Rates of antiepileptic drug reduction in active epilepsy — current practice

EpilepsyRes., 1 (1987) 357-364

357

Elsevier ERS 00152

Rates of antiepileptic drug reduction in active epilepsy current practice John S. Duncan and Simon D. Shorvon Institute of Neurology, Queen Square, London WCIN 3BG (U.K.), and Chalfont Centrefor Epilepsy, Chalfont St. Peter, Buckinghamshire SL9 0LR (U. K.) (Received 23 February 1987; accepted 27 March 1987)

Key words: Antiepileptic drug withdrawal; Active epilepsy; Phenytoin; Carbamazepine; Sodium valproate; Phenobarbitone

We have surveyed the rates at which clinicians in the U.K. and Eire withdraw antiepileptic drugs (AEDs) in patients with active epilepsy. Practice differed widely and there was a lack of consensus regarding the rates employed. Inpatient reductions were 2-4 times faster than outpatient reductions. AED reductions tended to be slower if reduction was from 2 to 1, than 4 to 3, agents; and in patients with adverse risk factors. In general, non-sedating AEDs were not reduced more quickly than was phenobarbitone.

INTRODUCTION The withdrawal of an antiepileptic drug (AED) from combination therapy in a patient with active epilepsy is a common clinical requirement; either when one A E D is being changed for another or when polytherapy is being reduced. In recent years there have been several studies of reduction of polytherapy 1'3'4'6'11'12'26'3°'31'32'36'37'39. Most reports do not detail the rates of reduction used, and the range of time taken, when given, extends from 7 days to 12 months. At a recent symposium it was recommended that, in active epilepsy, A E D decrements be made every 4 weeks in steps of 25 mg for phenobarbitone, 125 mg for primidone, 50 mg for phenytoin, 100 mg for carbamazepine, 200 mg for Correspondence to: Dr. J.S. Duncan, Department of Neurology, Radcliffe Infirmary, Oxford OX2 6HE, U.K.

sodium valproate and 250 mg for ethosuximide 33. Other recommendations have been for monthly reductions of 30 mg phenobarbitone, 100 mg phenytoin, 200 mg sodium valproate and 200 mg carbamazepine 2. In contrast, the discontinuance of an AED over 7 days has also been recommended7; there is clearly a lack of consensus, and several recent reviews and texts do not address this problem9,18,23-25,29,41. The main concern when reducing an A E D is that a serious exacerbation of seizures or status epilepticus may result, and it is generally held that such a risk is greater if reduction is rapid. The roots of these concerns may be identified hs follows: (1) Abrupt withdrawal of alcohol, benzodiazepines, barbiturates or other sedative drugs may precipitate seizures, even in a person with no prior history o f epilepsy5'8'17't9-22'42, (2) In patients with epilepsy, even gradual with-

0920-1211/87/$03.50 ~) 1987 Elsevier Science Publishers B.V. (Biomedical Division)

358 drawal of barbiturates has been reported to result in serious worsening of seizure control 13A6'34'35. (3) It has been demonstrated in patients, being considered for surgical treatment of their epilepsy, that rapid reduction of non-sedating AEDs, as well as phenobarbitone, may precipitate sei-

Phenobarbitone + Phenytoin + Carbamazepine + Sodium valproate

Dose (mg/day)

Serum level (#mol/l)

Therapeutic range (pmol/I)

180 350 1000 2500

140 67 47 482

Up Up Up Up

to to to to

17{) 8¢) 50 7{X}

z u r e s l O,la A 5,27,28,38

To ascertain current practice, regarding rates of AED reduction, a survey has been made of all consultant neurologists, and other physicians with expertise in epilepsy, in the U.K. and Eire. It must be emphasized that this survey was concerned with A E D reduction in patients with active epilepsy, and not with total withdrawal of AEDs from patients who were in remission.

