Fibromyalgia Overview: Controversies and Complexities of Diagnosis and Management

Fibromyalgia entails a lot of complexities in its assessment and treatment.

Fibromyalgia is a syndrome characterized by widespread chronic pain. The main symptoms include pain, sleep dysfunction, fatigue, anxiety, depression, and impaired cognitive function.

Pain mainly involves muscles and joints, along with stiffness. But other areas may also be painful. For example, patients may have visceral pain.1

Fibromyalgia can be associated with other conditions such as irritable bowel syndrome or diabetes. Also, with rheumatologic, neurological, or psychiatric diseases.2

Infections (such as Lyme disease, Epstein-Barr virus, and hepatitis), trauma, or psychological stress1 may trigger the development of fibromyalgia.

The incidence is higher in women. Its usual onset is at 30 to 35 years old,2 but it can develop at any age.1

Diagnostic criteria

In 1990, the American College of Rheumatology (ACR) published the first official classification criteria for Fibromyalgia Syndrome (FMS).

The following criteria3 needed to be satisfied to make a diagnosis:

  • History of generalized pain for at least 3 months:
    • In the axial skeleton
    • AND in at least 3 of the 4 body quadrants (left and right, above and below the waist).
  • Pain in response to a pressure up to 4 kg/cm2 in 11 of 18 specific body points.

Since then, several other methods of diagnosis have been proposed.3,4

The ACR 2010 criteria use two scales:

  • Widespread pain Index:
    • Considers the number of areas in which the patient has had pain over the past week, using a list of 19 painful areas.
  • Symptom Severity Scale:
    • Rating severity of:
      • fatigue
      • waking unrefreshed
      • cognitive symptoms (like recognition memory, verbal knowledge, anxiety, and depression)
    • Rating of somatic symptoms (using a checklist of 41 symptoms including irritable bowel syndrome, fatigue, muscle weakness, etc.)

After the 2010 ACR criteria, there have been additional reviews and modifications. These modifications help facilitate its use in epidemiological studies.3

ACR 2015 statement about the ACR 2010 criteria:

In 2015, the ACR clarified that it had endorsed preliminary classification and diagnostic criteria. It was no longer considering endorsement of diagnostic criteria. Classification criteria are more useful for research and as teaching tools. Diagnostic criteria are more useful in the practice setting.5

There is still controversy on the assessment and diagnosis of Fibromyalgia Syndrome.

Many health professionals and patients still have concerns about how this disease is diagnosed. Despite the difficulties in diagnoses, some experts recommend that the assessment is not based on a diagnosis of exclusion.3,4

In general, clinicians should use a multidimensional approach that considers the physical symptoms, psychosocial factors, and somatic complaints. However, basic laboratory tests can be done. Other pain disorders could be excluded as well,1 since other conditions may coexist with fibromyalgia.


The pathophysiology of fibromyalgia syndrome is not well understood but appears to be related to how the brain processes pain. FMS is considered a central nervous system (CNS) augmentation syndrome. But there seems to be involvement of both the central and peripheral nervous systems.2 It is believed that pain either originates or amplifies at the CNS.1 This process is called centralized pain.

Central nervous system pathophysiological factors:

  • Elevated levels of excitatory neurotransmitters: glutamate and substance P
  • Reduced levels of serotonin and norepinephrine (at the descending inhibitory pathways of the spinal cord)
  • Dopamine dysregulation
  • Altered activity of the endogenous opioids

Findings favoring peripheral nervous system involvement:

  • Peripheral sensitization may contribute to increased nociceptive signals in the spinal cord leading to central sensitization. 
  • There might be a neuropathic pain component:
    • Reduced number of epidermal nerve fibers in skin biopsies.
    • Patients score higher on neuropathic pain questionnaires.

Autonomic nervous system abnormalities apparently contribute to the pathogenesis of this disease.2

Other pathophysiologic pathways implicated, although some with inconsistent results are:2

Inflammation. Inflammation is one of the suspects involved in FMS. Inflammatory cytokines and immune cells could be mediating this inflammation.2

Genetics. Genetic factors could be contributing to this multifactorial disease. Several candidate genes along with environmental factors could predispose patients to FMS.

Endocrine pathways. The hypothalamic-pituitary-adrenal endocrine axis could be involved in fibromyalgia patients. Stress plays a role in FMS. For that reason, cortisol levels have been studied in this population.2

Psychopathological disorders. The impairment in serotonin and norepinephrine neurotransmitters and the patient’s response to antidepressants favor the involvement of psycho-affective pathways in the pathogenesis of this disease.

Endogenous opioid pathways. The Mu-opioid receptor on B lymphocytes has been mentioned as a biomarker for fibromyalgia.

Sleep disorders. It has been suggested that sleep disorders are a manifestation of the disease and also a causative factor.2

Autoimmune factors. Autoimmunity seems to be linked to fibromyalgia. Several autoantibodies have been studied as possible biomarkers of the disease. A higher frequency of thyroid autoimmunity has been reported in fibromyalgia patients.

