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31st January 2024

Fibromyalgia and Chronic Regional Pain Syndrome (CRPS)

Background

Epidemiology 

Fibromyalgia and chronic regional pain syndrome are both chronic pain syndromes. Fibromyalgia affects approximately 2% of people, typically occurring between the ages of 30 – 50 years, with women being more commonly affected than men. Fibromyalgia constitutes up to 10% of new referrals to the Rheumatology department. The condition is associated with several risk factors, including female sex, low household income, middle-aged, divorced, and low educational status. 

Chronic Regional Pain Syndrome (CRPS) is a less common syndrome. There are reports of incidence rates in Europe of 26 per 100,000 patient-years. Many cases may go undiagnosed or misdiagnosed, making estimates of prevalence difficult. This condition is more common in females and appears to be highest in postmenopausal women.

Pathophysiology 

Fibromyalgia causes disordered pain regulation. The pathophysiology of this condition is not fully understood, and there are many suggested theories. No causative gene has been found; however, studies have shown that first-degree relatives of fibromyalgia patients are more likely to develop the condition themselves. Evidence suggests that it is related to central rather than peripheral neurological mechanisms. Underlying central sensitisation is likely present, with exaggerated central nervous system neural signalling, resulting in greater than normal increases in perceived pain termed temporal summation of pain. There is also dysregulation of the spinal cord responses to painful stimuli via the descending inhibitory pain pathway. Alongside this, there is a reduced ability to inhibit non-painful sensory stimuli following repetitive stimulation. This occurs in the absence of muscle disease or inflammation. Biochemical factors also play a role in upregulation of pain receptors and neurotransmitters, including substance P, which has been found to be increased in the cerebrospinal fluid (CSF) of fibromyalgia patients. 

The pathogenesis of CRPS is poorly understood. There are proposed theories, including classic inflammation, neurogenic inflammation, peripheral and central sensitisation, altered sympathetic nervous system function and dysregulated pain perception within the central nervous system. Some studies have also demonstrated an increase in proinflammatory cytokines in affected tissue and CSF.

References

  • Macfarlane, G. J., Kronisch, C., Dean, L. E. et al. EULAR revised recommendations for the management of fibromyalgia. Annals of the Rheumatic Diseases, 2017;76(2), 318. 
  • National Health Service. Fibromyalgia. [Internet]. nhs.uk. 2019. [cited 29 April 2022]. Available from: https://www.nhs.uk/conditions/fibromyalgia/
  • Wilkinson, I. B., Raine, T., Wiles, K., Goodhart, A., Hall, C., & O’Neill, H. (2017). Oxford Handbook of Clinical Medicine (Tenth Edition). Oxford University Press. P. 558 
  • Dedhia, J. D., & Bone, M. E. (2009). Pain and fibromyalgia. Continuing Education in Anaesthesia Critical Care & Pain, 9(5), 162–166. https://doi.org/10.1093/bjaceaccp/mkp026
  • UpToDate [Internet]. Pathogenesis of Fibromyalgia. Uptodate.com. 2021 [cited 29 April 2022]. Available from: https://www.uptodate.com/contents/pathogenesis-of-fibromyalgia?search=pathogenesis%20of%20fibromyalgia&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
  •  Royal College of Physicians. Complex Regional Pain Syndrome in Adults, UK guidelines for diagnosis, referral and management in primary and secondary care. 
  • Goebel A, Barker CH, Turner-Stokes L et al. Complex regional pain syndrome in adults: UK guidelines for diagnosis, referral and management in primary and secondary care. Royal College of Physicians. 2012.
  • National Health Service. Complex Regional Pain Syndrome. [Internet]. nhs.uk. 2019. [cited 29 April 2022]. https://www.nhs.uk/conditions/complex-regional-pain-syndrome/
  • UpToDate [Internet]. Complex Regional Pain Syndrome in Adults: Pathogenesis, Clinical Manifestations and Diagnosis. Uptodate.com. 2021 [cited 29 April 2022]. Available from: https://www.uptodate.com/contents/complex-regional-pain-syndrome-in-adults-pathogenesis-clinical-manifestations-and-diagnosis?search=chronic%20regional%20pain%20syndrome&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1

Presentation

Fibromyalgia

Fibromyalgia is a somatic syndrome consisting of a wide range of symptoms. The principal feature of fibromyalgia is widespread pain. Generalised hypersensitivity to stimuli, sleep disturbance, fatigue, cognitive impairment such as memory loss or poor concentration, and bladder and bowel abnormalities can also occur. There is overlap between fibromyalgia and other functional somatic syndromes, such as chronic fatigue syndrome.

