Abstract
Rizatriptan is an effective and fast acting drug for the acute treatment of migraine. As with any other acute treatment for migraine, headache recurrence may occur in up to one-third of responders. Combination with non-steroidal anti-inflammatory drugs (NSAIDs) seems to reduce the incidence of headache recurrence in clinical practice. Rofecoxib is a member of a new class of NSAIDs, which selectively inhibits the COX-2 enzyme and therefore is associated with a lower risk of gastrointestinal side-effects; the drug has a long plasma half-life (17 h). This open label study compared rizatriptan with rizatriptan plus rofecoxib in the acute treatment of migraine. Fifty-six triptan naive patients from a tertiary centre (37 women and 19 men, ages 16-55 years, mean 35 years) with International Headache Society migraine were randomized into two groups. They were instructed to treat three consecutive moderate or severe attacks with either 10 mg rizatriptan (group 1: 18 women and 10 men) or with 10 mg rizatriptan plus 25 mg rofecoxib (group 2: 19 women and 9 men). The presence of headache and nausea at 1, 2 and 4 h, and of side-effects, use of rescue medication and recurrence were compared. Fifty-four patients completed the study. Group 1 treated 76 attacks and group 2 treated 81 attacks. Absence of headache at 1 h was seen in 19 attacks (25%) in group 1 and in 34 attacks (42%) in group 2 (P = 0.082); at 2 h absence of headache was seen in 60% of group 1 attacks and in 76% of group 2 attacks (P = 0.115). At 4 h, 75% of group 1 attacks and 88% of group 2 attacks were pain free (P = 0.122). With regard to nausea, of those who had nausea at baseline, 31% and 49% of attacks in groups 1 and 2, respectively, were nausea free at 1 h (P = 0.091), 75% and 79% at 2 h (P = 0.736) and 82% and 91% (P = 0.479) at 4 h. Recurrence, based on all attacks of those patients who achieved pain free at 4 h, was observed in 53% of group 1 and 20% of group 2 attacks (P< 0.001). Sustained pain- free rates (for the 4-h time point) were 45.6% of group 1 and 78.9% of group 2 attacks. There were no significant differences with regard to rescue medication consumption after 4 h and side-effects in both groups. There was a non-significant trend for the combination group to have a higher response rate. The group treated with rizatriptan and rofecoxib had a lower recurrence rate than the group treated with rizatriptan. This study demonstrated that combining a fast acting triptan such as rizatriptan with rofecoxib reduced headache recurrence rates, was well tolerated and may be more effective than the use of rizatriptan alone. Double-blind, placebo-controlled studies are necessary to confirm these observations.
Introduction
Triptans are effective drugs for the acute treatment of migraine (1–4). Rizatriptan, one of the newer triptans, shows good efficacy (pain free at 2 h in 40–42%) (5, 6) but headache recurrence within 24 h may occur in up to one-third of responders, requiring re-dosing (7). This may cause difficulties for patients in countries where medication is not covered by insurance or government authorities, as in Brazil. Some non-steroidal anti-inflammatory drugs (NSAIDs), such as acetylsalicylic acid, ibuprofen, diclofenac, naproxen sodium, mefenamic acid, tolfenamic acid and lysine clonixinate, have also demonstrated efficacy in treating migraine attacks (8–10). Interestingly, the combination of a triptan and an NSAID seems to reduce the risk of headache recurrence in clinical practice (11, 12). Rofecoxib is a member of a new class of NSAIDs, which selectively inhibits the COX-2 enzyme, being therefore better tolerated with regard to gastrointestinal side-effects (13, 14). Furthermore, the half-life of rofecoxib is 17 h, which may contribute to a prolonged protective effect with regard to recurrence. This randomized open label study thus compared rizatriptan with rizatriptan plus rofecoxib in the acute treatment of migraine.
Patients and methods
Fifty-six triptan-naive patients from a private tertiary centre (37 women and 19 men, ages 16–55 years, mean 35 years) with International Headache Society (IHS) migraine were studied in an open, prospective, parallel-group design. The patients were randomized to two groups. Group 1 (28 patients, 18 women and 10 men) were instructed to treat three consecutive moderate or severe migraine attacks with 10 mg rizatriptan tablets, while group 2 (28 patients, 19 women and 9 men) had to treat three consecutive moderate or severe attacks with 10 mg rizatriptan plus 25 mg rofecoxib. All patients were informed that the purpose of this study was to test potential differences in recurrence and efficacy and gave their informed consent. The presence of headache and nausea at 1, 2 and 4 h, as well as side-effects, rescue medication consumption after 4 h and recurrence were evaluated through a clear and objective written report to be filled out by each patient for each of the treated attacks, and were compared between groups. All patients were using different types of preventive medications other than propranolol and NSAIDs for longer than 1 month that were not changed, with regard to dosing and drugs, during the study. Patients were excluded if they had a history of active peptic disease, as well as those receiving treatment for any other medical or psychiatric conditions. The statistical analysis was performed using logistic regression models, whose fit accounted for the intrasubject correlation. Recurrence rates (4–24 h) were calculated from attacks where patients were pain free at 4 h (15).