Free radicals. Research has proposed decreased antioxidant capabilities leading to oxidative stress and susceptibility to reactive oxygen species in fibromyalgia.

Role of obesity in Fibromyalgia Syndrome

More than half of fibromyalgia patients are obese or overweight.6 The mechanisms underlying the relationship between obesity and fibromyalgia are still unclear. A cross-sectional study of 2,339 fibromyalgia patients showed that obesity/overweight is associated with increased symptoms severity and functional impairment.6

Pharmacologic Treatment

Not many drugs have been approved for the treatment of FMS. Pain relief is limited in part because many patients have side effects or do not benefit from drug treatment.4 The medication selection should be based on the predominant symptoms, such as sleep disturbance, pain, anxiety, or depression.

The FDA has approved duloxetine, milnacipran, and pregabalin for the treatment of FMS. In the clinical setting, several other medications are also used.

Drug classes used for FMS include:


Pregabalin is one of the principal drugs used in the treatment of FMS. It is FDA-approved for FMS.  It is a gamma-aminobutyric acid (GABA) analog and is a ligand for the alpha 2 delta subunit of the calcium channel.4

Gabapentin is also a GABA analog and is often used off-label for FMS.

Serotonin–Norepinephrine Reuptake Inhibitors (SNRIs)

Clinicians use the SNRIs desvenlafaxine, venlafaxine, duloxetine, and milnacipran for FMS. Of those, duloxetine and milnacipran are FDA-approved for fibromyalgia. 

Tricyclic antidepressants (TCAs)

Amitriptyline has been widely used for years in the treatment of FMS.

Serotonin selective reuptake inhibitors (SSRIs)

No SSRIs are FDA-approved for FMS. 

Other antidepressants

Mirtazapine is also mentioned in the literature for the treatment of fibromyalgia. 


The long-term use of opioids for the treatment of FMS is discouraged. However, for intractable pain, tramadol has been recommended. Besides being considered an opioid receptor agonist, it also shows serotonin-norepinephrine reuptake inhibitor properties.4

Low dose naltrexone

This opioid receptor antagonist is being used off-label for the treatment of fibromyalgia and continues to be under study.7


Melatonin, vitamin D, and Coenzyme Q10 have been studied in association with FMS and could be considered as potential complements to treatment.

Magnesium is one of the most commonly used supplements in FMS, although its role in this disease is still uncertain.8


Some studies have indicated an improvement in quality of life, body weight, pain, sleep quality, psychological disturbances, and general health in patients with FMS on mainly vegetarian or vegan plant-based diets. These diets consist mainly of vegetables, fruits, nuts and seeds, mushrooms, legumes, and whole grains.9

Nonpharmacological Treatment

A multidisciplinary approach is recommended. It should include a combination of the following interventions:

Patient education with an emphasis on stress reduction, exercise, and sleep1

Cognitive-behavioral therapy



Pain management

Natural remedies can be added if safe and tolerated.


Aerobic exercise

A meta-analysis and systematic review from 2010 showed that aerobic exercise reduces pain, fatigue, and depressed mood. It also improves health-related quality of life and physical fitness. Continuity is necessary to maintain its positive effects.10

This article proposed specific recommendations for exercise. An exercise protocol for patients with fibromyalgia may be as follow for a reduction of symptoms:

-Modality: water-based or land-based

-Intensity: slight to moderate

-Frequency: 2 to 3 times per week

-Duration: 4 to 6 weeks

According to a more recent Cochrane Review from 2017, aerobic exercise probably improves health-related quality of life in FMS. It may slightly decrease pain and stiffness while improving physical and cardiorespiratory function in adults with fibromyalgia. Based on this review, aerobic exercises seem to be well tolerated and may be integrated into treatment. Patients may be able to walk without exacerbating symptoms.11

Resistance Exercise

Not many studies have evaluated the effects of resistance exercise in FMS. A randomized controlled trial12 showed that a supervised progressive resistance exercise program could be feasible for women with FMS. In this study, there was an improvement in muscle function, health status, and pain intensity at the end of the intervention.

Flexibility exercise

There is not enough quality scientific data about flexibility exercise in fibromyalgia patients. No specific recommendations for flexibility exercise protocols have been made.13

Physical therapy modalities

Many physical therapy modalities can be used for pain in a variety of medical conditions. Physical therapy modalities, including cold packs, heating pads, electrical stimulation and myofascial release, are used in the clinical setting for pain and muscle spasms in general.

Literature specific for the treatment of fibromyalgia with these modalities is scant.

Myofascial release has moderately shown to be effective for improving pain, fatigue, stiffness, anxiety, depression, and quality of life of people with FMS.14

TENS (transcutaneous electrical nerve stimulation) may be effective for pain relief in FMS, based on low-quality evidence. Electroacupuncture shows a moderate level of evidence for relieving pain.14

Aquatic therapy seems to produce a mild improvement in pain and quality of life in patients with FMS.14

Alternative treatments

Some of the alternative therapies that have been studied for fibromyalgia are:

Body warming


Mud-bath treatment

Hyperbaric Oxygen Therapy

Laser Therapy and Phototherapy

Vibroacoustic and Rhythmic Sensory Stimulation



Mind-body approaches


Plant extracts such as Commiphora myrrha and Hypericum perforatum (St.John’s wort) have been investigated in pre-clinical trials. Crocus sativus (saffron) extract has also been studied.4

Most therapies in the list above are controversial and not used in the clinical setting.

