Why is there no long-term evidence for most fibromyalgia treatments?

A systematic review and meta-analysis published in JAMA Internal Medicine investigating the effectiveness of treatments for reducing pain and improving quality of life (QOL) in people diagnosed with fibromyalgia showed that there is insufficient evidence for most treatments (Mascarenhas et al 2020). After searching the MEDLINE, Cochrane, Embase, AMED, PsycInfo, and PEDro databases without language or date restrictions on December 11, 2018, and updated on July 15, 2020, a total of 224 trials including 29,962 participants were included in the study. The researchers found some high-quality, short-term evidence in favor of cognitive-behavioral therapy for pain, and for antidepressants, but these did not reach or exceed the minimum clinically important change (2 points on an 11-point scale for pain and 14 points on a 101-point scale for QOL). Evidence for long-term outcomes of interventions was lacking.

Of course, absence of evidence does not necessarily indicate evidence of absence (Alderson 2004), but with over 200 included trials, perhaps there are other factors that should be considered in determining why treatments for fibromyalgia were not effective. Even though the construct and diagnosis of fibromyalgia are widely accepted, it is conceivable they may not necessarily be correct, leading to ineffective treatments and poor efficacy. Since the initial 1990 publication of the American College of Rheumatology criteria for the classification of fibromyalgia (ACR criteria), fibromyalgia has become a well-recognized clinical entity (Wolfe et al 1990). The original ACR criteria included the tender point count with an arbitrary 11 out of 18-point cut-off, although the chosen points failed to differentiate fibromyalgia from other chronic widespread pain diagnoses with many of the same symptoms (Katz et al 2006, Kamaleri et al 2008a, Kamaleri et al 2008b). Of course, the selection of the points was also completely arbitrary (Dommerholt 2010).  The criteria have been revised and modified many times with new classifications and criteria (Arnold et al 2012, Martin et al 2014, Wolfe et al 2011, Wolfe et al 2016, Wolfe et al 2010, Marcus et al 2013). The most recent update and modification was published in 2019 (Arnold et al 2019).

Factors used to justify the fibromyalgia criteria may include patients’ sickness and symptom legitimization and economic gains for pharmaceutical companies (Häuser et al 2015). The pharmaceutical company Pfizer, which produces pregabalin (the first medication for fibromyalgia approved by the US Food and Drug Administration), supports many fibromyalgia researchers and support groups (Häuser et al 2015). Duloxetine has also been approved by the FDA, even though the drug was no better than placebo (Häuser et al 2013). Over 50% of patients first diagnosed with fibromyalgia had discontinued taking duloxetine after one year (Liu et al 2016). Of interest is that the European Medical Agency (EMA) has not approved duloxetine for fibromyalgia.

Fibromyalgia is generally considered a syndrome associated with central sensitization, even though there is convincing evidence that muscle pain (Staud et al 2009) and sensory abnormalities (Konopka et al 2012), including small-fiber neuropathy (Oaklander et al 2013), may be relevant peripheral drivers of persistent pain in fibromyalgia. Perhaps, the emphasis on central sensitization as the main feature of fibromyalgia and the belief in the validity of the diagnostic criteria have resulted in ineffective treatments, including pharmacological measures (Lawson 2008), exercise programs, and other interventions (Häuser et al 2015).

The 2019 10th International Classification of Diseases (ICD-10) lists fibromyalgia under “diseases of the musculoskeletal system and connective tissue” (World Health Organization 2019). Twenty years ago, I argued that the term “fibromyalgia” does not cover the etiology and characteristics of the syndrome, because it really is not a disease of the musculoskeletal system and connective tissue. In my humble opinion, the focus of researchers and clinicians was and continues to be too narrow (Dommerholt 2000). I suggested that perhaps a more appropriate name would be “complex widespread pain syndrome,” analogous to “complex regional pain syndrome,’’ which replaced the misleading terms ‘‘reflex sympathetic dystrophy’’ and ‘‘causalgia” (Stanton-Hicks et al 1995). The broader term would also account for those patients in which the widespread pain and associated symptoms could possibly be due to other diagnoses (Dommerholt 2010).

