Flurbiprofen in the prophylaxis of migraine GLEN D. SOLOMON, MD, AND ROBERT S. KUNKEL, MD • Flurbiprofen, a nonsteroidal anti-inflammatory drug with effects on prostaglandin synthesis, platelet serotonin release, and beta-endorphin, was studied for efficacy in migraine prophylaxis. Twenty-three patients completed the 20-week, placebo-controlled, double-blind, crossover trial. Flurbiprofen, in a dose of 100 mg twice daily, and placebo were each given for 8 weeks, with a 2-week "washout" period between the treatment periods. Flurbiprofen significantly reduced migraine intensity (P < .05), total hours with migraine (P < .015), and the dosing frequency of relief medication (P < .015). Total hours with migraine decreased by 41%, and the use of relief medication decreased by 31%. The reduction in migraine frequency did not reach statistical significance (P < .10). Adverse effects were infrequent. Based on the overall improvement in migraine parameters, flurbiprofen can be recommended for use in migraine prophylaxis. • INDEX TERMS: FLURBIPROFEN; MIGRAINE • CLEVE CLIN J MED 1993; 60:43-48 IGRAINE HEADACHE represents a WHAT CAUSES MIGRAINE? common disorder with an estimated prevalence of 41 per 1,000 in the United The pathophysiology of migraine is not completely States.1 Migraine is a frequent source of understood and is probably multifactorial. The initial Mabsenteeism and decreased productivity, costing event in migraine appears to involve the release of American business an estimated $4.5 billion per year.2 serotonin,4 either from platelet stores, the dorsal raphe Beyond societal costs, individual suffering is sig- nucleus, or both. Nociceptive transmission takes place nificant. Migraine patients consume more tran- through sensory branches of the trigeminal nerve,5 quilizers, amphetamines, and sleeping pills than which terminate within the smooth muscle of cerebral headache-free controls.3 blood vessels. The sensory axons trigger release of Currently available prophylactic treatment for vasodilating and permeability-promoting peptides,6 migraine consists primarily of beta blockers, calcium- with the production of a vascular inflammatory channel blockers, nonsteroidal anti-inflammatory response—the so-called "sterile arteritis" described by drugs (NSAIDs), antidepressants, and methysergide. Wolff.7 While these agents are useful, they are not uniformly Raskin states that the cardinal abnormality of effective and are associated with side effects. migraine is the defective modulation of serotonin release.4 Platelet activity in migraine sufferers differs from controls,8,9 with chronic aggregation and in- From the Headache Center, The Cleveland Clinic Foundation. creased platelet adhesiveness during the headache Address reprint requests to G.D.S., Headache Center, A91, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, phase of migraine. The aggregated platelets release OH 44195. vasoactive prostaglandins and serotonin. Prostaglan- JANUARY • FEBRUARY 1993 CLEVELAND CLINIC JOURNAL OF MEDICINE 3 43 Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. FIA Rnii'Roi R.NB Soi OMON AND KI VKU din Ei causes dilatation of the external carotid arteries, biprofen in the prophylaxis of migraine in a controlled while prostaglandin F2 induces intracerebral trial. vasoconstriction.10 Sicuteri has proposed a theory of migraine PATIENTS AND METHODS pathophysiology that suggests that substance P takes part in nociceptive transmission within the trigeminal The trial design was a double-blind, randomized, system.5 Substance P induces vasodilation, plasma ex- placebo-controlled, crossover of 20 weeks' duration. travasation, and nasal and conjunctival congestion. Flurbiprofen dosage was 100 mg twice daily. Patients Endogenous opioids inhibit the release of substance P who had migraine with aura, without aura, or both, as from primary sensory neurons.5 Drugs that affect beta- diagnosed using International Headache Society endorphin and methionine enkephalin (met- criteria,28 were included. All patients had migraine for enkephalin) may control both the abnormal pain at least 2 years, with between two and eight migraine response and vascular changes of migraine. attacks during the previous month. A previous attempt Moskowitz11 has shown acute inflammatory chan- at migraine prophylaxis with drugs was not cause for ges, including vasodilation and plasma extravasation, exclusion. Patients with cluster headache or frequent in the cerebral arteries during stimulation of the tension-type headaches were excluded, as were those trigeminal nerve. This suggests that stimulation of the with a history of aspirin or NSAID sensitivity, drug trigeminovascular complex induces a sterile arteritis