In Conclusion

Fibromyalgia syndrome diagnosis continues to be controversial and is still in debate. Treatment should be done in a multidisciplinary fashion. Several pharmacologic options are used in the clinical setting. Three medications are FDA-approved for this condition. Patient education, cognitive-behavioral therapy, and exercise are the principal tools to manage this disease. Additional research is needed to clarify its pathogenesis and delineate precise treatment protocols.


  1. Clauw DJ. Fibromyalgia: a clinical review. JAMA. 2014;311(15):1547-1555. doi:10.1001/jama.2014.3266
  2. Siracusa R, Paola RD, Cuzzocrea S, Impellizzeri D. Fibromyalgia: Pathogenesis, Mechanisms, Diagnosis and Treatment Options Update. Int J Mol Sci. 2021;22(8):3891. Published 2021 Apr 9. doi:10.3390/ijms22083891
  3. Galvez-Sánchez CM, Reyes Del Paso GA. Diagnostic Criteria for Fibromyalgia: Critical Review and Future Perspectives. J Clin Med. 2020;9(4):1219. Published 2020 Apr 23. doi:10.3390/jcm9041219
  4. Maffei ME. Fibromyalgia: Recent Advances in Diagnosis, Classification, Pharmacotherapy and Alternative Remedies. Int J Mol Sci. 2020;21(21):7877. Published 2020 Oct 23. doi:10.3390/ijms21217877
  5. Aggarwal R, Ringold S, Khanna D, et al. Distinctions between diagnostic and classification criteria?. Arthritis Care Res (Hoboken). 2015;67(7):891-897. doi:10.1002/acr.22583
  6. Atzeni F, Alciati A, Salaffi F, et al. The association between body mass index and fibromyalgia severity: data from a cross-sectional survey of 2339 patients. Rheumatol Adv Pract. 2021;5(1):rkab015. Published 2021 Mar 1. doi:10.1093/rap/rkab015
  7. Bruun KD, Amris K, Vaegter HB, et al. Low-dose naltrexone for the treatment of fibromyalgia: protocol for a double-blind, randomized, placebo-controlled trial. Trials. 2021;22(1):804. Published 2021 Nov 15. doi:10.1186/s13063-021-05776-7
  8. Boulis M, Boulis M, Clauw D. Magnesium and Fibromyalgia: A Literature Review. J Prim Care Community Health. 2021;12:21501327211038433. doi:10.1177/21501327211038433
  9. Nadal-Nicolás Y, Miralles-Amorós L, Martínez-Olcina M, Sánchez-Ortega M, Mora J, Martínez-Rodríguez A. Vegetarian and Vegan Diet in Fibromyalgia: A Systematic Review. Int J Environ Res Public Health. 2021;18(9):4955. Published 2021 May 6. doi:10.3390/ijerph18094955
  10. Häuser et al. Efficacy of different types of aerobic exercise in fibromyalgia syndrome: a systematic review and meta-analysis of randomised controlled trials. Arthritis Research & Therapy 2010, 12:R79.
  11. Bidonde J, Busch AJ, Schachter CL, Overend TJ, KimSY, Góes SM, Boden C, Foulds HJA. Aerobic exercise training for adults with fibromyalgia. Cochrane Database of Systematic Reviews 2017, Issue 6. Art. No.: CD012700. doi: 10.1002/14651858.CD012700.
  12. Larsson A, Palstam A, Löfgren M, et al. Resistance exercise improves muscle strength, health status and pain intensity in fibromyalgia–a randomized controlled trial. Arthritis Res Ther. 2015;17(1):161. Published 2015 Jun 18. doi:10.1186/s13075-015-0679-1
  13. Kim_SY, Busch_AJ, Overend_TJ, Schachter_CL, van der Spuy_I, Boden_C, Góes_SM, Foulds_HJA, Bidonde_J. Flexibility exercise training for adults with fibromyalgia. Cochrane Database of Systematic Reviews 2019, Issue 9. Art. No.: CD013419. doi: 10.1002/14651858.CD013419.
  14. Araújo FM, DeSantana JM. Physical therapy modalities for treating fibromyalgia. F1000Res. 2019;8:F1000 Faculty Rev-2030. Published 2019 Nov 29. doi:10.12688/f1000research.17176.1
  15. Cuyul-Vásquez I, Araya-Quintanilla F, Gutiérrez-Espinoza H. Comment on Siracusa et al. Fibromyalgia: Pathogenesis, Mechanisms, Diagnosis and Treatment Options Update. Int. J. Mol. Sci. 2021, 22, 3891. Int J Mol Sci. 2021;22(16):9075. Published 2021 Aug 23. doi:10.3390/ijms22169075

Fibromyalgia Overview: Controversies and Complexities of Diagnosis and Management