'Question Time' is meant to be a column in which common practical neurological and neurosurgical problems are to be discussed. The incentive for these most often concise discussions is to be provided by the readers. Therefore, we invite you to send us questions which arise during your daily practice. Either you will get a personal answer or if the problem is of wider interest, it will be discussed in this column by specialists.
It is traditional and common practice to treat epilepsy with a combination of two or more anticonvulsants. Presumably, it has been expected that this polypharmacy results in maximal efficacy, combined with minimal toxicity. Has this expectation been borne out by the facts in studies using blood level monitoring? Or is it preferable to treat epilepsy with a single drug? CLINICAL NEUROLOGY AND NEUROSURGERY MONOTHERAPY OF EPILEPSY
Among the therapies for patients, suffering from epileptic seizures, drug treatment is chosen most frequently. It is not uncommon that two or more anti-epileptic drugs are given concomitantly. In The Netherlands a randomly selected population of almost 5000 patients was receiving a mean of 3,76 drugs per patient in 1974, of which drugs over 80% were anticonvulsants (GUELEN and JOHANNESSEN, 1977). Different reasons are given for multiple drug treatment. If a patient fails to respond well on the existing therapy, another drug is added. When complete control of seizures in subsequently achieved, physicians are usually chary of discontinuing the drug(s) given previously. In other instances withdrawal seizures cause a hasty reinstitution of drugs the patient does not need any longer. It is also common practice to start treatment with a combination of drugs hoping that their therapeutic effects will summate while their toxic effects will not. Combination of anti-epileptic drugs often leads to unwanted and sometimes unex-
200 pected, adverse effects. Abundant literature is available on the topic of interactions of anti-epileptic drugs at the pharmacokinetic level (RICHENS, 1977; GUELEN and VAN DER KLEUN, 1978). Plasmaconcentrations of a drug even may be increased by 100% as has been reported for phenobarbital in combination with sodium valproate (SCHOBBEN et al., 1975), but also smaller changes may cause toxicity or serious side effects because of the narrow therapeutic range of most of these drugs. Addition of phenytoin to primidone therapy enhances the conversion of the latter drug into phenobarbital in vivo (REYr~OLDS, 1975). The supposed specific anti-epileptic activity of primidone itself then is negligible compared to that of its metabolite. It would be safer to replace primidone by phenobarbital in these instances. Drug interactions also may be more difficult to discover. If one drug replaces another from plasma albumin in binding sites, as may be the cause for sodium valproate and phenytoin (PATSALOSand LASCELLES, 1977), the concentration of the unbound drug in plasma increases. While total plasma concentrations may be unchanged or even lowered, the tissue concentrations and the related pharmacological effects, may be increased. So far increased side-effects parallel increased therapeutic effect. However, this is not always the case. Enzyme stimulation is a weUknown effect of some anti-epileptic drugs, especially of phenobarbital and carbamazepine. Addition of an enzyme inducing compound will usually increase the amount of metabolites in the body. Metabolites are thought resonsible for some of the side effects of carbamazepine and clonazepam (DAM, 1977; KNOPet al., 1977). Finally also at the receptor level potentiation or addition of the pharmacological effect may occur. Indeed several publications indicate a higher risk for side effects for combinations of drugs despite 'normal' plasmaconcentrations (SOMMERBEEKet al., 1977; KNOP et al., 1977). It may be clear now that the previously stated assumption that side effects of anti-epileptic drugs will not summate is not always valid. For the addition or potentiation of therapeutic effects on the other hand there is no scientific evidence. Of course interactions at the pharmacokinetic level can raise anti-epileptic activity but the same effect can be achieved in a more reliable and safe way by adjusting the dose of