Epilepsiu, 33(2):34&352, 1992 Raven Press, Ltd., New York 0 International League Against Epilepsy

Nifedipine for Epilepsy? A Double-Blind, Placebo-Controlled Trial John G. Larkin, *Frank M. C. Besag, "Angela Cox, "fohn Williams, and Martin J. Brodie Epilep.psy Research Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland; "Lingjleld Hospital School, Lingfield, Surrey, England; TDepartment of Pharmacology and Therapeutics, University o f Wales College of Medicine, Card#; Wales

Summary: The movement of calcium into neurons may be the common denominator for the triggering and propagation of seizure activity. We report results of the first double-blind, placebo-controlled, crossover trial with the dihidropyridine calcium antagonist nifedipine (NFD) as adjuvant therapy in refractory epilepsy. Twenty-two students (12 male, 10 female, age 17-22 years) attending Lingfield Hospital School received NFD retard and matched placebo for 8 weeks in 2 doses (20 and 40 mg b.i.d. each for 4 weeks) with a washout period of 8 weeks between treatment phases. In the 20 students who completed the trial, fewer partial seizures (p < 0.05) were documented during the first 2 weeks of NFD administration. Similarly, fewer seizure days (p < 0.05) were reported in the first month of active treatment. This response was not sustained into the second month of the

trial. Blind scoring of EEGs suggested a small improvement with NFD (p < 0.05). More patients reported headache when receiving NFD (p < 0.02) than placebo, but heart rate and erect and supine blood pressure remained unaffected. Mean maximum NFD concentrations were 13.1 ? 10.4 ng/ml. A weak correlation was noted between total (p < 0.05) and partial (p = 0.025) seizure numbers and NFD concentrations following 8 weeks of treatment. This study does not support important anticonvulsant efficacy for NFD as adjuvant therapy for refractory epilepsy at doses appropriate for the treatment of angina or hypertension. Further trials are recommended using higher doses of NFD in less severely affected patients. Key Words: Nifedipine-AnticonvuIsants-Neurotransmitters-Calcium antagonists-Epilepsy-Clinical trials.

At a cellular level, release of excitatory neurotransmitters is dependent on calcium influx (De Lorenzo and Freedman, 1977), as is the abnormal action potential-the paroxysmal depolarizing shift (PDS) (Goldensohn and Purpura, 1963)-which initiates seizure activity (Wong and Prince, 1979). The PDS can be inhibited by calcium antagonists (Witte et al., 1987) or exacerbated by a calcium agonist (Walden et al., 1986). In animal models of epilepsy, flunarizine (Desmedt et al., 1975; Ashton and Wauquier, 1979; De Sarro et al., 1986, 1988), nimodipine (Morocutti et al., 1986; Meyer et al., 1987; De Sarro et al., 1988; D o h et al., 1988; Larkin et al., 1989; O'Neill and Bolger, 1989; Meyer et al., 1990), nifedipine (De Sarro et al., 1988; Larkin et al., 1989;

Wong and Rahwan, 1989), and nitrendipine ( D o h et al., 1988; Meyer et al., 1990) all possess anticonvulsant properties. There are few controlled clinical trials of calcium antagonists in epilepsy. Initial studies with flunarizine (FNR) suggested that it may have useful antiepileptic activity (Overweg et al., 1986). However, while one subsequent double-blind, crossover study confirmed this finding (Starreveld et al., 1989), others have reported only modest efficacy (Keene et al., 1989;Nakane et al., 1989) or none (Alving et al., 1989). It is likely that FNR does have some anticonvulsant activity, but that its extrapyramidal and sedative side effects (Binnie et al., 1985; Chouza et al., 1986) may discount its general use. Treatment with i.v. nimodipine abolished continuous focal epileptic seizures in two patients in whom conventional therapy was unsuccessful (Brandt et al., 1988). Other calcium antagonists, such as verapamil (Macphee et al., 1986) and diltiazem (Brodie and

Received August 1990; revision accepted March 1991. Address correspondence and reprint requests to Dr. M. J . Brodie at Epilepsy Research Unit, Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT, Scotland.

