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Safety and efficacy of flunarizine in childhood migraine: 11 years experience, with emphasis on its effect in hemiplegic migraine

DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY Safety and efficacy of flunarizine in childhood migraine: 11 years'experience, with emphasis on its effect in hemiplegic migraine BASHEER PEER MOHAMED1 | PETER J GOADSBY1,2 | PRAB PRABHAKAR1 1 Children's Headache Clinic, Great Ormond Street Hospital, London, UK. 2 UCSF Headache Center, University of California, San Francisco, San Francisco, CA, USA.
Correspondence to Dr Prab Prabhakar at Children's Headache Clinic, Great Ormond Street Hospital, London, UK. E-mail:prabhp@gosh.nhs.uk This article is commented on by Abu-Arafeh. To view this paper visit http://dx.doi.org/10.1111/j.1469-8749.2011.04152.x AIM The aim of this study was to report a single-centre experience of flunarizine in childhood Accepted for publication 4th September 2011.
migraine with focus on safety and efficacy.
METHOD We conducted a retrospective observational audit of 72 individuals (40 male, 32 female;mean age 13y; age range 1y 6mo–17y) at a tertiary paediatric neurology unit between 1998 and2009. Children were included if they had a diagnosis of migraine and at least one follow-up assess-ment and a minimum of 3 months’ treatment with flunarizine.
RESULTS Of 102 individuals identified, 30 were excluded for the following reasons: no outcomedata (n=13), non-migraineurs (n=9), missing records (n=4), or inadequate treatment duration (n=4).
Of the final cohort (72 individuals), 44 had migraine without aura, 15 had migraine with aura orchildhood migraine equivalents, eight had sporadic hemiplegic migraine, and five had familialhemiplegic migraine. The median age was 13 years (1y 6mo–17y) and median duration ofmigraine was 48 months. Starting dose was 5mg. Other doses used were 2.5mg (three individu-als), 7.5mg (one individual), and 10mg (six individuals). Treatment duration was 12 months.
Successful prophylaxis, defined as at least a 50% reduction in attack frequency, was observed in57% (41 ⁄ 72). Response rate was higher among those with hemiplegic migraines (85%) than inthose who did not have hemiplegic migraines (51%). Side effects were noted in 15 (21%) individu-als (depression, n=6; weight gain ⁄ increased appetite, n=5; tiredness ⁄ sedation, n=2; and worseningheadache, n=2), and led to discontinuation of treatment in 13.
INTERPRETATION In our cohort of children with migraine, flunarizine appears to be more effectivein the hemiplegic migraine group. Adverse effects were seen in one-fifth of the individuals, leadingto discontinuation in 18%.
Migraine is a common neurological problem in children that in migraine is unclear, although its calcium and dopaminergic can cause considerable disability.1 The prevalence rate varies antagonism may offer some insights into possible subcortical with age and ranges from 3 to 17%.2,3 The symptomatology brain targets.7 Several studies have demonstrated its efficacy in can vary considerably from that of adults, which is reflected in the International Headache Society’s revised diagnostic crite- The Children’s Headache Clinic at Great Ormond Street Hospital, London, is a national referral centre and flunarizine Management of migraine is multimodal, including pharma- has been used in this clinic since 1998. An audit into the use of cological and non-pharmacological strategies. Factors which flunarizine was conducted as part of clinical governance relat- influence the need for preventative therapy include attack severity, frequency, and impairment of social or educationalactivities.5 A wide range of pharmacological agents such as antihypertensives, antiserotoninergics, antidepressants, anti- This study was registered as an audit with our local research convulsants, and calcium channel blockers have been used for this purpose with variable rates of success. Hemiplegic We searched our hospital electronic database for all chil- migraine, in which the aura symptoms include motor weakness, dren treated with flunarizine from 1998 to 2009. These data poses a particular challenge as the diagnosis is often delayed and were cross-referenced with the hospital pharmacy records.
