Memantine as a migraine prophylactic agent in adolescents: A retrospective analysis

Migraine is highly prevalent in children and can significantly impair their quality of life, however safe and effective preventive options are still limited. This single-center retrospective review assessed the efficacy of memantine in reducing headache frequency and improving daily functioning in adolescents. Findings showed that memantine treatment was associated with a significant decrease in headache days and improved overall function, suggesting that this medicine may be a safe and effective preventive option for pediatric migraine that should be investigated in future studies. Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist primarily United States Food and Drug Administration-approved for the treatment of moderate–severe Alzheimer's disease. Emerging evidence suggests its potential utility in migraine management due to its effects on excitatory neurotransmission.1, 2 By modulating NMDA receptor activity, memantine may attenuate excitotoxicity and reduce migraine frequency and severity. Given the high prevalence of migraine in children (8–23% by the age of 15 years),3 current practice guidelines for pediatric migraine prevention emphasize the limited number of approved preventive treatments and the need for additional therapeutic options.3 Hence, it is important to consider medications that are effective in the adult population. This study aimed to evaluate memantine's effectiveness in reducing headache frequency and improving functional outcomes in children and adolescents with migraine. Our primary hypothesis was that preventive treatment with memantine in adolescents with migraine would significantly reduce the number of monthly headache days compared to their pre-treatment baseline. Our secondary hypothesis was that memantine use may lead to meaningful improvements in pre-determined functional outcomes related to adolescent migraine management. A further hypothesis was that memantine would be well tolerated with limited side effects. This was a retrospective cohort study that involved analyzing electronic medical records (EMR) from child and adolescent patients followed at The University of Texas at Austin's Dell Children's Pediatric Headache Clinic. All patients prescribed memantine between January 1, 2021, and February 1, 2024, were included for review. Migraine diagnosis was based on the International Classification of Headache Disorders, third edition criteria, as documented in the EMR by headache specialists. Patients were excluded if they did not have a primary headache diagnosis, had no follow-up appointment, or did not start memantine. Notes in the EMR were reviewed for data collection for the appointment in which memantine was prescribed and the subsequent follow-up appointment. Patients were prescribed memantine at doses ranging from 5 mg to 10 mg twice daily (20 mg/day), with titration based on clinical response and tolerability. All headache providers utilize a standardized note template. Functional improvement was assessed using a clinician-documented, patient-reported, pre-determined global improvement measure rather than a validated pediatric quality-of-life scale. This study was approved by The University of Texas at Austin's Institutional Review Board and conducted in accordance with institutional guidelines. A waiver of informed consent was granted due to the retrospective nature of the study. Approval was also obtained for access to EMR and publication of de-identified data. Data collected included patient demographics, primary headache diagnosis, headache frequency, severity, and duration. Adverse events were collected from patient reports at the follow-up appointment. The primary outcome was an absolute reduction in headache days per month from the baseline visit to the first follow-up visit. The secondary outcomes included a qualitative assessment of functional improvement and an analysis of adverse events. Functional improvement was based on pre-specified patient well-being criteria and was classified into three categories: (i) improved, (ii) no change, or (iii) worse. No a priori statistical power calculation was conducted. The sample size was determined based on the available data from our retrospective chart review. Data distributions for continuous variables were assessed visually using histograms and density plots, as well as statistically using the Shapiro–Wilk test for normality. Descriptive statistics were reported as medians with interquartile ranges (IQRs) for non-normally distributed continuous data, and as means with standard deviations for normally distributed data. Categorical variables were presented as counts and percentages. Due to non-normal data distribution, differences in headache days before and after memantine treatment were analyzed using the Wilcoxon signed-rank test. A chi-square test of independence was used to assess differences in functional outcomes. For analysis, the three-level outcome (“Improved,” “No Improvement,” and “Worse Outcome”) was dichotomized into two categories: “Improved” and “Not Improved”. This dichotomization was performed to assess whether there was any measurable benefit associated with the intervention. All analyses were conducted using R version 4.3.3 (R Foundation for Statistical Computing, Vienna, Austria). All hypothesis tests were two-tailed, with statistical significance set at p < 0.05. A total of 43 patient charts were reviewed, with 26 patients included in the final analysis after excluding 17 patients due to non-adherence in three, alternative diagnosis in eight, or absent follow-up data in six. The most common