Alcohol Withdrawal Syndrome: Treatment and Assessment of Therapeutic Efficacy

Transcription

1 J Int Med Res (1979) 7,174 Alcohol Withdrawal Syndrome: Treatment and Assessment of Therapeutic Efficacy Juhani Janne, MD, Associate Professor ofbiochemistry, University ofhelsinki, Finland Laila Malinen, MSci, elba-geigy, Medical Department, Helsinki, Finland The acute alcohol withdrawal syndrome is a disease of many different symptoms. Although the metabolism of ethanol is well-known, no specific treatment of the withdrawal syndrome has been developed. When assessing the therapeutic efficacy ofdrugs in this syndrome one ofthe main symptoms to be followed is sleep disturbances, because inability to sleep often maintains the drinking cycle. Besides different target symptoms, the visual analogue scale and the ability to work are useful parameters. The assessment of the efficacy relies mainly on subjectiveparameters and comparisons with placebo are needed. Introduction The acute withdrawal syndrome associated with prolonged drinking has been known for a long time as a disease entity requiring some kind of treatment. The diversity (psychic and somatic) and the number (up to thirty) of the symptoms associated with the syndrome have greatly complicated the development of a specific treatment for this condition. This may appear somewhat surprising because we know quite well the fate and metabolism of ethanol in the human body. Metabolic changes produced by ethanol The biochemistry of ethanol in mammalian liver is extremely simple, only involving two Requests for reprints should be addressed to: Juhani Janne, MD, Associate Professor, University of Helsinki, Department of Biochemistry, Unioninkatu 35, SF-OOI70HELSINKI 17, Finland oxidation or dehydrogenation reactions leading to the formation of acetate via acetaldehyde. This simple reaction chain, however, causes a number of well-established metabolic changes in man, but only a few of them correlate with the intensity of withdrawal symptoms (Table 1). When taken together with alcohol, disulfiram (Antabuses) causes very unpleasant symptoms, resembling withdrawal symptoms. It inhibits acetaldehyde dehydrogenase thus resulting in an accumulation of acetaldehyde. However, acetaldehyde itself appears not to be responsible for the symptoms as there is no correlation between the levels of acetaldehyde and the intensity of the withdrawal symptoms (Ylikahri et al 1974a). Nor is there any correlation between the well-known alcoholinduced hypoglycaemia and the intensity of the symptoms (Ylikahri et ai1974a). The same holds true for the increased blood lactate and the enhanced formation of ketone bodies (Ylikahri et al 1974a, Ylikahri et at 1976) as /79/ $02 00 Cambridge Medical Publications Limited

2 J Jdnne and L Malinen 175 Table 1 Metabolic changes associated with the alcohol withdrawal syndrome (see also the text) Correlation with the intensity of the symptoms References Acetaldehyde none Ylikahri et al1974a Hypoglycaemia none Ylikahri et al1974a Lactate none Ylikahri et al1974a Ketone bodies none t Ylikahri et al1976 Electrolytes none Ylikahri et al1974b Metabolic acidosis + Ylikahri et al1974b Respiratory alkalosis + (-+ convulsions) Victor 1973 Low serum Mg++ Victor (-+ convulsions) Sullivan et al 1969 Increased catecholamines possibly Unpublished results well as for the established changes of electrolyte concentrations (Ylikahri et al 1974b). There is, however, some correlation between the degree of metabolic acidosis and the intensity of the symptoms (Ylikahri et al 1974b). The idea that acidosis would be a causal factor is unlikely since the correction of the ph status does not improve the symptoms (Ylikahri et ai1976). The intensity of the withdrawal syndrome developed after prolonged drinking appears to correlate with respiratory alkalosis, which itself lowers the threshold of convulsions (Victor 1973). The same holds true for the low levels of serum magnesium often associated with chronic abuse of alcohol and with the withdrawal