1228
cases of Kamper et al. We recommend careful haematological monitoring of patients receiving VPA, and special caution must be taken when VPA is given at high dose.’ I. SAFA KAYA Department of Paediatrics, UGUR DILMEN Medical Center Hospital, METE TOPPARE Turkish Health and Therapy Foundation, DURSUN ALI SENSES Ankara, Turkey
may reflect a cutaneous vasculitis similar to the
Department of Haematology, Royal Free Hospital and School of Medicine, London, UK
H. GRANT PRENTICE
1. Pellock JM. Efficacy and adverse effects of antiepileptic drugs. Ped Clin N Am 1989; 36: 435-48. 2. Schmidt D. Toxicity of antiepileptic drugs. In: Pedley TA, Meldrum BS, eds. Recent advances in epilepsy No 3. New York: Churchill-Livingstone, 1986: 211-32. 3. Dreifuss FE, Langer DH. Side effects of valproate. Am J Med 1988; 84 (suppl 1A):
34-41. 4. Watts RG, Emanuel PD, Zuckerman KS, Howard TH. Valproic acid-induced cytopenias: evidence for a dose-related suppression of hematopoiesis. J Pediatr 1990; 117: 495-99
Acamprosate, citalopram, and alcoholism 770) andMentionseditorialby(pNaranjo
discusses our study on et al on citalopram Z The implication seems to be that citalopram gave clearer results than acamprosate. We feel that this apposition of the two studies is unfair, or rather incomplete. The acamprosate study was a large-scale multicentre investigation in severely dependent alcoholism, patients being evaluated for relapse three months after .weaning from alcohol. The aim was to approximate to a normal therapeutic setting. We had a 38% drop-out rate. Five (not one) tests were significantly in favour of acamprosate and five more, including the patient and physician evaluations, had a p between 0-05 and 0-10. No test was in favour of placebo, even at the 0-10 level. One of our problems was that there is no universally accepted criterion, clinical or biological, for treatment success in alcoholism. Monitoring daily alcohol intake and/or obtaining daily urine samples was not feasible, given the numbers of centres and patients. Naranjo’s single-centre study was in "problem drinkers" recruited by advertisements: only 1 had signs of alcohol dependence. No weaning was attempted, and the participants had to complete daily diary cards and send in daily urine specimens. The study had a crossover design and each treatment period lasted a month. Abstinent days were counted and alcohol ingestion on non-abstinent days was monitored: there was a mean reduction in the number of daily drinks from about 6-5 with placebo to 6 with citalopram 40 mg (the exact numbers are not given). Although this change is significant, its clinical relevance to the treatment of alcoholism or alcohol dependence remains to be shown. Even though that study was more experimental than therapeutic, it also had a high drop-out rate (34%). Since 1987, Naranjo’s group had published two other studies of serotonin uptake inhibitors (viqualine3and fluoxetine4) in similar patients. Your editorial could have mentioned these: they used essentially the same procedure, except that the fluoxetine study used a parallel rather than a crossover design. Viqualine at the higher dose of 200 mg daily resulted in a significant reduction in mean daily drinks from 7-7 to 64; the drop-out rate was 38%. Fluoxetine did not have any significant effect compared with placebo (in a less powerful parallel design in only 29 patients), though 60 mg fluoxetine seemed more effective than 40 mg; there was a 30% drop-out rate. Despite much emphasis on the potential of serotonin uptake inhibitors in the treatment of alcoholism5,6 there has been no study of their effects in dependent alcoholics. We need results obtained from large-scale randomised studies in dependent alcoholics and data on the effects of acamprosate on drinking behaviour in the problem drinkers of the sort Naranjo’s team has studied before any comparison, explicit or implicit, of these drugs is made. Fluoxetine is the only one of these serotonin uptake inhibitors to be marketed; Acamprosate is marketed in France, specifically for the prevention of alcohol relapse, and is being studied in other European countries, including the UK.