METHOD After a pilot study, a questionnaire was sent to all 260 consultant neurologists, and other consultants with expertise in epilepsy, in the U.K. and Eire (as identified by membership of the Association of British Neurologists and/or the International League against Epilepsy). As complete coverage was attempted, this number will undoubtedly have included many doctors who were not in active practice, and who would not have been expected to reply. Questionnaires consisted of 3 case histories with questions about the rates at which specified A E D reductions would be made. Consultants were not asked whether they would or would not initiate the specified changes but, given the decision, to indicate the rates of reduction that they would employ; specifying the size of, and the intervals between, decrements; for both inpatients and outpatients. The case histories were as follows: (1) A 24-year-old unemployed female has had a seizure disorder since meningitis at age 1 year and currently has 10 complex partial seizures and 4 generalized convulsions each week. She has an IQ of 70, a hemiparesis and is depressed. Status epilepticus occurred 2 years ago when she discontinued her medication. All conventional AEDs have been used in optimum doses. Current medication is:

A decision is made to reduce therapy to three of the above AEDs to limit chronic adverse drug effects. Specify sizes of dose decrement and the interval between decrements that would be used to discontinue each 1 of the 4 AEDs above, leaving the other 3 unchanged. (2) The same patient, but only taking two of the above AEDs, and to reduce to monotherapy. Specify sizes of dose decrement and interval between decrements that would be used to discontinue each one of the above AEDs, leaving her on monotherapy. (3) A 28-year-old accountant has had a seizure disorder since age 14 years and continues to have a complex partial seizure every 7 weeks despite treatment with an optimal dose of one of the following AEDs.

Phenobarbitone + Phenytoin + Carbamazepine + Sodiumvalproate

Dose (mg/day)

Serum level (umol/l)

Therapeutic range (~mol/l)

180 350 1400 25(X}

160 70 5(1 580

Upto Up to Up to Up to

17(I 80 50 700

Otherwise, he is well, IQ 130, with no neurological deficit or psychosocial problems. A decision is made to change the treatment to monotherapy with another AED. After a second A E D has been started and increased to yield optimal serum levels, what size of decrement and what interval between decrements would be used to discontinue the initial A E D ? If this patient also had a generalized convulsion every 12 weeks, would reduction schedules be slower? Statistical analysis

The durations of the reduction periods of the 4 AEDs in the 3 cases were compared with Fried-

359 man's two-way analysis of variance by ranks and Wilcoxon's matched-pairs signed-ranks test. Computation was with the Statistical Package for the Social Sciences (SPSS-X) at the University of London Computer Centre. RESULTS One hundred and thirty-eight replies were received from 260 enquiries (53%), with 116 (45%) completed questionnaires. The ranges of duration of reduction, means, medians and modal size of dose decrement are summarized in Table I and sample distributions in Figs. 1-3. The very wide

ranges of time taken to effect removal of individual AEDs are readily apparent.

Median reduction regimens The median regimens for reducing each A E D in the 3 cases were determined from the median durations of reduction and the modal size of dose decrement (Table II).

Comparison between inpatient and outpatient In all cases, some consultants indicated that they would stop an A E D abruptly if the patient was in hospital. The other extreme for inpatient reduction was about 1 year. The range for outpatient re-

TABLE I

Time taken to remove individual A E D s

A E D removed

Inpatient/ outpatient

Duration o f reduction (weeks)

Range

Mean

Median

Modal dose decrement (mg)

(N = 116) Case 1

Phenobarbitone 180 mg Phenytoin 350 mg Sodium valproate 2500 mg Carbamazepine 1000 mg

IP OP IP OP IP OP IP OP

0-48 1-88 0-56 2.5-56 0-50 1-75 0-39 2-60

8.1 19.5 7.4 15.8 7.6 17.1 6.6 14.0

5 20 5 12 4 12 4 9

30 30 50 50 500 500 200 200

IP OP IP OP IP OP IP OP

0-48 1-120 0-56 2.5-78 0-100 0.5-150 0-78 2-117

9.4 23.3 9.5 19.1 9.2 22.9 8.2 18.7

5 20 6 12 5 13 4 16

30 " 30 50 50 500 200 200 200

IP OP IP OP IP OP IP OP

0-44 0.5-87 0-56 2-112 0-50 0.5-150 0-56 2-170

8.7 19.3 7.0 16.1 8.3 20.0 8.3 20.3

5 13 6 12 4 12 6 12

30 30 50 50 500 500 200 200

Case2

Phenobarbitone 180 mg Phenytoin 350 mg Sodium valproate 2500 mg Carbamazepine 1000 mg

Case3

Phenobarbitone 180 mg Phenytoin 350 mg Sodium valproate 2500 mg Carbamazepine 1400 mg

360

20_ CASE 1 SODIUM VALPROATE 2500rag 4~

0~rPATI~E

~15_ C

o

10

! !

