Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

49th Annual Scientific Meeting of the American Headache Society

Chicago, Illinois / June 7-10, 2007

Perception has been that pure menstrual migraine—defined as migraine that occurs two days prior to and three days following onset of menstrual flow—was more refractory to triptan therapy than migraine not related to the menses. An analysis designed to evaluate the efficacy and tolerability of a triptan in pure menstrual migraine as well as menstrually-related migraine was carried out by Dr. Robert Nett, Medical Director, Texas Headache Associates, San Antonio, and colleagues. The two randomized, placebo-controlled single-attack studies involved over 700 menstrual migraineurs with moderate to severe migraine, among whom 146 had pure menstrual migraine.

The main end point was pain relief at two hours as well as 24-hour sustained pain relief. At two hours, 73% of patients with pure menstrual migraine treated with rizatriptan 10 mg reported pain relief as did 71% of those with menstrually-related migraine vs. approximately half of placebo controls. At 24 hours, 42% of women with pure menstrual migraine reported sustained pain relief as did 47% of women with menstrually-related migraine vs. approximately one-third of placebo controls.

Importantly as well, associated symptoms including light and sound sensitivity were eliminated in approximately 60% of treated patients with either pure or menstrually-related migraine vs. approximately 45% of placebo controls. Over 70% of patients with either type of migraine reported relief from nausea with active therapy vs. about 55% of placebo patients. “We have always assumed menstrual migraine is a more refractory type of migraine due to the profound influence of estrogen but what we have elegantly shown is that rizatriptan is just as effective in pure menstrual migraine as it is in menstrually-related migraine, so women can rest assured that better than 70% of the time, they will have resolution of not just the pain but other components of migraine that are sometimes equally, if not more disabling,” said Dr. Nett.

Related findings from the same group of experts reinforced these sentiments. In further analyses of the same study groups, researchers first noted that approximately 60% of patients in both studies reported mild impairment in their ability to perform daily activities, while 25% reported severe impairment and 9% needed bed rest. Two hours after treatment, approximately 50% of patients randomized to active therapy were functioning normally vs. approximately one-third of placebo patients.

Premonitory symptoms that occur anywhere from hours to days prior to pain onset—the most common being fatigue, irritability and light and noise sensitivity—were similarly shown to respond well to rizatriptan and there was no substantive difference in its efficacy between those with and without premonitory symptoms.

Symptoms of cutaneous sensitivity—reported by over 80% of patients at baseline in both placebo-controlled studies—also did not predict for response to rizatriptan, noted Loretta Mueller, DO, University Headache Center, Stratford, New Jersey. Comparing responses to active therapy vs. placebo in those who reported baseline cutaneous sensitivity and those who did not, Dr. Mueller and colleagues found no difference in the efficacy of rizatriptan and that it significantly reduced symptoms of cutaneous sensitivity relative to placebo.

Other Treatment Strategies

It has been previously reported that high-dose acetaminophen can relieve migraine in a certain proportion of migraineurs, but it was hypothesized that the combination of acetaminophen plus a triptan might be appreciably more effective than either therapy alone. This hypothesis was tested in a placebo-controlled trial in which migraineurs with moderate to severe migraine were randomized to the combination of rizatriptan 10 mg/acetaminophen 1000 mg, rizatriptan 10 mg, acetaminophen 1000 mg or placebo. A total of 200 patients (50 per group) were enrolled and the primary outcome measure was pain relief at two hours.

Freedom from pain at two hours was reported by 54% of patients taking the combination, 40% of those taking rizatriptan alone and 25% for those taking acetaminophen alone. Some 15% of patients on placebo also were pain-free at two hours. “All treatments had a significant effect on reducing associated symptoms, including placebo,” reported Dr. Frederick Freitag, Diamond Headache Clinic, Chicago, Illinois, although photophobia was significantly reduced in patients receiving the combination and those on rizatriptan monotherapy vs. both acetaminophen and placebo. About one-third of patients taking rizatriptan in combination or alone experienced an adverse event attributable to the treatment as did 20% of patients on either acetaminophen or placebo. The adverse events were typical of triptan-related side effects, Dr. Freitag noted, but interestingly enough, the only chest adverse events were reported in placebo patients.

Dr. Henry Hu, West Point, Pennsylvania, and colleagues sought to evaluate how often patients take both a triptan and an NSAID for the treatment of migraine. An analysis of over 1500 participants in a managed-care setting revealed that approximately 38% of them used both a triptan and an NSAID. During the next migraine attack, almost three-quarters of them changed their approach to treating the migraine, with about 23% reporting the use of triptan monotherapy and about the same percentage taking an NSAID first and then a triptan. Only 10% reported taking both a triptan and an NSAID together, while the remaining 5% reported they took a triptan first and then an NSAID.

“More triptan-only patients became nausea-free within one hour after initial dosing than patients using the other treatment regimens,” investigators observed, “and two-thirds of triptan-plus-NSAID patients and triptan-only patients did not use rescue medication.” Commenting on the findings, Dr. Hu noted that the use of a triptan plus an NSAID or NSAID monotherapy had a relatively limited effect on nausea one hour post-dosing. “If you are taking an NSAID, it might compromise the anti-nausea effect of the triptan,” he explained in an interview. If patients are very satisfied with monotherapy, “there is frankly no reason why you would want to add another medication and if it is an NSAID, it might compromise some of the triptan’s anti-nausea [effects],” he remarked.