SIR,-Your acamprosate1
Since 1987, other studies have been published on drug treatment of alcohol abuse and dependence (eg, with calcium carbamide and lithium) but the only trial we have found that bettered the results we had initially with acamprosate7 is a study of bromocriptine,8 in which the relapse rate at the sixth month was 5 % on bromocriptine and 60% on placebo. Only 8 of the 50 patients who entered the
study dropped out (16%). What we would like to emphasise is the very small number of well-conducted clinical trials of drug treatment of alcoholism and the difficulties of such studies, including high drop-out rates (10% drop-outs or less is a marker of a high-quality trial in this respect) and the lack of clear-cut endpoints. This paucity of trials is unfortunate, in view of the huge cost of alcoholism in terms of morbidity, mortality, and social disruption. If as much effort were put into the methodological and practical issues of the treatment of alcoholism as has been put, for example, into the treatment of hypertension or hypercholesterolaemia, the gains to public health could be tremendous. of Pharmacology and Alcohol Treatment Unit, Hôpital de Boisguillaume, 76233 Boisguillaume, France
Department
N. MOORE C. LIBERT
30
one
1. Lhuintre JP, Moore N, Tran G, et al. Acamprosate appears to decrease alcohol intake in weaned alcoholics. Alcohol Alcoholism 1990; 25: 613-22. 2. Naranjo C, Sellers E, Sullivan J, Woodley D, Kadlec K, Sykora K. The serotonin uptake inhibitor citalopram attenuates ethanol intake. Clin Pharmacol Ther 1987, 41: 266-74. 3. Naranjo C, Sullivan J, Kadlec K, Woodley-Remus D, Kennedy G, Sellers E. Differential effects of viqualine on alcohol intake and other consummatory behaviors. Clin Pharmacol Ther 1989; 46: 301-09. 4. Naranjo C, Kadlec K, Sanhueza P, Woodley-Remus D, Sellers E. Fluoxetine differentially alters alcohol intake and other consummatory behaviors m problem drinkers. Clin Pharmacol Ther 1990; 47: 490-98. 5. Naranjo C, Sellers E. Serotonin uptake inhibitors attenuate ethanol intake in problem drinkers. Recent Dev Alc 1989; 7: 255-66. 6. Meyer R. Prospects for a rational pharmacotherapy of alcoholism J Clin Psychiatry
1989; 50: 403-12. J, Daoust M, Moore N,
7. Lhuintre a
GABA agonist,
to
prevent
al. Ability of calcium bis acetyl homotaurine, relapse m weaned alcoholics. Lancet 1985; i:
et
1014-16.
8.
Borg V. Bromocriptine in the treatment of alcohol abuse. Acta Psychiatr Scand 1983; 68: 100-10.
Moderate alcohol
consumption
SIR,-Professor Shaper (April 13, p 911) seeks to explain the association between moderate alcohol consumption and lower mortality on the basis that non-drinkers tend to be sicker than drinkers. However, he has misrepresented the data from the Nurses’ Health Study.l He reports that non-drinkers in that cohort are less healthy than drinkers because they had a higher prevalence of diabetes, hypertension, obesity, and high blood cholesterol. These women- had a lower prevalence of current smoking, and Shaper infers that this too is a sign of ill-health, believing that it suggests a higher proportion of former smokers. However, it is current, not past, smoking that confers most of the smoking-related risk of coronary heart disease (CHD). Anyway, the non-drinkers had the lowest prevalence of former smoking. Because of the high prevalence of smoking and its. large impact on CHD risk, the drinkers are actually at higher CHD risk overall than the non-drinkers, apart from their alcohol intake. The distribution of risk factors by alcohol category is shown in table i: the large difference for smoking more than counterbalances the smaller differences in other risk factors. In multivariate analyses, adjustments for these risk factors further revealed the apparent benefit of moderate alcohol that was partly obscured by the heavy smoking among the drinkers. Shaper further claims that the trend we observed was driven by the non-drinkers and heavy drinkers, with little trend between. Not so. The multivariate relative risks are shown in table n. Even without the non-drinkers, there is a two-fold difference between the lightest and heaviest categories. The middle three categories with relative risk of 0-6 are fine gradations and correspond approximately to the category of light drinkers in Shaper’s classification scheme. Had we used his scheme, we would have observed relative risks of 1-0, 0-8, 0-6, and 0’4 for successive categories of alcohol intake. It is important to note that the highest