!

!

10

8/7

15

,,F1|

I--1

I

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|

2O

25

45

,,II KI 50

75

Weeks Fig. 1. Time taken to discontinue sodium valproate 2500 mg, in case 1, as an outpatient.

duction was a few days to 1-3 years. Overall, inpatient reduction was 2-4 times quicker than the same drug change being made as an outpatient (P < 0.0001).

Comparison between cases Effect of number of AEDs taken. The times taken to make all drug reductions, inpatient (IP) and

outpatient (OP), were longer in case 2 (2-1 AEDs) than in case 1 (4-3 AEDs) (phenobarbitone IP P = 0.0002, OP P = 0.0004; phenytoin IP P < 0.0001, OP P = 0.0002; sodium valproate IP P = 0.006, OP P < 0.0001; carbamazepine IP P = 0.002, OP P < 0.0001). Effect of patient risk factors. The times taken to effect 4 of 6 comparable reductions, of 2-1 AEDs,

TABLE II

Medianreductionregimens AED Phenobarbitone Phenytoin Sodium valproate Carbamazepine

IP OP IP OP IP OP IP OP

C~el

C~e2

C~e3

30 mg weekly 30 mg 4 weekly 50 mg weekly 50 mg 2 weekly 500 mg weekly 500 mg 3 weekly 200 mg weekly 200 mg 2 weekly

= = = = = 200 mg weekly = 200 mg 4 weekly

= 30 mg 3 weekly = = = 500 mg 3 weekly = 200 mg 2 weekly

361

25. CASE 3 CJ~,BAI'f~.Z~,gn~ lh0Oml~ OVI'~tL~IX~T

°2o.

10.

5.

h rr-

Fi

n

n '20

'25

55

36

78 Weeks

Ih5

170

53

65

Fig. 2. Time taken to discontinue carbamazepine 1400 rag, in case 3, as an outpatient.

20

CASE 3

q

i~S~OBA~r~O~ 1 8 o ~

0VI~PATI~IT

I '~15

3o

ro o

10

nl F

5

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10

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it

25

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35

II

Weeks

Fig. 3, Time taken to discontinue phenobarbitone 180 mg, in case 3, ~ :m • .~atient.

8?

362 were longer in the case with adverse risk factors (case 2) than in the patient without such factors (case 3) (phenobarbitone OP P = 0.006; phenytoin IP P = 0.001, OP P = 0.03; sodium valproate OP P = 0.01). Carbamazepine reduction in cases 2 and 3 cannot be compared directly because of the different doses specified in these 2 cases.

Comparison between AEDs In cases 1 and 2 (inpatient) discontinuance of carbamazepine 1000 mg took less time than did the other AEDs (phenobarbitone 180 mg: P = 0.03 (case 1), P = 0.03 (case 2); phenytoin 350 mg: P = 0.03 (case 1), P = 0.01 (case 2); sodium valproate 2500 mg: P = 0.02 (case 1), P = 0.01 (case 2)). In the same cases, as outpatients, reduction of carbamazepine took a shorter time than did sodium valproate 2500 mg (P = 0.001 (case 1), P = 0.0001 (case 2)) or phenobarbitone 180 mg (P = 0.0001 (case 1), P = 0.001 (case 2)). In case 3, reduction of carbamazepine 1400 mg took longer than phenytoin 350 mg (IP P = 0.03; OP P = 0.01). There were no other significant differences between the durations of reduction of AEDs in the 3 cases. Effect of generalized convulsions on reduction rates One hundred and one consultants answered the question of whether A E D reduction rates in case 3 would be different if the patient also had generalized convulsions. Ninety-one indicated that schedules would not be different and 10 indicated that they would proceed more slowly. DISCUSSION This investigation was undertaken to determine whether, in clinical practice, reduction rates of the individual AEDs differed from each other, and to identify factors which influenced rates of reduction. The wide range of times taken to discontinue individual AEDs reflects a lack of consensus amongst experienced physicians regarding optimal rates of A E D reduction, when effecting drug changes in patients with active epilepsy (Table I and Figs. 1-3). A higher response rate to this survey could only have increased, and not decreased,