syndrome (Sullivan et al 1969, Victor 1973). There are a few reports indicating that the administration of magnesium may have beneficial effect on withdrawal symptoms (Mendelson, Ogata & Mello 1969, Victor 1973). However, low serum magnesium concentration is not always found among alcoholics (Heaton et al 1962, Martin, McCuskey & Tupikova 1959). The withdrawal syndrome is also characterized by an excessive sympathetic activity, which certainly contributes to some of the autonomic symptoms of the syndrome. According to our experience, the increase in plasma catecholamines in response to ethanol and during hangover is quite modest (unpublished results) and does not directly support the idea that catecholamines would be exclusively responsible for the syndrome. In summary, it appears unlikely that any single metabolic change would create the whole syndrome. However, metabolic changes, such as respiratory alkalosis and low serum magnesium, may be responsible for the decreased threshold for convulsions commonly associated with the alcohol withdrawal syndrome. Symptoms ofthe withdrawal syndrome The alcohol withdrawal syndrome consists of many symptoms of different types (Tables 2 and 3). Symptoms coming from the autonomic nervous system include sweating, tremor, anorexia, vomiting and nausea. Among the psychic symptoms, restlessness, depression, anxiety and especially sleep disturbances are exceedingly common. Treatment ofthe withdrawal syndrome The treatment of the syndrome is often rather a social than a medical problem, with the primary intention to get the patient back to work as soon as possible. However, one should also take into consideration that the mortality of developed delirium tremens may be as high as 10%. When selecting the treatment for the alcohol withdrawal syndrome it should be remembered that the syndrome is a self-curing disease of short duration and that the treatment is not the

3 176 The Journal ofinternational Medical Research Table 2 Somatic symptoms of the withdrawal syndrome Glatt Asander Bjorkqvist Ritola et al et al Symptom (n = 97) (n = 78) (n =105) (n = 68) Sweating Tremor Dizziness 43 Headache Cardiovascular symptoms Anorexia Vomiting and nausea Gastro-intestinal symptoms Table 3 Psychic symptoms ofthe withdrawal syndrome Glatt Asander Bjorkqvist Ritola et al et al Symptom (n = 97) (n = 78) (n = 105) (n =68) Restlessness Sleep disturbances Discontinued sleep 81 Difficulties in falling asleep 68 Nightmares Depression Fear and anxiety Aggression Hallucinations 5 II treatment of alcoholism but is aimed at stopping the drinking period. The ideal drug (i) should not have any interaction with alcohol nor (ii) any addiction-inducing properties. It should (iii) be effective in target symptoms and (iv) preferably prevent the potentially fatal delirium tremens. One of the possibilities is the concept of 'soft landing', i.e, treatment of the syndrome with decreasing doses of alcohol. At least we know that it does not have any unpredictable interactions with alcohol itself, and it is most probably effective in the target symptoms of alcohol withdrawal. In fact, this possibility has been explored (Golbert et al 1967, Schmitz 1978), but it appears that in most cases alcohol is not the treatment of choice. The reasons are surprisingly pharmacological: (i) the duration of its effect is far too short and (ii) its therapeutic index is too narrow (Golbert et al 1967). In addition, it continues the existing metabolic disturbances. These limitations of alcohol as a drug are quite unexpected, especially if you think of the common use of alcohol for enjoyment and relaxation. Nevertheless, under strictly controlled conditions alcohol can be used in the prevention and treatment of the alcohol withdrawal syndrome (Schmitz 1978). Barbiturates possess sedative and anticonvulsive properties, which should be important in the treatment of alcohol withdrawal syndrome. However, barbiturates are cross-addictive with alcohol and there

