USES AND ABUSES OF CHLORMETHIAZOLE

1093

pylobacter cholecystitis. It demonstrates that the intestine was the source of the infection which spread to the gallbladder. Since C.

jejuni was isolated from the bile in pure culture it is this microorganism may play a role in acute cho-

possible that lecystitis.

BX’e thank Prof. J. P. Butzler

(Brussels) for the serology and serotyp-

ing of the strains. Departments of Microbiology and Surgery, Stuivenberg Hospital, 2000 Antwerp, Belgium

A. MERTENS M. DE SMET

like concentrations of nitrazepam, plasma levels fall to less than 10 c of the effective level within about 12 h. Significant drug accumulation does not occur on long-term administration in recommended dosage. These characteristics, which are not shared by most hypnotics, make chlormethiazole a valuable drug for use in the elderly; it is relatively free from hangover effects and other adverse reactions and it has been shown to be as effective as or superior to existing medication in the treatment of insomnia.7,8 We suggest that the criticisms made by Hession et al. should more appropriately be levelled at other hypnotics rather than at chlormethiazole which is rarely associated with withdrawal symptoms when used in the correct

dosage. USES AND ABUSES OF CHLORMETHIAZOLE

SIR,-Dr Hession and his colleagues (May 5, p. 953) have drawn attention to the dependence which can result from the prolonged use of chlormethiazole and to the psychiatric disorders which may develop upon its withdrawal. The doses prescribed in the first patients they describe, however, were far in excess of the recommended dosage. Doctors should be aware of possible dangers of overdosage of drugs, especially when they are administered to the elderly, but Hession’s recommendation’ that "information about the dangers of this drug should be sent out to all doctors as a matter of urgency" is quite unjustified on the evidence provided. All hypnotics are liable to produce the side-effects of dependence and hangover. These in turn are related to the size of dose and to accumulation of the drug in the body, and they vary from one drug to another. Dependence results both from effects on mood and also from a continual demand for the drug in order to avoid the insomnia and nightmares that follow the cessation of therapy. Accumulation occurs when residual amounts of the drug remain in the body and are not cleared before the next dose. Hangover is characterised by persistence of pharmacological activity into the next day, and the intensity and duration of this effect is also related to the half-life of the drug. The dangers of barbiturates are well recognised since they produce marked dependence, accumulation, and hangover effects and they have been largely replaced by other hypnotics, particularly the benzodiazepines. Nitrazepam is the most widely prescribed and its clinical efficacy as a hypnotic has been well established as equal to that of the barbiturates. Moreover, reports of dependence and of death from overdosage are rare, and the drug retains its hypnotic effect on prolonged dosage. Hangover effects, however, are marked because of the long half-life (about 30 h); even after a single dose in young people impairment of psychomotor performance is found the following dayI.2 and these effects are greater in the elderly because the ageing brain is more sensitive. This, together with the high blood and tissue levels which result from repeated administration, makes nitrazepam an unsuitable hypnotic for long-term use in the elderly who may present with a variety of neuropsychiatric manifestations.4 There is also evidence that treatment after prolonged use of nitrazepam as a night sedative, produces marked withdrawal symptoms.5 Thus to avoid hangover effect after single dose administration and the cumulative effects (confusion, ataxia, and worsened mental condition) resulting from long-term administration, the "ideal" hypnotic should have a short half-life. Of the hypnotics commonly prescribed chlormethiazole has a half-life which is one of the shortest (about 4 h6). Plasma concentrations reach the effective level rapidly after oral dosing and, un-

Departments of Geriatric Medicine and Clinical Pharmacology, University College Hospital Medical School, London WC1

A. N. EXTON-SMITH A. E. M. MCLEAN

years this unit has been using chlormeththe main drug in conventional detoxification therapy to counter alcohol-withdrawal syndrome, and I have treated more than a thousand chronic alcoholics with oral chlormethiazole over the past three years. Chlormethiazole is potentially a safe drug for routine use for a short period for inpatient management of alcohol-withdrawal syndrome. We use the following dosage schedule: chlormethiazole edisylate (’Heminevrin’) capsules equivalent to 192 mg base per capsule three three times a day for 3 days, two three times a day for 2 days, and one three times a day for 1 day. The total average dose is thus about 8 mg chlormethiazole base tailed off over a period of 6 consecutive days. The drug is well tolerated and does not precipitate any untoward or alarming reactions; its use on an outpatient basis, however, is not advised. Chronic alcoholics may acquire hyperprolactinxmia with impotence and hypogonadism,9.1O biochemical hypothyroidism," and hypercortisolaemia,12 and hepatic microsomal enzymes may be induced as a result of chronic drinking." Interestingly, chlormethiazole, when given to chronic alcoholics, does not raise serum-prolactin concentrations as phenothiazines, butyrophenones, and so on do; on the contrary, it lowers prolactin levels significantly.-14 It does not interfere with thyroid function,15 nor does it affect serum-cortisol (unpublished) and it has no effect on hepatic microsomal enzymes. 16 In view of these observations, chlormethiazole seems to be an ideal drug to treat alcohol-withdrawal syndrome. It is the wrong use of a right drug which was responsible for the reactions reported by Hession et al.