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Macphee, 1986), inhibit the hepatic metabolism of established anticonvulsants, making them difficult to use clinically. Nifedipine (NFD) is a dihydropyridine that has been in widespread clinical use for the treatment of hypertension and angina for many years. It does not inhibit drug metabolism (Bauer et al., 1986; Dickinson et al., 1988), and in a pilot open study appeared to reduce seizure frequency without altering anticonvulsant concentrations (Larkin et al., 1988).The anticonvulsant efficacy of NFD in refractory epilepsy was initially supported anecdotally (Sander and Shorvon, 1988), although more recent results with the drug by the same group have been disappointing (Sander and Trevisol-Bittencourt, 1990). Accordingly, we undertook a double-blind, placebo-controlled crossover study to investigate further the antiepileptic potential of this widely used calcium antagonist. PATIENTS AND METHODS Twenty-two students (12 male, 10 female; age 1722 years) with refractory epilepsy attending Lingfield Hospital School, Surrey, England, were recruited into the study. Fourteen suffered from complex partial seizures secondarily generalized, five from tonic-clonic seizures, and three from partial seizures alone. Most were receiving two (n = 9) or three (n = 11) antiepileptic drugs (AEDs). One young man was receiving carbamazepine (CBZ) monotherapy while another was being treated with four drugs. Informed consent was obtained for all students to take part in the trial, which was approved by the local ethical committee. The trial was conducted as a balanced, placebocontrolled, crossover study with an 8-week run-in period and an 8-week washout between treatment phases, each of which also lasted 8 weeks. Participants received either NFD tablets (Adalat Retard, Bayer), 20 mg, twice daily for 4 weeks, then 40 mg twice daily for a further 4 weeks, or matched placebo in a similar fashion. Previous anticonvulsant therapy was continued throughout the study in unchanged timing and dosage. Partial and generalized tonic-clonic seizures were recorded by staff at the school for the duration of the trial. At baseline and at two weekly intervals during the treatment phases, erect and supine blood pressures and heart rates were measured at 0900 and 1600 h each day. Students also completed a sideeffect profile. This consisted of questions on 15 specific symptoms either associated with NFD administration (e.g., flushing, headache, palpitations) or unassociated “dummy” symptoms (e.g., itching,

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dry mouth). These were graded as absent (O), mild (l), moderate (2), or severe (3). Blood was withdrawn around 1 h after the morning dose by venepuncture every 2 weeks for assay of NFD concentrations. Samples were centrifuged immediately and the serum stored in black plastic bags at - 25°C until batch analysis. NFD was measured by capillary gas chromatography using electron captive detection with nicardipine as internal standard. All procedures involved in sample extraction were performed under sodium light. The limit of detection was 1 ng/ml, and interassay coefficients of variation at 2.5, 10, and 20 ng/ml were 22.7, 5 , and 4.3%, respectively. A surface EEG was also performed every 2 weeks. These were graded by an experienced neurophysiologist in a blinded manner with reference to a “baseline” EEG for each student ( + 1 / + 2 = slight/definite improvement, - 1/ - 2 = slight/ definite deterioration). These were summed to produce an overall score for the active and placebo phases of the trial. Statistical comparisons between placebo and NFD phases of t h e trial were made using the Wilcoxon rank pairs test for nonparametric data. Power calculations using the equivalent parametric test-the paired Student t test-suggested a power of 0.95 to pick up a fall in total seizure numbers (at p < 0.05) of 50%, which was reported in the previous open study with NFD (Larkin et al., 1988). The power to detect a 25% fall was 0.6. Calculations were also made to identify a 25% fall in generalized seizures (0.5), partial seizures (0.95), and seizure days (0.95). Correlations are Pearson’s moment correlation coefficients.

