migraine is a common neurological illness worldwide leading to significant effects on morbidity , productivity and quality of life . the anticonvulsant topiramate is known in the western setting to be effective in migraine prevention [ 24 ] . these previous studies , of which asians form the minority , have employed dosages at or above 100  mg / day for prophylaxis . however , there is evidence that lower dosages of topiramate may be effective in migraine prevention , particularly in the asian population [ 57 ] . to our knowledge , three previous studies comprising koreans , chinese and indians , have addressed the use of topiramate in the asian patients [ 57 ] . two studies had employed dosages of at or above 50  mg / day [ 5 , 6 ] , while the third , utilizing a variable titration method , had suggested that daily dosages as low as 25  mg may be effective . in addition , two other studies involving iranian patients have utilized topiramate dosages up to 50  mg / day and concluded it to be as effective as propanolol and sodium valproate in migraine prophylaxis [ 8 , 9 ] , providing further evidence of its efficacy in asians . in this study , we sought to further clarify dosage issues in a prospective dosing study of migraine patients in the multiracial asian setting . with local ethical committee ( singapore general hospital institutional review board ) approval , we prospectively screened 82 patients having migraine with or without aura , as defined by the international classification of headache disorders 2nd edition . in particular , we had ensured that patients included should have at least four headache episodes in the preceding 4  weeks , with each episode at least four of ten in severity on the visual analogue scale ( vas ) . 42 were excluded : 7 patients became un - contactable prior to randomization , 23 were screen failures and 12 had withdrawn consent during the study . a total of 40 patients ( age range 1864 , mean age 38 , 30 females , 10 males ) were randomized into the study . patients were recruited in a consecutive fashion from a headache specialist clinic in a tertiary general hospital . each was briefed upon randomization on how to record symptoms and side effects into the headache diary . each patient had kept a headache diary 4  weeks prior to randomization , documenting baseline migraine attacks over this period . patients documented frequency as the number of days with headache in the preceding 4  weeks , duration of the most severe attack in a day in hours , and severity measured as the worst period during an attack on a vas from 0 to 10  cm . during the entire treatment period , they were allowed symptomatic medications such as paracetamol , but triptans and opioids were disallowed . however , any prior use of prophylactic medication of any class at any time documented was an exclusion criterion . this was defined as usage of triptans > 3  days a week , simple analgesics > 4  days a week or narcotic analgesics > 2  days a week . each patient was randomized to receive 25 , 50 , 75 or 100  mg of topiramate as an evening dose , with 10 patients in each arm . for the 50  mg arm , patients started on 25  mg for 1  week before continuing with 50  mg for the rest of the study . similarly , for the 75  mg arm , patients started with 25  mg for 1  week , 50  mg for the second week , and 75  mg for the subsequent weeks . the end - point of the study was 12  weeks after achieving the intended topiramate dosage for that particular treatment arm , and patients returned for follow - up every 4  weeks after starting treatment . comparisons were made between migraine attacks at baseline and the 4-week period prior to the end - point ( fig .  2 ) . it should be noted that upward titration of dosages were gradual and necessary to minimize side effects and drop outs . for the 50 , 75 and 100  mg arms , each patient would have received a total of 12  weeks of the intended dose of that particular arm before study end - point was achieved . statistical calculations were performed with spss for windows package , employing the wilcoxon signed rank , kruskal  wallis and pearson s correlation tests . a p value  <  0.05 was regarded as statistically significant . of the 40 patients who had completed the trial , no significant differences in baseline headache frequency , duration and severity was found between the four treatment arms . overall , we found that topiramate significantly reduced headache frequency ( headache days ) comparing baseline to end - point ( wilcoxon signed rank test , z  =  3.47 , p  =  0.001 ) . however , no significant differences were found for headache duration ( wilcoxon signed rank test , z  =  0.23 , p  =  0.82 ) or severity ( wilcoxon signed rank test , z  =  0.31 , p  =  0.76 ) . in terms of side effects , paresthesia was by far the most commonly encountered in 55% of patients . however , its incidence was highly correlated with increasing dosage ( pearson s correlation , r  =  0.96 , p  <  0.001 ) . 