The NMDA (N-methyl-D-aspartate) receptor is thought to play a part in mood, cognition, memory and learning. Overactivity of the receptor resulting in central sensitization has been implicated in chronic pain, including fibromyalgia and migraines. It could also explain other symptoms of fibromyalgia and chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).
Excessive activation of the NMDA receptors can lead to a phenomenon called excitotoxicity, which destroys brain cells. This can happen in epilepsy and some neurodegenerative illnesses. NMDA antagonists (blockers) are neuroprotective, but they may adversely affect memory in healthy people. On the other hand, if the receptor is overactive, blocking it can alleviate cognitive problems.
NMDA antagonists are primarily used in epilepsy, Alzheimer's disease and amyotrophic lateral sclerosis (ALS/Lou Gehrig's disease), but also chronic pain syndromes, especially neuropathic pain. They boost the analgesic effects of narcotic painkillers (opioids) while reducing the development of tolerance. Several studies have found NMDA antagonists helpful in mood and anxiety disorders and irritable bowel syndrome (IBS).
NMDA Antagonists, CFS/ME and Fibromyalgia
NMDA receptor overactivity may be an important part of the pathology of CFS/ME and fibromyalgia. Several studies have found NMDA antagonists an effective treatment, supporting this theory. There are many NMDA antagonists with different properties, so if one drug does not feel right, another one could be tried.
NMDA receptor antagonists are usually well-tolerated. Side effects vary depending on the drug, but tiredness, dizziness, headaches and problems concentrating tend to be the most common ones. Memantine and dextromethorphan also have several possible drug interactions.
The Medications
The cough suppressant dextromethorphan has shown efficacy in fibromyalgia treatment. Many studies have found intravenous ketamine, another NMDA antagonist, highly effective, but as this is an expensive therapy and ketamine is also a drug of abuse, it has mostly been used for research purposes.
Amantadine is a drug used to treat influenza and Parkinson's disease. It is also a common choice to combat fatigue caused by neurological illnesses like CFS/ME and multiple sclerosis. It increases the brain levels of dopamine and blocks the NMDA receptor. Unfortunately many people who are sensitive to medications tolerate amantadine poorly.
Other choices are riluzole (Rilutek), used for ALS, and memantine (Namenda), used for Alzheimer's disease. Riluzole, however, is highly expensive and memantine is also somewhat costly. Amantadine and dextromethorphan are very inexpensive, but may not be as well tolerated.
Several other drugs also block the NMDA receptor. They include muscle relaxants dantrolene and orphenadrine, opiates methadone and (dextro)propoxyphene, many anticonvulsants and progesterone. Guaifenesin, a mucolytic drug used experimentally as a fibromyalgia therapy, may be an NMDA antagonist.
Calcium channel blockers, a class of heart medications used in the treatment of CFS/ME, also have NMDA antagonistic activity. So does magnesium, which has been used to treat CFS/ME and fibromyalgia as a supplement and as intramuscular injections.
Medications that increase the neurotransmitter GABA decrease NMDA activity. This includes many anticonvulsants and most tranquilizers, including the benzodiazepines, the "Z drugs" (zolpidem, zopiclone/eszopiclone and zaleplone), L-theanine and valerian root. It may explain why small doses of benzodiazepines offer major relief for some people with CFS/ME/FM.
References
Sarchielli P, Di Filippo M, Nardi K, et al. Sensitization, glutamate, and the link between migraine and fibromyalgia. Curr Pain Headache Rep. 2007 Oct;11(5):343-51.
Plioplys AV, Plioplys S. Amantadine and L-carnitine treatment of Chronic Fatigue Syndrome. Neuropsychobiology. 1997;35(1):16-23.
Cohen SP, Verdolin MH, Chang AS, et al. The intravenous ketamine test predicts subsequent response to an oral dextromethorphan treatment regimen in fibromyalgia patients. J Pain. 2006 Jun;7(6):391-8.
Haavisto Maija. Reviving the Broken Marionette: Treatments for CFS/ME and Fibromyalgia. 2008. pp. 232-235.
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