Flunarizine Plasma Concentrations and Side Effects in Migraine Patients
Fiorenzo Albani, Anna Baldrati, Pietro Cortelli, Roberto Riva and Agostino Baruzzi Institute of Neurology, University of Bologna, Italy. Reprint requests to: Dr. Fiorenzo Albani, Institute of Neurology, University of Bologna, Via Foscolo 7, 40123 Bologna, Italy. Accepted for Publication: February 22, 1990. SYNOPSIS
Flunarizine plasma concentrations and side effects were evaluated in migraine patients during a 3 month course of prophylactic treatment. Plasma concentrations did not correlate with daily dose (in mg/kg). Mean flunarizine levels were higher in patients showing sleepiness or sedation. Weight gain was independent of plasma concentrations. Future clinical trials of flunarizine should be supported by drug monitoring in order to clarify the relationship between plasma levels and drug effects. (Headache 30:369-370, 1990) INTRODUCTION
Flunarizine is a calcium entry blocker used in the treatment of peripheral and cerebral circulatory disorders and in the prophylaxis of migraine.1-5 Flunarizine is also currently under clinical investigation as an anticonvulsant.6 Different reports have focused attention on the clinical toxicity of flunarizine, particularly depression and extrapyramidal symptoms.7,8 In view of this, and following inconclusive evidence of its efficacy as a "cerebroactive drug",9 the clinical utility of flunarizine has been questioned.10 However, to evaluate correctly the overall therapeutic value of flunarizine, we should weigh on the one hand the definite role it maintains in migraine prophylaxis,1-5 and on the other the full range and incidence of side effects. Pharmacokinetic studies in patients taking flunarizine and other, enzyme-inducing anti-epileptic, drugs11 have shown a wide variability between flunarizine and resulting plasma concentrations. We studied the relationship between daily dose and plasma levels, and plasma levels and side effects in a group of migraine patients who had received the drug prophylactically as the only chronic treatment. PATIENTS AND METHODS
Forty patients were admitted to the study; they received flunarizine (5 or 10 mg) once daily at bedtime, for three months. In most cases this was their first prophylactic therapy. Side effects were evaluated before and during treatment using an appropriate check-list, which included expected and non-expected symptoms. Five subjects did not appear at the second visit and five were excluded for admitted non-compliance with the therapy. Thirty patients (19 females) were included in the analysis: age range was 12-67 years (mean ± SD, 33 ± 16); weight 46-82 kg (60 ± 11); daily dose 0.061-0.196 mg/kg (0.121 ± 0.036). Blood samples were collected in the morning (8-12 hours after the last dose). In three cases the treatment was halted for side effects and blood samples taken at the time of suspension; these subjects were excluded from the dose/level correlation study. Plasma samples were stored at-20°C until analyzed by HPLC. Detection limit of the method was 5 ng/ml; inter- and intra-assay coefficients of variation were about 9%.12 Statistical comparisons were made by Mann-Whitney test and linear regression analysis. RESULTS
Plasma concentrations were in the range 10.0-180.3 ng/ml (mean ± sd, 40.3 ± 38.1) and did not correlate with the dose (r = 0.209, NS). The correlation did not improve by considering the subjects by age or sex. The observed side effects were sleepiness or sedation (no. = 13), weight gain (no. = 11), gastric discomfort (one case), insomnia (one case) and aggravated postural tremor (one case). The subjects who stopped the treatment after one month complained of sleepiness or sedation and weight gain (two cases) and aggravated postural tremor. Mean plasma concentrations were significantly higher in patients with sleepiness compared to patients without (mean ± sd, 65.3 ± 42.2 ng/ml vs 20.4 ± 8.4 ng/ml; range 10.0-180.3 vs 10.0-40.1 ng/ml; p
Fiorenzo Albani, Anna Baldrati, Pietro Cortelli, Roberto Riva and Agostino Baruzzi Institute of Neurology, University of Bologna, Italy. Reprint requests to: Dr. Fiorenzo Albani, Institute of Neurology, University of Bologna, Via Foscolo 7, 40123 Bologna, Italy. Accepted for Publication: February 22, 1990. SYNOPSIS
Flunarizine plasma concentrations and side effects were evaluated in migraine patients during a 3 month course of prophylactic treatment. Plasma concentrations did not correlate with daily dose (in mg/kg). Mean flunarizine levels were higher in patients showing sleepiness or sedation. Weight gain was independent of plasma concentrations. Future clinical trials of flunarizine should be supported by drug monitoring in order to clarify the relationship between plasma levels and drug effects. (Headache 30:369-370, 1990) INTRODUCTION
Flunarizine is a calcium entry blocker used in the treatment of peripheral and cerebral circulatory disorders and in the prophylaxis of migraine.1-5 Flunarizine is also currently under clinical investigation as an anticonvulsant.6 Different reports have focused attention on the clinical toxicity of flunarizine, particularly depression and extrapyramidal symptoms.7,8 In view of this, and following inconclusive evidence of its efficacy as a "cerebroactive drug",9 the clinical utility of flunarizine has been questioned.10 However, to evaluate correctly the overall therapeutic value of flunarizine, we should weigh on the one hand the definite role it maintains in migraine prophylaxis,1-5 and on the other the full range and incidence of side effects. Pharmacokinetic studies in patients taking flunarizine and other, enzyme-inducing anti-epileptic, drugs11 have shown a wide variability between flunarizine and resulting plasma concentrations. We studied the relationship between daily dose and plasma levels, and plasma levels and side effects in a group of migraine patients who had received the drug prophylactically as the only chronic treatment. PATIENTS AND METHODS
Forty patients were admitted to the study; they received flunarizine (5 or 10 mg) once daily at bedtime, for three months. In most cases this was their first prophylactic therapy. Side effects were evaluated before and during treatment using an appropriate check-list, which included expected and non-expected symptoms. Five subjects did not appear at the second visit and five were excluded for admitted non-compliance with the therapy. Thirty patients (19 females) were included in the analysis: age range was 12-67 years (mean ± SD, 33 ± 16); weight 46-82 kg (60 ± 11); daily dose 0.061-0.196 mg/kg (0.121 ± 0.036). Blood samples were collected in the morning (8-12 hours after the last dose). In three cases the treatment was halted for side effects and blood samples taken at the time of suspension; these subjects were excluded from the dose/level correlation study. Plasma samples were stored at-20°C until analyzed by HPLC. Detection limit of the method was 5 ng/ml; inter- and intra-assay coefficients of variation were about 9%.12 Statistical comparisons were made by Mann-Whitney test and linear regression analysis. RESULTS
Plasma concentrations were in the range 10.0-180.3 ng/ml (mean ± sd, 40.3 ± 38.1) and did not correlate with the dose (r = 0.209, NS). The correlation did not improve by considering the subjects by age or sex. The observed side effects were sleepiness or sedation (no. = 13), weight gain (no. = 11), gastric discomfort (one case), insomnia (one case) and aggravated postural tremor (one case). The subjects who stopped the treatment after one month complained of sleepiness or sedation and weight gain (two cases) and aggravated postural tremor. Mean plasma concentrations were significantly higher in patients with sleepiness compared to patients without (mean ± sd, 65.3 ± 42.2 ng/ml vs 20.4 ± 8.4 ng/ml; range 10.0-180.3 vs 10.0-40.1 ng/ml; p
