Fibromyalgia (FM) is a chronic rheumatic disease of currently unknown aetiology that is characterized by the presence of diffuse musculoskeletal pain and painful sensitivity to touch in at least 11 of 18 defined trigger points
. The prevalence of this syndrome in Europe is calculated to be approximately 2.9% (95% CI: 2.4 to 3.4)
. The prevalence of FM in rheumatology consultations in Spain was found to be 12% (2.2% in men and 15.5% in women)
. Because of its high prevalence, there is great clinical impact on patients in terms of disability and loss of quality of life, and significant health care costs. FM treatments are believed to have limited efficacy, with an effect size of approximately 0.5
Pain is the most common and debilitating symptom of FM. The cause of hyperalgesia in FM is poorly understood. It is suspected that there is an alteration of the function of structures of the central nervous system. In recent years, the neurophysiology of the phenomenon of pain has led to increased interest in employing different neuroimaging methods such as positron emission tomography (PET)
, single photon emission computed tomography (SPECT)
[6, 7], functional magnetic resonance imaging (fMRI) and, more recently, magnetic resonance diffusion and diffusion tensor spectroscopy to identify the brain structures activated during episodes of pain in patients and controls
. These structures include the primary and secondary sensory and motor cortices, insula, anterior cingulate cortex, thalamus, dorsolateral prefrontal cortex and basal ganglia - regions that have been named the ‘pain matrix’ because they are activated in response to a painful stimulus. A growing body of evidence suggests that glutamate (Glu), an excitatory neurotransmitter in the central nervous system, may play a part in the pathophysiology of FM, given that its concentration is elevated in the insula
 and posterior cingulate cortex
As a consequence, a number of authors have suggested that glutamate-blocking drugs may be useful in the treatment of FM
. Studies suggest that memantine could reduce the harmful effects that result from the excessively high levels of brain glutamate found in a number of conditions, such as FM
. Memantine is not believed to act by reducing levels of glutamate or by preventing its release; rather, it is believed to reduce glutamate’s neurotoxic effect by blocking the N-methyl-D-aspartate (NMDA) receptor, thereby preventing the entry of excess calcium
. Memantine belongs to the family of drugs known as NMDA receptor antagonists.
NMDA receptor antagonists have neuroprotective and analgesic properties and are widely used in clinical practice. Dextromethorphan and ketamine have demonstrated efficacy in the treatment of pain in fibromyalgia
[15, 16], although their use as long-term treatment presents significant difficulties
. The NMDA receptor antagonist memantine is a derivative of amantadine, a drug which has been used to treat Parkinson’s disease, spasticity, convulsions, vascular dementia and Alzheimer's disease, and has an excellent clinical safety record spanning more than 20 years. It is a non-competitive open-channel blocker that dissociates from the channel, which allows it to limit the pathological activity of the NMDA receptor without affecting normal synaptic activity
Memantine has shown a very low incidence of side effects in clinical trials on humans
[19, 20], while a recent extension of trials has demonstrated the drug’s clinical tolerability, even with prolonged use
. Similar low rates of adverse effects are expected with the treatment with memantine of other disorders such as pain
[22, 23], migraine
 and fibromyalgia
. The clinically approved dose of memantine for humans starts with 5 mg/day, increasing progressively over a period of several weeks to 20 mg/day. This progressive dose adjustment may contribute to the drug’s lack of side effects
. While this progression reduces the NMDA receptor affinity, it contributes to the safety and efficacy of memantine as a neuroprotective agent. However, the process also makes memantine less effective than high-affinity antagonists (for example, ketamine) in the treatment of chronic pain
[21, 26]. Nevertheless, recent research has highlighted the efficacy of memantine for the treatment of complex regional pain syndrome
 and phantom limb pain
, which suggests that the extent of analgesia depends on the type of pain being treated. We have carried out a preliminary open, uncontrolled, three-month follow-up study of memantine in patients with FM (EudraCT Number: 2011-000802-23). As will be commented later on in the discussion, in this preliminary study there was a trend toward improvement in pain, but it was not significant, probably due to the small sample size. Glutamate levels did not show modifications from baseline as a longer period follow-up is usually required. After three months, memantine-treated patients in our study showed significant improvement in cognitive function, symptoms of depression and global functioning (personal communication).
The primary objective is to evaluate the efficacy of memantine in the treatment of pain (pain perception) in patients with fibromyalgia.
The secondary objectives of this study are the following: 1) To evaluate the efficacy of memantine in the treatment of other symptoms of fibromyalgia, such as pain threshold, impaired cognitive function, reduced health status, anxiety, depression, quality of life and perceived improvement of symptoms; 2) To evaluate the efficacy of memantine in reducing brain levels of glutamate, as measured by spectrometry, in patients with fibromyalgia.