SIR,-For several

iazole

as

Elmdene Alcoholic Treatment

Bexley Hospital, Bexley, Kent DA5

2BW

Unit,

SISIR K.

MAJUMDAR

cessation of

1. 2

Walters, A. J., Lader, M. H. Nature, 1971, 229, 637. Malpas, A., Rowan, A. J., Joyce, C. R. B., Scott, D. F. Br. med. J. 1970, ii, 762. 3. Castleden, C. M., George, C. F., Marcer, D., Hallett, C. ibid. 1977, i, 10. 4. Grimley Evans, J., Jarvis, E. H. ibid. 1972, ii, 487. 5. Adam, K., Adamson, L., Brezinová, V., Hunter, W. M., Oswald, I. ibid. 1976, i, 1558. 6 Witts, D. J., Bowhay, A. A., Garland, M., McLean, A. E. M., Exton-Smith, A. N. Age Ageing, (in the press).

SiR,-In alcoholics and patients with other unstable personalities any sedative-hypnotic drug can lead to dependence1.2 with the risk of psychological and physical abstinence symptoms. Chlormethiazole is no exception, especially when used without regard to correct indication-a finding stressed by a 7 8

Grunstein, J A. H. Mod Geriat. 1971, 1, 472. Dehlin, O., Falkheden, T, Gatzinska, R. Nordqvist, P Clin Ther. 1978, 2,

41. 9 Majumdar, S. K. Lancet, 1978, i, 101 10 Majumdar, S. K Practitioner in the press). 11 Goldberg, M Lancet, 1962, n, 746. 12 Smals, A., Kloppenborg. P. ibid. 1977, i, 1369. 13 Gelehrter, T D. New Engl J Med. 1976, 294, 589. 14 Majumdar, S K, Shaw, G. K, Thomson, A D Br. 15 Majumdar, S K Pharmatherapeutica. 1978. 2, 67. 16. Majumdar, S K. ibid. p. 27 1. Glatt, M. M Br med.J 1957, i, 164. 2 Glatt, M. M. ibid. 1958, ii, 1100

med. J. 1978, ii,

1266.

1094 number of observers from various countries at an international symposium arranged by the manufacturers of the drug in 1965.3 The need is, as Dr Hession and his colleagues rightly emphasise, to restrict the use of chlormethiazole in alcoholics to inpatients and for a period of no longer than 9 days-a point stressed again and again by clinicians who, however, at the same time, often describe chlormethiazole as the best drug for the treatment of serious alcohol withdrawal symptoms, including delirium tremens.3-5 Used for the right indications and under proper supervision this drug is safe. The right indications include ones not mentioned by Hession et al.-namely, states of insomnia and restlessness in geriatric patients.6-10 Geriatric patients (except those with a history of alcohol or drug misuse or other evidence of emotional instability) do not generally tend to misuse drugs. At least four of the fiye patients described by Hession et al. belonged to the emotionally unstable type of personality prone to misuse sedative-hypnotic drugs unless kept under strict supervision; using chlormethiazole in such cases does not constitute proper use of the drug. As with any other hypnoticsedative drug used and misused for some time, abrupt cessation carries the risk of physical as well as mental abstinence symptoms. Too few details (e.g., dosage, use of other drugs) are given about the 71-year-old man who took an overdose of nitrazepam. There is the risk of potentiation of chlormethiazole with nitrazepam-and this might also have affected the symptoms and intensity of the abstinence symptoms. The report by Hession et al. once more underlines the frequently given warning not to prescribe chlormethiazole to alcoholics and other unstable personalities as outpatients; they are also right to warn of the need for care when withdrawing the drug in patients who, with or without correct medical prescription, have taken it for longish periods. There seems little basis for Hession’s other conclusions. Many clinicians in Britain and in Scandinavia and Germany (where the drug has been used widely) regard chlormethiazole as a valuable, effective, and safe drug; and the sensational publicity which the article received in the national Press two days before its publication in The Lancet therefore seems all the more deplorable. U.C.H. Alcoholism OP St. Pancras Hospital, London NW1

(Teaching) Centre, M. M. GLATT

SIR,-Chlormethiazole is widely used in elderly patients as sedative and hypnotic, many geriatricians regarding it as first choice of treatment. Long experience has shown that it is in many cases more suitable and safer than the alternative phenothiazines and benzodiazepines, and this is supported by the paucity of serious adverse reactions reported to the Committee on Safety of Medicines. The cases reported by Dr Hession and his colleagues (May 5, p. 953) do not change my view that chlormethiazole is safe at normal doses, and do not justify the sweeping conclusions drawn about the use of this drug. My main concern, however is that this work was widely reported on the radio and in newspapers, in terms certain to cause distress to patients and their doctors, several days before its publication in The Lancet. Headlines such as "Doctor Warns of Madness Drug" (Daily Record, May 3) and Press statements comparing chlormethiazole unfavourably with heroin as a cause of addiction were hardly supported by the contents of the paper by Hession et al. when it appeared. Unfora