cases of Kamper et al. We recommend careful haematological monitoring of patients receiving VPA, and special caution must be taken when VPA is given at high dose.’ I. SAFA KAYA Department of Paediatrics, UGUR DILMEN Medical Center Hospital, METE TOPPARE Turkish Health and Therapy Foundation, DURSUN ALI SENSES Ankara, Turkey
may reflect a cutaneous vasculitis similar to the
Department of Haematology, Royal Free Hospital and School of Medicine, London, UK
H. GRANT PRENTICE
1. Pellock JM. Efficacy and adverse effects of antiepileptic drugs. Ped Clin N Am 1989; 36: 435-48. 2. Schmidt D. Toxicity of antiepileptic drugs. In: Pedley TA, Meldrum BS, eds. Recent advances in epilepsy No 3. New York: Churchill-Livingstone, 1986: 211-32. 3. Dreifuss FE, Langer DH. Side effects of valproate. Am J Med 1988; 84 (suppl 1A):
34-41. 4. Watts RG, Emanuel PD, Zuckerman KS, Howard TH. Valproic acid-induced cytopenias: evidence for a dose-related suppression of hematopoiesis. J Pediatr 1990; 117: 495-99
Acamprosate, citalopram, and alcoholism 770) andMentionseditorialby(pNaranjo
discusses our study on et al on citalopram Z The implication seems to be that citalopram gave clearer results than acamprosate. We feel that this apposition of the two studies is unfair, or rather incomplete. The acamprosate study was a large-scale multicentre investigation in severely dependent alcoholism, patients being evaluated for relapse three months after .weaning from alcohol. The aim was to approximate to a normal therapeutic setting. We had a 38% drop-out rate. Five (not one) tests were significantly in favour of acamprosate and five more, including the patient and physician evaluations, had a p between 0-05 and 0-10. No test was in favour of placebo, even at the 0-10 level. One of our problems was that there is no universally accepted criterion, clinical or biological, for treatment success in alcoholism. Monitoring daily alcohol intake and/or obtaining daily urine samples was not feasible, given the numbers of centres and patients. Naranjo’s single-centre study was in "problem drinkers" recruited by advertisements: only 1 had signs of alcohol dependence. No weaning was attempted, and the participants had to complete daily diary cards and send in daily urine specimens. The study had a crossover design and each treatment period lasted a month. Abstinent days were counted and alcohol ingestion on non-abstinent days was monitored: there was a mean reduction in the number of daily drinks from about 6-5 with placebo to 6 with citalopram 40 mg (the exact numbers are not given). Although this change is significant, its clinical relevance to the treatment of alcoholism or alcohol dependence remains to be shown. Even though that study was more experimental than therapeutic, it also had a high drop-out rate (34%). Since 1987, Naranjo’s group had published two other studies of serotonin uptake inhibitors (viqualine3and fluoxetine4) in similar patients. Your editorial could have mentioned these: they used essentially the same procedure, except that the fluoxetine study used a parallel rather than a crossover design. Viqualine at the higher dose of 200 mg daily resulted in a significant reduction in mean daily drinks from 7-7 to 64; the drop-out rate was 38%. Fluoxetine did not have any significant effect compared with placebo (in a less powerful parallel design in only 29 patients), though 60 mg fluoxetine seemed more effective than 40 mg; there was a 30% drop-out rate. Despite much emphasis on the potential of serotonin uptake inhibitors in the treatment of alcoholism5,6 there has been no study of their effects in dependent alcoholics. We need results obtained from large-scale randomised studies in dependent alcoholics and data on the effects of acamprosate on drinking behaviour in the problem drinkers of the sort Naranjo’s team has studied before any comparison, explicit or implicit, of these drugs is made. Fluoxetine is the only one of these serotonin uptake inhibitors to be marketed; Acamprosate is marketed in France, specifically for the prevention of alcohol relapse, and is being studied in other European countries, including the UK.