no specific preventative agent has been found to be effective.6 Individuals with a diagnosis of migraine and who had had at Flunarizine, a long-acting calcium channel blocker, was least one follow-up assessment and a minimum of 3 months’ originally introduced in the 1970s for the treatment of occlu- treatment with flunarizine were included in the study. Head- sive vascular diseases. The mechanism of action of flunarizine ache diagnosis was based on the International Classification of ª The Authors. Developmental Medicine & Child Neurology ª 2012 Mac Keith Press Headache Disorders. The second edition of the International Classification of Headache Disorders4 was used from 2004 Flunarizine appears to be more effective in treating hemiplegic migraine than A total of 102 children were initially identified. Of these, 72 Side effects lead to withdrawal of flunarizine in around one in five patients.
children (40 male; 32 female; mean age 13y; age range 1y before flunarizine, dosage and duration of treatment with 6mo–17y; diagnoses are listed in Table I) were included in the flunarizine, side effects, and reason for discontinuation of final analysis (Fig. 1). Thirty children were excluded for the following reasons: 13 had not had a follow-up assessment at Therapeutic outcome was measured by analysing the fre- the time of the study, nine were non-migraineurs, four had quency of attacks before and after starting treatment. Success- incomplete medical records, and four had an inadequate treat- ful prophylaxis was defined as a 50% reduction in frequency of attacks over a 3-month period. In most cases, frequency of For each individual, the following data were collected: basic attacks was based on the recollection of the individual ⁄ care- demographic details, disease characteristics before and after giver. Daily diary monitoring was also used, where available.
treatment with flunarizine, prophylactic medications tried Statistical analysisSummary data are presented as median and ranges.
RESULTSThe median duration of the disease until referral was 4 years (range 3mo–13y 10mo). The duration was shorter in individu- als with hemiplegic migraine (3y 1mo) than in individuals with non-hemiplegic migraine (4y). Apart from six, all individuals had tried at least one preventative medication before trying flunarizine therapy. An average of three preventives (range 1–10) had been tried per individual before commencement of flunarizine. Table II lists these medications and the number ofchildren that used each of these medications.
ICHD2, International Classification of Headache Disorders: 2nd edition.
The median duration of migraine at the time of commencing flunarizine therapy was 4 years and 10 months (range 6mo–14y). The median frequency of attacks for the entire cohortwas eight per month (range 0.3–30). The frequency of attacks was four per month (range 0.3–12) in the group with hemiple-gia and 12 per month in the remainder.
Flunarizine dosingThe initial dose of flunarizine for individuals was determined by the clinician (PJG, PP). The standard dose was 5mg. Doseescalation was made when there was no response to the start-ing dose or in order to optimize response to treatment. This was done at the discretion of the clinician, usually at the firstfollow-up.
Flunarizine treatment was commenced after a median inter- val of 6 months (range 2mo–4y) after referral to the clinic.
Figure 1: Flow chart depicting the selection of patients for the final Developmental Medicine & Child Neurology 2012 This interval was similar in the groups with and without hemi- hemiplegic group (n=8), none was mutation positive. In this plegic migraine (6mo). The starting dose of flunarizine was group, 11 individuals (85%) showed improvement in the fre- 5mg in 62 individuals, 10mg in six, 2.5mg in three, and 7.5mg quency of the attacks by at least 50%.
in one. The dose was escalated in 43 individuals after a medianduration of 5 months (range 1–24mo).
DISCUSSIONThis is a retrospective, observational audit in a highly selec- tive individual group, thus limiting the conclusions that can Individuals were followed up for a median of 24 months be drawn from the data. The headache clinic in which the (range 3mo–8y 6mo), at 6-monthly intervals, with follow-up audit was conducted is a national referral centre, which over telephone in the interim, if needed. The duration of flu- partly explains the significantly long duration of migraine narizine use in this cohort was 12 months (range 3mo–8y).
