Memantine for Migraine and Tension-Type Headache Prophylaxis
Memantine has only recently been introduced in the U.S. for dementing disorders, although it has been used in Europe for some time. It blocks N-methyl-D-aspartate (NMDA) glutamate receptors that are thought to be intrinsic to pain transmission, windup, long-term potentiation and central sensitization. Excitatory amino acid systems, like glutamate and its receptor subtypes, play a role in promoting pain mechanisms. Therefore, blockade of NMDA might reduce the central barrage of afferent signals that might contribute to maintenance of migraine states. Agents whose activity, in part, impinges on the glutamate system are already in use for migraine prophylaxis (topiramate). We studied the efficacy of a new, moderate affinity NMDA-receptor antagonist in the treatment of migraines and tension-type headaches (TTH). The primary endpoint of this open label study was reduction of frequency and severity of migraines. Secondary endpoints included reduction of TTH and pain related to the head and neck in our study patients. Patients were asked to keep headache diaries for migraines and TTH together with pain scores.
We wanted to explore the efficacy of blockade of NMDA receptors in the treatment of migraines and chronic tension-type headaches using a low-affinity antagonist, memantine. If one considers that there might be a commonality or overlap of signal barrage to the spinal cord or brainstem in chronic pain and chronic headache states, the glutamate system might be a point of amplification or reinforcement of the pain transmission cascade in these clinical conditions. In particular, memantine blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an uncompetitive, low-affinity, open-channel blocker. It enters the receptor-associated ion channel preferentially when it is excessively open and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission. 1-4 Numerous studies, both in animal models and in human clinical pain states, have demonstrated the ability of memantine to alter pain behaviors or parameters. 5-7 Some studies failed to demonstrate clinical efficacy. We have presented preliminary data for memantine in treating migraine or TTH. 8 The primary objective in this open-label study was to treat a cohort of refractory clinic patients from our clinic with memantine to see if the migraine and headache patterns would change over time. The primary objective was to look for a reduction in the frequency of migraines per month. The secondary objective consisted of reduction in tension-type headache frequency and severity.
Thirty patients (20 females, 10 males) with chronic migraines and who had not responded to other prophylaxis measures were studied. The average age of study patients was 49.9 years. All had International Headache Society (IHS) criteria migraine headaches on a chronic basis (with an average duration of 8.7 years). At baseline, study patients had an average of 9.6 migraines per month. Eighteen out of thirty (60%) also had TTH as well with average of 12.5 days per month. We added memantine, 5mg per day with weekly increases of 5mg (up to a maximum of 20mg per day), as tolerated. The average dose of memantine was 19.25mg per day across all study patients and ranged from 10 to 20mg. Patients kept headache diaries for migraines and TTH, as well as pain scores. Evaluations were conducted after one month of therapy for those being treated with 20mg dose of memantine. For those on a lesser, maximally tolerated dose of memantine, evaluations were conducted after at least 1.5 to 2 months’ therapy. The average length of treatment, including the initial titration of memantine dosage, was 4.2 months, with an average daily dosage of 19.25mg (ranging from 10 to 20mg/day).
Migraine frequency fell to an average of 4.1 migraines per month from a baseline of 9.6 migraines per month—almost 58% less than at baseline in 24 of 30 patients (p <.002; see Table 1). Remaining migraines were rated as less severe and easier to treat. Acute migraine and rescue medication use dropped by almost two-thirds. TTH frequency fell by 52%, from a baseline of 12.5 to 6 headaches per month (p<.005; see Table 2). Seven of eighteen patients saw no response of their tension-type headaches after memantine treatment. Four patients reported dizziness, one reported dry eyes and one nausea. Three of the patients experiencing side effects had betterment of their migraines but eventually discontinued the study medication because of the side effects.
We conclude from this preliminary open-label study that memantine has the ability to offer successful prophylaxis of migraines and TTH in situations where other regimens have not benefited the patient. While six of thirty patients had no demonstrable change in their migraine frequency, migraines in responders were rated as less severe and easier to treat. Acute migraine and rescue medication use dropped by almost two-thirds. Recent studies also support this form of prophylaxis 9,10 and speaks to the potential role of NMDA glutamate receptors in the maintenance of migraine and headache states—as well as its reduction after treatment with an NMDA-type glutamate antagonist. The side effect profile was minimal and the medication was very well tolerated and is corroborated in other studies, including a meta analysis. 11,12 It is recommended that memantine be studied in migraine and headache therapy in a double-blind manner.n Disclosure Design, execution and analysis of the data are solely the work of the author; this study was not supported by any outside funding from the pharmaceutical manufacturer.