CRPS

CRPS is a painful condition affecting a limb. It commonly arises after injury to the limb; however, there may be no precipitating trauma. Injuries precipitating CRPS include sprains, surgical wounds, fractures, burns or even venepuncture or cannula sites. Symptoms of CRPS usually develop at the time of injury or days to weeks later, and occasionally, it can occur months later. The symptoms tend to start within one month of the trauma. The syndrome usually affects one limb, but in a small number of cases, it spreads to involve additional limbs. In addition to pain, symptoms include:

  • Functional motor impairment, for example, reduction in handgrip 
  • Sensory disturbance with hyperalgesia and allodynia
  • Autonomic features such as differences in sweat, skin colour, temperature or oedema
  • Trophic changes, including skin atrophy, changes in hair growth and contractions of joints

References

Diagnosis 

Fibromyalgia 

Diagnosis can be challenging due to the heterogeneous nature of the condition. Diagnosis is based on symptoms, with the principal feature being widespread pain. However, sleep disturbance, fatigue, cognitive impairment such as memory loss or poor concentration, and bladder and bowel abnormalities can also occur. The American College of Rheumatology have laid out diagnostic criteria for fibromyalgia:

  • Widespread pain index of at least 7, defined as the number of areas in which the patient has experienced pain in the last week (out of 19)
  • Symptom severity score of 5 or more, based on the sum of severity of fatigue, waking unrefreshed and cognitive symptoms
  • Symptoms lasting for at least 3 months 
  • No other disorder diagnosed to otherwise explain the pain

On physical examination, there is usually tenderness present without erythema or swelling of soft tissues or joints. The condition is thought to be caused by a central nervous system dysfunction; there are no routine laboratory tests or imaging modalities to diagnose fibromyalgia. 

Investigations should be guided by the history; routine tests such as FBC and CRP/ESR are used to rule out other causes of inflammatory pain. More specialist testing, such as autoimmune or viral screening, should be considered if the history is suggestive. It should be noted that patients with rheumatological diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis or osteoarthritis are at higher risk for fibromyalgia. 

Chronic Regional Pain Syndrome 

The Budapest criteria is used for diagnosis of CRPS. The patient must have continued pain, which is disproportionate to any inciting event, as well as symptoms and signs in the following categories:

  • Sensory: allodynia or hyperalgesia 
  • Vasomotor: temperature asymmetry, skin colour changes or skin colour asymmetry
  • Sudomotor/oedema: oedema, sweating changes or sweating asymmetry
  • Motor/trophic: decreased range of motion, motor dysfunction (weakness, tremor, dystonia) or trophic changes (hair, nail or skin)

References

Differential Diagnoses 

Fibromyalgia 

Given that the cardinal symptom of fibromyalgia is widespread pain, the list of differential diagnoses is broad. Many systemic diseases such as Rheumatoid arthritis (RA), Systemic lupus erythematosus (SLE), Sjögren’s syndrome, spondyloarthropathies or polymyalgia rheumatica (PMR) may initially present similarly. In patients that have prominent symptoms of fatigue and mood or cognitive disturbance, history is vital as there is an extensive list of differentials ranging from endocrine pathologies such as thyroid dysfunction and Addison’s disease to viral infections. Thorough history taking is key, and associated risk factors, including female sex, low household income, middle age, divorce, and low educational status, should be considered. 