Results
Fifty-four patients completed the study. Two patients from group 1 took a different medication and two patients from group 1 and three patients from group 2 took their medication during one mild attack. Group 1 treated 76 attacks and group 2 treated 81 attacks. The proportion of attacks with moderate and severe intensity was similar in the two groups (group 1, 50 moderate and 26 severe attacks; group 2, 55 moderate and 26 severe attacks). Nausea was present in 55 attacks (72.4%) in group 1 and in 53 attacks (65.4%) in group 2. Absence of headache pain at 1 h was seen in 19 attacks (25%) in group 1 and in 34 attacks (42%) in group 2 (P=0.082); at 2 h in 60% of attacks in group 1 patients and in 76% of attacks in group 2 (P=0.115). At 4 h, 75% of group 1 attacks and 88% of group 2 attacks were pain free (P=0.122) (Table 1). With regard to nausea elimination, 31% and 49% of attacks in groups 1 and 2 were nausea free at 1 h (P=0.091), 75% and 79% at 2 h (P=0.736) and 82% and 91% (P=0.479) at 4 h, respectively (Table 2).
Percentage of attacks that were pain free
∗ P-values from logistic regression model, which accounted for correlation within subjects. All other P-values are from Fishers exact test.
Percentage of attacks without nausea (based on those attacks with nausea at baseline)
∗ P-values from logistic regression model, which accounted for correlation within subjects. All other P-values are from Fishers exact test.
Recurrence, based on all attacks where patients achieved pain-free status at 4 h, was observed in 53% of group 1 and 20% of group 2 attacks (P<0.001) (Table 3); the 2 h rates were 63.8% and 22.6%, respectively. No statistical analysis was performed between groups. Sustained pain-free rates (attacks pain free at 4 h, no recurrence within 4–24 h, and no use of any additional migraine medication) (7) were 45.6% of group 1 and 78.9% of group 2 attacks. The 2–24 h sustained pain-free rates were 36.2% in group 1 and 77.4% in group 2 attacks. Side-effects were mild and didn't cause any patient withdrawals. There were no significant differences with regard to side-effects in either group. The overall incidence of adverse events in the first attack was 29% in the rizatriptan group and 32% in the combination group, although nausea and pirosis (burning pain in the epigastric region) appeared more common in the combination group (four vs. one and four vs. two patients, respectively). Rescue medication consumption after 4 h was similar in both groups.
Recurrence rates (based on all attacks that were pain free at 4 h)
∗ P-values from logistic regression model, which accounted for correlation within subjects. All other P-values are from Fishers exact test.
Discussion
The triptans are a class of compounds that are agonists at 5-HT1B/1D receptors. Rizatriptan revealed pain-free rates at 2 h of 41% (40–42%) in phase III studies (5, 6). At the 4-h time point, up to 65% of the patients taking 10 mg were pain free (after escape medication had been allowed) (6). Recurrence does represent a limiting prescribing factor but may happen with any other acute migraine treatment (7, 11). The combination of a triptan such as rizatriptan with a well-tolerated and long-acting NSAID could promote greater efficacy and lower recurrence, better matching patients' expectations of acute migraine treatments (16, 17). Rofecoxib, a new compound that selectively inhibits cyclo-oxygenase-2 in a dose-dependent manner in humans, was chosen in this study as it has a long half-life (17 h) and shows clinical efficacy in studies of patients with osteoarthritis and reumathoid arthritis, similar to diclofenac, naproxen and ibuprofen, all proven effective in the acute treatment of migraine (10, 18, 19). In addition, the use of rofecoxib is followed by a significantly lower incidence of upper-gastrointestinal adverse events, such as perforations, ulcers and bleeds (13, 14, 19, 20).
This study demonstrated not only reduced recurrence rates with the combination of drugs, as already suggested previously (11, 12), but also better sustained pain-free rates. The presentation of sustained pain-free measures, even though not initially planned in this study, is preferred over isolated endpoints of efficacy and recurrence as differences in recurrence rates need to be assessed within the context of initial efficacy rates (21). In addition, sustained efficacy measures may provide a clearer assessment of single-dose drug efficacy over 24 h and may be useful for comparing the efficacy of different drugs in direct head-to-head studies (7). Our figures of sustained pain-free measures were higher than those encountered in the review of all phase III placebo-controlled studies (7) and this may have been related, specifically in the group combining drugs, to the accessory effect exerted by the NSAID, as suggested by Peroutka (22). On the other hand, the fact that we principally used the 4-h time point for recurrence and sustained pain free instead of the usually assessed 2-h time point may be justified as an attempt to obtain a better indication of response in ‘real life’ clinical practice (23). The reduced recurrence rate and better numbers of sustained pain-free measures may be related to the long half-life, with the additional anti-inflammatory effect of the COX2 inhibitor used. Furthermore, the trend for better response with the combination may well be confirmed by an appropriately powered placebo-controlled study. More work is clearly required to confirm these initial observations.
Footnotes
Acknowledgements
The authors wish to thank Dr Chris Allen for his guidance, help and revision, Dr Alan Rapoport for his guidance and Michel Ferrari for his final revision of the manuscript. Also, Dr Kathleen McCarroll for performing the statistics. This study didn't have any financial support.