the term “fibromyalgia” does not cover the etiology and characteristics of the syndrome

As outlined previously (Katz et al 2006, Kamaleri et al 2008a, Kamaleri et al 2008b, Dommerholt 2010), there are multiple other diagnoses that feature widespread pain and myalgia, and based on empirical and clinical observations, it appears that many patients with widespread pain who were diagnosed with fibromyalgia, should have been diagnosed with hypothyroidism, parasitic infestations, or Ehlers Danlos Syndrome, among others.  They may also be taking certain medications, such as cholesterol-lowering medications or citalopram (Alnwick 2008), that can mimic the symptoms of fibromyalgia. One fibromyalgia patient, who was prescribed pregabalin and the cholesterol-lowering drug simvastatin developed rhabdomyolysis (Kaufman et al 2012), which illustrates that these medications are not harmless and feature significant possible side-effects. Myalgia is a common adverse event associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, better known as statins (Jacobson 2008).

None of the therapeutic interventions commonly used in the medical management of patients with fibromyalgia will be effective if the widespread pain is due to taking atorvastatin, for example, which may cause widespread myalgia (Chou et al 2013) or to fascioliasis, which features generalized myalgia and joint pain in 67% of patients (de Gorgolas et al 1992). It seems that when patients diagnosed with fibromyalgia come to our offices, we need to conduct a thorough investigation into other possible causes of their symptoms. As long as clinicians accept the simple diagnostic construct of fibromyalgia, future systematic reviews and meta-analyses will continue to show poor outcomes.


Alderson, P, 2004. Absence of evidence is not evidence of absence. BMJ, 328, 476-477.

Alnwick, GM, 2008. Misdiagnosis of serotonin syndrome as fibromyalgia and the role of physical therapists. Physical Therapy, 88, 757-765.

Arnold, LM, Bennett, RM, Crofford, LJ, Dean, LE, Clauw, DJ, Goldenberg, DL, Fitzcharles, MA, Paiva, ES, Staud, R, Sarzi-Puttini, P, Buskila, D & Macfarlane, GJ, 2019. AAPT Diagnostic Criteria for Fibromyalgia. J Pain, 20, 611-628.

Arnold, LM, Stanford, SB, Welge, JA & Crofford, LJ, 2012. Development and testing of the fibromyalgia diagnostic screen for primary care. J Womens Health (Larchmt), 21, 231-239.

Chou, Y-C, Wang, Y-K, Charng, M-J & Ueng, Y-F, 2013. Determination of serum atorvastatin concentrations in lipid-controlling patients with and without myalgia syndrome. Journal of Food and Drug Analysis, 21, 147-153.

De Gorgolas, M, Torres, R, Verdejo, C, Garay, J, Robledo, A, Ponte, MC & Fernandez Guerrero, ML, 1992. Infestacion por Fasciola hepatica. Biopatologia y nuevos aspectos diagnosticos y terapeuticos. Enfermedades Infecciosas y Microbiologia Clinica, 10, 514-519.

Dommerholt, J, 2000. Fibromyalgia: time to consider a new taxonomy? J Musculoskeletal Pain, 8, 41-47.

Dommerholt, J 2010. Differential diagnosis of fibromyalgia. In: CHAITOW, L. (ed.) Fibromyalgia syndrome; a practitioner’s guide to treatment. Edinburgh: Churchill Livingstone.

Häuser, W, Ablin, J, Fitzcharles, MA, Littlejohn, G, Luciano, JV, Usui, C & Walitt, B, 2015. Fibromyalgia. Nat Rev Dis Primers, 1, 15022.

Häuser, W, Urrútia, G, Tort, S, Uçeyler, N & Walitt, B, 2013. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome. Cochrane Database Syst Rev, Cd010292.

Jacobson, TA, 2008. Toward “pain-free” statin prescribing: clinical algorithm for diagnosis and management of myalgia. Mayo Clinic Proceedings, 83, 687-700.