alternative diagnosis among excluded patients was post-traumatic headache in three, followed by tension-type headache in two, and new daily persistent headache in three. Among the non-adherent patients, the chart review indicated that one patient discontinued due to perceived lack of efficacy, and two discontinued due to concerns about medication use, though no documented adverse effects were reported. There was no missing data in the final analyzed dataset. While headache severity and duration were documented during data collection, variability in reporting and incomplete data limited meaningful statistical analysis. The final sample consisted of two males and 24 females, with a median (IQR) age of 16 (15–18) years. All patients had a diagnosis of migraine. In all, 19 patients were diagnosed with chronic migraine, and seven with episodic migraine. Aura was present in two patients with episodic migraine. The median (IQR) follow-up time between treatment initiation and the first follow-up was 3.2 (2.0–4.3) months. Memantine was used as monotherapy in 10 patients (38%) and as an adjunctive therapy in 16 (62%) who were already on at least one other preventive medication. At the first clinic follow-up appointment, there was a significant decrease in the median (IQR) monthly headache days from 22 (18–27) to 15 (10–21), a median (IQR) reduction of 7 (4–12) headache days (p = 0.001, Wilcoxon signed-rank test) (Figure 1). In all, 73% (19/26) of patients reported functional improvement, 12% (3/26) experienced no change, and 15% (4/26) reported worsening functional outcomes. These results were statistically significant (chi-square test of independence: χ2 = 16.88, df = 2, p < 0.001), showing patients on memantine were more likely to report improvement in functional outcomes. Two of the 26 patients (8%) reported fatigue. No other side effects were reported. Our findings of a significant reduction in monthly headache days align with previous studies in adults that demonstrated the efficacy of memantine in reducing migraine frequency.1, 2, 4 A recent systematic review and network meta-analysis comparing memantine with existing preventive treatments in adults found that memantine's efficacy was not inferior to first-line migraine preventives, further supporting its potential role in treatment.5 Side effects reported are uncommon and mild, supporting its safety profile.5, 6 While only two patients (8%) reported fatigue as a side effect, adverse events may have been underreported due to reliance on retrospective documentation. Future prospective studies and randomized controlled trials should systematically assess and document adverse events to ensure comprehensive safety profiling. Given that NMDA receptor antagonists play a role in synaptic plasticity and neurodevelopment, potential neuropsychiatric and neurodevelopmental concerns should be considered when using memantine in pediatric populations. While no neuropsychiatric adverse effects were reported in this cohort, further investigation is warranted to assess any long-term effects on cognitive and behavioral outcomes. This study has several limitations. First, as a retrospective study, causality cannot be inferred, and there is potential for selection and information biases due to reliance on EMR. Second, the small sample size may limit the generalizability of the findings and increase the risk of a type II error. Third, while all headache providers used a standardized note template, these notes were not validated against standardized measures of headache-related disability, which may introduce variability in outcome reporting. Fourth, this study included a mixed population of patients with episodic and chronic migraine, reflecting real-world clinical practice. While this enhances generalizability, a more rigorous prospective study may consider stratifying patients based on migraine subtype to better assess differential treatment responses. Lastly, the lack of a control group prevents direct attribution of the observed effects to memantine alone. Although larger prospective studies are necessary, this retrospective study suggests that memantine could be a safe and effective preventive therapy option for youth with migraine. M. Ismail K. Yousaf: Conceptualization; investigation; methodology; project administration; resources; visualization; writing – original draft; writing – review and editing. Francis D. Hussey: Data curation; formal analysis; methodology; software; writing – original draft; writing – review and editing. Sara Pavitt: Conceptualization; methodology; supervision; visualization; writing – review and editing. Samantha Irwin: Conceptualization; methodology; supervision; visualization; writing – review and editing. None. Muhammad Ismail K. Yousaf and Francis D. Hussey have no conflicts of interest. Sara Pavitt is a site Principal Investigator (PI) on a clinical trial investigating rimegepant as an acute treatment in pediatric patients with migraine. She is a site Sub-Investigator (SubI) investigating ubrogepant as an acute treatment in pediatric patients with migraine. She receives no salary support from these trials. She is a site PI for a Patient-Centered Outcomes Research Institute (PCORI)-funded REACH study for which she receives salary support. Samantha Irwin is a site PI on a clinical trial investigating ubrogepant in pediatric patients with migraine. She is a site SubI investigating rimegepant in pediatric patients with migraine. She receives no salary support from these trials. Additionally, in the last 24 months, she has received consulting income from Pfizer, Theranica, and Merz and a speaking honorarium from The Hospital for Sick Children.