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 is a leading cause of outpatient care and emergency room visits and has a cost of approximately 13–17 billion dollars annually in the United States.[1] In the 2018 Global Burden of Disease study, migraine was found to be the sixth most prevalent disorder in the world and was ranked as the second leading cause of disability after back pain.[2] Migraine has also been shown to cause significant reductions in health-related quality of life (QoL), in both mental and physical health, when compared with healthy cohorts.[3]

Migraine is a primary headache disorder classified as recurrent headache episodes that can occur with or without aura by the International Classification of Headache Disorders, 3rd edition. Chronic migraine is a headache occurring on 15 or more days per month for greater than 3 months, with at least 8 days per month having migraine headache features. If migraine occurs less than 15 days per month, it is considered episodic.[4]

Pain associated with migraine can be managed with acute and/or prophylactic therapy. The American Headache Society recommends prophylactic treatment in frequent headaches (≥4 headache days per month), if the episodes significantly disable or reduce QoL despite acute treatment, when there is contraindication or failure of acute therapy, if there is risk for medication overuse headache, or based on patient preference. Currently available prophylactic treatments for migraine aim to reduce the frequency of migraine days, intensity of headache pain during episodes, and use of medications for acute treatment of migraine episodes.[5,6] Options for migraine with established efficacy include antiseizure medications (valproate acid, topiramate), beta-blockers (metoprolol, propranolol, timolol), triptans (frovatriptan), and onabotulinumtoxinA.[7] Although these medications have been found to be effective, their mechanism of action is not well understood in migraine treatment, and many can be expensive and/or have adverse effects that can make them difficult to tolerate. In women of childbearing potential, or who are currently pregnant, breastfeeding, or attempting to conceive, preventive treatment selection is especially limited as many preventive treatment options, such as valproic acid and topiramate, need to be discontinued due to risk of fetal harm.[5] Additionally, because of variation of migraine characteristics between individuals, treatment plans should be based on patient preference, comorbidities, frequency and severity of episodes, contraindications, and concomitant medications.[5–8]

Recently, there has been an emergence of research assessing novel mechanisms of new and existing medication therapies for migraine prophylaxis. The exact pathophysiology of migraine is not completely understood, although it is thought that there is a link between abnormal neuronal excitability and activation of the trigeminovascular complex.[9,10] Glutamate is one of the most abundant excitatory neurotransmitters in the central nervous system.[11,12] It binds to N-methyl-D-aspartate (NMDA) receptors, and in patients with migraine, it has been found to be elevated in the cerebrospinal fluid.[13] This suggests that excessive glutamate receptor activation may be linked to cortical hyperexcitability and therefore may contribute to migraine episodes.[12–14] Clinical research has evolved with this finding, assessing the efficacy and safety of targeting glutamate in migraine therapeutics.[15,16]

Memantine is a noncompetitive glutaminergic NMDA receptor antagonist, with potential as a prophylactic treatment option in migraine. The mechanism of action for memantine in migraine is unclear, but the inhibition of the NMDA receptors is theorized to impede prolonged calcium ion influx and reduce neuronal hyperexcitability.[11] Memantine is currently approved by the Food and Drug Administration for the treatment of moderate to severe Alzheimer dementia. It has a recommended starting dose of 5 mg daily and should be gradually titrated to 10 mg twice daily.[17] Moreover, memantine also has exploratory indications as adjunct treatment for schizophrenia, phantom limb pain, and opioid use disorder.[18,19] Side effects are generally minimal for memantine and most commonly include dizziness, confusion, headache, or constipation (5%–7%). Memantine is also classified as pregnancy category B.[17]

Migraine poses a heavy burden on patients and the health care system when not adequately managed.[1,3] Memantine may be a potential migraine treatment option because of its novel mechanism and low risk for adverse effects. The purpose of this systematic review is to assess the efficacy and safety of memantine for the prophylactic treatment of migraine.