Nonsteroidal Anti-Inflammatory and Miscellaneous Drugs in Migraine Prophylaxis

Stefan Evers

Ewan J. Mylecharane

INTRODUCTION

In addition to the recognized drugs of first choice for migraine prophylaxis such as β-adrenoceptor blockers, antiserotonin drugs, calcium antagonists, and antiepileptic drugs, many other drugs and remedies have been tested in migraine prophylaxis. Most of these other drugs have not been tested in controlled randomized clinical trials. However, their use is sometimes recommended even in modern handbooks. This chapter aims to present the data on miscellaneous drugs that have been tested for migraine prophylaxis and for which controlled randomized trials are available. For drugs with established efficacy in migraine prophylaxis, details of their therapeutic use are mentioned briefly. The description will focus on the clinical evidence for efficacy of these drugs rather than on their pharmacologic properties.

NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS)

The rationale for using NSAIDs in the prophylaxis of migraine is based on the observation that some patients taking NSAIDs for other reasons (e.g., secondary prophylaxis of stroke) experience fewer migraine attacks and on the possible general involvement of prostaglandins in the inflammatory pathophysiologic components of the migraine process. The NSAIDs that have been most extensively tested in migraine prophylaxis are acetylsalicylic acid (ASA) (aspirin), naproxen and naproxen sodium, and tolfenamic acid.

Pharmacologic Background

The pharmacologic actions of the NSAIDs relevant to migraine prophylaxis are described in Chapter 49. Briefly, NSAIDs possess antiinflammatory, analgesic, and antipyretic properties. They exert their effect by inhibiting the ubiquitous cyclooxygenase-1 and cyclooxygenase-2 enzymes, thereby preventing the synthesis of prostaglandins and thromboxanes from ASA. The inhibition by ASA, but not other NSAIDs, is irreversible because ASA acetylates cyclooxygenase. The NSAIDs usually are classified as peripheral analgesics, although they have central effects as well.

Absorption after oral ASA, as with other NSAIDs, is high, in excess of 80% (1). ASA is metabolized rapidly by plasma and tissue esterases to salicylic acid before it reaches the systemic circulation. The peak plasma concentration of ASA is achieved 15 minutes after oral administration, whereas the peak concentration of salicylate is reached after 30 to 60 minutes. The plasma half-life of ASA is 15 to 30 minutes. Salicylic acid exhibits dose-dependent kinetics; thus, its half-life after 250 mg of ASA is about 3 hours and after 1 g about 6 hours. The range of bioavailability is between greater than 90% for naproxen/naproxen sodium and 60% for tolfenamic acid. The plasma half-lives of these NSAIDs are in the range of 2 to 4 hours, with the exception of naproxen, which has a half-life of 12 to 15 hours.

Possible Mode of Action in Migraine Prophylaxis

The mode of action of NSAIDs in migraine therapy and whether this mode of action involves prostaglandins in the migraine process are discussed in Chapter 49. One of
the major obstacles to inhibition of cyclooxygenase being responsible for the prophylactic efficacy of these agents is the lack of effect of the potent NSAID indomethacin in a double-blind, placebo-controlled trial in migraine patients (2).

It has been suggested that the prophylactic usefulness of NSAIDs in migraine could be through the inhibition of platelet aggregation, thereby correcting an underlying hyperaggregability (3,4). However, high oral doses of ASA (650 to 1300 mg daily) in combination with 75 to 300 mg dipyridamole daily were marginally superior to placebo in migraine prophylaxis in one trial (5) and superior to placebo in another (3), but these effects were not correlated with whether the patients had hyperaggregable platelets. In one placebo-controlled crossover trial in which a low dose of ASA (160 mg) was evaluated for migraine prophylaxis (see below), the active medication was of no benefit despite inhibition of platelet function (6). In the Physicians’ Health Study (7) of ASA (325 mg on alternate days), however, a 20% reduction in the incidence of migraine was suggested compared with placebo (see below). No correlation was observed between the degree of platelet inhibition and the efficacy as a migraine prophylactic drug for naproxen (8). Therefore, it is most unlikely that an action of platelets is responsible for the beneficial prophylactic effect of NSAIDs. Thus, the mode of action of NSAIDs in migraine prophylaxis is—as it is for any other migraine prophylactic drug—still not fully understood.