Emerging Evidence

This evidence suggests that CGRP has a pivotal role in the pathophysiology of migraine as well as other primary headache disorders, notably cluster headache. It was hypothesized that CGRP inhibition could block vasodilation and reduce pain transmission without causing vasoconstriction or the same vascular side effects associated with triptan use.

The first CGRP antagonist to be developed was olcegepant, an intravenous (i.v.) formulation. In a phase II study in which 126 patients with migraine received one of six doses of olcegepant i.v. or placebo, results showed that the 2.5-mg treatment dose was the most effective and best tolerated, eliciting response (defined as the absence of headache or the presence of a mild headache two hours after treatment) in 66% of patients compared with 27% in placebo controls. Response to the compound was seen to increase with time as well, so that some 24 hours after infusion, 47% of patients given active treatment were pain-free vs. 15% of placebo patients.

Accompanying nausea, sound and light sensitivity all improved in parallel with headache response and the rate of recurrence was 19% for olcegepant patients vs. 46% for placebo controls. The rate of adverse events was virtually identical in both groups, “so the side-effect profile [of the CGRP antagonists] looked very good,” noted Dr. Stewart Tepper, Director, New England Center for Headache, Stamford, Connecticut.

Until the development of MK-0974, there had been no oral CGRP antagonist but both early and more mature studies indicated that it has potent anti-migraine activity and is well tolerated. The first suggestion that the agent could prove active against pain states was reported by researchers in the US, where its effect on inhibition of capsaicin-induced dermal microvascular blood flow response was evaluated. Twelve healthy volunteers received a single oral dose of the new agent followed by two topical doses of capsaicin in a three-period crossover study. Results showed that both high- (800 mg) and lower-dose (300 mg) MK-0974 significantly reduced capsaicin-induced increases in dermal microvascular blood flow—a clear sign of its analgesic effects.

Phase I clinical studies evaluating MK-0974 have involved some 330 migraineurs and to date, there have been no reports of any treatment-related serious adverse events, no significant effect from gender or age on treatment response and no significant effect on the agent’s bioavailability from migraine-associated gastric stasis.

Study Results

As presented by Dr. Tony Ho, Whitehouse Station, New Jersey, results from a phase IIb dose-finding study of MK-0974 were encouraging. An interim analysis was planned in order to discontinue ineffective doses of MK-0974 early. Approximately 320 patients were included in the primary and secondary efficacy analyses in which it was administered in doses of 300 mg, 400 mg and 600 mg. There was also an arm in which rizatriptan 10 mg was given. All patients had moderate to severe migraine and the primary efficacy end point was pain relief at two hours.

At two hours, 68.1% of patients on the 300-mg dose, 48.2% on the 400-mg dose and 67.5% on the 600-mg dose reported pain relief. Some 69.5% of rizatriptan patients also reported pain relief at two hours. At the same time period, 45.2% of patients on the 300-mg dose, 24.3% on the 400-mg dose and 32.1% on the 600-mg dose reported they were free from pain, as did 33.4% of rizatriptan controls.

Results for sustained pain relief and sustained freedom from pain at 24 hours were the most significant, with 52.6% of patients on the 300-mg dose, 37.8% on the 400-mg dose and 52.5% on the 600-mg dose experiencing sustained relief from pain, as did 35.3% on the triptan. Regarding 24-hour sustained freedom from pain, more patients on any dose of MK-0974 were still pain-free at 24 hours at 39.6% for the 300-mg dose, 22% for the 400-mg dose and 32% for the 600-mg dose. Some 18.4% of triptan patients also had sustained freedom from pain at 24 hours. Associated symptoms at two hours were also considerably reduced in all four treatment arms.

The CGRP antagonist was well tolerated, without the typical triptan side effects including chest pressure, paresthesia, dysesthesia and hyperesthesia. “These early results are very promising,” noted Dr. Ho, “and there is potential for the new drug to be superior to the triptans 24 hours after the medication is taken, although this needs to be confirmed in a larger trial,” he added.

Questions and Answers

The following question-and-answer session was conducted with Dr. Peter Goadsby, National Hospital for Neurology and Neurosurgery, London, UK, and Dr. Alan Rapoport, Clinical Professor of Neurology, David Geffen School of Medicine, University of California-Los Angeles, during the AHS scientific sessions.

Q: Why is it so important that the CGRP antagonists do not cause vasoconstriction?

Dr. Goadsby: To the well-educated practitioner, it is not important. Other physicians would rather not have to be concerned with the vascular aspects of the triptans, so it really is about removing the vascular baggage associated with the use of triptans in primary care.

Q: Why do you think there is so much excitement surrounding the new CGRP antagonists?

Dr. Rapoport: The real excitement is that this drug has a different mechanism of action from the triptans and the hope is that it will have fewer side effects and safety concerns. It does not constrict blood vessels and therefore it can be given to patients who might not be able to take the triptans such as patients who have had a stroke or transient ischemic attack, a myocardial infarction, peripheral artery disease or even high blood pressure. There is a whole new group of people who will be able to take this good migraine medication if it makes it through phase III trials, and there is good reason to believe that at least some people will respond to this drug even if they do not respond to the triptans.