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Tuesday, 14 October 2014 20:52

The Fibromyalgia Syndrome - an overview of contemporary treatment methods

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Gabriel J. Ellul


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

 

Epidemiology

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

Diagnosis

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

Non-pharmacological treatment

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

 

Conclusion

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.

Bibliography

1.              Fitzcharles MA and Yunus MB. The clinical concept of fibromyalgia as a changing paradigm in the past 20 years. Pain Res Treat. 2012; 2012: 184835.

2.              Juuso P, Skär L, Olsson M and Söderberg S. Living with a double burden: Meanings of pain for women with fibromyalgia. Int J Qual Stud Health Well-being. 2011; 6(3): 10.3402/qhw.v6i3.7184.

3.              Grodman I, Buskila D, Arnson Y, Altaman A, Amital D and Amital H. Understanding fibromyalgia and its resultant disability. Isr Med Assoc J. 2011 Dec;13(12):769-72.

4.              Wolfe F, Anderson J, Harkness D, Bennett RM, Caro XJ, Goldenberg DL, Russell IJ and Yunus MB. Health status and disease severity in fibromyalgia: results of a six-center longitudinal study. Arthritis Rheum. 1997 Sep;40(9):1571-9.

5.              Wuytack F and Miller P. The lived experience of fibromyalgia in female patients, a phenomenological study. Chiropr Man Therap. 2011 Sep 19;19(1):22

6.              Yunus M, Masi AT, Calabro JJ, Miller KA and Feigenbaum SL. Primary fibromyalgia (fibrositis): clinical study of 50 patients with matched normal controls. Semin Arthritis Rheum. 1981 Aug;11(1):151-71.

7.              Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990 Feb;33(2):160-72.

8.              Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, Russell AS, Russell IJ, Winfield JB and Yunus MB. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken). 2010 May;62(5):600-10.

9.              Jones KD, King LA, Mist SD, Bennett RM and Horak FB. Postural control deficits in people with fibromyalgia: a pilot study.  Arthritis Res Ther. 2011 Aug 2;13(4):R127.

10.          Rehm SE, Koroschetz J, Gockel U, Brosz M, Freynhagen R, Tölle TR and Baron R. A cross-sectional survey of 3035 patients with fibromyalgia: subgroups of patients with typical comorbidities and sensory symptom profiles. Rheumatology (Oxford). 2010 Jun;49(6):1146-52. Epub 2010 Mar 17.

11.          Becker S and Schweinhardt P. Dysfunctional neurotransmitter systems in fibromyalgia, their role in central stress circuitry and pharmacological actions on these systems. Pain Res Treat. 2012;2012:741746. Epub 2011 Oct 2.

12.          Lee YC, Nassikas NJ and Clauw DJ. The role of the central nervous system in the generation and maintenance of chronic pain in rheumatoid arthritis, osteoarthritis and fibromyalgia. Arthritis Res Ther. 2011 Apr 28;13(2):211.

13.          Staud R. Clinical Management of Fibromyalgia: An Update. Current Medical Literature: Rheumatology. 2011 Nov;30(4):109-119

14.          Smith HS, Bracken D and Smith JM. Pharmacotherapy for fibromyalgia. Front Pharmacol. 2011;2:17. Epub 2011 Mar 31.

15.          Younger J and Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med. 2009 May-Jun;10(4):663-72. Epub 2009 Apr 22.

16.          Lee YC and Chen PP. A review of SSRIs and SNRIs in neuropathic pain. Expert Opinion on Pharmacotherapy. 2010;11(17):2813–2825.

17.          Seidel MF and Müller W. Differential pharmacotherapy for subgroups of fibromyalgia patients with specific consideration of 5-HT3 receptor antagonists. Expert Opinion on Pharmacotherapy. 2011;12(9):1381–1391.

18.          Suzuki R, Rygh LJ and Dickenson AH. Bad news from the brain: descending 5-HT pathways that control spinal pain processing. Trends in Pharmacological Sciences. 2004;25(12):613–617.

19.          Coderre TJ, Kumar N, Lefebvre CD and Yu JSC. Evidence that gabapentin reduces neuropathic pain by inhibiting the spinal release of glutamate. Journal of Neurochemistry. 2005;94(4):1131–1139.

20.          Fehrenbacher JC, Taylor CP and Vasko MR. Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C. Pain. 2003;105(1-2):133–141.

21.          Crofford LJ, Rowbotham MC, Mease PJ, Russell IJ, Dworkin RH, Corbin AE, Young JP, LaMoreaux LK, Martin SA and Sharma U. Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, doubleblind, placebo-controlled trial. Arthritis Rheum. 2005;52:1264–1273.

22.          Crofford LJ, Mease PJ, Simpson SL, Young JP, Martin SA, Haig GM and Sharma U. Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief (FREEDOM): a 6-month, double-blind, placebo-controlled trial with pregabalin. Pain. 2008;136:419–431.

23.          Moldofsky H, Harris HW, Archambault WT, Kwong T and Lederman S. Effects of bedtime very low dose cyclobenzaprine on symptoms and sleep physiology in patients with fibromyalgia syndrome: a double-blind randomized placebo-controlled study. J Rheumatol. 2011 Dec;38(12):2653-63. Epub 2011 Sep 1.

24.        van Koulil S, van Lankveld W, Kraaimaat FW, van Helmond T, Vedder A, van Hoorn H, Cats H, van Riel PL and Evers AW. Tailored cognitive-behavioral therapy for fibromyalgia: two case studies. Patient Educ Couns. 2008 May;71(2):308-14. Epub 2008 Jan 9.

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