Results of Controlled Clinical Trials

A summary of 20 controlled double-blind randomized trials on the efficacy of oral NSAIDs in migraine prophylaxis is given in Table 58-1. All but two trials (3,10) included migraine patients both with and without aura; the two exceptions did not include any aura patients.

Higher doses of aspirin (1300 mg and 900 mg daily, respectively) showed superior efficacy compared with placebo (11) and were apparently comparable in efficacy to propranolol (9) in two small trials (12 patients in each), although the latter trial was too small to demonstrate comparability. In another trial, however, ASA (1500 mg daily) was less effective than metoprolol (10). This was confirmed by a recent large trial showing a superiority of 200 mg of metoprolol over 300 mg of ASA for all efficacy parameters (12). The outcome results for ASA were regarded by the investigators as in the range of typical placebo response. Trials of low doses of ASA have also failed to provide convincing evidence of efficacy. ASA (160 mg daily) did not achieve better results than placebo (6), and no correlation was found between the number of attacks and inhibition of adenosine diphosphate (ADP)-induced platelet aggregation. In children aged 7 to 17 years, the effect of ASA (100 to 200 mg daily) was comparable to that of flunarizine (13); however, because no placebo was used in this trial, conclusions concerning the efficacy of ASA cannot be made.

There are three large cohort studies with a comparison between ASA and placebo not primarily designed to examine the influence on migraine prophylaxis but showing interesting relevant results. The Physicians’ Health Study (7) indicated some effect of low-dose ASA (325 mg every other day for the prevention of cardiovascular disease) with the finding that 6% of subjects reported migraine compared with 7.4% of subjects taking placebo during a 60-month period (i.e., a 20% reduction in migraine frequency). Similar results were obtained in the earlier British Doctors Trial showing a reduction of migraine attacks by about 30% in the group taking 500 mg of ASA (14). However, in the Women’s Health Study, 100 mg of ASA daily did not result in a significant reduction of migraine frequency as compared to placebo, but showed a trend to a decrease in severity, duration, and migraine-related incapacitation (15). The study result was regarded as only a small treatment effect of ASA in the prophylaxis of migraine among middle-aged women. The question of whether low-dose ASA has a minor effect in migraine prophylaxis thus remains open.

In the first trial of naproxen (500 mg daily), this drug proved only questionably better than placebo (16). Naproxen sodium (1100 mg daily), however, was demonstrated to have better efficacy than placebo in three trials (4,8,17), and in one of these trials (17) it was comparable to pizotifen. In another trial (18), naproxen sodium (1100 mg daily) was comparable to propranolol, but the superiority of both drugs over placebo was restricted to patients’ evaluations. Comparability in each of these trials was not substantiated by narrow confidence intervals.

Tolfenamic acid had significantly better results than placebo (19,20), and comparability to propranolol was indicated in one of the trials (20) by rather narrow confidence intervals. In another trial (21), tolfenamic acid was comparable to propranolol, but no placebo control was included.

Only single trials are available for the remaining NSAIDs listed in Table 58-1. Ketoprofen showed marginally superior results compared with placebo in a group of severely afflicted migraine patients (22). In one small trial (17 patients), mefenamic acid had superior efficacy compared with placebo (23), but the claimed comparability to propranolol cannot be substantiated from a trial that included so few patients. Fenoprofen (1800 mg daily but not 600 mg daily) was superior to placebo (24), indobufen also had greater effects than placebo in one trial (25), and even flurbiprofen led to a significant decrease of headache intensity but not frequency in a double-blind placebo-controlled trial (26). Very recently, the new selective cyclooxygenase-2 inhibitor rofecoxib was studied for migraine prophylaxis. In a double-blind, placebo-controlled trial with 175 randomized (147 evaluated) patients, rofecoxib 25 mg/day was superior to placebo with respect to the responder rate but not to the absolute decrease of migraine frequency; there were no significant differences in the rate of adverse events between rofecoxib and placebo (27).

