Conference Coverage
SAN FRANCISCO—Although highly compelling data support the theory of glutamatergic involvement in migraine mechanisms, the evidence that glutamatergic modulation is clinically effective for patients with migraine remains elusive, according to an overview presented at the Eighth Annual Winter Conference of the Headache Cooperative of the Pacific.
Research suggests that modulating glutamate receptors’ functions would be an effective way to treat migraine, but “it’s just not that simple,” said Nabih M. Ramadan, MD, MBA, a neurologist. The number of glutamate receptor subtypes, their many functions, and the complexity of their neurochemistry make it difficult to identify safe and effective treatments.
Favorable Clinical Data
Various studies conducted since the early 1990s have found increased levels of glutamate in CSF or in the blood among migraineurs, compared with controls, although the data have varied according to the type of migraine. In 2009, Ferrari and colleagues found that prophylactic treatment with flunarizine, amitriptyline, or topiramate decreased plasma glutamate levels and reduced headache frequency.
Other studies suggest that intranasal ketamine, an NMDA receptor antagonist (GluN), may benefit patients with migraine. A study published in 2000 suggested that the drug reduced the duration or the severity of aura in patients with familial hemiplegic migraine. In 2013, Afridi and colleagues found that intranasal ketamine reduced the severity of aura among participants with migraine with prolonged aura.
Several open-label studies have examined memantine, another nonselective GluN antagonist, in doses as large as 20 mg for migraine. A retrospective study indicated that prophylactic treatment with memantine reduced headache frequency among migraineurs. In a prospective open-label study published in 2008, Bigal and colleagues found that prophylactic treatment with memantine reduced monthly headache frequency and the number of days with severe pain among patients with refractory migraine.
Four Randomized Controlled Trials
Four randomized controlled trials have tested the efficacy of glutamate modulation as a therapy for migraine. In 2004, Sang and colleagues studied LY293558, an AMPA (GluA) and kainate (GluK) receptor antagonist that was effective in preclinical models of migraine. The researchers administered 1.2 mg/kg of LY293558 IV, 6 mg of sumatriptan subcutaneously, or placebo to 44 patients with acute migraine. The headache response rate was 69% for LY293558, 86% for sumatriptan, and 25% for placebo. Compared with placebo, LY293558 and sumatriptan provided superior improvement in pain and other symptoms associated with migraine.
In 2008, Johnson and colleagues analyzed LY466195, a selective GluK5 antagonist, as a treatment for acute migraine attacks. Patients received 1 mg of the drug IV, 3 mg of the drug IV, or 6 mg of sumatriptan subcutaneously as an active control. LY466195 was not superior to placebo on primary efficacy measures, but the rate of pain freedom was significantly higher for 3 mg LY466195 (29%) and for sumatriptan (50%), compared with placebo (0%). Approximately 21% of patients who received 3 mg of LY466195 had clinically reversible visual disturbances.
More recently, investigators examined ADX10059, a negative allosteric modulator of the metabotropic glutamate (mGlu5) receptor subtype, as a treatment for acute migraine attacks. In this proof-of-concept study of 129 migraineurs, the rate of pain freedom was 16.1% among patients who received ADX10059 and 4.5% among participants who received placebo. Adverse events, however, were reported more frequently in the intervention group than in the control group (73% vs 36%). Compared with placebo, ADX10059 was more commonly associated with CNS adverse events such as dizziness, vertigo, and blurred vision.
Finally, in 2013, Gomez-Mancilla and colleagues randomized 75 participants with acute migraine attacks to 250 mg of BGG492, a nonselective GluA receptor antagonist; 100 mg of sumatriptan; or placebo. The trial’s primary outcome was improvement from severe or moderate pain to mild or no pain. This outcome was reported at two, three, and four hours after treatment by 58%, 58%, and 54% of patients receiving BGG492, respectively. The outcome also was reported at these time points by 68%, 84%, and 92% of patients receiving sumatriptan, respectively, and by 40%, 48%, and 44% of patients receiving placebo, respectively. CNS-related adverse events were more common in the BGG492 group than in the sumatriptan or placebo groups, as were adverse events overall. The trial did not meet its proof-of-concept criterion.
Current Evidence Has Shortcomings
Randomized controlled trials such as the abovementioned studies provide the best-available evidence about glutamatergic modulation as a migraine treatment, but they have significant shortcomings, said Dr. Ramadan. Overall, the studies examined small numbers of participants. Furthermore, the noncontrolled clinical trials were heterogeneous and included patients with various migraine subtypes (eg, familial hemiplegic migraine, migraine with aura, migraine without aura, and migraine with prolonged aura). Lastly, some of the clinical trials addressed acute migraine treatments, while others studied the role of glutamate modulation in migraine prevention. Collectively, these studies do not allow neurologists to draw definitive conclusions on the clinical efficacy of glutamate receptor modulation in migraine. In addition, all studies raise concerns about potential adverse events, particularly in the CNS.