SIR,-Your acamprosate1
Since 1987, other studies have been published on drug treatment of alcohol abuse and dependence (eg, with calcium carbamide and lithium) but the only trial we have found that bettered the results we had initially with acamprosate7 is a study of bromocriptine,8 in which the relapse rate at the sixth month was 5 % on bromocriptine and 60% on placebo. Only 8 of the 50 patients who entered the
study dropped out (16%). What we would like to emphasise is the very small number of well-conducted clinical trials of drug treatment of alcoholism and the difficulties of such studies, including high drop-out rates (10% drop-outs or less is a marker of a high-quality trial in this respect) and the lack of clear-cut endpoints. This paucity of trials is unfortunate, in view of the huge cost of alcoholism in terms of morbidity, mortality, and social disruption. If as much effort were put into the methodological and practical issues of the treatment of alcoholism as has been put, for example, into the treatment of hypertension or hypercholesterolaemia, the gains to public health could be tremendous. of Pharmacology and Alcohol Treatment Unit, Hôpital de Boisguillaume, 76233 Boisguillaume, France
Department
N. MOORE C. LIBERT
30
one
1. Lhuintre JP, Moore N, Tran G, et al. Acamprosate appears to decrease alcohol intake in weaned alcoholics. Alcohol Alcoholism 1990; 25: 613-22. 2. Naranjo C, Sellers E, Sullivan J, Woodley D, Kadlec K, Sykora K. The serotonin uptake inhibitor citalopram attenuates ethanol intake. Clin Pharmacol Ther 1987, 41: 266-74. 3. Naranjo C, Sullivan J, Kadlec K, Woodley-Remus D, Kennedy G, Sellers E. Differential effects of viqualine on alcohol intake and other consummatory behaviors. Clin Pharmacol Ther 1989; 46: 301-09. 4. Naranjo C, Kadlec K, Sanhueza P, Woodley-Remus D, Sellers E. Fluoxetine differentially alters alcohol intake and other consummatory behaviors m problem drinkers. Clin Pharmacol Ther 1990; 47: 490-98. 5. Naranjo C, Sellers E. Serotonin uptake inhibitors attenuate ethanol intake in problem drinkers. Recent Dev Alc 1989; 7: 255-66. 6. Meyer R. Prospects for a rational pharmacotherapy of alcoholism J Clin Psychiatry
1989; 50: 403-12. J, Daoust M, Moore N,
7. Lhuintre a
GABA agonist,
to
prevent
al. Ability of calcium bis acetyl homotaurine, relapse m weaned alcoholics. Lancet 1985; i:
et
1014-16.
8.
Borg V. Bromocriptine in the treatment of alcohol abuse. Acta Psychiatr Scand 1983; 68: 100-10.
Moderate alcohol
consumption
SIR,-Professor Shaper (April 13, p 911) seeks to explain the association between moderate alcohol consumption and lower mortality on the basis that non-drinkers tend to be sicker than drinkers. However, he has misrepresented the data from the Nurses’ Health Study.l He reports that non-drinkers in that cohort are less healthy than drinkers because they had a higher prevalence of diabetes, hypertension, obesity, and high blood cholesterol. These women- had a lower prevalence of current smoking, and Shaper infers that this too is a sign of ill-health, believing that it suggests a higher proportion of former smokers. However, it is current, not past, smoking that confers most of the smoking-related risk of coronary heart disease (CHD). Anyway, the non-drinkers had the lowest prevalence of former smoking. Because of the high prevalence of smoking and its. large impact on CHD risk, the drinkers are actually at higher CHD risk overall than the non-drinkers, apart from their alcohol intake. The distribution of risk factors by alcohol category is shown in table i: the large difference for smoking more than counterbalances the smaller differences in other risk factors. In multivariate analyses, adjustments for these risk factors further revealed the apparent benefit of moderate alcohol that was partly obscured by the heavy smoking among the drinkers. Shaper further claims that the trend we observed was driven by the non-drinkers and heavy drinkers, with little trend between. Not so. The multivariate relative risks are shown in table n. Even without the non-drinkers, there is a two-fold difference between the lightest and heaviest categories. The middle three categories with relative risk of 0-6 are fine gradations and correspond approximately to the category of light drinkers in Shaper’s classification scheme. Had we used his scheme, we would have observed relative risks of 1-0, 0-8, 0-6, and 0’4 for successive categories of alcohol intake. It is important to note that the highest
