Evidence of a genetic background predisposing to complex regional pain syndrome type 1.

BACKGROUND: Complex regional pain syndrome type 1 (CRPS-1) is a rare, disabling and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared with those who do not have the condition. METHODS: Exome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a discovery cohort of well-characterised patients with chronic CRPS-1 (n=34) compared with population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a replication cohort (n=50). Gene expression of peripheral blood macrophages was assessed. RESULTS: In the discovery cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The replication cohort confirmed this finding. In a chronic pain cohort, these alleles were not overexpressed. In total, 25 out of 84 (29.8%) patients with CRPS-1 expressed a rare allele. The SNPs were rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1 and rs80308281 in SLC12A9. Males were more likely than females to have a rare SNP allele, 8 out of 14 (57.1%) vs 17 out of 70 (24.3%) (Fisher's p=0.023). ANO10, P2RX7, PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls. CONCLUSION: A single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1.

Results from an expedited spinal nerve root block clinic at a UK tertiary neurosurgical centre.

STUDY DESIGN: Retrospective Observational Study. INTRODUCTION: Lumbar radicular pain has a prevalence of 3-5%. Level 1 evidence has demonstrated equivalence between surgical and injection treatment. We assess the outcomes from a transforaminal epidural steroid injection clinic in a tertiary neuroscience referral centre. METHODS: We performed an analysis of data from consecutive patients entered into a new internal referral database between August 2018 to May 2021. Radicular pain was classified as one of "first presentation" or "recurrence". Outcomes were obtained from follow up clinic letters and recorded in a binary manner of "positive result" or "negative result". Spinal pathology was documented from radiology reports and MRI images. RESULTS: We analysed 208 patients referred to the clinic. Excluding those who improved to a point of not requiring treatment, and those who underwent surgical intervention, 119 patients undergoing injection were included, of which 14 were lost to follow-up. 68 % of patients had a positive result from injection. Subgroup analysis demonstrated good outcomes for both hyperacute (<6 weeks) and chronic (>12 months). Contained disk pathologies had better outcomes than uncontained. There was no difference in outcomes across grades of compression, but previous same level surgery was associated with poorer response rates. CONCLUSIONS: There is a high rate of natural resolution of symptoms in patients with LSRP. In those where pain persists, TFESI is a valuable first line treatment modality. This study suggests the efficacy of TFESI is potentially independent of grade of stenosis and chronicity of symptoms. Contained disc pathologies respond better than uncontained.

Discovery of novel targets in a complex regional pain syndrome mouse model by transcriptomics: TNF and JAK-STAT pathways.

Complex Regional Pain Syndrome (CRPS) represents severe chronic pain, hypersensitivity, and inflammation induced by sensory-immune-vascular interactions after a small injury. Since the therapy is unsatisfactory, there is a great need to identify novel drug targets. Unbiased transcriptomic analysis of the dorsal root ganglia (DRG) was performed in a passive transfer-trauma mouse model, and the predicted pathways were confirmed by pharmacological interventions. In the unilateral L3-5 DRGs 125 genes were differentially expressed in response to plantar incision and injecting IgG of CRPS patients. These are related to inflammatory and immune responses, cytokines, chemokines and neuropeptides. Pathway analysis revealed the involvement of Tumor Necrosis Factor (TNF) and Janus kinase (JAK-STAT) signaling. The relevance of these pathways was proven by abolished CRPS IgG-induced hyperalgesia and reduced microglia and astrocyte markers in pain-associated central nervous system regions after treatment with the soluble TNF alpha receptor etanercept or JAK inhibitor tofacitinib. These results provide the first evidence for CRPS-related neuroinflammation and abnormal cytokine signaling at the level of the primary sensory neurons in a translational mouse model and suggest that etanercept and tofacitinib might have drug repositioning potentials for CRPS-related pain.

Aftersensations and Lingering Pain After Examination in Patients with Fibromyalgia Syndrome.