(5y 1mo) and therapy with a number of preventative drugsprior to referral to this clinic. The reasons for the thera- peutic failure with preventative medications used before Of the 89 individuals who started treatment with flunarizine, referral to this clinic were not studied in detail but could side effect data were available in 76, including all 72 individu- potentially include inadequate treatment duration, parental als in the final cohort. Of the 72 individuals, 15 (21%) experi- and individual reluctance to persevere, and side effects.
enced side effects: depression or mood swings in six, weight Therefore, this cohort does not necessarily represent refrac- gain and ⁄ or increased appetite in five, tiredness or sedation in two, worsening of headache in one, and both tiredness and A systematic Cochrane review13 of migraine prophylactics worsening of headache in one. Thirteen individuals discontin- in children found beneficial effects for only two drugs, namely ued treatment, whereas the remaining two continued despite propranolol and flunarizine, from a small pool of data, that is, feeling tired as their migraine frequency had improved. Of the one study for each drug. There is now emerging evidence that four individuals who were not included in the cohort owing to topiramate is also effective.14,15 Few studies have been carried inadequate treatment duration, two developed tiredness lead- out to date regarding the effectiveness and side effects of ing to withdrawal within 6 weeks. The incidence of side effects flunarizine in children with migraine. A double-blind, pla- in this cohort of 76 individuals was 22%. All the side effects cebo-controlled crossover trial of 70 children conducted by resolved promptly on cessation of therapy.
Sorge et al.16 in the late 1980s showed a significant reductionin frequency and duration of attacks. The reported side effects in this study were weight gain in 22% and drowsiness in 9%.
Flunarizine was discontinued in 34 individuals: 16 individuals A similar side effect profile has been noted in other adult (22%) discontinued after a median interval of 7.5 months studies.8,9,12 A large study in adults comparing treatment with (range 3–24mo) because of lack of response, and 13 (18%) flunarizine and propranolol found that the incidence and because of side effects, and in five children the drug was with- severity of the side effects were similar in the two groups.17 drawn after a median duration of 16 months following com- In this audit, side effects were reported in 21% of the children, leading to discontinuation of the medication in themajority of affected children. Depression and ⁄ or mood swings were the commonly seen side effects. In one child, there was a Forty-one individuals (57%) experienced at least a 50% past history of depression which appeared to have been reacti- reduction in frequency (Table III) of attacks. A reduction in vated by flunarizine. Actual weight gain was seen in only one frequency of less than 50% was seen in five individuals child, with the remainder of cases reporting perceived weight (7%), while no change was seen in 25 individuals (35%).
gain or increased appetite. All the side effects resolved on dis- An increase in the frequency of attacks was observed in one continuation of treatment. The side effect profile in this cohort was more or less similar to that seen in previous adultand paediatric studies.12,16 In terms of efficacy, 57% of children in the cohort benefited In the familial hemiplegic group (n=5), of the three individuals by way of reduction in attack frequency. This is comparable to tested, two were CACNA1A mutation positive. In the sporadic the outcome data already available from adult and paediatric Flunarizine in Childhood Migraine Basheer Peer Mohamed et al.