TABLE 58-1 Double-Blind Randomized Clinical Trials Comparing NSAIDs with Placebo and Other Drugs in the Prophylaxis of Migraine

*Trial*	*Drug and Dosage (mg)*	*Study Design*	*No. of Patients (no. Evaluated)*	*Run-in Period*	*Duration of Treatment*	*Efficacy Parameter*	*Investigators’ Conclusions*
(11)	ASA 650 bid Placebo bid	CO	12	Nil	3 mo × 2	Frequency	ASA > placebo
(9)	ASA 4.5/kg tid Propranolol 0.6/kg tid	CO	18 (12)	30 days open	3 mo × 2 (2 wk washout)	Frequency, headache index^a	ASA vs propranolol, ns; both > run-in
(6)	ASA 160 od Placebo od	CO	38 (27)	Nil	3 mo × 2	Frequency, severity	ASA vs placebo, ns
(13)	ASA 100-200 od Flunarizine 5-10 od	Pa	30 (29)^b	4 wk open	3 mo	Frequency	ASA vs flunarizine, ns; both > run-in
(10)	Metoprolol 200 od ASA 1,500 od	CO	28 (21)	8 wk	12 wk × 2	Frequency, 50% frequency decrease	Metoprolol > ASA; both > run-in
(16)	Naproxen 250 bid Placebo bid	CO	28	2 mo (no drug)	6 wk × 2 (1 wk washout)	Frequency, duration, headache index^c, preference	Naproxen > placebo for preference, other parameters dubious
(4)	Naproxen-sodium 550 bid Placebo bid	CO	34 (28)	2 wk placebo	8 wk × 2 (2 wk washout)	rating of efficacy, headache index^c, duration, medication	naproxen, sodium > placebo for all parameters
(8)	Naproxen-sodium 550 bid Placebo bid	CO	51 (33)	2 wk placebo	8 wk × 2 (2 wk washout)	Rating of efficacy, headache index, days with severe headache	Naproxen, sodium > placebo for all parameters
(18)	Naproxen-sodium 550 bid Propranolol 40 tid Placebo	Pa	170 (129)	2 wk placebo	14 wk	Headache days, severity, overall evaluation	Naproxen, sodium vs propranolol vs placebo ns for headache days and severity; naproxen, sodium = propranolol > placebo for patients’ evaluation
(17)	Naproxen-sodium 550 bid Pizotifen 0.5 tid Placebo tid	Pa	176 (151)	8 wk placebo	12 wk	Headache unit index	Naproxen, sodium = pizotifen > placebo
(19)	Tolfenamic acid 100 tid Placebo tid	CO	38 (31)	Nil	10 wk × 2 (2 wk washout)	Frequency, severity, duration, preference	Tolfenamic acid > placebo for all parameters
(20)	Tolfenamic acid 100 tid Propranolol 40 tid Placebo tid	CO	39 (31)	Nil	12 wk × 3	Frequency, duration, severity, medication	Tolfenamic acid = propranolol > placebo for frequency and medication; tolfenamic acid > propranolol = placebo for severity
(21)	Tolfenamic acid 100 tid Propranolol 40 tid	CO	76 (56)	4 wk (no drug)	12 wk × 2 (4 wk washout)	Migraine days, duration, severity	Both > run-in; tolfenamic acid = propranolol for all parameters
(22)	Ketoprofen 50 tid Placebo tid	CO	26 (24)	Nil	6 wk × 2 (1 wk washout)	Headache index^c, headache days	Ketoprofen > placebo for both parameters
(23)	Mefenamic acid 500 tid Propranolol 80 tid Placebo tid	CO	29 (17)	1 mo open	3 mo × 3	Frequency, duration, severity	Frequency, mefenamic acid = propranolol > placebo; severity and duration, ns
(24)	Fenoprofen 200 tid Fenoprofen 600 tid Placebo tid	Pa	118 (110)	4 wk placebo	12 wk	Frequency, headache index, medication	Fenoprofen 600 > placebo for all parameters; fenoprofen 200 vs placebo, ns
(25)	Indobufen 200 bid Pl bid	Pa	42 (35)	4 wk (no drug)	3 mo	Frequency, duration, headache index^c, evaluation of treatment	Indobufen > placebo for all parameters
(12)	ASA 300 od Metoprolol 200 od	Pa	270 (115)	4 wk placebo	4 mo	Frequency, responders	Metoprolol > ASA for all parameters
(27)	Rofecoxib 12.5 bid Placebo bid	Pa	175 (147)	2 mo	3 mo	Responders, frequency	Rofecoxib > placebo for responders; ns for frequency
(26)	Flurbiprofen 100 bid Placebo bid	CO	23	Nil	8 wk × 2 (2 wk washout)	Intensity, frequency	Flurbiprofen > placebo for intensity but not for frequency
ASA = aspirin; ns = not significant; od = once daily; bid = twice daily; tid = three times daily; co = crossover; pa = parallel-groups comparison; wk = week(s); mo = month(s); > = more effective than.
^a= frequency × severity × duration ^b= children, 7 to 17 years old ^c= frequency × severity.