BACKGROUND: Fibromyalgia syndrome (FMS) is a chronic widespread pain condition with mixed peripheral and central contributions. Patients display hypersensitivities to a spectrum of stimuli. Patients' blunt pressure pain thresholds are typically reduced, and sometimes (∼15%) gentle brushstroke induces allodynia. However, aftersensations after these stimuli have not, to our knowledge, been reported. METHODS: We examined the perception of blunt pressure and "pleasant touch" in FMS. Patients were first interviewed and completed standard psychometric questionnaires. We then measured their sensitivity to blunt pressure and perception of pleasant touch, including aftersensations; patients were followed up for 5 days to evaluate lingering pain from blunt pressure. RESULTS: We recruited 51 patients with FMS and 16 pain-free healthy controls (HCs) at a UK Pain Management Centre. Forty-four patients completed the aftersensation protocol. Most patients reported pain after the application of less mechanical pressure than the level of pressure at which HCs reported pain; median arm and leg thresholds for the patients with FMS were 167 kPa and 233 kPa, respectively. Eighty-four percent (31/37) of patients reported ongoing pain at the site of pressure application 1 day after testing, and 49% (18/37) still perceived pain at 5 days. Aftersensations after brushstroke were common in the FMS group, reported by 77% (34/44) of patients with FMS vs 25% (4/16) of HCs; 34% (15/44) of patients, but no HCs, perceived these aftersensations as uncomfortable. For patients with FMS who experienced aftersensations, brushstroke pleasantness ratings were reduced, and the skin was often an important site of pain. CONCLUSION: Pain after blunt pressure assessment typically lingers for several days. Aftersensations after brushstroke stimulation are a previously unreported FMS phenomenon. They are associated with tactile anhedonia and might identify a clinically distinct subgroup.

Complex Regional Pain Syndrome: Practical Diagnostic and Treatment Guidelines, 5th Edition.

There have been some modest recent advancements in the research of Complex Regional Pain Syndrome, yet the amount and quality of the work in this complicated multifactorial disease remains low (with some notable exceptions; e.g., the recent work on the dorsal root ganglion stimulation). The semi-systematic (though in some cases narrative) approach to review is necessary so that we might treat our patients while waiting for "better research." This semi-systematic review was conducted by experts in the field, (deliberately) some of whom are promising young researchers supplemented by the experience of "elder statesman" researchers, who all mention the system they have used to examine the literature. What we found is generally low- to medium-quality research with small numbers of subjects; however, there are some recent exceptions to this. The primary reason for this paucity of research is the fact that this is a rare disease, and it is very difficult to acquire a sufficient sample size for statistical significance using traditional statistical approaches. Several larger trials have failed, probably due to using the broad general diagnostic criteria (the "Budapest" criteria) in a multifactorial/multi-mechanism disease. Responsive subsets can often be identified in these larger trials, but not sufficient to achieve statistically significant results in the general diagnostic grouping. This being the case the authors have necessarily included data from less compelling protocols, including trials such as case series and even in some instances case reports/empirical information. In the humanitarian spirit of treating our often desperate patients with this rare syndrome, without great evidence, we must take what data we can find (as in this work) and tailor a treatment regime for each patient.

Research Recommendations Following the Discovery of Pain Sensitizing IgG Autoantibodies in Fibromyalgia Syndrome.