1overall headache parameters comparing baseline ( time point 1 ) to study end - point ( time point 2)fig .  2flow diagram showing protocol from screening to end of studytable  1summary of most common side effects in 40 patientsside effectdose ( number of patients)25  mg50  mg75  mg100  mgparesthesia4567fatigue1132giddiness1211diarrhoea3001nausea1102drowsiness1120table 2summary of results of all recruited patientstimebaselinetime 1time 2time 3frequency ( days )  25  mg10.2 ( 5.1)7.6 ( 6.4)3.5 ( 2.2)4.1 ( 1.9 )  50  mg6.9 ( 2.6)8.1 ( 4.2)6.5 ( 4.8)6.8 ( 5.7 )  75  mg8.8 ( 4.4)6.2 ( 5.9)5.8 ( 6.6)3.3 ( 4.4 )  100  mg8.0 ( 2.5)8.8 ( 8.2)4.3 ( 2.4)2.3 ( 1.5)p  =  0.001*duration ( h )  25  mg8.4 ( 3.8)9.2 ( 5.5)10.1 ( 8.0)6.9 ( 7.7 )  50  mg8.8 ( 8.6)6.0 ( 6.1)5.3 ( 5.3)5.9 ( 5.4 )  75  mg5.3 ( 4.7)7.7 ( 6.3)10.9 ( 2.6)12.3 ( 8.0 )  100  mg7.9 ( 7.1)6.4 ( 8.8)7.3 ( 3.1)8.0 ( 5.7)p  =  0.82severity ( vas )  25  mg5.1 ( 1.2)5.1 ( 1.9)5.6 ( 1.7)4.9 ( 0.8 )  50  mg6.3 ( 1.3)6.0 ( 0.5)5.1 ( 1.3)5.8 ( 1.4 )  75  mg5.0 ( 1.5)4.4 ( 1.4)4.0 ( 1.4)4.3 ( 1.4 )  100  mg5.7 ( 1.2)5.8 ( 1.5)4.8 ( 1.4)4.8 ( 1.4)p  =  0.75each row denotes mean and ( sd)each time point denotes headache diary data of the preceding 4-week period *  statistical significance ( p  <  0.05 ) overall headache parameters comparing baseline ( time point 1 ) to study end - point ( time point 2 ) flow diagram showing protocol from screening to end of study summary of most common side effects in 40 patients summary of results of all recruited patients each row denotes mean and ( sd ) each time point denotes headache diary data of the preceding 4-week period *  statistical significance ( p  <  0.05 ) to our knowledge , this is the first fixed dose ranging study designed specifically to address this issue employing a simple and straightforward clinical approach . here , we show that a low daily dose of 25  mg of topiramate was equally effective as 50 , 75 and 100  mg in reducing headache frequency . the first study   assessed topiramate against placebo had found responder rates ( 50% reduction in headache frequency ) at 39% ( 50  mg / day ) , 49% ( 100  mg / day ) and 47% ( 200  mg / day ) . however , it is comparable to our study only for headache days , which were significantly reduced for the 100 and 200  mg / day groups only . another study , employing a similar placebo - controlled protocol , reported fairly similar findings . our findings can be compared to a previous study comprising only chinese patients , which found that some patients appeared to benefit with doses as low as 25  mg / day , despite the mean dose being 80  mg for that entire study which had employed a physician - led upward dose titration depending on clinical response . as the end results of this and our study were contributed by chinese patients , it should be noted that this study was based on an escalating dose titration determined by the treating physician depending on clinical response , and concomitant prophylactic medications were allowed . a second asian study comprising indian patients had employed topiramate at 50  mg / day in a 4-week crossover protocol . in this study , topiramate was administered at a fixed dose of 50  mg / day for only 4  weeks in a crossover design with lamotrigine . these vital differences likely contributed to incomparable findings with our study . to this end , we are of the opinion that a fixed daily dosing regimen would offer maximal practicality and convenience both for the patient and the treating physician . in terms of adverse events , its incidence was increased with higher dosages , as previously noted in other studies [ 11 , 12 ] . hence , lower dosages may potentially benefit patients in terms of better compliance as a result of lower side effect occurrences . in addition as asians display clinically different pharmacology compared to western patients , its is likely that our findings of lower dosage requirements can be explained by these physiological factors [ 13 , 14 ] . in conclusion , our novel findings highlighting efficacy of a fixed low dose of topiramate of 25  mg / day in migraine prophylaxis also attest to advantages in terms of reduced cost and favourable side effect profile .
topiramate is known to be efficacious in migraine prophylaxis , but its optimal dose has not been systematically studied in the asian population . here , we show that a fixed low dose of topiramate 25  mg / day is efficacious in migraine prophylaxis and also attest to advantages in terms of medication cost savings and more favourable side effect profile .