the diversity of opinion. The median reduction regimens (Table II) indicate 'middle of the road' practice, but clearly different physicians show widely varying preferences. The median reduction regimens of the individual drugs were similar in all 3 cases, with decremental steps of 1/5-1/7 of the total dose and decrements made weekly in inpatients and every 2-4 weeks in outpatients. Several factors were identified which influenced reduction rates. Inpatient reduction regimens were significantly faster (2-4 times) than outpatient schedules. Presumably, this was because it was felt that a greater risk of a serious exacerbation of seizures could be taken if the patient was under close supervision. Interpretation of these data should be cautious because, apart from patients in long-term institutions, it would be rare to make these drug changes in inpatients. Drug reductions were made significantly more slowly if 2drug treatment was being reduced to monotherapy than if 1 of 4 drugs was being removed. Reduction to monotherapy was usually made more slowly in the patient with adverse risk factors than in the patient without such factors. The doses of AEDs specified were, of course, arbitrary and apparent differences in the times taken to stop the 4 AEDs should not be over-interpreted. In the first 2 cases, removal of 1000 mg of carbamazepine generally took a shorter time than did removal of the other AEDs; whereas, in case 3, removal of 1400 mg of carbamazepine took a longer time than did 350 mg of phenytoin. It is noteworthy, however, that the time taken to discontinue non-sedating AEDs was generally no different from the time taken to reduce phenobarbitone, suggesting that the established practice of slow reduction of barbiturates may have influenced the rates at which non-sedating AEDs are tailed off, so that they too tend to be reduced very slowly. In conclusion, the principal factors influencing reduction rates appeared to be: inpatient or outpatient status, the number of AEDs being taken and, to a lesser extent, the presence or absence of adverse patient risk factors; rather than the type of A E D being removed. Occasional generalized convulsions, in an otherwise low risk patient, were not generally viewed as a risk factor.

363 The rationale for making AED reductions slowly is the belief that rapid reductions carry an increased risk of a serious exacerbation of seizures. There are, however, problems associated with making AED changes very slowly, over months or even years. It is difficult to supervise a patient closely over such a time, the patient and the prescribing doctor are liable to forget the schedule of changes and the underlying strategy, other doctors are liable to interfere with the strategy if a cluster of seizures occurs and intercurrent illnesses may mask the effect of the AED change. Further, if each drug change takes many months to accomplish, it may take years to explore different AED treatments that may benefit the patient. It must also be recognized that if a patient requires a particular AED, worsened seizure control will follow its removal, however slowly that is done. There are, then, several arguments in favour of making AED changes and reductions as quickly as can be done without causing serious exacerbation of seizures. The optimal rates of AED reduction to employ in clinical practice have not been clearly defined. It has been our suspicion that, in routine

practice, drug reductions are often made unnecessarily slowly, and this may be borne out by the resuits of this survey. Furthermore, there seems no a priori reason why the reduction rates of individual AEDs should be similar. Our finding that the nonsedating AEDs were treated in a similar manner to phenobarbitone, a drug well known to require slow reduction, suggests that experience with phenobarbitone may have influenced attitudes to other drugs; and that the generally slow reduction regimens are derived from this experience. To date, there have been no satisfactory studies of different rates of AED reduction and we are in the process of carrying out such investigations. Until such studies are completed, practice is bound to be empirical and rational schedules for AED reduction cannot be formulated.

