Complex Regional Pain Syndrome and Fibromyalgia: Recent Evidence on Causes and Diagnosis

29 Oct 2019

Complex Regional Pain Syndrome (CRPS) and fibromyalgia (FM) are both chronic pain conditions, but whereas CRPS is restricted to one specific area of the body, FM is characterised by widespread pain. Neither condition is well-understood in terms of causation, and diagnosis is based on subjective reporting of signs and symptoms by the sufferer. However, research is shedding new light on the possible causes of these diseases, which may lead to definitive diagnostic tests becoming available in the future.  

In 2016, the criteria for diagnosis of FM were revised and ‘generalised pain criteria’ introduced, defined as pain in four out of five possible painful body regions. This change now excludes regional pain syndromes from the diagnosis of FM. Further work by the ACTTION-APS Pain Taxonomy initiative, a collaboration between Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks and the American Pain Society, has allowed the identification of four possible classes of the condition, which suggest that FM represents a continuum in which pain in the central nervous system becomes more centralised as the disease progresses and other symptoms, such as anergia, memory loss and sleep disturbance, develop (1,2). 

Much of the recent research into the causes of fibromyalgia has centred around neuropathies, particularly small fibre neuropathy (SFN). These appear to occur with relatively high frequency in FM patients and are represented by a reduction in dermal unmyelinated nerve fibre bundles in skin biopsy, increased temperature detection thresholds in sensory testing and hyperexcitability of nociceptors (1,3), the sensory receptors for painful stimuli. Additionally, a study of large fibre neuropathy found that 90% of patients with FM only exhibited a demyelinating and/or axonal sensory-motor polyneuropathy and 63% had SFN, suggesting that mixed fibre neuropathies are predominant in FM. Electromyograph evidence of non-myotomal axonal motor denervation of the lower limbs, found in a high proportion of patients, was a suggested cause of the polyneuropathy. The presence of rheumatoid arthritis (RA) alongside the FM did not alter these findings, but a comparison group, without either condition, showed no pathologic findings at all (1).   

One of the major issues in the diagnosis of FM is the lack of a reliable biomarker but there have been several recently reported breakthroughs in this field which may prove to be clinically useful. Recent research has identified particular miRNA profiles in blood, saliva and cerebrospinal fluid which have the ability to diagnose and characterise FM. Whilst encouraging, these studies took place in small populations and will need to be validated in larger cohorts. Furthermore, proteomic analysis of whole saliva and plasma showed increased expression of numerous proteins compared to subjects without the condition. This suggests that there may be a distinctive  inflammatory protein signature in FM, which is possibly related to a neuroinflammatory process (1). Further evidence for an inflammatory pathway in the causation of FM comes from a report of lowered levels of interleukin-10 in the serum of women with FM, regardless of age, body mass index and comorbid conditions (4).  

Similarly, metabolomics may provide valuable biomarkers for diagnosing the presence of FM.  The authors of a study describing analysis of low-molecular weight fraction metabolites of human blood were able to identify FM patients and discriminate them from patients with systemic lupus erythematosus (SLE) or RA without misclassification. Aromatic and carboxylic acid molecules, such as tryptophan and its metabolite serotonin, appeared to be particularly important as potential biomarkers and this has been borne out by observations in other studies and the common use in FM treatment of selective serotonin uptake inhibitors. However, although serotonin may be useful in the diagnosis of FM, it does not appear to be related to the severity of the disease. A study in women showed that while serotonin levels in blood were reduced in FM sufferers, there was no correlation with clinical manifestation (1). However, another study identified biomarkers,  including protein backbones and pyridine-carboxylic acids, which not only discriminated FM sufferers from patients with RA, osteoarthritis and SLE, but were correlated with FM pain severity (5).  