Rheumatoid Arthritis 

RA is a chronic systemic inflammatory disease. Patients with RA present with symmetrical joint pain in multiple areas. Mood disturbance, fatigue and symptoms lasting for at least 3 months may all be present in RA, which fits with the diagnostic criteria for fibromyalgia. A defining feature of RA is inflammation. Patients will characteristically have a history of swollen joints with morning stiffness, which is not seen in fibromyalgia. To differentiate these, a careful history and clinical examination should be taken. Blood tests for CRP and ESR should be normal in patients with fibromyalgia. Autoantibodies can also be helpful, particularly rheumatoid factor and anti-CCP, which should be negative. However, it should be noted that autoantibody tests can be positive in healthy individuals. 

Systemic Lupus Erythematosus 

SLE can present with generalised arthralgia, myalgia and fatigue, as seen in fibromyalgia. However, in fibromyalgia patients do not go on to develop the other classical SLE symptoms of rashes, photosensitivity, alopecia, oral ulcers, serositis, synovitis, neurological features, inflammation of the eye or dry mucous membranes. Similarly, a thorough history and examination should be taken to identify any of these features. Laboratory tests can be helpful if there is clinical suspicion of SLE, looking specifically for anaemia suggesting haemolytic anaemia, ANA, Anti-dsDNA, Antiphospholipid antibodies, complement and ENA. 

Spondyloarthropathies 

The spondyloarthropathies are a group of chronic inflammatory conditions, including ankylosing spondylitis (AS), enteric arthropathy, psoriatic arthritis and reactive arthritis. All the spondyloarthropathies can present with widespread pain and fatigue. As with RA, these conditions can be deforming, which is not seen in fibromyalgia. These are seronegative conditions; therefore, laboratory investigations are less helpful. Although many patients will be HLA-B27 positive. Diagnosis of AS is clinical and supported by imaging. Most patients are male with low back pain and morning stiffness improving throughout the day. This differs from fibromyalgia, where there are at least 7 pain areas and no prolonged morning stiffness. Enthesitis, iritis, aortic valve incompetence and pulmonary fibrosis are associated AS features and not classically seen in fibromyalgia. Enteric arthropathy should be differentiated from fibromyalgia by the presence of inflammatory bowel or coeliac symptoms. Psoriatic arthritis should be considered in any patient with joint pains and psoriasis. Radiology will show erosive changes, which are not seen in fibromyalgia. Finally, reactive arthritis is less likely to be a differential for fibromyalgia given the unilateral monoarthritis it tends to present with. 

Polymyalgia Rheumatica

PMR is a condition with a similar presentation to fibromyalgia. There is bilateral aching, tenderness in shoulders, hips, proximal limbs and often fatigue and depression. Patients tend to be older, with stiffness as opposed to pain as the primary complaint. Additionally, PMR is associated with giant cell arteritis. Typically, there is a raised CRP and ESR in these patients, differentiating it from fibromyalgia. 

Inflammatory myositis 

Polymyositis, dermatomyositis, and inclusion body myositis can all present with myalgia and fatigue; however, pain is a less common symptom. These conditions can be differentiated from fibromyalgia due to the presence of muscle weakness and raised creatinine kinase on blood tests. Furthermore, there are characteristic electromyography and muscle biopsy findings. 

Drug-induced myositis 

Statins can cause myositis, and patients present with widespread muscle discomfort. Interestingly, patients with fibromyalgia are more likely to develop statin-induced muscle pain. With statin-induced myositis, the temporal relationship between treatment with statin and the elevation in muscle enzymes distinguishes these diagnoses. 

Thyroid Disease 

Hypothyroidism can present with a myriad of symptoms. Similar symptoms to fibromyalgia include tiredness, low mood, impaired cognition or memory and myalgia. However, cold intolerance, non-pitting oedema of legs, myopathy and goitre are more specific to hypothyroidism. Thyroid function tests will differentiate the diagnoses. 

Addison’s Disease

Addison’s disease tends to cause myalgia, arthralgia, mood disturbance and gastrointestinal upset. Features specific to adrenal insufficiency include pigmented palmar creases, postural hypotension, and vitiligo. The condition is less commonly associated with widespread pain. 

Viral Infections 

Viral infections such as hepatitis, chikungunya, CMV, EBV and lyme disease are associated with arthralgias and myalgias. These can be distinguished from fibromyalgia based on the history, including travel history, illness duration and lack of positive serology. 

