate in patients with alcoholism who do not have a response to the conventional fractionation of the drug4; among the 119 patients who received this treatment, no abuse of GHB was reported.

Giovanni Addolorato, M.D.
Catholic University, 00168 Rome, Italy

Giuseppe Francesco Stefanini, M.D.
Ospedale degli Infermi, 48018 Faenza, Italy

Giovanni Gasbarrini, M.D.
Catholic University, 00168 Rome, Italy

4 References

1
Gallimberti L, Canton G, Gentile N, et al. Gamma-hydroxybutyric acid for treatment of alcohol withdrawal syndrome. Lancet 1989;2:787-789
CrossRef | Web of Science | Medline

2
Gallimberti L, Ferri M, Ferrara SD, Fadda F, Gessa GL. γ-Hydroxybutyric acid in the treatment of alcohol dependence: a double-blind study. Alcohol Clin Exp Res 1992;16:673-676
CrossRef | Web of Science | Medline

3
Addolorato G, Castelli E, Stefanini GF, et al. An open multicentric study evaluating 4-hydroxybutyric acid sodium salt in the medium-term treatment of 179 alcohol dependent subjects. Alcohol Alcohol 1996;31:341-345
Web of Science | Medline

4
Addolorato G, Cibin M, Caprista E, et al. Maintaining abstinence from alcohol with gamma-hydroxybutyric acid. Lancet 1998;351:38-38
CrossRef | Web of Science | Medline

To the Editor:

The article on patients with alcohol problems is both comprehensive and up to date. In recommending an approach to obtaining alcohol-related information, the authors suggest first asking about the quantity and frequency of consumption and then asking the CAGE questions. This is also the approach suggested in The Physicians' Guide to Helping Patients with Alcohol Problems. 1

However, asking patients first about amounts of alcohol consumed may be confrontational and, if so, may result in less accurate and less useful information. A small study confirmed this hypothesis, finding that when patients with alcoholism were randomly assigned to be asked the CAGE questions after an open-ended question (“Please tell me about your drinking”) or after being asked about amounts of alcohol consumed, the CAGE questions were much less sensitive for detecting alcoholism in the latter group (32 percent) than in the former group (95 percent).2 Therefore, I would recommend routinely asking the CAGE questions just after finding out that a patient drinks and before asking about amounts.

Physicians should at least be cognizant that questions about amounts of alcohol consumed can be threatening to some patients, particularly those with alcohol problems. Regardless of the order in which the questions are asked, the history should be taken in an empathetic, nonconfrontational manner.3

Richard Saitz, M.D., M.P.H.
Boston Medical Center, Boston, MA 02118

3 References

1
National Institute on Alcohol Abuse and Alcoholism. The physicians' guide to helping patients with alcohol problems. Washington, D.C.: Government Printing Office, 1995. (NIH publication no. 95-3769.)

2
Steinweg DL, Worth H. Alcoholism: the keys to the CAGE. Am J Med 1993;94:520-523
CrossRef | Web of Science | Medline

3
Miller WR, Rollnick S. Motivational interviewing: preparing people to change addictive behavior. New York: Guilford Press, 1991.

Author/Editor Response

The authors reply:

To the Editor: Concerning the comments of Drs. Garcia-Monco and Gomez Beldarrain, chlormethiazole is an interesting agent about which there are few data. Although one study compared chlormethiazole with chlordiazepoxide and found them to be “equally effective,” only 22 patients were randomly assigned to these treatments.1 As we stated in our article, we believe that agents such as beta-blockers, clonidine, and carbamepazine are best viewed as adjunctive rather than primary therapies, especially since benzodiazepines have been established as effective in managing withdrawal symptoms and preventing severe withdrawal and seizures.

The comments of Dr. Addolorato and his colleagues concerning GHB are also of interest, given the potential of this agent for both ameliorating withdrawal and preventing relapse. As with chlormethiazole, GHB needs to be evaluated more extensively and compared with benzodiazepines in the treatment of withdrawal before it can be considered for routine use. In addition, there is no evidence that either agent is effective in reducing delirium or seizures.2 The potential use of GHB as a therapy to prevent relapse will also require clinical trials. Finally, GHB has recently emerged as an important drug of abuse,3 and at least one GHB-associated death has been reported.4 Along with physical dependence, the adverse effects of GHB abuse include delirium, seizures, and coma,3 and GHB has been identified as a potential “date rape” drug.4

Dr. Saitz brings up an interesting point about how to use screening instruments such as the CAGE questionnaire. Clearly, an empathetic and nonconfrontational approach is needed whenever alcohol problems are discussed. Before asking the CAGE questions, the physician needs to determine whether a patient has used any alcohol. Whether the physician should then ask the CAGE questions or obtain a detailed history of quantity and frequency may be more a matter of style than of science. Some patients may feel threatened by being asked about quantity and frequency or by being asked the CAGE questions, regardless of when they are asked. Physicians who are alert to these issues and who ask the questions in an open-ended, matter-of-fact manner might decide on the order in which the questions are asked according to the individual patient and the flow of the interview.

Patrick G. O'Connor, M.D., M.P.H.
Richard S. Schottenfeld, M.D.
Yale University School of Medicine, New Haven, CT 06520-8025

4 References

1
Burroughs AK, Morgan MY, Sherlock S. Double-blind controlled trial of bromocriptine, chlordiazepoxide and chlormethiazole for alcohol withdrawal symptoms. Alcohol Alcohol 1985;20:263-271
Web of Science | Medline

2
Mayo-Smith MF. Pharmacological management of alcohol withdrawal: a metaanalysis and evidence-based practice guideline. JAMA 1997;278:144-151
CrossRef | Web of Science | Medline

3
Galloway GP, Frederick SL, Staggers FE Jr, Gonzales M, Stalcup SA, Smith DE. Gamma-hydroxybutyrate: an emerging drug of abuse that causes physical dependence. Addiction 1997;92:89-96
CrossRef | Web of Science | Medline

4
Marwick C. Coma-inducing drug GHB may be reclassified. JAMA 1997;277:1505-1506
CrossRef | Web of Science | Medline

Citing Articles (3)

Citing Articles

1
Manuel Chanavaz. (2001) Patient Screening and Medical Evaluation for Implant and Preprosthetic Surgery. Implant Dentistry 10:2, 76-84
CrossRef
2
Giovanni Addolorato, Fabio Caputo, Esmeralda Capristo, G.Francesco Stefanini, Giovanni Gasbarrini. (2000) Gamma-hydroxybutyric acid Efficacy, potential abuse, and dependence in the treatment of alcohol addiction. Alcohol 20:3, 217-222
CrossRef
3
G. Addolorato, E. Capristo, A.V. Greco, F. Caputo, G.F. Stefanini, G. Gasbarrini. (1998) Three months of abstinence from alcohol normalizes energy expenditure and substrate oxidation in alcoholics: a longitudinal study. The American Journal of Gastroenterology 93:12, 2476-2481
CrossRef