BACKGROUND: Fibromyalgia syndrome (FMS) is the most common chronic widespread pain condition in rheumatology. Until recently, no clear pathophysiological mechanism for fibromyalgia had been established, resulting in management challenges. Recent research has indicated that serum immunoglobulin Gs (IgGs) may play a role in FMS. We undertook a research prioritisation exercise to identify the most pertinent research approaches that may lead to clinically implementable outputs. METHODS: Research priority setting was conducted in five phases: situation analysis; design; expert group consultation; interim recommendations; consultation and revision. A dialogue model was used, and an international multi-stakeholder expert group was invited. Clinical, patient, industry, funder, and scientific expertise was represented throughout. Recommendation-consensus was determined via a voluntary closed eSurvey. Reporting guideline for priority setting of health research were employed to support implementation and maximise impact. RESULTS: Arising from the expert group consultation (n = 29 participants), 39 interim recommendations were defined. A response rate of 81.5% was achieved in the consensus survey. Six recommendations were identified as high priority- and 15 as medium level priority. The recommendations range from aspects of fibromyalgia features that should be considered in future autoantibody research, to specific immunological investigations, suggestions for trial design in FMS, and therapeutic interventions that should be assessed in trials. CONCLUSIONS: By applying the principles of strategic priority setting we directed research towards that which is implementable, thereby expediating the benefit to the FMS patient population. These recommendations are intended for patients, international professionals and grant-giving bodies concerned with research into causes and management of patients with fibromyalgia syndrome.

Transfer of complex regional pain syndrome to mice via human autoantibodies is mediated by interleukin-1-induced mechanisms.

Neuroimmune interactions may contribute to severe pain and regional inflammatory and autonomic signs in complex regional pain syndrome (CRPS), a posttraumatic pain disorder. Here, we investigated peripheral and central immune mechanisms in a translational passive transfer trauma mouse model of CRPS. Small plantar skin-muscle incision was performed in female C57BL/6 mice treated daily with purified serum immunoglobulin G (IgG) from patients with longstanding CRPS or healthy volunteers followed by assessment of paw edema, hyperalgesia, inflammation, and central glial activation. CRPS IgG significantly increased and prolonged swelling and induced stable hyperalgesia of the incised paw compared with IgG from healthy controls. After a short-lasting paw inflammatory response in all groups, CRPS IgG-injected mice displayed sustained, profound microglia and astrocyte activation in the dorsal horn of the spinal cord and pain-related brain regions, indicating central sensitization. Genetic deletion of interleukin-1 (IL-1) using IL-1αß knockout (KO) mice and perioperative IL-1 receptor type 1 (IL-1R1) blockade with the drug anakinra, but not treatment with the glucocorticoid prednisolone, prevented these changes. Anakinra treatment also reversed the established sensitization phenotype when initiated 8 days after incision. Furthermore, with the generation of an IL-1ß floxed(fl/fl) mouse line, we demonstrated that CRPS IgG-induced changes are in part mediated by microglia-derived IL-1ß, suggesting that both peripheral and central inflammatory mechanisms contribute to the transferred disease phenotype. These results indicate that persistent CRPS is often contributed to by autoantibodies and highlight a potential therapeutic use for clinically licensed antagonists, such as anakinra, to prevent or treat CRPS via blocking IL-1 actions.

Mechanistically informed non-invasive peripheral nerve stimulation for peripheral neuropathic pain: a randomised double-blind sham-controlled trial.

BACKGROUND: Induction of long-term synaptic depression (LTD) is proposed as a treatment mechanism for chronic pain but remains untested in clinical populations. Two interlinked studies; (1) A patient-assessor blinded, randomised, sham-controlled clinical trial and (2) an open-label mechanistic study, sought to examine therapeutic LTD for persons with chronic peripheral nerve injury pain. METHODS: (1) Patients were randomised using a concealed, computer-generated schedule to either active or sham non-invasive low-frequency nerve stimulation (LFS), for 3 months (minimum 10 min/day). The primary outcome was average pain intensity (0-10 Likert scale) recorded over 1 week, at 3 months, compared between study groups. (2) On trial completion, consenting subjects entered a mechanistic study assessing somatosensory changes in response to LFS. RESULTS: (1) 76 patients were randomised (38 per group), with 65 (31 active, 34 sham) included in the intention to treat analysis. The primary outcome was not significant, pain scores were 0.3 units lower in active group (95% CI - 1.0, 0.3; p = 0.30) giving an effect size of 0.19 (Cohen's D). Two non-device related serious adverse events were reported. (2) In the mechanistic study (n = 19) primary outcomes of mechanical pain sensitivity (p = 0.006) and dynamic mechanical allodynia (p = 0.043) significantly improved indicating reduced mechanical hyperalgesia. CONCLUSIONS: Results from the RCT failed to reach significance. Results from the mechanistic study provide new evidence for effective induction of LTD in a clinical population. Taken together results add to mechanistic understanding of LTD and help inform future study design and approaches to treatment. Trial registration ISRCTN53432663.

