Fibromyalgia (FM) syndrome is a chronic condition mainly characterised by widespread muscoloskeletal pain whose unknown aetiology and cure remain the subject of considerable medical research and debate.3 The first medical literature related to the disorder goes back to an American clinical study done in 1981, but FM started receiving its deserved medical attention following the publication of classification criteria by the American College of Rheumatology (ACR) in 1990.6, 7 Further studies have revealed an underlying neurological cause to FM.1
Symptoms of FM
The characteristic feature of fibromyalgia is a constant diffuse bodily pain, with considerable functional impact on the patients’ lives.2, 3 The pain is sometimes worsened, especially when the patient is fatigued or in a depressed mood.1 In some, the pain is even aggravated with bad weather conditions or according to the time of day, with some patients describing increased pain in the morning and the evening.6 The pain can be triggered by manually applying pressure to a variety of defined myofascial trigger points, including those in the trapezius and the quadratus lumborum muscles.9 The disorder also includes localised tenderness in a number of anatomical sites.7 These two features formed the definitive basis for the diagnosis of the disease up till 2010.3, 7
However, the syndrome also includes a constellation of other relevant symptoms, which are now recognised as relevant classification criteria of FM by the ACR.8 These include mood disorders, lethargy, non-restorative sleep and diminished cognitive function (Figure 1).1, 3, 14
Figure 1: The various symptomatic domains of FM disease.14
The presentation of FM may also include muscular stiffness, headaches, irritable bowel syndrome, restless leg syndrome, temporomandibular joint disorder, interstitial cystitis, sleep apnoea and postural imbalance, amongst others.1, 6, 9 Although these associated symptoms are by no means a central part of the disease, they can significantly impair patients with FM.1
Fibromyalgia affects 2% to 4% of the global population, thus making it a relatively common medical condition.1, 5 Its manifestation is not limited by geographical, cultural or ethnic differences in the human population.3 More than 90% of FM cases are women, with most of them being between 20 and 50 years old.2, 3 Despite the relatively high incidence rate of FM, the severity of the disorder varies considerably between one patient and the other and between the sexes, such that men usually have milder symptoms than females.1, 4, 10
The first diagnostic procedure for the disease involved localisation of 11 out of 18 tender points in the patient.7 This observation had to be accompanied with the manifestation of widespread bodily pain which could not be explained by other pathological processes.7 Increased awareness of the disease by the medical community has led the ACR to publish a new set of diagnostic criteria in 2010.8 With these new criteria, diagnosis of FM can be made after a patient presents with pain as well as impaired memory, fatigue, altered moods and non-restorative sleep.8 The tender point test is no longer required for diagnosis of FM.1, 8
Treatment of FM
Neurotransmitter abnormalities as the target of pharmacological treatment
Since FM is characterised by depressed levels of serotonin and nor-adrenaline, drugs that raise their concentrative prove beneficial in treatment of the disorder.11 By inhibiting reuptake transporters at presynaptic nerve terminals, serotonin and noradrenaline dual reuptake inhibitors, along with tricyclic antidepressants, have a relative efficacy in treatment of FM.11,13 However, these effects are not present in all the patients.11 Several studies on the tricyclic antidepressant amitriptyline have proved the drug moderately effective in low doses of 25mg daily.12 This was not so in the case of higher doses, which did not result in significant pain reduction.12
With regards to the dual reuptake inhibitors, the significant results obtained by the use of duloxetine and milnacipran in the relief of pain has led the FDA to approve them as treatments for FM.12 When these are compared to selective serotonin reuptake inhibitors, such as fluoxetin, paroxetine and citalopram, the latter prove less effective.16
Interestingly, serotonin (5-HT3) receptor antagonists have proven effective in the treatment of FM in non-depressed patients.17This finding is probably due to the antagonists' effect in inhibiting the descending pain facilitation mentioned previously.18 Overall, this effect counteracts the hyperalgesia of the disorder. Nevertheless, the effect of these antagonists on certain FM patients has led some researchers to propose that non-depressed FM patients do not have decreased serotonin levels. However, one must also consider the variability in serotonin concentrations in different sites of the central nervous system.11
Additionally, μ-opioid receptors agonists, such as tramadol, also impede nor-adrenaline and serotonin reuptake.13 In combination with acetaminophen, tramadol has been found to act as an effective central analgesic in animal studies, although side-effects such as vertigo and nausea have been reported.13