One feature frequently described in FM is an abnormality of the central nervous system and neuroimmune activation may be a potential mechanism for this observation. A combined Swedish and US research group has recently demonstrated the presence of activated glia, and consequently active neuroinflammation, in the brain of FM patients. An increased uptake of the radioligand that binds to 18-kDa translocator protein (TSPO) was particularly evident in areas of the brain that have previously been implicated in FM. TSPO expression is normally low in healthy brain tissue but is upregulated in activated glial cells that have undergone inflammatory stimulus. These findings strongly suggest an association between neuroinflammation and FM (1,2).  

Recent research in CRPS has also centred around the role of inflammation in the condition, and in particular the role that potential biomarkers of inflammation may play in diagnosis and management (6–8). Gene analysis has shown that immune-related genes previously linked to CRPS are differentially methylated in patients with CRPS compared to those with non-CRPS neuropathic pain (9). Methylation changes the activity of DNA segments and typically acts to repress gene transcription, the first step in gene expression.  

Furthermore, a study of the role of autoantibodies in CRPS found that they are commonly present in patients with the condition and the level appears to be correlated with the severity of pain experienced by the patient. Experiments in mice indicate that the autoantibodies maintain the painful hypersensitivity characteristic of CRPS by sensitising A and C nociceptors (10), while the peptide CTK 01512-2 can reverse allodynia, both in the acute and chronic phases of the disease (7). In humans, expansion and activation of several distinct populations of T lymphocytes, participants in the immune response, has been demonstrated in patients with CRPS. Compared to healthy controls, the levels of some cell groups were increased five-fold. This increased activation of pro-inflammatory signalling pathways may be indicative of ongoing inflammation and cellular damage in CRPS (8). It has also recently been demonstrated that limb nerve trauma releases a proalgesic immunodominant myelin basic protein fragment which is homologous to muscarinic-2 acetylcholine receptor, thought to be involved in the development of CRPS. Activity of the proalgesic myelin basic protein is prevalent in females and may explain why the occurrence of CRPS is also higher in women (11). 

Alterations in physiological trauma recovery may also be important in the development of CRPS. Compared to control patients with fractures, CRPS sufferers appear to be more sensitive to pinprick pain and blunt pressure on their affected side. Fracture controls have a higher level of immunobarrier-protective factors compared to patients with CRPS or healthy controls, and low levels were particularly observed in subjects with oedema, suggesting barrier breakdown. It seems likely that while normal healing includes some CRPS signs and symptoms, a combination of different factors distinguishes the condition from fracture controls (12).   

One of the features of CRPS is a discrepancy between a patient’s subjective perception of temperature and objectively measured temperature. Therefore, the diagnostic validity of temperature measurements is questionable. However, perfusion index (PI), which is derived from pulse oximetry, a test used to measure the oxygen saturation of the blood, may be a more reliable indicator. Variation in PI is reported to be significantly larger in CRPS patients compared to healthy controls, while variation in temperature shows no difference between the two groups. PI also accurately reflects subjective thermal symptoms and is far superior to simple temperature measurements in this respect (13).  

Despite recent advances, none of these potential diagnostic tests are currently sufficiently validated to be introduced into clinical practice. However, exosomal miRNAs appear to be good candidates for potential biomarkers due to their stability and their known dysregulation in diseases such as CRPS (14). Much of the recent evidence suggests that FM and CRPS are immunological conditions, with disruption to the levels of cytokines and chemokines, lipid mediators, oxidative stress and plasma-derived factors possibly responsible for the inflammatory response underlying these diseases, although the pathways are still not fully understood (15,16). Concentrated research in this area may identify other biomarkers which could be used to provide a reliable means of diagnosing these challenging conditions.  

About our pain experts

At Medicolegal Partners we have two Medicolegal experts who are Consultants in Pain Medicine:

References: 

1. Atzeni F, Talotta R, Masala IF, Giacomelli C, Conversano C, Nucera V, et al. One year in review 2019: fibromyalgia. Clin Exp Rheumatol. 2019;37 Suppl 1(1):3–10.  