Patient consultation about a trial of therapeutic plasma exchange for complex regional pain syndrome.

BACKGROUND: Complex regional pain syndrome (CRPS) is a severe post-traumatic chronic pain condition affecting distal limbs, for which few effective treatments exist. Complex regional pain syndrome is listed in the 2016 American Society for Apheresis guidelines as an indication for plasma exchange treatment, but patient perspectives are lacking. STUDY DESIGN AND METHODS: We convened a "patient and public consultation exercise." Supervised by a clinical ethicist, the case for using therapeutic plasma exchange (TPE) was presented by a researcher and two TPE experts to five patients with severe, long-standing CRPS and to one relative. Discussions were recorded and transcribed. RESULTS: Participants supported the technology's use but expressed concern that the small trauma of repeat cannulations of CRPS unaffected limbs might theoretically cause a spread of the condition, a risk which requires highlighting when taking consent. For a preliminary trial, the participants proposed to include no less than 10, preferably 20 participants. They suggested that the threshold for a decision to conduct a definite trial based on preliminary trial results should be set no higher than 1/5 patients achieving >30% pain reduction in the preliminary trial, with half of these responders achieving >50%. The use of sham-TPE and a long trial duration (1 year) of a definite, parallel trial was considered acceptable, provided patients would be offered voluntary swap to the other trial arm at the end of the main trial period. CONCLUSION: These results provide pertinent patient views about TPE treatment which can inform both clinical consultation and consent procedure and the design of future trials.

Low-Dose Intravenous Immunoglobulin Treatment for Long-Standing Complex Regional Pain Syndrome: A Randomized Trial.

BACKGROUND: Two small trials suggest that low-dose intravenous immunoglobulin (IVIg) may improve the symptoms of complex regional pain syndrome (CRPS), a rare posttraumatic pain condition. OBJECTIVE: To confirm the efficacy of low-dose IVIg compared with placebo in reducing pain during a 6-week period in adult patients who had CRPS from 1 to 5 years. DESIGN: 1:1 parallel, randomized, placebo-controlled, multicenter trial for 6 weeks, with an optional 6-week open extension. Patients were randomly assigned to 1 of 2 study groups between 27 August 2013 and 28 October 2015; the last patient completed follow-up on 21 March 2016. Patients, providers, researchers, and outcome assessors were blinded to treatment assignment. (ISRCTN42179756). SETTING: 7 secondary and tertiary care pain management centers in the United Kingdom. PARTICIPANTS: 111 patients with moderate or severe CRPS of 1 to 5 years' duration. INTERVENTION: IVIg, 0.5 g/kg of body weight, or visually indistinguishable placebo of 0.1% albumin in saline on days 1 and 22 after randomization. MEASUREMENTS: The primary outcome was 24-hour average pain intensity, measured daily between days 6 and 42, on an 11-point (0- to 10-point) rating scale. Secondary outcomes were pain interference and quality of life. RESULTS: The primary analysis sample consisted of 108 eligible patients, 103 of whom had outcome data. Mean (average) pain scores were 6.9 points (SD, 1.5) for placebo and 7.2 points (SD, 1.3) for IVIg. The adjusted difference in means was 0.27 (95% CI, -0.25 to 0.80; P = 0.30), which excluded the prespecified, clinically important difference of -1.2. No statistically significant differences in secondary outcomes were found between the groups. In the open extension, 12 of the 67 patients (18%) who received 2 IVIg infusions had pain reduction of at least 2 points compared with their baseline score. Two patients in the blinded phase (1 in the placebo and 1 in the IVIg group) and 4 in the open IVIg phase had serious events. LIMITATIONS: Results do not apply to patients who have had CRPS for less than 1 year or more than 5 years and do not extend to full-dose treatment (for example, 2 g/kg). The study was inadequately powered to detect subgroup effects. CONCLUSION: Low-dose immunoglobulin treatment for 6 weeks was not effective in relieving pain in patients with moderate to severe CRPS of 1 to 5 years' duration. PRIMARY FUNDING SOURCE: Medical Research Council/National Institute for Health Research Efficacy and Mechanism Evaluation Program, Pain Relief Foundation, and Biotest United Kingdom.