Kamaleri, Y, Natvig, B, Ihlebaek, CM, Benth, JS & Bruusgaard, D, 2008a. Number of pain sites is associated with demographic, lifestyle, and health-related factors in the general population. Eur J Pain, 12, 742-748.

Kamaleri, Y, Natvig, B, Ihlebaek, CM & Bruusgaard, D, 2008b. Does the number of musculoskeletal pain sites predict work disability? A 14-year prospective study. Eur J Pain.

Katz, RS, Wolfe, F & Michaud, K, 2006. Fibromyalgia diagnosis: a comparison of clinical, survey, and American College of Rheumatology criteria. Arthritis and Rheumatism, 54, 169-176.

Kaufman, MB & Choy, M, 2012. Pregabalin and simvastatin: first report of a case of rhabdomyolysis. P t, 37, 579-595.

Konopka, KH, Harbers, M, Houghton, A, Kortekaas, R, Van Vliet, A, Timmerman, W, Den Boer, JA, Struys, MM & Van Wijhe, M, 2012. Bilateral sensory abnormalities in patients with unilateral neuropathic pain; a quantitative sensory testing (QST) study. PLoS One, 7, e37524.

Lawson, K, 2008. Pharmacological treatments of fibromyalgia: do complex conditions need complex therapies? Drug Discov Today, 13, 333-340.

Liu, Y, Qian, C & Yang, M, 2016. Treatment Patterns Associated with ACR-Recommended Medications in the Management of Fibromyalgia in the United States. J Manag Care Spec Pharm, 22, 263-271.

Marcus, DA, Bernstein, C & Albrecht, KL, 2013. Brief, self-report fibromyalgia screener evaluated in a sample of chronic pain patients. Pain Med, 14, 730-735.

Martin, SA, Coon, CD, Mcleod, LD, Chandran, A & Arnold, LM, 2014. Evaluation of the fibromyalgia diagnostic screen in clinical practice. Journal of Evaluation in Clinical Practice, 20, 158-165.

Mascarenhas, RO, Souza, MB, Oliveira, MX, Lacerda, AC, Mendonca, VA, Henschke, N & Oliveira, VC, 2020. Association of Therapies With Reduced Pain and Improved Quality of Life in Patients With Fibromyalgia: A Systematic Review and Meta-analysis. JAMA Intern Med.

Oaklander, AL, Herzog, ZD, Downs, HM & Klein, MM, 2013. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain, 154, 2310-2316.

Stanton-Hicks, M, Jänig, W, Hassenbusch, S, Haddox, JD, Boas, R & Wilson, P, 1995. Reflex sympathetic dystrophy: changing concepts and taxonomy. Pain, 63, 127-133.

Staud, R, Nagel, S, Robinson, ME & Price, DD, 2009. Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: a randomized, double-blind, placebo-controlled study. Pain, 145, 96-104.

Wolfe, F, Clauw, DJ, Fitzcharles, MA, Goldenberg, DL, Häuser, W, Katz, RL, Mease, PJ, Russell, AS, Russell, IJ & Walitt, B, 2016. 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria. Seminars in Arthritis and Rheumatism, 46, 319-329.

Wolfe, F, Clauw, DJ, Fitzcharles, MA, Goldenberg, DL, Häuser, W, Katz, RS, Mease, P, Russell, AS, Russell, IJ & Winfield, JB, 2011. Fibromyalgia criteria and severity scales for clinical and epidemiological studies: a modification of the ACR Preliminary Diagnostic Criteria for Fibromyalgia. Journal of Rheumatology, 38, 1113-1122.

Wolfe, F, Clauw, DJ, Fitzcharles, MA, Goldenberg, DL, Katz, RS, Mease, P, Russell, AS, Russell, IJ, Winfield, JB & Yunus, MB, 2010. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken), 62, 600-610.

Wolfe, F, Smythe, HA, Yunus, MB, Bennett, RM, Bombardier, C, Goldenberg, DL, Tugwell, P, Campbell, SM, Abeles, M, Clark, P & Et Al., 1990. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis and Rheumatism, 33, 160-172.

World Health Organization 2019 International Statistical Classification of Diseases and Related Health Problems 10th Revision. World Health Organization.

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