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

Disclosures

Headache. 2021;61(8):1207-1213. 

In This Article

Results

Study Selection

A total of 973 results were identified in the initial search of PubMed (n = 57), Embase (n = 847), and CENTRAL (n = 69). Of these results, 75 were identified as duplicates and were removed (Figure 1). The remaining references were evaluated during the initial screening based on title and abstract. A total of four studies were included in the final review. A description of the included studies is summarized in Table 1.[24–27]

Figure 1.

Flow diagram for search and selection for analysis

Literature Evaluation

Prospective Open-label Studies. Bigal et al. conducted a prospective, open-label 12-week study in 28 patients who were mostly female (75%), with a mean age of 43.5 years. Patients were included if they had 8 to 14 episodic migraine days per month, had not responded to an adequate trial of at least one prophylactic medication, and were on a stable migraine prophylaxis regimen for at least 1 month. Approximately 51.8% of patients were using two or more medications for migraine prophylaxis. Patients with superimposed tension-type headaches were also allowed in the study. An initial dose of 10 mg daily of memantine was started and increased to 20 mg daily after 1 month based on patient satisfaction. Outcome measures were assessed using a patient headache calendar. Of the 28 patients who received at least one dose of memantine, 23 completed the study. In the intention-to-treat analysis (n = 28), 67.8% (n = 19) of patients used 10 mg daily of memantine, and 32.1% (n = 9) were titrated up to 20 mg daily. At baseline, patients had a mean of 21.8 headache days per month; a significant reduction in headache frequency was observed starting at Week 8 (15.4, p < 0.01) and lasting until the Week 12 endpoint (16.1, p < 0.01). Additionally, mean number of headache days and mean Migraine Disability Assessment Scale (MIDAS) scores were significantly reduced. In the per protocol assessment (n = 23), the number of headache days was significantly reduced at the end of the 12-week study compared with baseline. In addition, there was also a significant reduction in severe headaches (3.0 ± 2.7 vs. 7.5 ± 3.3, p < 0.01), headache score (27.1 ± 15.0 vs. 44.3 ± 19.2, p < 0.01), and MIDAS (31.3 ± 17.0 vs. 52 ± 22.4, p = 0.01). Ten patients (35.7%) reported side effects during the study, and two patients dropped out due to poor tolerability.[24]

Assarzadegan and Sistanizad performed a prospective, open-label, 12-week study in 102 patients who were mostly female (77%), with a mean age of 38.9–41.1 years. Patients were included if they had 8 to 14 episodic migraine days per month and had not responded to an adequate trial of migraine prophylaxis. All patients were on at least one prophylactic medication, with approximately 59.6% using more than two. The majority of patients (74.3%) had migraine with aura, and 77.4% complained of bilateral headache symptoms. Patients were started on memantine 5 mg per day and titrated by 5 mg every 2 weeks to a maximum of 20 mg per day based on side effects and patient satisfaction. Of the 127 patients who were enrolled, 102 completed the study and were assessed for efficacy. The average dose of memantine was not reported during the study. At 12 weeks, a significant reduction in the mean number of headache days was found compared with baseline (5.0 ± 6.8 vs. 9.9 ± 8.0, p < 0.001). Headache severity also had a statistically significant reduction (3.6 ± 1.5 vs. 6.9 ± 1.6, p < 0.001). The duration of each migraine at 12 weeks was improved compared with baseline. More patients had headache durations less than 4 h (58.8% vs. 8.8%, p < 0.001), and fewer patients had durations greater than 24 h (5.9% vs. 55.9%, p < 0.001). Two patients were lost to follow-up, and five patients (4.6%) dropped out of the study due to intolerance, although no assessment of side effects was reported in this study.[25]