4 J Jdnne and L M alinen exists cross-tolerance of alcohol and barbiturates. If sleeping disturbances are considered as a major symptom associated with the withdrawal syndrome, there is an important disadvantage in using barbiturates for treatment. Just like alcohol, barbiturates suppress the REM-sleep, and may give rise to a rebound phenomenon similar to that observed upon alcohol withdrawal (Greenblatt & Greenblatt 1972). As evidenced by expressive mortality and induction of convulsions, phenothiazines should probably not be used in the treatment of the alcohol withdrawal syndrome (Schmitz 1978). Also paraldehyde, a polymer of acetaldehyde, which is a sedative and crossaddictive drug, appears to be rather oldfashioned (Schmitz 1978). Benzodiazepines are cross-reactive and cross-addictive with alcohol and are effective anti-convulsives, but only when given intravenously (Schmitz 1978). Chlormethiazole (Heminevrin'") has been widely used in Europe. This drug, which is certainly effective in the withdrawal syndrome (Glatt, George & Frisch 1966, Asander 1966) is addictive and there have been several reports of deaths associated with the use of the drug in Finland (Pentikainen, Valtonen & Miettinen 1975). The use of carbamazepine (Tegretol'") in the alcohol withdrawal syndrome is the topic of the paper by Sillanpaa & Sonck (I979) which appears in this issue of the Journal of International Medical Research (page 168). 177 Assessment oftherapeutic efficacy For the assessment of the therapeutic efficacy of a given medication one has to have some target symptoms to be followed. According to our experience, one of the most critical symptoms is the sleep disturbances. It is likely that inability to sleep maintains the drinking cycle since many of the patients appear to drink to get sleep. After alcohol is suddenly withdrawn, some kind of rebound effect occurs greatly amplifying the REM-sleep thus possibly causing nightmares (Greenblatt & Greenblatt 1972). Therefore, in some of our trials special weight has been given to the sleep disturbances as a parameter for the assessment of the therapeutic efficacy (Bjorkqvist et at 1976, Poutanen 1978). This can be done, for instance, by dividing the sleep disturbances in to several subgroups with independent scoring. The excessive sympathetic activity commonly associated with the withdrawal syndrome usually rapidly subsides without any treatment, and is, thus, quite useless as a follow-up parameter. The quantitation of psychic symptoms is likewise quite difficult, but is, of course, possible. Because of the great diversity of the symptoms, it was of special interest whether this kind of heterogeneous mixture of psychic and somatic symptoms could be measured globally using a visual analogue scale (VAS) (Figure 1). In one of our trials (Sonck, Malinen & Janne 1975) we have compared total 3 point symptom scores and VAS-measures. As expected, a highly significant correlation was Visual analogue scale the condition could not be worse Global evaluation of the condition the condition could not T be better x i 1-0( cm ~I Fig I Visual analogue scale

5 178 found between the average symptom scores and VAS-measures during the treatment. In the light of these results the visual analogue scale appears to be a reliable global measure in a syndrome consisting of diverse symptoms. A possible disadvantage of the visual analogue scale (or of any of this kind of global evaluation) is that it also includes possible unwanted effects of the drug and does not necessarily represent the progress of the disease condition itself. In addition to the conventional symptom scores and VAS-measures there exists a simple but valuable question to be asked: 'Would you be able to start your normal work today?' Especially from the social point of view the assessment of the withdrawal patient's ability to work appears to be a useful parameter for the follow-up of the therapeutic efficacy of the treatment. Discussion It should be remembered that the withdrawal syndrome usually is (i) a self-curing syndrome of relatively