2. Cardinal TM, Antunes LC, Brietzke AP, Parizotti CS, Carvalho F, De Souza A, et al. Differential Neuroplastic Changes in Fibromyalgia and Depression Indexed by Up-Regulation of Motor Cortex Inhibition and Disinhibition of the Descending Pain System: An Exploratory Study. Front Hum Neurosci. 2019;13:138.  

3. Brietzke AP, Antunes LC, Carvalho F, Elkifury J, Gasparin A, Sanches PRS, et al. Potency of descending pain modulatory system is linked with peripheral sensory dysfunction in fibromyalgia: An exploratory study. Medicine (Baltimore). 2019 Jan;98(3):e13477.  

4. Andres-Rodriguez L, Borras X, Feliu-Soler A, Perez-Aranda A, Rozadilla-Sacanell A, Arranz B, et al. Machine Learning to Understand the Immune-Inflammatory Pathways in Fibromyalgia. Int J Mol Sci. 2019 Aug;20(17).  

5. Hackshaw K V, Aykas DP, Sigurdson GT, Plans M, Madiai F, Yu L, et al. Metabolic fingerprinting for diagnosis of fibromyalgia and other rheumatologic disorders. J Biol Chem. 2019 Feb;294(7):2555–68.  

6. Bharwani KD, Dik WA, Dirckx M, Huygen FJPM. Highlighting the Role of Biomarkers of Inflammation in the Diagnosis and Management of Complex Regional Pain Syndrome. Mol Diagn Ther. 2019 Jul;  

7. De Pra SDT, Antoniazzi CT de D, Ferro PR, Kudsi SQ, Camponogara C, Fialho MFP, et al. Nociceptive mechanisms involved in the acute and chronic phases of a complex regional pain syndrome type 1 model in mice. Eur J Pharmacol. 2019 Sep;859:172555.  

8. Russo MA, Fiore NT, van Vreden C, Bailey D, Santarelli DM, McGuire HM, et al. Expansion and activation of distinct central memory T lymphocyte subsets in complex regional pain syndrome. J Neuroinflammation. 2019 Mar;16(1):63.  

9. Bruehl S, Gamazon ER, Van de Ven T, Buchheit T, Walsh CG, Mishra P, et al. DNA methylation profiles are associated with complex regional pain syndrome following traumatic injury. Pain. 2019 May;  

10. Cuhadar U, Gentry C, Vastani N, Sensi S, Bevan S, Goebel A, et al. Autoantibodies produce pain in complex regional pain syndrome by sensitizing nociceptors. Pain. 2019 Jul;  

11. Shubayev VI, Strongin AY, Yaksh TL. Structural homology of myelin basic protein and muscarinic acetylcholine receptor: Significance in the pathogenesis of complex regional pain syndrome. Mol Pain. 2018;14:1744806918815005.  

12. Dietz C, Muller M, Reinhold A-K, Karch L, Schwab B, Forer L, et al. What is normal trauma healing and what is complex regional pain syndrome I? An analysis of clinical and experimental biomarkers. Pain. 2019 May;  

13. Chung K, Kim KH, Kim ED. Perfusion index as a reliable parameter of vasomotor disturbance in complex regional pain syndrome. Br J Anaesth. 2018 Nov;121(5):1133–7.  

14. Ramanathan S, Douglas SR, Alexander GM, Shenoda BB, Barrett JE, Aradillas E, et al. Exosome microRNA signatures in patients with complex regional pain syndrome undergoing plasma exchange. J Transl Med. 2019 Mar;17(1):81.  

15. Coskun Benlidayi I. Role of inflammation in the pathogenesis and treatment of fibromyalgia. Rheumatol Int. 2019 May;39(5):781–91.  

16. Konig S, Bayer M, Dimova V, Herrnberger M, Escolano-Lozano F, Bednarik J, et al. The serum protease network-one key to understand complex regional pain syndrome pathophysiology. Pain. 2019 Jun;160(6):1402–9.