RESULTS Twenty-one students completed the study. Eleven received placebo in the first phase, and 10 received NFD first. One student was withdrawn after 5 weeks of treatment because of aggressive outbursts. He was found to have been receiving the placebo. Another had very poor recording of seizures while on vacation, and his data were omitted from much of the analysis of seizure frequency. The total number of seizures in the two treatment periods are shown in Fig. 1. Only in the first 2 weeks of the trial was seizure control better with NFD (p < 0.05). Subgroup analysis suggested that this was due to a fall in the number of partial seizures (Fig. 2), which was lost by the second month. There were fewer seizure days in the NFD phase during the first month of treatment (from a mean of 13.2 to 11.6, p < 0.05), but this did not carry Epilepsiri, V o f .33, N o . 2,1992

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TABLE 1. Students reporting a 50% reduction in seizures from baseline following treatment with nifedipine or matched placebo for 2 months each

Nod SEIZURES 707

Second month

Entire 2-month phase

3

2 5

0 2

10 6

I 4

8 3

3 4

2 3

2 2

First month

First two weeks First month Second month

Total

FIG. 1. Total number of seizures in 20 students with refractory epilepsy receiving nifedipine and placebo. (Values are mean + SEM)

through to the second month of the trial. The number of patients reporting a 50% fall in seizure numbers on both treatments is shown in Table 1. There were no significant differences for any seizure type. Although there was a trend for patients to fare better during the second treatment phase, there was no significant difference between the two legs, and no difference in the performance of NFD whether given first or second (Fig. 3). Blood pressure showed a small drop after 2 weeks with NFD and placebo. This effect had settled by 4 weeks in both phases. There was no evidence of a postural drop in blood pressure in any of the students. Heart rate was not affected by either treatment. “Severe” side effects reported included headache in two students (both active drug), dry mouth in two (one active, one placebo), drowsiness (one placebo), and poor memory (one active). Scores for specific and dummy side effects did not differ between the NFD and placebo treatment phases. Scores for headache, however, were significantly higher with NFD (p < 0.02). NFD concentrations are shown in Table 2. Students with maximum levels >10 ng/ml (n = 12) did no better in terms of seizure control than those with concentrations below this arbitrary figure (n = 10). PARTIAL SEIZURES 701

First two weeks

First month

Second month

Total

FIG. 2. Number of partial seizures in 20 students with refractory epilepsy receiving nifedipine and placebo. (Values are mean SEM)

+

Epilepsia, Vol. 33, N o . 2, 1992

Partial“ (n = 17) Placebo N ifedi p ine Generalized“ (primary or secondarily) (n = 17) Placebo Nifedipine Total (n = 21) Placebo Nifedipine

1

Twenty-one students were evaluated, four with partial seizures only, four with generalized seizures only and 13 with both partial and secondarily generalized seizures. One student with poor compliance in seizure recording supplied insufficient data for this assessment.

A weak but significant correlation was obtained between seizure counts (placebo minus drug) and NFD concentrations at week 8 for total ( r = 0.443, p < 0.05; Fig 4) and partial (r = 0.455, p = 0.025; Fig. 5 ) seizures. Measurement of concomitant AED concentrations was intended but not achieved due to small sample size. Total EEG scores for the four tracings during NFD treatment were compared with those during placebo treatment. More students had improved scores while receiving the active drug than with placebo treatment (Fig. 6; p < 0.05). DISCUSSION

Despite the widespread success of calcium antagonists in animal models of epilepsy (Desmedt et al., 1975; Ashton and Wauquier, 1979; De Sarro et al., 1986, 1988; Morocutti et al., 1986; Meyer et al., 1987; Dolin et al., 1988; O’Neill and Bolger, 1989; Larkin et al., 1989), clinical use of these drugs in epilepsy is still at an early stage. Following early successes with FNR (Overweg et al., 1986), recent results have not been particularly promising (Alving et al., 1989; Keene et al., 1989; Nakane et al., 1989). Intravenous nimodipine has been reported to control resistant epilepsia partialis continuans in two patients (Brandt et al., 1988), but we have been unable to confirm antiepileptic efficacy in a placebo-controlled, add-on, crossover trial in refractory epilepsy (Larkin et al., 1991). Although one or two “significant” improvements were seen with NFD in this study, a large number of comparisons were made, and allowance for this make their clinical relevance doubtful. Minor favorable changes appeared to occur early in treatment, largely as a

NIFEDIPINE FOR EPILEPSY

349

"1 First Phase Better

FIG. 3. Seizure difference (second phase total minus first phase total) in 20 individual students showing drug order.