short duration which, however, should be treated in order to stop the cycle and (ii) there are a few, if any, objective parameters to assess the efficacy of a given treatment. Therefore any drug intended to be used in the treatment of the alcohol withdrawal syndrome should be primarily tested against placebo under actual field conditions. Unfortunately this is not the case for most of the treatment regimens currently used for the syndrome. REFERENCES Asander H (1966) Ambulatory treatment of alcoholic patients with chlormethiazole. Acta Psychiatrica Scandinavica Supplement 192,42, 121 Bjorkqvlst S-E, Isohannl M, Makela R & Malinen L (1976) Ambulant treatment of alcohol withdrawal symptoms with carbamazepine: a formal multicentre double-blind comparison with placebo. Acta Psychiatrica Scandinavica 53, 333 Glatt M M, George H R & Frisch E P (1966) Evaluation of chlormethiazole in treatment for alcohol withdrawal syndrome. A eta Psychiatrica Scandinavica Supplement 192,42,121 Golbert T M, Sanz C J, Rose H D & Leitschuh T H (1967) Comparative evaluation of treatments of alcohol withdrawal syndromes. Journal ofthe American Medical Association 201, 99 The Journal ofinternational Medical Research Greenblatt D J & Greenblatt M (1972) Which drug for alcohol withdrawal? The Journal ofclinical Pharmacology and New Drugs 12,429 Heaton F W, Pyrah L N, Beresford C C, Bryson R W & Martin D F (1962) Hypomagnesaemia in chronic alcoholism. Lancet 1,802 Martin H E, McCuskey C & Tupikova N (1959) Electrolyte disturbance in acute alcoholism, with particular reference to magnesium. American Journal of Clinical Nutrition 7, 191 Mendelson J H, Ogata M & Mello N K (1969) Effects of alcohol ingestion and withdrawal on magnesium states of alcoholics: Clinical and experimental findings. Annals of the New York Academy ofsciences 162, 918 Pentlkalnen P, Valtonen V & Miettinen T (1975) Kuolemantapaukset klometiatsolihoidon (Heminevrin )yhteydessa. Duodecim 91, 1319 Poutanen P (1978) Experience with carbamazepine in the treatment of withdrawal symptoms in alcohol abusers. British Journal ofaddiction, 73, (in press) Ritola E (1975) Klometiatsolin (Heminevrin ) ja karbamatsepiinin (Tegretol ) kaksoissokkovertailu k atkaisuhoidossa. In: Alkoholistien katkaisuhoito. Ed. by U G Ahlfors and J Janne, p. 51. GEIGY, Helsinki. Schmitz R E (1978) The prevention and management of the acute alcohol withdrawal syndrome by the use of alcohol. In: Currents in alcoholism. Biological, Biochemical and Clinical Studies. Vol. III. Ed. by F A Seixas, p Grune & Stratton, New York. Sillanpaii M & Sonck T (1979) Finnish experiences with carbamazepine in the treatment of acute withdrawal symptoms in alcoholics. The Journal ofinternational Medical Research 7,3, 168 Sonck T, Malinen L & Jiinne J (1975) Carbamazepine in the treatment of acute withdrawal syndrome in alcoholics: Methodological aspects. In: Rationality of drug development. Excerpta Medica International Congress Series No. 383, p Excerpta Medica, Amsterdam. Sullivan J F, Wolpert P W, Williams R & Egan J D (1969) Serum magnesium in chronic alcoholism. Annals ofthe New York Academy ofsciences 162,947 Victor M (1973) The role of hypomagnesemia and respiratory alkalosis in the genesis of alcohol withdrawal symptoms. In: Alcoholism and the Central Nervous System. Ed. by F Seixas. Annals ofthe New York Academy ofsciences 215,235 Ylikahri R H, Huttunen M 0, Eriksson C J P & Nikkilii EA (1974a) Metabolic studies on the pathogenesis of hangover. European Journal ofclinical Investigations 4, 93 Ylikahri R H, Leino T, Huttunen M 0, Poso A R, Eriksson C J P & Nikkila E A (1976) Effects of fructose and glucose on ethanolinduced metabolic changes and on the intensity of alcohol intoxication and hangover. European Journal of Clinical Investigations 6, 93 Y1ikahri R H, Poso A R, Huttunen M 0 & Hillbom M E (1974b) Alcohol intoxication and hangover: Effects on plasma electrolyte concentrations and acid-base balance. Scandinavian Journal of Clinical Laboratory Investigation 34, 327