REFERENCES

cents and adults. In: H.F. Conn (Ed.), Current Therapy, 1983, Saunders, Philadelphia, PA, 1983, pp. 707-717. 10 Engel, J. and Crandall, P.H., Falsely localizing ictal onsets with depth EEG telemetry during anticonvulsant withdrawal, Epilepsia, 24 (1983) 344-355. 11 Feely, M.P. and Callaghan, N., Changing to single drug therapy in epilepsy, Lancet, i (1981) 847. 12 Fischbacher, E., Effect of reduction of anticonvulsants on wellbeing, Brit. rned. J., 285 (1982) 423-424. 13 Fox, J.T., Luminal-sodium in the treatment of epilepsy, Lancet, ii (1927) 589-592. 14 Goldstick, L.P., Lesser, R.P., Ltiders, H., Morris, H.H. and Dinner, D.S., The need for anticonvulsant drug withdrawal in the diagnosis of supplementary motor seizures, Epilepsia, 26 (1985) 531. 15 Gotman, J. and Marciani, M.G., Electroencephalographic spiking activity, drug levels, and seizure occurrence in epileptic patients, Ann. Neurol., 17 (1985) 597-603. 16 Grinker, R.R., The proper use of phenobarbital in the treatment of the epilepsies, J. Amer. reed. Ass., 93 (1929) 1218-1219. 17 Hollister, L.E., Motzenbecker, F.P. and Degan, R.O., Withdrawal reactions from chlordiazepoxide ('Librium'), Psychopharmacologia (Berl.), 2 (1961) 63-68. 18 Hopkins, A., Epilepsy. In: D.J. Weatherall, J.G.G. Le-

1 Albright, P. and Bruni, J., Reduction of polypharmacy in epileptic patients, Arch. Neurol. (Chic,), 42 (1985) 797-799. 2 Brodie, M.J., Adverse effects of oral anticonvulsants, Prescr. J., 26 (1986) 17-25. 3 Callaghan, N., O'Callaghan, M., Duggan, B. and Feely, M., Carbamazepine as a single drug in the treatment of epilepsy, J. Neurol. Neurosurg. Psychiat., 41 (1978) 907-910. 4 Callaghan, N., O'Dwyer, R. and Keating, J., Unnecessary polypharmacy in patients with frequent seizures, Acta neurol. scand., 69 (1984) 15-19. 5 Chan, A.W.K., Alcoholism and epilepsy, Epilepsia, 26 (1985) 323-333. 6 Covanis, A., Gupta, A.K. and Jeavons, P.M., Sodium valproate: monotherapy and polytherapy, Epilepsia, 23 (1982) 693-720. 7 Dalessio, D.J., Seizure disorders and pregnancy, New Engl. J. Med., 312 (1985) 559-563. 8 De la Fuente, J.R., Rosenbaum, A.H., Martin, H.R. and Niven, R.G., Lorazepam-related withdrawal seizures, Mayo Clin. Proc., 55 (1980) 190-192. 9 Delgado-Escueta, A.V., Treatment of epilepsies in adoles-

ACKNOWLEDGEMENTS We are grateful to Ciba Geigy Pharmaceuticals and the Brain Research Trust for support for this study.