Second Phase Better

consequence of a decreased number of partial seizures. The EEG findings also suggest a positive pharmacological response to NFD. The loss of effect during the second month of treatment despite higher NFD doses and concentrations is rather puzzling and could suggest the rapid development of tolerance. Down-regulation of [3H]nitrendipine binding sites in mice has been reported following treatment with NFD for 28 days (Panza et al., 1985). More rapid down-regulation of [3H]nimodipine binding occurred following electroconvulsive shock and lidocaine-induced seizures in rat brain (Gleiter et al., 1989). In the cat, electroconvulsive shock produced an increase of 45% in the density of [3H]nitrendipine binding sites in the cerebral cortex and a decrease of 33% in the cerebellum (Bolger et al., 1987). The relevance of these findings to the clinical situation remains unclear. This study leaves an inconsistency that requires explanation. Why are calcium antagonists so impressive in animal models of epilepsy, yet appar-

ently less effective in epileptic patients? One problem relates to the screening of potential AEDs in individuals with poorly controlled epilepsy despite treatment with multiple AEDs. The students in the present trial reported an average of nearly 30 seizures per month in the baseline period and were receiving, in the main, two or three established AEDs. It is perhaps not surprising that results with NFD are disappointing in such a patient population. Next, the dose must be taken into consideration. Circulating NFD concentrations in this study were low. The NFD doses effective in angina and hypertension did not achieve similar concentrations when Nifedipine ng/ml

Concentration

1

40

30

r = 0.443 p < 0.05

El

11 El

TABLE 2. Serum nifedipine concentrations (nglml) 1 h post-dosing in students with refractory epilepsy receiving 20 and 40 mg of the drug twice daily for 4 weeks n

20 mg nifedipine twice daily (at 4 weeks) 40 mg nifedipine twice daily (at 8 weeks) Maximum concentration attained at any time during study

Mean -+ SD

20

4.3

2

19

9.8

21

Median

Range

1.9

b16.6

2 11.3

5.7

M 7

13.1 -+ 10.4

11.3

5.3

2.1-49

-100

-50 Total Seizures

0 (Placebo

-

50

100

Drug)

FIG. 4. Correlation between improvement in total seizure numbers and nifedipine concentrations following 8 weeks of treatment. Improvement ( x axis) is calculated by subtracting total number of seizures during drug phase from total number during placebo phase; i.e., positive value signifies improvement with active drug.

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given to treated epileptic patients (Breimer et al., 1989). All of the participants were taking enzymeinducing AEDs, which are likely to accelerate the metabolism of NFD (Schellens et al., 1989), whose elimination half-life may be as short as 4 h in healthy drug-free subjects (Ramsch et al., 1986). Even the use of a controlled-release formulation may not ensure effective circulating NFD levels. Doubts have been expressed whether NFD can cross the blood-brain barrier (Wen, 1988). This has been deduced from the failure of NFD to increase cerebral blood flow and inhibit vasoconstriction in vivo (Edvinsson et al., 1983), while it had marked effects on cerebral arteries in vitro (Anderson et al., 1983). No direct measurements of nifedipine were carried out, while the possibility of different mechanisms for the two separate models of vasoconstriction was simply dismissed. By measuring concentrations, Janicki et al. (1988) have shown NFD to cross the blood-brain barrier in the rat, and we have had similar results in mice (Larkin et al., 1989). It is worth noting that Edvinsson et al. (1983) found nimodipine also to be ineffective, while this dihydropyridine is now generally accepted to cross into the brain (Heffez et al., 1985). NFD has performed successfully in a number of studies using animal seizure models (De Sarro et al., 1988, 1990; Wong and Rahwan, 1989). The increased incidence of headache in patients receiving NFD hints at pharmacologically active concentrations in some individuals. The correlation between improvement in seizure control and NFD concentration, although weak, is an indication of an anticonvulsant action for NFD. Inadequate concentrations may account for important lack of efficacy in this study. Nifedipine

Concentration

ng/ml

50

1

Q

:!

r= 0.455 p= 0.025

13

20

10

-40

1

-20

0

20

Partial Seizures

I

I

60 80 (Placebo-Drug)

40

I

100

FIG. 5. Correlation between improvement in partial seizure numbers and nifedipine concentrations following 8 weeks of treatment. Improvement (x axis) is calculated by subtracting number of partial seizures during drug phase from number during placebo phase; i.e., positive value signifies improvement with active drug.