Dorsal Root Ganglion Stimulation for Complex Regional Pain Syndrome (CRPS) Recurrence after Amputation for CRPS, and Failure of Conventional Spinal Cord Stimulation.

BACKGROUND: Limb amputation is sometimes being performed in long-standing complex regional pain syndrome (CRPS), although little evidence is available guiding management decisions, including how CRPS recurrence should be managed. METHODS: This report details the management of a young soldier with CRPS recurrence 2 years after midtibial amputation for CRPS. RESULTS: Conventional spinal cord stimulation did not achieve paraesthetic coverage, or pain relief in the stump, whereas L4 dorsal root ganglion stimulation achieved both coverage and initially modest pain relief, and over time, substantial pain relief. CONCLUSIONS: Current evidence does not support the use of amputation to improve either pain or function in CRPS. Before a decision is made, in exceptional cases, about referral for amputation, dorsal root ganglion stimulation should be considered as a potentially effective treatment, even where conventional spinal cord stimulator treatment has failed to achieve reliable paraesthetic cover. Furthermore, this treatment may provide pain relief in those patients with CRPS recurrence in the stump after amputation.

A technique to assess perineuronal mediators.

Perineural activity of a variety of inflammatory and immune system mediators can activate peripheral nerves leading to the perception of pain. One example of such effects includes the activity of interleukin 1 beta (IL-1ß); this inflammatory mediator, upon binding to IL-1R1 neuronal membrane receptors will rapidly induce protein kinases in damage-sensing neurons, consequently altering heat-activated ionic inward currents leading to increased neuronal sensitivity to harmful heat. The ability to detect such mediators in proximity to sensory nerves is therefore crucial to investigating the contributing roles of inflammation in human chronic pain. To date there is no recognized method to assess mediator profiles around human sensory nerve roots in vivo. A novel method is described that can assess these mediators in the human trigeminal system where the nerve leaves the brain stem in its pre-ganglionic portion. Mediator levels are shown to change between sample locations on the trigeminal nerve root in patients with trigeminal neuralgia. This methodology may therefore be used to shed insights as to the pathophysiology of trigeminal neuralgia, which may in turn influence clinical decisions concerning the natural history, and treatment options.

The Treatment of Longstanding Complex Regional Pain Syndrome with Oral Steroids.

OBJECTIVE: Evaluate the effectiveness of oral steroids in relieving pain in patients with Complex Regional Pain Syndrome (CRPS) of more than 3 months duration. DESIGN: Service evaluation/Open label uncontrolled trial. SETTING: Two pain outpatient clinics specialized in CRPS diagnosis and treatment in the period 2009-2012. SUBJECTS: Thirty-one patients diagnosed with CRPS with the Budapest criteria in two specialized centers, with a disease duration of more than 3 months and not responsive to standard treatment were included. METHODS: Patients were treated with oral prednisolone in both centers [100 mg daily tapered by 25 mg every 4 days to zero (Σ1g) at center 1 (C1) and 60 mg daily for 2 weeks lowered 20 mg every 4 days to zero (Σ1.06g) at center 2 (C2)]. The average pain intensity was recorded by patients using a numeric rating scale before the treatment start, and 6 weeks after treatment onset (treatment duration was respectively 16 days and 22 days at the two centers). RESULTS: Overall the authors observed no significant reduction in the average pain intensity (P = 0.059), but 2 patients had a consistent reduction in pain intensity with return to baseline pain levels 9 weeks after treatment onset, and 1 patient had ongoing stable pain relief of >50%. CONCLUSIONS: This study provides indications that the efficacy of oral corticosteroids is limited in treating CRPS of more than 3 months duration who did not respond to previous treatment. Randomized controlled studies (with enriched designs), or single subject designs would be required to identify the possible existence of a patient subgroup with a specific disease profile that may benefit from a steroid treatment.