CRPS

Unilateral limb pain commonly presents to general practitioners, and there is a wide range of differentials. Again, the history is very important, particularly noting prior trauma or surgery. With a history of preceding notable trauma, bone or soft tissue injury, joint instability, and ligamental damage should be ruled out with imaging. 

Nerve injury 

Nerve injury can occur at the level of the spinal cord, spinal root, or peripheral nerve. Spinal cord injuries, specifically cauda equina lesions, present with bilateral symptoms. Nerve entrapment at the lumbar spinal root classically causes radicular pain from the back to the legs, sensory disturbances, and weakness. Peripheral nerve entrapment or injury also causes pain, sensory disturbance, and weakness. Clinical examination is key as CRPS does not affect specific dermatomes, myotomes and the specific distribution of peripheral nerves as seen in these conditions. 

Peripheral Vascular Disease (PVD)

PVD can present with similar symptoms to CRPS; however, it is classically bilateral, associated with night pain and intermittent claudication. Patients have cardiovascular risk factors such as older age, smoking, hypertension, diabetes and hypercholesterolaemia. Specifically for PVD, there are weak or absent pulses, arterial ulcers, and a positive Buerger test. A bedside ankle brachial pressure index can diagnose PVD. 

Infection 

Skin, soft tissue, bone or joint infections all present with unilateral limb pain. The lack of chronicity, fever and raised inflammatory markers differentiates this from CRPS.

Post-surgical complications

CRPS is a diagnosis of exclusion, and ongoing pathology should be excluded in post-operative patients. 

Compartment syndrome 

Compartment syndrome presents with unilateral severe pain, typically in the legs and often after trauma. Signs include swollen compartments and pain with any movement of the affected muscle. As opposed to CRPS, it is acute onset. 

Erythromelalgia

This condition is a rare neurovascular, peripheral pain disorder characterised by erythema, increased skin temperature and burning of the feet and hands, occurring periodically. Similar to CRPS, there can be reduced sweating in the affected area and swelling. Conversely to CRPS, there are triggers for erythromelalgia, including stress, heat such as hot baths, exercise, and insomnia. Erythromelalgia also tends to be bilateral and intermittent in nature, with pain-free periods.

References

Management

Fibromyalgia

Optimal management consists of prompt diagnosis and patient information, including written information. There should be a comprehensive assessment of pain, functional status, and psychosocial well-being. A multidisciplinary approach with GPs, rheumatologists, physiotherapists, and psychologists should be used. The management is graduated, starting with exercise programmes and physiotherapy, slowly increasing the intensity of exercise. Additional therapies such as hydrotherapy or acupuncture can be helpful. Patients should be encouraged to continue working if able. Response should be reassessed, and if there is insufficient effect, additional individualised management instituted. These include psychological therapies, usually cognitive behavioural therapy for pain-related depression, anxiety or poor coping mechanisms. Pharmacotherapy can be used for severe pain or sleep disturbance. The common medications used include duloxetine, pregabalin and tramadol for severe pain. Low-dose amitriptyline, cyclobenzaprine or pregabalin at night are often used for severe sleep issues. Multimodal rehabilitation programs can be used for severe disability.

CRPS 

Prompt diagnosis and early treatment are best practice to avoid complications associated with disuse and the psychological consequences of living with undiagnosed chronic pain. Patients should receive education on the condition and be encouraged to use the limb. Patients should be informed that the pain associated with CRPS does not indicate tissue damage. Physiotherapy and occupational therapy input is considered first line treatment. Psychological therapies such as desensitisation therapy can also be used. In more complex cases, patients may be referred to rheumatology to confirm the diagnosis or to exclude the ongoing pathology, particularly after an operation. There is limited high-quality data for pharmacotherapy, and these should be started on an individual basis. Medications can include NSAIDs, neuropathic pain medications, and topical treatments such as lidocaine or capsaicin. In some cases, bisphosphonates can be used in CRPS if there is abnormal uptake on a bone scintigraphy scan. Referral to the pain team may also be beneficial. 

References

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