Role of Memantine in the Prophylactic Treatment of Episodic Migraine

A Systematic Review

Vinita M. Mistry PharmD; Paige L. Morizio PharmD, BCPS; Marc J. Pepin PharmD, BCPS, BCGP; William E. Bryan PharmD, BCPS; Jamie N. Brown PharmD, FCCP, BCPS, BCACP


Headache. 2021;61(8):1207-1213. 

In This Article


Migraine headaches are a prevalent condition associated with disability, reduced QoL, and high economic burden.[1–3] Additionally, migraine can be difficult to treat due to variability in patient factors, including failure of recommended therapy, comorbidities, headache frequency and severity, and contraindications to therapy. Currently available prophylaxis treatment options for migraine headaches, such as antiseizure medications, beta-blockers, and triptans, although effective, can be difficult to tolerate and/or expensive.[5–8] Memantine is a potential prophylactic treatment option that is well tolerated and thought to work within the pathophysiology of migraine.[11–16]

The findings from this systematic review suggest that memantine may be safe and efficacious for the prevention of episodic migraine. In studies evaluating migraine frequency, patients in the memantine group had on average of 2.3–2.5 fewer migraine episodes per month compared with placebo.[26,27] Compared with baseline, average headache days were reduced by 4.9–7.2 days after 3 months of treatment.[24–26] Established efficacy for the prophylactic treatment of episodic migraine is defined by at least a 50% reduction in migraine frequency in at least two Class I trials (Level A) or probably effective if found in one Class I trial or two Class II studies (Level B).[5–7] Agents with known established efficacy include divalproex, topiramate, and propranolol. The two randomized controlled trials included in this review appear to meet criteria for a Class II study, and both clinical trials demonstrated a greater than 50% reduction in migraine frequency at Week 12.[26,27] Therefore, memantine has probable efficacy with regard to migraine reduction shown in two class II trials, classifying it as a Level B migraine-preventive therapy based on American Academy of Neurology criteria.[26,27]

In the two open-label trials, patients were included and maintained on prophylactic treatment if the medication had been stable for at least 3 months prior to enrollment. All participants were using preventive medication; 51.8%–59.6% used at least two preventive medications during treatment with memantine.[24,25] Patients in both randomized controlled trials were taken off preventative therapy prior to randomization using a washout period of 1–3 months.[26,27] The response rates appear to be similar regardless of use of concomitant preventive medications.

All endpoints evaluating headache severity showed statistically significant improvement with memantine.[24–26] One study evaluated patient-reported 50% response rate for memantine, with 85.7% of patients meeting this criteria in the memantine group compared with 51.7% in the placebo group.[26] Acute medication use was evaluated by two studies, one with a significant reduction and another with no difference found.[26,27] MIDAS scores were also evaluated in two trials with a significant reduction found with memantine use.[24,26] One study assessed factors related to QoL and found that days absent from work were reduced. However, sleep, anxiety, and depression scores did not significantly improve.[26]

Doses of memantine ranged from 5 to 20 mg per day between studies, aligning with the recommended prescribing doses in Alzheimer dementia.[17,24–27] However, mean treatment doses in two studies were not fully described.[24,25] Two studies had an initial dosing at 10 mg daily, which is higher than the Food and Drug Administration-approved initial dosing of 5 mg daily.[17,24,27] Efficacy at different doses of memantine was not evaluated in the studies nor were differences in reported side effects. Efficacy outcomes for memantine were assessed between 4 and 24 weeks with a statistically significant reduction in monthly migraine days beginning as early as after 8 weeks of treatment.[24–27] There is currently no clinical evidence to support efficacy beyond 24 weeks.

Based on the available data, memantine was well tolerated overall with no serious adverse effects reported. The most commonly reported adverse effects included somnolence, sedation, and nausea, which appeared to be mild.[24,26,27] The two open-label studies reported discontinuation due to side effects, with five patients in one study and two patients in another; however, the specific side effects that led to discontinuation were not reported.[24,25] Studies without the use of concomitant prophylactic medications appear to have less overall reported side effects compared with the studies that allowed for prophylactic medication use, which could be a confounding factor.[24,26,27] Additionally, memantine is considered pregnancy category B, with the lowest dose of observed maternal toxicity in animal studies found to be double the maximum recommended dose in humans. Memantine is therefore recommended for use in pregnancy if the potential benefits justify the potential risk to the fetus.[17,20] In regard to current literature, memantine appears to be a safe and efficacious treatment option for adults with episodic migraine. Memantine may be better tolerated than other treatment options with established efficacy, and therefore could be used in patients with a history of side effects to other treatment options or where previous medication trials have not been effective. Additional benefits of memantine over other migraine prophylaxis options include its shorter titration duration of 3 days to 2 weeks compared with several weeks with other agents, and consideration as pregnancy category B, making it a safer option in women of childbearing potential or who are pregnant. Given the chronic burden of migraine, clinical evidence regarding the long-term efficacy and safety of memantine is still needed.