Gastrointestinal problems were the most common side effects during NSAID treatment, including dyspepsia and diarrhea, but their frequencies of occurrence were generally not greater than those encountered in subjects who took placebo, probably because of the relatively small size of the trials. In only one trial (naproxen sodium) was it necessary for a patient to withdraw because of peptic ulceration (17). The possibility that rofecoxib (recently withdrawn in several countries) and other selective cyclooxygenase-2 inhibitors may increase the risk of adverse cardiovascular events might preclude their use in migraine prophylaxis.

Menstrual Migraine

Since about 50% of women migraineurs suffer migraine exclusively or also during menstruation (28), it has been suggested that NSAIDs might be particularly effective for menstrual-related migraine. Naproxen sodium (550 mg twice daily) has been shown to reduce pain including headache in the premenstrual syndrome (29). Its specific effects on menstrual migraine (550 mg twice daily) have also been evaluated (18,30,31). In one trial (18), a subset of 30 of 129 patients taking naproxen sodium or placebo continuously was analyzed for headache activity occurring before and after the onset of menstruation; patients treated with naproxen sodium reported fewer and less severe headaches during the week before menstruation than patients treated with placebo, but only severity was significantly reduced. In the other two placebo-controlled trials, naproxen sodium, given during 1 week before and 1 week after the start of menstruation, resulted in fewer perimenstrual headaches; in one study, severity was not reduced (31), but in the other both severity and analgesic requirements were decreased (30). Recently, 25 or 50 mg of rofecoxib, the selective cyclooxygenase-2 inhibitor, was studied in a small randomized open trial in 14 women with perimenstrual migraine (32). Both doses resulted in a significant decrease of days with migraine as compared to baseline, but the absence of a placebo control does not allow any final conclusion on the efficacy of this drug.

Therapeutic Use

When first-line migraine prophylactics (i.e., β-adrenoceptor blockers and antiepileptic drugs) are ineffective, contraindicated, or inappropriate, NSAIDs may be tried. Only naproxen sodium (500 to 1000 mg) and tolfenamic acid (300 mg) have been demonstrated convincingly to be superior to placebo. For ASA (at least 300 mg) there is, however, only some inconsistent evidence of efficacy in migraine prophylaxis. For migraine occurring at the time of menstruation, which often does not respond to prophylactic treatment, naproxen sodium, 550 mg twice daily (or equivalent dose of naproxen), can be tried for 1 week before and 1 week after menstruation. The main adverse effects include dyspepsia, erosive gastritis, peptic ulceration, diarrhea, hematologic complications, and hypersensitivity reactions. Contraindications include hypersensitivity to ASA or any NSAID, active peptic ulceration, liver or kidney disease, coagulation disorders or treatment with other anticoagulants, and (for most of the NSAIDs) age below 12 years.

ERGOT ALKALOIDS

Dihydroergotamine (DHE) is extensively used in the acute treatment of migraine (see Chapter 50, which also describes its pharmacology); however, it has also been subjected to seven controlled double-blind clinical trials of its efficacy in migraine prophylaxis, using a long-acting oral formulation. In three trials (33, 34, 35) with treatment periods from 30 to 45 days, DHE (10 mg daily) was superior to placebo in reducing the frequency of attacks. In one study (33), however, most patients probably did not suffer from migraine, and one study (34) was reported only briefly, making it difficult to judge, although this trial suggested that DHE was most effective in migraine occurring in the night. In one very large study (384 randomized patients), DHE 10 mg/day was not superior to placebo with respect to the responder rate in the total sample but reduced significantly the duration of attacks and the intake of symptomatic medication; in the subgroup of migraine patients with poor quality of life, however, the responder rate was significantly higher in the DHE group than in the placebo group (36). Three other trials showed that drugs like flunarizine (10 mg once daily) (37), indoramin (25 mg twice daily) (38), and dihydroergocryptine (20 mg twice daily) (39) are better than run-in and no different from DHE (5 mg twice daily); all these comparative studies, however, suffer from a lack of placebo control, and the results may be merely a time effect.

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