Epilepsia, Vol. 33, No. 2 , 1992

NlFEDlPlNE BETTER

PLACEBO BETTER

FIG. 6. Comparison of total EEG scores with nifedipine and placebo in 19 students with refractory epilepsy.

Does concomitant medication interfere with the anticonvulsant effect of NFD? In preliminary studies in mice, NFD and CBZ in combination were less effective than either drug given alone against pentylenetetrazol-induced seizures (Larkin et al., 1989). Although NFD does not alter CBZ disposition (Larkin et al., 1988), there may be a pharmacodynamic interaction between the drugs, possibly related to the calcium antagonist activity of CBZ (Crowder and Bradford, 1987). We have shown decreased affinity of cerebellar adenosine A, receptors in mice treated with NFD, which may counteract the increased numbers of binding sites produced by CBZ (Larkin et al., 1991). Interestingly, a potentiating effect of NFD on the anticonvulsant action of CBZ against maximal electroshock seizures has also been reported (Czuczwar et al., 1990). Our study does not suggest that NFD will prove to be a useful adjuvant anticonvulsant, although a higher dose in less severely affected patients may be more effective. Nevertheless, the calcium antagonists remain an important group of compounds, which have the potential for development as nonsedative AEDs. Perhaps another calcium antagonist with a more suitable pharmacokinetic profile will succeed where NFD has shown only promise. Other dihydropyridines with longer elimination half-lives, such as amlodipine, may offer a route for progress (Reid et al., 1988). Acknowledgment: We thank Anne Somers for secretarial assistance and Dr. W. A. Kennedy for EEG reports.

13

0 ,

.

Total EEG scores

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&SUME L’entrke d e calcium dans les neurones peut t t r e le dknominateur commun du declenchement et de la propagation de I’activitC critique. Les auteurs rapportent les rCsultats de la premiere Ctude en double-aveugle, contrdlee, contre placebo, avec croisement, utilisant la nifedipine (NFD), un antagoniste calci-dihydropyridinique, en traitement adjuvant dans 1’Cpilepsie rkfractaire. Vingt-deux Clbves (M = 12, F = 10, &gCsde 17 a 22 ans) de 1’Ecole HBpital de Lingfield ont r e p la NFD retard (Adalat Retard, Bayer) et un placebo assorti pendant 8 semaines ?I deux doses (20 mg deux fois parjour et 40 rng deux fois parjour chacun, pendant 4 semaines), avec une pCriode de washout de 8 semaines avant chaque pCriode de traitement. Chez les 20 Cleves qui ont completC l’ktude, il y a eu moins de crises partielles (p < 0.05) pendant les deux premibres semaines d’administration de NFD. De mtrne, il y a eu moins de jours avec crises pendant le premier mois de traitement actif. Cette rCponse ne se maintenait pas pendant le second rnois de l’etude. Une Cvaluation aveugle de I’EEG suggtre une discrtte amelioration sous NFD (p < 0.05). Davantdge de patients ont signal6 des cCphalCes sous NFD (p < 0.02) que sous placebo, mais la frequence cardiaque et la pression arttrielle debout et couche, n’ont pas etC modifiees. Des concentrations maximales de NFD Ctaient de 13.1 It 10.4 ng/ml. Une faible correlation etait notee entre le nombre total des crises (p < 0.05) et le nombre de crises partielles (p = 0.025) et les concentrations de NFD aprts 8 semaines de traitement. Cette Ctude ne met pas en evidence une efficacite anticonvulsivante importante de la NFD comme traitement adjuvant de I’Cpilepsie refractaire, a des doses qui sont efficaces pour le traitement de I’angor ou de I’hypertension. D’autres essais sont recommandks, utilisant des doses supkrieures de NFD chez des patients presentant une Cpilepsie moins sevtre. (P. Genton, Marseille)