364

19 20

21

22

23 24

25

26

27

28

29

dingham and D.A. Warrell (Eds.), Oxford Textbook of Medicine, Oxford University Press, London, 1983, pp. 21.128-21.142. Howe, J.G., Lorazepam withdrawal seizures, Brit. reed. J., 1 (1980) 1163-1164. Isbell, H., Altschul, S., Kornetsky, C.H., Eisenman, A.J., Flanary, H.G. and Fraser, H.F., Chronic barbiturate intoxication, Arch. Neurol. Psychiat. (Chic.), 64 (1950) 1-28. Isbell, H., Fraser, H.F., Wikler, A., Belleville, R.E. and Eisenman, A.J., An experimental study of the aetiology of 'rum fits' and delerium tremens, Quart. J. Stud. Alcohol 16 (1955) 1-33. Kalinowsky, L.B., Convulsions in nonepileptic patients on withdrawal of barbiturates, alcohol and other drugs, Arch. Neurol. Psychiat. (Chic.), 48 (1942) 946-956. Laidlaw, J. and Richens, A., A Textbook of Epilepsy, Churchill Livingstone, Edinburgh, 1982. Leppik, I.E., Drug treatment of epilepsy. In: R.T. Johnson (Ed.), Current Therapy in Neurologic Disease 1985-1986, Dekker, Philadelphia, PA, 1985, pp. 41-46. Livingston, S., Comprehensive Management of Epilepsy in Infancy, Childhood and Adolescence, Thomas, Springfield, IL, 1972. Maheshwari, M.C. and Padmini, R., Role of carbamazepine in reducing polypharmacy in epilepsy, Acta neurol. scand., 64 (1981) 22-28. Marciani, M.G., Gotman, J., Andermann, F. and Olivier, A., Patterns of seizure activation after withdrawal of antiepileptic medication, Neurology (NY), 35 (1985) 1537-1543. Marossero, F., Cabrini, G.P., Sironi, V.A. and Baruzzi, A., Correlations of anticonvulsant plasma levels with depth EEG recordings in epileptic patients, Electroenceph. clin. Neurophysiol., 43 (1977) 527. Meinardi, H. and Magnus, O., Drug therapy, clinical application. In: O. Magnus and A.M. Lorentz de Haas (Eds.), The Epilepsies. Handbook of Clinical Neurology, Vol. 15, North-Holland Publ., Amsterdam, 1974, pp. 664-672.

30 Milano Collaborative Group for Studies on Epilepsy, Long term intensive monitoring in the difficult patient. Preliminary results of 16 months of observations - - usefulness and limitations. In: C. Gardner Thorpe, D. Janz, H. Meinardi and C.E. Pippenger (Eds.), Antiepileptic Drug Monitoring, Pitman, Tunbridge Wells, 1977, pp. 197-213. 31 Roman, E.J., Lambert, J.B., Buchanan, N. and Barrah, N., Rationalization of therapy in severe epilepsy, Aust. N.Z.J. Med., 13 (1983) 601-604. 32 Schmidt, D., Reduction of two drug therapy in intractable epilepsy, Epilepsia, 24 (1983) 368-376. 33 Schmidt, D., Withdrawal of antiepileptic drugs. In: Proc. 16th Epilepsy Int. Congr., 1987, in press. 34 Schmidt, D., Kupferberg, H.J., Porter, R.J. and Penry, J.K., Primidone withdrawal in patients with intractable epilepsy. In: J.A. Wada and J.K. Penry (Eds.), Advances in Epileptology. Xth Epilepsy Int. Symp., Raven Press, New York, 1980, p. 132. 35 Schmidt, G., Erscheinungen bei Luminalentzug, M~inch. med. Wschr., 85 (1938) 1944-1946. 36 Schobben, A.F.A.M., Pharmacokinetics and Therapeutics in Epilepsy, Stichting Studentenpers, Nijmegen, 1979, pp. 251-258. 37 Shorvon, S.D. and Reynolds, E.H., Reduction in polypharmacy for epilepsy, Brit. med. J., 2 (1979) 1023-1025. 38 Spencer, S.S., Spencer, D.D., Williamson, P.D. and Mattson, R.H., Ictal effects of anticonvulsant medication withdrawal in epileptic patients, Epitepsia, 22 (1981) 297-307. 39 Theodore, W.H. and Porter, R.J., Removal of sedative hypnotic antiepileptics from the regimens of patients with intractable epilepsy, Ann. Neurol., 13 (1983) 320-324. 40 Thompson, P.J. and Trimble, M.R., Anticonvulsant drugs and cognitive functions, Epilepsia, 23 (1982) 531-544. 41 Wilder, B.J., Drug therapy for seizures, Clin. Ther., 7 (1985) 246-253. 42 Wulff, M.H., The barbiturate withdrawal syndrome. A clinical and electroencephalographic study, Electroenceph. clin. Neurophysiol., Suppl. 14 (1959).