US Pharm. 2010;35(5):28-35.
Headaches are one of the most common afflictions encountered in clinics today.1 The International Headache Society (IHS) classifies headaches into two categories: primary and secondary. Secondary headaches are caused by an underlying disorder, whereas primary headaches are themselves the disorder.1 Migraine is a common, debilitating primary headache disorder that affects people of a variety of ages.2 A migraine attack is a throbbing or pulsating headache that is unilateral and often involves nausea, vomiting, and sensitivity to light or sound.3 These attacks can affect sufferers for up to 72 hours and impact their work productivity as well as their personal lives.4
In the United States alone, nearly 30 million people suffer from migraines, and the numbers are on the rise.3 In light of this increase in prevalence, researchers are working harder than ever to find appropriate treatments for this disorder.
Pathophysiology of Migraine
The exact pathophysiology of migraine remains something of a mystery; for that reason, there is no cure for the disorder. This makes treatment strategy challenging and renders migraines difficult to control.
The cortical spreading depression (CSD) theory is increasingly being accepted as the cause of most or all migraines.5 CSD is a self-propagating wave of depolarizing cortical neurons that is associated with a large efflux of potassium ions from intracellular to extracellular compartments.5 CSD is a regenerative all-or-none process that spreads across the brain at the rate of 3 mm/min.5 The overall effects of CSD include long-lasting changes in extracranial blood flow, dilation of the middle meningeal artery due to the leakage of blood-borne factors, opening of the blood-brain barrier, and leakage of plasma proteins.6 Unlike patients with aura, migraine patients without aura are thought to have CSD waves in regions of the brain, such as the cerebellum, that do not transmit stimuli to the patient.6
The CSD theory was introduced in 1943 by the Brazilian neurophysiologist Aristides Leão while he was a doctoral student.5 This theory was connected to migraine auras in 1958 by the Canadian psychologist Peter Milner.6 Milner noticed that auras spread at the same rate as CSD. This led to the realization that CSD has the biological foundation to cause most, or possibly all, migraines.6
The link between migraine and CSD has been studied extensively. There are two theories that have attained the most acceptance. First, Grafstein hypothesized that levels of potassium released during neuronal depolarization increase and accumulate, leading to regenerating waves of CSD.7 Second, Van Harreveld hypothesized that glutamate release may induce CSD.7 At this time, the exact connection is still unknown, but it is likely that both factors contribute to migraines.7
The link between glutamate receptors and CSD has been known for years.7 Glutamate is extensively involved with the excitation process because it is the most abundant neurotransmitter in the brain.8 Glutamate exerts its effects on brain excitability via the N-methyl-d-aspartate (NMDA), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate), kainite, and metabotropic glutamate receptors.8 It acts on these NMDA and non-NMDA receptors in postsynaptic neuronal plasma membranes in the central nervous system (CNS).9 These NMDA receptors are ionotropic; therefore, when they are activated, calcium and sodium enter the neurons and potassium exits.5,9 During CSD, calcium levels in the neurons continue to increase. In response, glutamate is released, and extracellular potassium levels escalate.6 When potassium levels reach a threshold of 10 to 12 mmol, CSD is initiated.6
In one animal study, excitation of NMDA and non-NMDA receptors caused pain stimulation in the neurons of the trigeminal nucleus complex.10 This excitation initiates the headache phase or migraine.7,8 Pain travels from the trigeminal nucleus complex to the thalamus by means of the quintothalamic tract, after which it proceeds to the cortex.11
NMDA Receptor Antagonists
Blockage of glutamate release from NMDA and non-NMDA receptors has been shown to inhibit pain transmission to the trigeminal nucleus complex.10 This inhibition of pain by NMDA receptor antagonists was a key discovery. NMDA antagonists are being studied extensively for the prophylactic treatment of migraines. Older NMDA receptor antagonists, such as ketamine and dextromethorphan, cause major CNS side effects; therefore, they are not used in a clinical setting for migraine prophylaxis.5,9
Memantine is a moderate-affinity uncompetitive NMDA receptor antagonist that is approved in the U.S. for the treatment of Alzheimer’s disease. This antagonist, which has fewer side effects than other NMDA antagonists, is believed to work by competing with magnesium in the synapse, which inhibits the prolonged influx of calcium.9,12 This inhibition blocks neuronal excitation or CSD and therefore is thought to inhibit migraine pain.12 For this reason, memantine is now being prescribed as off-label prophylactic therapy for migraine.