RESUMEN La entrada de calcio en las neuronas puede ser un denominador comlin que actue como desencadenante y agente de propagaci6n de la actividad de 10s ataques. Los autores publican 10s resultados de un ensayo cruzado, doble ciego y controlado con placebo utilizando la nifedipina (NFD), una dhidropiridina antagonista del calcio, como complemento de la terapia en epilepsia refractaria. Veintid6s estudiantes (12M, 10F, edad 17-22 anos) que atendian la escuela del Hospital de Lingfield, recibieron NFD retardado (Adalat Retard, Bayer) y placebo durante 8 semanas en 2 dosis (20 mg dos veces diarias y 40 mg dos veces diarias durante 4 semanas) con un period0 de lavado de 8 se-

Epilepsiu, V o l . 33, No. 2,1992

manas entre 10s 2 brazos de tratamiento. En 20 estudiantes que completaron el ensayo se documentaron menos ataques parciales (p > 0.05) durante las 2 primeras semanas de la administraci6n de NFD. De mod0 semejante se observaron menos dias de ataques (p < 0.05) en el primer rnes de tratamiento activo. Esta respuesta no se rnantuvo en el segundo mes del ensayo. Un estudio “ciego” de 10s EEGs sugirio una pequeda mejoria con la NFD (p < 0.05). Mfis enfermos se quejaron de dolor de cabeza cuando tomaban la NFD (p < 0.02) que el placebo pero el ritmo cardiac0 y la presi6n arterial, en supino y en bipedestacibn, no se afect6. Las concentraciones medias mAximas de NFD fueron de 13.1 A 10.4 ngiml. Se anot6 una dtbil correlaci6n entre el nlimero de ataques totales (p < 0.05) y parciales (p = 0.025) y las concentraciones de NFD tras 8 semanas de tratamiento. Este estudio no apoya una importante eficacia anticonvulsiva de la NFD como terapia de cornplemento para epilepsia refractaria en dosis apropiadas para tratamiento del angor o de la hipertensibn. Mfis ensayos deben realizarse utilizando dosis mas elevadas de NFD en pacientes afectados menos severamente. (A. Portera-SAnchez, Madrid)

ZUSAMMENFASSUNG Der Calciumeinstrom in Neurone ist moglicherweise ein gerneinsamer Faktor fur die Auslosung und Ausbreitung von Anfallsaktivitat. Wir berichten uber Ergebnisse einer ersten Doppelblind-Placebo kontrollierten crossover Untersuchung mit dem Dihidropyridin Calciumantagonisten Nifedipin (NFD) als Zusatztherapie bei refraktarer Epilepsie. 22 Kandidaten (12 M, 10 F. zwischen 17 und 22 Jahren) an der Lingfield Hospital School erhielten NFD retard (Adalat retard, Bayer) und zugeordnet ein Placebo fur 8 Wochen in 2 Dosierungen (20 mg bd und 40 rng bd jeweils fur 4 Wochen) mit einer Auswaschphase von 8 Wochen zwischen den Behandlungsarmen. Bei den 20 Versuchspersonen wurden weniger partielle Anfalle (p < 0.05) wahrend der ersten 2 Wochen der NFD-Gabe registriert. Vergleichbar wurden weniger Anfallstage (p < 0.05) im ersten aktiven Behandlungsmonat berichtet. Dieser Erf‘olg wurden beim 2. Behandlungsmonat nicht aufrechterhalten. Eine EEG-Blind-Auswertung legt eine geringe Verbesserung unter NFD nahe (p < 0.05). Unter NFD berichteten mehr Patienten uber Kopfweh als unter Placebo (p < 0.02), die Herzfrequenz und Blutdruck im Stehen und Liegen blieben jedoch gleich. Die mittleren maximalen NFDKonzentrationen betrugen 13.1 5 10.4 ng/ml. Es bestand eine schwache Korrelation zwischen den gesamten Anfallen (p < 0.05) und der Teilmenge partieller Anfalle (p < 0.025) und den NFD-Konzentrationen nach 8-wochiger Behandlung. Diese Untersuchung erbringt keine deutliche antikonvulsive Wirksamkeit von NFD als Adjuvans bei refraktaren Epilepsien in Dosierungen, wie sie bei einer Angina (pectoris) oder Hypertension verwendet werden. Weitere Untersuchungen mit hoheren NFDKonzentrationen bei weniger stark beeintrichtigten Patienten werden empfohlen. (C. K. Benninger, Heidelberg)