the drug in question. In many patients combinations of several anti-epileptic drugs are given, each to produce plasma levels that are generally accepted as therapeutic, without sufficient protection against epileptic seizures. Shorvon and Reynolds (1977) concluded from a retrospective study of 50 patients that only 36% had benefited from addition of a second drug to their previous phenytoin therapy. Interactions and effectiveness of the second drug on its own may be still responsible for the clinical improvement in a major part of these patients. The authors even wonder whether the observed results are significantly better than that which might have been obtained with a placebo. So the group of patients that really
needs more than one anticonvulsant appears to be rather limited. In a controlled prospective study REYNOLDSet al. (1976) succesfully treated 28 out of 31 previously untreated patients with phenytoin alone. In an identical study with carbamazepine comparable results were obtained: 85% of the patients were well controlled on this drug only (SHORVAN et al., 1977). Without use of plasmaconcentration determinations of anti-epileptic drugs, however, the score would have been considerably lower. In the few patients who continued to have seizures addition of further drugs did not make any significant difference so far. In our own experience the average anti-epileptic medication of a group of 38 'difficult' patients could be reduced from 2.8 to 2.0 drugs per patient until now with equal or improved clinical control. In the whole field of epilepsy treatment and research there is a trend to monotherapy. Patients should be treated with one drug, which should be increased in dose stepwise until desired control of seizures is reached or side effects or high plasmaconcentrations argue against it. Only when the most appropriate drugs have failed on their own, combinations of anti-epileptic drugs should be considered. This policy will make epilepsy treatment safer and more understandable. At the cost of the rise of a few more seizures during the search for the effective drug, the resulting therapy will be more reliable and less disagreeable for the epileptic patient at the long term. F. Schobben and E. van der Kleijn Department of Clinical Pharmacy, Radboud Hospital, Nijmegen, The Netherlands. REFERENCES
Discussion in: Antiepileptic drug monitoring, C. Gardner-Thorpe et al., Eds. Pittman Medical, London, 109. GUELEN, P.J.M. a n d JOHANNESSEN, S. (1977) Prescription pattern of antiepileptic drugs to epileptic patients: A comparison between The Netherlands and Norway In: Antiepileptic drug monitoring, C. Gardner-Thorpe et al., Eds. Pittman Medical, London, 345. GUELEN, P.J.M. a n d VAN DER KLEIJN, E. (1978) Rational antiepileptic drug therapy, Elsevier Biomed. Press, Amsterdam, (in press). DAM, M. (1977)
KNOP, a.J., EDMUNDS L.C., BLOM G.F., BRUENS, J.H., BONGERS, E., MEINARDI, H., MEYER, J.W.A,, GUELEN, P.J.M. and VAN DER KLEIJN, E. (1977) C l o n a z e p a m : A clinical trial. Pharmacokinetic and Clinical Aspects In: Antiepileptic Drug Monitoring, C. Gardner-Thorpe et al., Eds. Pittman Medical, London, 226 PATSALOS, P.N. a n d LASCELLES, P.T. (1977) Valproate may lower serum phenytoin, Lancet, 50. REYNOLDS, E.M. (1975) Longitudinal studies ofserum anti-epileptic drug levels. Preliminary observations; Interaction of phenytoin and primidone In: Clinical Pharmacology of anti-epileptic drugs. H . Schneider et al., Eds. Springer Verlag, Berlin, 79. REYNOLDS, E., CHADWlCH, D. a n d GALBRAITH, A.W. (1976) One drug (Phenytoin) in the treatment of epilepsy, Lancet, 924. RICHENS, A. (1977) Interactions with antiepileptic drugs, Drugs 1 3 , 2 6 6 . SCHOBBEN, F., VAN DER KLEIJN, E., a n d GABREELS, F.J.M. (1975) Pharmacokinetics ofdi-n-propylacetate in epileptic patients. E u r . J. Clin. Pharmacol., 8, 97. SHORVAN, S.A. a n d REYNOLDS, E.M. (1977) Unnecessary polypharmacy for epilepsy, Brit. M e d . J., 1635. SHORVAN, S., CHADWICK, D., GALBRAITH, A.W. a n d REYNOLDS, E.M. (1978) One drug for epilepsy. Brit. M e d . J., I, 474. SOMMERBECK, K.W., THEILGAARD, A., RASMUSSEN, K.E., LOHREN, V., GRAM, L. a n d WULFF, K. (1977) V a l p r o a t e sodium, evaluation of so-called psychotropic effect. A controlled study. Epilepsia 18, t59.