studies.8,18,19 However, of note is the relatively higher rate of therapeutic efficacy in hemiplegic migraine (85% vs 51%) in Within the limitations associated with the highly selective nat- this cohort. Moreover, as far as we are aware, this is the largest ure of the individuals and the study methodology, flunarizine reported cohort of paediatric hemiplegic migraine treated with appears to be effective in reducing attack frequency in child- flunarizine. Hemiplegic migraine is very rare, so randomized hood migraine in 57% of children in this cohort, which is con- controlled trials are simply not feasible, and this underlines sistent with published data. The efficacy, however, appears to the necessity of carefully collecting clinical data in referral be much higher (85%) in children with hemiplegic migraine than in those with the other subtypes. The present authors use In terms of treatment duration, 3 months is usually consid- flunarizine as first-line medication in children with hemiplegic ered adequate to assess efficacy in adults, although one of the migraine. Reversible side effects were seen in about one in five authors (PJG) would typically treat for 6 months, especially in of the children studied, with depression and weight gain or hemiplegic migraine. In children, a longer duration has usually increased appetite being the commonest. A multicentre pro- been necessary19 to reach therapeutic efficacy, as seen in our spective, blinded randomized controlled trial would be needed cohort. The treatment effect may be delayed and when it to substantiate the therapeutic difference observed between occurs is often robust and long-lasting. Our experience has led children with and without hemiplegic and non-hemiplegic us to regard flunarizine as the treatment of choice for hemiple- migraines, although given the rarity of hemiplegic migraine 1. Tkachuk GA, Cottrell CK, Gibson JS, O’Donnell FJ, Hol- 8. Diener HC, Matias-Guiu J, Hartung E, et al. Efficacy and 15. Lewis D, Winner P, Saper J, et al. Randomized, double- royd KA. Factors associated with migraine-related quality of tolerability in migraine prophylaxis of flunarizine in reduced blind, placebo-controlled study to evaluate the efficacy and life and disability in adolescents: a preliminary investigation.
doses: a comparison with propranolol 160 mg daily. Cephalal- safety of topiramate for migraine prevention in pediatric subjects 12 to 17 years of age. Pediatrics 2009; 123: 924– 2. Lateef TM, Merikangas KR, He J, et al. Headache in a 9. Sørensen PS, Larsen BH, Rasmussen MJ, et al. Flunarizine national sample of American children: prevalence and com- versus metoprolol in migraine prophylaxis: a double blind, 16. Sorge F, De Simone R, Marano E, Nolano M, Orefice G, orbidity. J Child Neurol 2009; 24: 536–43.
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3. Lipton RB. Diagnosis and epidemiology of pediatric A double-blind, placebo-controlled, crossover study. Cepha- migraine. Curr Opin Neurol 1997; 10: 231–6.
10. Mitsikostas DD, Polychronidis I. Valproate versus flunarizine 4. Headache Classification Subcommittee of the International in migraine prophylaxis: a randomized, double-open, clinical 17. Lu¨cking CH, Oestreich W, Schmidt R, Soyka D. Flunarizine Headache Society. The International Classification of Head- trial. Funct Neurol 1997; 12: 267–76.
vs. propranolol in the prophylaxis of migraine: two double- ache Disorders: 2nd edition. Cephalalgia 2004; 24 (Suppl. 1): 11. Mendenopoulos G, Manafi T, Logothetis I, Bostantjopoulou blind comparative studies in more than 400 patients. Cepha- S. Flunarizine in the prevention of classical migraine: a 5. Evers S, Afra J, Frese A, et al. EFNS guideline on the drug placebo-controlled evaluation. Cephalalgia 1985; 5: 31–7.
18. Gawel MJ, Kreeft J, Nelson RF, Simard D, Arnott WS.
treatment of migraine–revised report of an EFNS task force.
12. Shimell CJ, Fritz VU, Levien SL. A comparative trial of Comparison of the efficacy and safety of flunarizine to pro- flunarizine and propranolol in the prevention of migraine.
pranolol in the prophylaxis of migraine. Can J Neurol Sci 6. Russell MB, Ducros A. Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical character- 13. Victor S, Ryan SW. Drugs for preventing migraine head- 19. Visudtibhan A, Lusawat A, Chiemchanya S, Visudhiphan P.
istics, diagnosis, and management. Lancet Neurol 2011; 10: aches in children. Cochrane Database Syst Rev 2003; (4): migraine. J Med Assoc Thai 2004; 87: 1466–70.
7. Goadsby PJ, Charbit AR, Andreou AP, Akerman S, Holland 14. Ferraro D, Di Trapani G. Topiramate in the prevention of PR. Neurobiology of migraine. Neuroscience 2009; 161: pediatric migraine: literature review. J Headache Pain 2008; Developmental Medicine & Child Neurology 2012

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