abuse, alcoholism, and renal, hepatic, or cardiac dis- that is the final common pathway of migraine. ease. Patients using other NSAIDs or migraine prophylactic drugs were also excluded. BASIS FOR TREATMENT WITH NSAIDS The study was approved by the Cleveland Clinic Foundation Institutional Review Board. Written in- NSAIDs act to inhibit inflammation through their formed consent was obtained from each participant. effects on chemotaxis, phagocytosis, lysosomal enzyme The study design included a 2-week single-blind release, kinin generation, complement generation, and placebo "washout" period, followed by an 8-week formation of prostaglandins.12 Furthermore, certain double-blind treatment period. Patients then under- NSAIDs act as analgesics through central pain went a 2-week single-blind placebo washout to lessen mechanisms. These most likely involve mediation of the likelihood of crossover pharmacologic effects of substance P, beta-endorphin, and met-enkephalin.13 As flurbiprofen. A second 8-week double-blind crossover these activities all affect the proposed pathway of treatment period then followed. Throughout the study, migraine, it is logical to evaluate NSAIDs in migraine patients were interviewed at 4-week intervals during prophylaxis. treatment periods and every 2 weeks during washout Several NSAIDs have been reported to have periods. prophylactic activity in migraine. Among these are A laboratory evaluation that included complete aspirin,14 naproxen,1015""17 ketoprofen,18 flufenamic blood count, urinalysis, and chemistry profile (SMA acid,19 tolfenamic acid,20 and fenoprofen calcium.21 16) was obtained at the screening visit and again at the Flurbiprofen, an NSAID derived from propionic end of both treatment periods. Urine pregnancy test acid, has several unique properties that suggest poten- was performed at the screening visit for female tial benefit in migraine prophylaxis. Flurbiprofen can patients. Stool was tested for occult blood every 4 inhibit platelet serotonin release22 and increase levels weeks during treatment periods. of beta-endorphin,23 and it may alter tissue levels of Patients were required to keep a daily diary, which immunoreactive bradykinin.24 These actions theoreti- was used to assess therapeutic efficacy. This diary cally allow flurbiprofen to prevent migraine attacks at measured the following for each headache: time of the level of platelet serotonin release, trigeminal onset; severity (on a scale of 1 to 5: 1, no limitation in nociception, and cerebrovascular inflammation. daily activity; 2, some limitation; 3, moderate limita- In addition, Awidi25 studied flurbiprofen in the tion; 4, severe limitation; 5, bedridden); duration of acute treatment of migraine and found it to be effec- headache; when and if concomitant relief medication tive. Other NSAIDs that have been effective in acute was taken; and any other health changes. This per- treatment, including naproxen sodium26 and aspirin,27 mitted examination of five parameters: migraine fre- have also been effective in migraine prophylaxis. quency, migraine severity, total hours with migraine, We investigated the efficacy and safety of flur- relief medication dosing frequency, and adverse effects. 44 CLEVELAND CLINIC : JOURNAL OF MEDICINE VOLUME 60 • NUMBER 1 Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. I'Ll.'RHIPROFhNI SOLOMON ANI) KL NKI.L Data were analyzed using TABLE 1 two-tailed tests and two- EFFICACY OF FLURBIPROFEN VS PLACEBO IN MIGRAINE way analysis of variance Study variable Flurbiprofen (mean ± SD) Placebo (mean 1 SD) P value (ANOVA) fixed-effects Flurbiprofen first model for a two-period Migraine frequency 4.412.7 5.613.2 crossover design, using the (attacks/8 weeks) statistical package SAS. Migraine duration 64.2140.2 104.01100.0 (hours/8 weeks) Power calculations deter- Relief medication dosing frequency 10.717.1 13.718.8 mined a sample size of 12 (doses/8 weeks) patients in each treatment Placebo first sequence (total 24 Migraine frequency 4.314.1 5.813.6 patients) would be able to Migraine duration 41.4143.2 74139 Relief medication dosing frequency 8.718.9 14.3112.7 detect a reduction of 50% Means or more in the mean num- Migraine frequency 4.39 5.73 P< .10 ber of headaches observed Migraine duration 51.7 87.6 P< .015 in an 8-week period. For Relief medication dosing frequency 9.7 14.0 P< .015 the measurement of SD, standard deviation migraine frequency, a single migraine attack was defined TABLE 2 as preceded and followed by EFFECT OF FLURBIPROFEN ON FREQUENCY OF MIGRAINE ATTACKS (NUMBER OF ATTACKS) 8 hours awake and headache-free. A P < .05 Flurbiprofen first Placebo first was regarded as significant Washout (2 weeks) 1.8 Washout (2 weeks) 2.1 and, a