| Backgrounds:Migraine, as a common, chronic, easy relapsing clinical brain dysfunction, has become a serious public health problem leading to significant effects on morbidity, productivity and quality of life and declining work productivity of patients as well as occupying a great quantity of social medical resources and causing a great deal of burden on the individuals and society. Refractory migraine, as the name suggests, was more intractable compaired with other kinds of headache and occupied an extremely important position with regard to the individuals and society harm induced by the migraine. The therapeutic principles of refractory migraine are the same as other types of migraine, including acute (migraine attack) phase of treatment and prevention (remission) treatment. At present, drugs used for preventing migraine attack includes (3-receptor blocks, calcium channel blocks, anticonvulsants and antidepressants with good efficacy and tolerability. However, there are no reports published in China about the new antiepileptic drugs of levetiracetam in application to the fields of migraine. In addition, the combination of levetiracetam with flunarizine, a calcium channel blocks, for prophylaxis of refractory migraine has never reported home and abroad. Based on the effectiveness of anticonvulsants in migraine prevention confirmed by the placebo-controlled double-blind trials, more and more international guidelines recommended the anticonvulsants drugs in prophylaxis of migraine attack. This preliminary study purposes to observe the efficacy and safety of levetiracetam monotherapy and combination with flunarizine in prophylaxis of refractory migraine. Objective:Open label pilot study to observe the efficacy and safety of levetiracetam monotherapy and combination with flunarizine in prophylaxis of refractory migraine. Methods:This prospective, open-label, pilot study was conducted by the headache center of neurology clinic of shandong provincial hospital. According to the criteria proposed by Refractory Headache Special Interest Section of America Headache Society in2006,120refractory migraineurs who had not taken any analgesics or preventive medicine at least4weeks prior to participating in this study were enrolled in the study and the mean MIDAS score of them were above of11. All the cases were randomly divided into two groups:one were treated with0.25g levetiracetam as an evening dose, while the others with0.25g levetiracetam plus5mg flunarizine as an evening dose, the treatment phase lasted12weeks. Each patient had kept a headache diary4weeks prior to randomization, documenting baseline migraine attacks over this period. All the patients recorded the frequency of headache attacks, duration as the number of hours with each episode and at least four of ten in severity on the visual analogue scale (VAS) in the preceding4weeks, and severity measured as the worst period during an attack on a VAS from0to10cm. In addition, according to frequency, duration and severity conferred different scores. In the same way, patients documented the same indicators at every4weeks and returned for follow-up every4weeks after starting treatment. The end-point of the study was at the end of12weeks. Specialed clinician calculate every indicator scores and total scores. Comparisons were made between migraine attacks at baseline and every4weeks to the end-point. Beyond that, we have observed the occurrence of adverse events and the disability of migraineurs. Results:In the monotherapy group, two subjects had withdrawn the study, one of them lost follow up and the other retreated during the test. In the combined group, there were three subjects withdrawn the study, one became uncontactable, the other withdrawn consents during the study, and the third one discontinued due to intolerance of adverse events. Of all the patients who had completed the trial, there were no significant differences in sex, age, baseline headache frequency, duration, severity and MIDAS scores was found between the two treatment arms (P＞0.05). Overall, in the two groups, headache frequency, duration and severity reduced significantly comparing baseline with the end-point of the study (P<0.05); At the end-point of the study, headache duration between the two groups was significantly difference (P<0.001), Compared with baseline headache duration decreased by52.5%and64.0%respectively in monotherapy group and combination group. After treatment headache frequency between the two groups was significantly difference (P=0.009), At the end of12weeks headache frequency decreased by58.1%in monotherapy group, whereas71.8%in combination group, headache frequency between the two groups was significantly difference at the end of treatment (P<0.001); Headache severity between the two groups was significantly difference at the end of the observation(P=0.033), Compared with baseline headache severity declined by47.3%and53.3%respectively in monotherapy group and combination group; The difference of headache severity was significantly between the two treatment methods (P<0.001). MIDAS score was no significant difference after treatment (P=0.518), however, MIDAS score decreased by50.1%and59.1%respectively in monotherapy group and combination group after treatment. The difference in MIDAS score was also significantly when comparing the group of monotherapy against the group of combination (P<0.001). At the end-point of the study, total effective rate of monotherapy group and combination group were50%and75.4%respectively compared with basline, the difference was significantly (P＜0.05). Both levetiracetam monatherapy and pus flunarizine were well tolerated, with few side effects. Conclutions:Small dosage of levetiracetam alone and combination with flunarizine in the prophylaxis of refractory migraine were efficacy and safety. The two-drug combination to prevent refractory mingraine was better, whereas the side effects did not increased. |
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