3. Frisch, E. P. (editor) Chlormethiazole. Acta psychiat. scand. 1966, 42, suppl. 192. 4. Hudolin, V., Frisch, E. P. Proc. 3rd int Congr. soc. psychiat. 1973, vol. VI. 5. Schoid, W., Reitmann, R., Huhn, A. in Sucht und Missbrauch (edited by W. Steinbrecher and H. Solms); part VI, p. 3-32. Stuttgart, 1973. 6. Grunstein, J. A. H. Mod. geriat. 1971, 1, 472. 7. Harenko, A. Curr. med Res. Opin. 1975, 2, 657. 8. Pathy, M. S. ibid. 1975, 2, 648. 9. Dehlin, O. and others. Clin. Ther. 1978, 2, 41. 10. Magnus, R. V. ibid 1978, 1, 387.

tunately it is these that all the general public and many doctors will remember and not the Lancet paper itself. While not being complacent about this or any other drug, particulaily in the elderly, and while accepting that a close look at chlormethiazole as a cause of dependence and withdrawal symptoms is now necessary, I feel that the evidence available does not warrant the wholesale withdrawal of chlormethiazole from clinical practice and the substitution of drugs which themselves have well-substantiated serious side-effects. Woodend General Hospital, Aberdeen AB9 2YS

C. J. SCOTT

*** Copies of The Lancet are made available to journalists and broadcasters every Thursday morning and those who receive them are asked to make no reference to the contents before Friday. Reports about Dr Hession’s work appeared in newspapers and elsewhere on the Wednesday and Thursday of that week and were based, we understand, on a Press Association release incorporating information and comment supplied by the author and not by The Lancet or by anyone who had been given an advance copy of the journal.-ED.L.

ATTEMPT AT ENZYME REPLACEMENT BY FETAL LIVER TRANSPLANTATION IN FABRY’S DISEASE

SIR,-Fabry’s disease is an inherited sphingolipidosis due to the lack of x-galactosidase A activity. The metabolic disorder results in systemic manifestations, and the involvement of the kidney usually leads to chronic renal failure during the fourth decade of life. Transplantation of a normal kidney has been suggested partly to correct the metabolic disorder.’-’ However, this may not represent a direct effect on the enzyme deficiency: improvement could be due to the disappearance of haemolysis resulting from correction of the renal failure, or to the effects of steroids or immunosuppressive drugs, and there may be no consistent increase of x-galactosidase A even when x-galactosidase B activity is augmented.5-8 Two of our patients, with as yet only slight renal involvement, have been treated with fetal liver transplantation. These 33 and 26 year old male patients presented with clinical manifestations of Fabry’s disease, and the diagnosis was confirmed by ophthalmological, histological, and enzymatic analyses. After plasma transfusions and symptomatic therapy had proved ineffective, fetal liver cells with normal enzyme activities were transplanted. In the first case, there was a prompt and significant symptomatic response: sweating appeared for the first time, becoming and remaining normal; pains completely disappeared; cutaneous lesions seemed slightly decreased. This improvement in extrarenal manifestations of Fabry’s disease was comparable with that obtained with kidney transplantation, and has persisted for 32years after fetal-liver transplantation. In the second patient, treated 9 months ago, it is too early to evaluate a possible clinical benefit of the procedure, especially since this patient had almost normal sweating and relatively few pains except at the cold season. Both patients previously had evidence of progressing disease with 1. Desnick, R.

J., Simmons, R. L., Allen, K. Y., Wood, J. E., Anderson, C F. Najarian, J. S., Krivit, W. Surgery, 1972, 72, 203. 2. Philippart, M., Franklin, S. S., Gordon, A. Ann. intern. Med 1972, 77, 195 3 Buhler, F R., Thiek, G., Duback, U. E., Enderlin, F., Gloor, F, Tholen, H Br med J 1973, iii, 28. 4 Simmons, R L., Desnick, R J , Najarian, J. S., Krivit, W. Cours International de Transplantation, p. 59. Lyon, 1973. 5. Clarke, J. T. R., Guttmann, R. D., Wolfe, L S., Beaudoin, J C. Morehouse, D. D. New Engl.J. Med. 1972, 287, 1215. 6 Krivit, W., Desnick, R. J., Bernlohr, R. W., Wold, F. ibid 1972. 287, 1248 7. Spence, M. W., Mac Kinnon, K. E , Burgess, J. K., D’Entremont, D W Belitsky, P., Lannon, S. G., MacDunald, A. J. Ann intern Med 1978 84,13 8. Van Den Bergh, F , Rietra, P., Kolk-Vegter, A., Bosche, E., Tager. M Acta med scand. 1976, 200, 249.