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.

13th Congress of the International Headache Society

Stockholm, Sweden / June 28-July 1, 2007

Clinicians have long noted that migraine attacks in women triggered just before the onset of or early in menstruation are more painful, longer-lasting and more difficult to treat than attacks at other times of the month. Until recently, however, no consistent definition of menstrual migraine had been established on which to base clinical trials for selecting the most effective triptan for this patient population.

That has now changed with the International Headache Society’s proposed research criteria classification of menstrual migraine and menstrually-related migraine, according to Dr. Lisa K. Mannix, Medical Director, Headache Associates and ClinExcel Research, West Chester, Ohio. She reported that the new criteria define menstrual migraine as attacks without aura occurring within a five-day window of the perimenstrual period, from two days before bleeding begins to three days into the period of bleeding in at least two of three menstrual cycles. Those criteria are divided into two subtypes. Women who suffer attacks without aura exclusively within the five-day menstruation window, but in no other weeks of the month, are said to have pure menstrual migraine. Those who also have attacks at other times of the cycle are said to have menstrually-related migraine. Pure menstrual migraine is markedly less common than menstrually-related migraine, but is more severe, lasts longer, recurs more often and responds less optimally to medication.

“The first two prospective studies using the new International Classification of Headache Disorders [ICHD-II] diagnostic criteria for menstrual migraine have demonstrated that acute treatment with rizatriptan 10 mg is effective and well tolerated for menstrual migraine compared to placebo,” Dr. Mannix noted. She reported that the two studies (MM1 and MM2), which employed identical protocols, assigned 707 patients, mean age 37 years, experiencing a moderate-to-severe attack of menstrual migraine to treatment with single doses of rizatriptan 10 mg or placebo and recorded two- and 24-hour pain relief. Slightly more than 75% of participants had menstrually-related migraine and the remainder had pure menstrual migraine without aura.

The percentage of patients achieving pain relief at two hours was significantly greater in the active-treatment group than with placebo, at 70% vs. 53% in the MM1 population (P=0.001) and 73% vs. 50% among the MM2 cohort (P<0.001), Dr. Mannix informed delegates. The percentage of patients achieving 24-hour sustained pain relief was also significantly greater in the treated group than the placebo group, at 46% vs. 33% among those in both the MM1 and MM2 populations (P=0.016 and P=0.024, respectively).

Several associated signs and symptoms, including nausea, cutaneous sensitivity, photo- or phonophobia were eliminated or reduced, some significantly. Actively-treated patients were also more likely to function normally at two hours compared to placebo-treated patients and did not require any rescue medication. There were no serious adverse events in the groups, she observed.

“These are the first reported studies using the new ICHD-II definitions of menstrual migraine,” Dr. Mannix concluded. “They demonstrate the efficacy of rizatriptan for the treatment of menstrual migraine for both two- and sustained 24-hour pain relief.”

Early vs. Late Treatment

Although evidence supporting early intervention in migraine with acute medication is being accumulated, Dr. Michel Ferrari, Professor of Neurology, Leiden University Medical Center, The Netherlands, warned there may be potential pitfalls in that concept.

“Waiting for moderate or severe migrainous pain can better ensure that we are actually treating migraine and not tension headache effects, for example, or short-lasting non-migraine headache,” he told delegates during the scientific sessions. “Early intervention may equate with treating mild migraine in slowly progressing attacks, but not necessarily in rapidly progressing ones, so it is important to distinguish between treating mild vs. early.”

In Dr. Ferrari’s opinion, treating different attacks requires different end points. “We really need an outcome measure which includes both initial response and duration of response,” he suggested. “In other words, a single dose that will thwart the attack within two hours and for at least a day, and require no subsequent medication for three days.”

His group’s meta-analysis of 53 controlled clinical trials of acute migraine treatment with oral triptans found that rizatriptan 10 mg, almotriptan 12.5 mg and eletriptan 80 mg achieved pain-free rates at two hours that were greater than the active comparator sumatriptan 100 mg. In addition, rizatriptan and eletriptan 80 mg achieved a 59% improvement in headache response rates at two hours over sumatriptan. Sustained pain-free rates were also higher for rizatriptan, almotriptan and eletriptan 80 mg (but not 20 mg) compared to sumatriptan.

Although there is still only limited scientific support for migraine treatment while the pain is still mild, Dr. Ferrari maintained, “Treat as soon as possible when you are sure the patient is developing a migraine attack, but not as early as in the aura phase.”

Dr. Hans-Christoph Diener, Professor of Neurology, and Chairman, Department of Neurology, University of Duisburg-Essen, Essen, Germany, noted that although aura does not respond to treatment with analgesics or triptans in randomized placebo-controlled studies, patients can be assured that the use of the 5-HTIB/ID agonists in the aura phase will not increase the incidence of adverse events or initiate strokes, which he considers to be an important safety message. However, he remarked that an experimental treatment option for aura status may be ketamine nasal spray, but only if it is reserved for preventive therapy in patients suffering repeated episodes of aura.

While patients should take migraine medication as early as possible, they should be instructed not to take a triptan while suffering from aura symptoms, he concluded. A compromise would be to take the tripan when symptoms of aura are resolving.

Novel Treatment Strategy

“The first orally bioavailable calcitonin gene-related peptide [CGRP] antagonist has the potential to be the precursor of the next generation of potent drugs for the treatment of acute migraine,” according to Dr. Stefanie Kane, West Point, Pennsylvania.

CGRP is a powerful neurotransmitter expressed in the trigeminovascular system and released into the cranial circulation during migraine and cluster headache. It is even possible that triptans currently mediate their anti-migraine effects at least in part through inhibition of CGRP release, since high CGRP levels are reportedly normalized by treatment with those agents. This dynamic suggests that CGRP-mediated activation of the trigeminovascular system may play a key role in migraine pathogenesis and that the inhibition of CGRP-driven pathophysiologic processes could provide a novel therapeutic approach to treating migraine without the usual undesirable cardiovascular side effects, Dr. Kane explained. CGRP receptors in the meningeal blood vessels are thought to be involved in migraine pain, and CGRP-induced meningeal vasodilation may be involved in the allodynia associated with that disease. CGRP receptor antagonism can block some properties that are believed to be involved during a migraine attack.

Results from a dose-finding study which evaluated the efficacy and tolerability of the novel CGRP inhibitor MK-0974 were discussed here by Dr. Tony Ho, Whitehouse Station, New Jersey. “Estimated pain relief proportions at two hours’ post-treatment in 330 patients were 68.1% (n=38) for 300-mg doses of MK-0974, 48.2% (n=45) for 400-mg doses and 67.5% (n=40) for 600-mg doses,” he reported. “In addition, 45.2% of patients taking 300-mg, 24.3% taking 400-mg and 32.1% receiving 600-mg doses reported being pain-free.”

Dr. Ho added that 24-hour sustained freedom from pain was greatest among more patients at any active dose: 39.6% for 300 mg, 22% among those receiving 400 mg and 32% for the 600-mg treatment population. Primary hypothesis testing, comparing mean two-hour pain relief response values of the three active treatment groups in this study, was also significant vs. placebo (P=0.015).

Note: At the time of printing, MK-0974 is not available in Canada.