Randomized, Double-blind, Placebo-controlled Trials. Noruzzadeh et al. conducted a 12-week randomized, double-blind, placebo-controlled study in 52 patients who were mostly female (77%), with a mean age of 34.0–34.8 years. Patients were included if they were 18–65 years old, had migraine without aura, and experienced two or more migraine episodes per month. Patients were excluded if they had greater than 15 migraine days per month, received migraine prophylaxis in the last 3 months, or had medication overuse headaches. A total of 60 patients were randomized, with 52 patients included in the final analysis (n = 25 in memantine, n = 27 in placebo). Patients in the memantine group were titrated from 5 to 10 mg per night after 3 days. Outcome measures were assessed using patient migraine diaries. At baseline, monthly attack frequency was numerically higher in the memantine group compared with placebo (5.4 ± 2.5 vs. 4.5 ± 2.0). After 12 weeks of treatment, a significant reduction in migraine frequency was found with memantine compared with placebo, with a 45% absolute reduction in migraine attack frequency. Reduction of mean monthly frequency in the memantine group compared with placebo was significant in both the per protocol analysis (1.9 ± 0.3 vs. 3.6 ± 0.3, p < 0.001) and the intention-to-treat analysis (1.9 ± 0.4 vs. 3.7 ± 0.4, p = 0.001). In addition, a significant reduction in migraine days was found between memantine and placebo, with a mean difference of 4.9 days (2.7 ± 0.6 vs. 8.1 ± 0.8, p < 0.001) in the per protocol analysis and 5.2 days (2.5 ± 0.9 vs. 8.4 ± 0.9, p = 0.004) in the intention-to-treat analysis. Number of absent work days was significantly reduced in the per protocol assessment (0.4 ± 0.1 vs. 0.8 ± 0.2, p = 0.004) and in the intention-to-treat analysis (0.3 ± 0.2 vs. 0.9 ± 0.2, p = 0.018) with memantine compared with placebo. MIDAS scores were found to be significantly decreased compared with placebo in the per protocol analysis (8.5 ± 1.1 vs. 13.0 ± 1.1, p < 0.001) and the intention-to-treat analysis (7.6 ± 1.5 vs. 13.2 ± 1.5, p = 0.017). Additionally, there was a reduction of MIDAS scores by at least one category in 84% of patients in the memantine group compared with 30% in the placebo group, and at least two categories in 44% in the memantine group versus 11% in the placebo group. Improvement in QoL and sleep was found in the per protocol analysis, although not in the intention-to-treat analysis. No difference in anxiety, depression, and median number of acute analgesics pills was found in either analysis. No patients in the memantine group withdrew due to side effects, whereas one patient in the placebo group withdrew due to vertigo.[26]

Shanmugam et al. conducted a 24-week randomized, double-blind, parallel-interventional study in 57 patients who were mostly female (64% in memantine; 69% in placebo), with the majority of patients in the 18- to 30-year age group (61.4%). Patients were included if they were aged 18–55 years, had 3–12 migraine episodes per month, but no more than 15 headache days. Participants were excluded if they did not respond to two or more migraine-preventive medications. Most patients had migraine without aura, except for two patients in the memantine group and one patient in the placebo group. Eligible participants were entered into a 4-week washout period during which migraine-preventive medications were tapered and discontinued. This washout was followed by an analysis of baseline migraine frequency for 12 weeks, during which patients could only use rescue medications, and monthly headache frequency was assessed. After completion of the washout, 60 patients were randomized to either memantine 10 mg daily or matching placebo (n = 28 in memantine; n = 29 in placebo). A total of 57 patients were included in the analysis (n = 3 lost to follow-up). Outcomes were assessed using patient diaries. At 24 weeks, there was a significant reduction in migraine frequency. A decline in mean number of migraine days was observed from initiation of treatment until Week 12 in both groups. This decline continued in the memantine group through the end of the study at Week 24, whereas no further decline was observed in the placebo group in the Week 12–24 posttreatment period. In the memantine group, a significant reduction in migraine frequency began at 16 weeks and remained statistically significant until the end of the study. The 50% response rate was significantly higher in the memantine group (85.7% vs. 51.7%, p = 0.005). Days of rescue medication were also significantly reduced beginning at Week 8 through Week 24 in the memantine group compared with placebo. No severe side effects occurred during the study.[27]

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