The elevated levels of substance P and glutamate has led various studies to investigate the effect of pregabalin, an anti-convulsant, on FM symptoms. Pregabalin impedes the release of these neurotransmitters by interacting with neuronal voltage-dependent calcium channels at their α2δ subunit.13,19,20 This hinders the calcium influx necessary for neurotransmitter release at the synaptic terminal, thus making pregabalin particularly effective in treating the pain and sleep disorders of FM.11 Studies report a significant and consistent amelioration of FM symptoms when this drug is used.21,22 This led the FDA to approve it as the first treatment drug for FM in 2007.13 Nevertheless, although this drug is commonly used to treat anxiety, research does not indicate that it improves the sensation of anxiety in FM patients.11 Gabapentin, a similar drug, has also proved effective in the treatment of insomnia and pain.13
Although the role of GABA in FM is still being investigated, drugs which act as GABAB receptor agonists, such as γ-hydroxybutyrate, along with drugs that enhance the effects of GABA, such as benzodiazepines, have proved effective in the treatment of primary FM symptoms, such as pain, fatigue and sleep.11 The same can be said for hypnotics (nonbenzodiazepines), which act as GABAA receptor agonists.11 In general, both hypnotics and benzodiazepines inhibit hypothalamic-pituitary-adrenal axis functioning, but further research is required to evaluate the specific effects that these drugs may have in FM patients that present with variable abnormalities in their stress systems.11 More research is also necessary to investigate the viability of using such a drug to improve slow-wave sleep in FM.13
Use of muscle relaxants
The muscle relaxant cyclobenzaprine has resulted in significant positive benefits for the treatment of FM, with analgesia at doses of 1 to 4 mg.13,23 The results of this muscle relaxant are comparable to that of amitriptyline.13 Similar results were obtained for tizanidine, an adrenergic α2 receptor agonist.13 These findings have made muscle relaxants a popular area of research in FM treatment.13
The NMDA receptor as a target
Since NMDA receptor hyperactivation is responsible for the temporal summation of FM, drugs that antagonise this receptor have proved beneficial in the treatment of symptoms.13 Ketamine and dextrometorphan have significant analgesic properties in FM, although this was accompanied with feelings of dizziness and depersonalization.13
Drugs that target glial cells
Research reveals that glia are activated in chronic states of pain and thus possibly release proinflammatory cytokines which support the widespread hyperalgesia.13 The drug naltrexone deactivates these glia.13 A pilot study investigated the effects of low-dose naltrexone administration in the treatment of FM.15 The patients reported a 32.5% decrease in FM severity when compared to the 2.3% for the placebo. More studies are required to verify these results.13
Studies indicate that exercise proves beneficial to FM patients, be it in the form of swimming, resistance training or spa therapy.13 FM patients who exercise have been found to benefit from moderate symptom relief, including decreased pain and lethargy, along with better sleep and lighter moods.13 Exercise has also been shown to have beneficial effects on the way in which the body copes with stress by inhibiting the sympathetic activation associated with acute and chronic stress.19
Cognitive behavioural therapy has also been found to help FM patients in coping with the psychological stresses posed by the disorder.24 FM patients which undergo such therapy learn how to healthily cope with their pain and how to be more self-efficient.24 This treatment practice requires further research, particularly to determine whether individual behavioural therapy is more beneficial than group-based or internet-based therapy.13
FM is a disorder characterized by multi-focal pain and other principal symptoms such as cognitive dysfunctions, sleep disorders and altered mood. Although the disease requires further scientific research, a neurological basis for the disease is a well-established and well-evidenced fact amongst the medical community. Central sensitization, also caused by decreased descending inhibition on dorsal root ganglia cells, explains the widespread noxious sensation of the disorder, and the accomppanying hyperalgesia and allodynia. FM patients also present with decreased serotonin and noradrenaline in their CSF, along with increased levels of glutamate and substance P, both of which are linked to the symptomology of the disease.
Treatment for this disorder act on the pathological mechanisms of the disorder. Serotonin and noradrenaline dual reuptake inhibitors, along with tricyclic antidepressants, have proven efficacious in the treatment of disease by increasing the levels of serotonin and noradrenaline. Pregabalin, an anticonvulsant, is used to lower release of substance P and glutamate. Along with these pharmacological treatments, FM patients are also encouraged to regularly engage in physical exercise sessions.
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