A clinical trial examined the use of memantine (5 mg, 10 mg, 15 mg, or 20 mg) as preventive therapy for migraine in patients at a headache clinic.13 Of the 60 patients, 54 continued therapy for 2 months. Prior to therapy, headache frequency in these patients was 4 to 30 (mean 15.2, SD 8.8) per month. After therapy, headache frequency was 0 to 22 (mean 6.1, SD 6) per month. The majority of patients also experienced reduced headache severity, needed fewer migraine medications, and experienced improvements in level of functioning.13 Forty-five patients reported no side effects.13 Limitations of this trial are that it was retrospective and that patients continued taking their previous migraine medications.13
A different clinical study investigated memantine for refractory migraines.14 Subjects received memantine 10 mg to 20 mg per day. Twenty-three of 38 subjects completed the study. All subjects were taking other preventive medications, but had been on stable doses of these medications for a minimum of 3 months.14 The mean number of days with severe pain decreased from 7.8 at baseline to 5.9 after 1 month, to 4.0 after 2 months, and to 3.2 after 3 months.14 The mean headache frequency decreased from 21.5 at baseline to 14.3 days per month by the conclusion of the study.14 Side effects were reported by 10 patients, and two patients dropped out because of tolerability issues.14 Limitations were that there was no placebo and that previous preventive medications were continued throughout the trial.14
One case study describes a 75-year-old patient with a history of memory deficits and daily chronic migraines in whom memantine therapy was initiated.15 While on a 10-mg dose, the patient reported cessation of her chronic daily migraines. After 5 months, she reported an improved quality of life and claimed to be symptom-free.15 This is one case only, and the assumption of NMDA antagonism as effective treatment is not reliable.15
Memantine was studied for the treatment of chronic migraines and tension-type headaches (TTH) in 20 patients who had failed all other prophylactic treatments.16 After 1 month of treatment with memantine 20 mg, migraine frequency decreased 56%—to 4.1 migraines per month—in 14 patients.16 TTH frequency decreased 62%, and acute migraine medication use decreased by two-thirds.16 Limitations of this clinical trial were that placebo was not used, other medications were not stopped, and the trial was open-label.16
All of the aforementioned studies have limitations. Therefore, there is still a need for a prospective, double-blind, randomized control study for migraine prophylaxis.16 Nevertheless, these studies suggest that memantine may be useful for migraine prophylaxis.
Clinical Pharmacology of Memantine
As mentioned, memantine is a low- to moderate-affinity uncompetitive NMDA antagonist that reduces excitation in the brain. This action is thought to yield therapeutic effects by binding to NMDA receptor–operated ion channels.17 Memantine is an oral medication with 100% bioavailability, and it can be taken with or without food.17 Exact dosing of memantine for migraine prophylaxis has not yet been determined, but in recent clinical trials the range was 5 to 20 mg.16 It is recommended that the drug be titrated in 5-mg increments to the target dose for treatment. Memantine’s volume of distribution is 9 to 11 L/kg, with a low plasma protein-binding level of 45%. The drug concentration peaks in the plasma in 3 to 7 hours at a level of 22.08 ng/mL ± 5.07 ng/mL, with an AUC of 1,941 ng/h/mL.18 High concentrations occur in the brain, cerebrospinal fluid, kidneys, and lungs.18 Memantine is partially metabolized by the liver, and it is excreted by the kidneys 50% unchanged.17
Memantine is metabolized into three polar metabolites: the N-glucuronide conjugate (25%), 6-hydroxy memantine, and 1-nitroso-deaminated memantine.17 These metabolites have minimal NMDA receptor antagonist activity.17 Memantine has a half-life of 60 to 80 hours, which increases to 117 to 156 hours in patients with severe renal impairment (creatinine clearance [CrCl] 5-29 mL/min). No adjustment is necessary for mild renal impairment (CrCl 30-49 mL/min); however, in severe renal impairment (CrCl 5-29 mL/min), the adjusted dose is 5 mg twice a day.17 Memantine should be used with caution in hepatic impairment owing to the lack of research in these patients.17
Toxicities and Special Considerations
Memantine is contraindicated in patients with hypersensitivity to the drug.17 Precautions include concomitant use of drugs that make the urine alkaline; concomitant use of other NMDA antagonists; genitourinary conditions that raise urine pH; moderate-to-severe renal impairment; and seizure disorder.17 Drug interactions involve acetazolamide, cimetidine, dichlorphenamide, hydrochlorothiazide, methazolamide, nicotine, quinidine, ranitidine, and sodium bicarbonate.17 Adverse drug events include skin reaction, hypertension (4%), tachycardia, weight gain, weight loss, sweating, nausea, vomiting (5%), diarrhea, constipation, anorexia, depression, insomnia, akathisia, agitation, dizziness (7%), headache (6%), psychosis, hallucinations (3%), blurred vision, coughing (4%), and dyspnea (2%).19 As with any medication, the safety and effectiveness of memantine therapy should be assessed on an individual basis.
The use of memantine for the prophylaxis of migraines could prove to be an effective treatment. Although memantine is not the first NMDA antagonist used to target migraines, it is one of the first with a low side-effect profile that has been shown to be efficacious.10 Clinical trials have demonstrated that memantine is effective as add-on therapy only.12 Therefore, research needs to be conducted with memantine for monotherapy in migraine prophylaxis.12 Until the FDA approves memantine for migraine prophylaxis, many insurance plans may refuse coverage.20 With the price of the 5-mg tablets at $181.46 (60 tabs) and the 10-mg tablets at $180.19 (60 tabs), this may be frustrating for patients. Nevertheless, memantine and possibly future NMDA antagonists hold promise for migraineurs.
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