Long-Term Treatment of Chronic Neuropathic Pain Using External Noninvasive External Peripheral Nerve Stimulation in Five Patients.

BACKGROUND: External noninvasive peripheral nerve stimulation (EN-PNS) is a neuromodulation technique in which a low-frequency electrical stimulation is applied via a ball-shaped electrode that is placed directly onto the skin. OBJECTIVES: To examine how this modality is being used in the long term, by patients with chronic neuropathic pain who had responded to this treatment in a short-term trial. MATERIALS AND METHODS: All patients with a diagnosis of neuropathic pain who had obtained a machine for continued long-term use (via special funding requests), following a successful trial between 2009 and 2012 were contacted. A successful trial was considered as >50% pain reduction, duration of any beneficial treatment effect ≥12 hours, and improvements to function/reduced medication use. Data were collected from case notes and a telephone interview. RESULTS: Thirteen trials were recorded successful, out of 21 conducted. Eleven individual funding applications were made, of which seven were successful. Five patients were contactable. All reported continued stimulator use at follow-up (average = 3.5 years) and ongoing pain relief associated with treatment. Pain intensities (numerical rating scale 0-10) had reduced in all five cases when baseline scores were compared with follow-up scores; average pain 5.6-3.5 and worst pain 8.6-4.8. All patients reported a reduction in frequency of pain flare-ups during device use. CONCLUSION: Patients reported EN-PNS to provide ongoing benefit at long-term follow-up. Further prospective investigations are justified.

External Noninvasive Peripheral Nerve Stimulation Treatment of Neuropathic Pain: A Prospective Audit.

BACKGROUND: Peripheral nerve stimulation (PNS) is a neuromodulation technique in which electrical current is applied to the peripheral nerves to ameliorate chronic pain through preferential activation of myelinated fibres, inducing long-term depression of synaptic efficacy. External noninvasive peripheral nerve stimulation (EN-PNS) is a novel and simple form of PNS that involves stimulation via an external nerve-mapping probe that is placed on the skin and connected to a power source. OBJECTIVES: We aimed to assess the clinical utility of EN-PNS in patients with refractory neuropathic pains referred to a tertiary pain treatment center. METHODS: We undertook a prospective audit of EN-PNS. Patients with a diagnosis of either complex regional pain syndrome or neuropathic pain after peripheral nerve injury who met inclusion criteria were included. Participants completed three stages of the audit: stage 1, six weekly outpatient treatment sessions; stage 2, six-week equipment home loan; stage 3, six weeks of no EN-PNS treatment. The primary outcome was the average post-treatment instantaneous pain intensity during the last week in stage 2 compared with baseline (11-point numerical rating scale). RESULTS: EN-PNS provided significant short-term pain relief (n = 20 patients, average reduction of 2.8 numerical rating scale points, 95% CI 1.6-4.0, p < 0.001, intention-to-treat analysis). Eight patients (40%) improved in several outcome parameters ("responders"), including quality of life and function. CONCLUSION: In this first prospective report on the use of EN-PNS in neuropathic pain, this technology provided significant clinical benefit for some patients. Controlled studies are required to confirm our results and the place of EN-PNS in future neuromodulation treatment algorithms. Given the refractory nature of these conditions, these results are encouraging.

Immunoglobulin g for the treatment of chronic pain: report of an expert workshop.

BACKGROUND: The treatment of chronic pain is still unsatisfactory. Despite the availability of different drugs, most patients with chronic pain do not receive satisfactory pain relief or report side effects. Converging evidence implicates involvement of the immune system in the pathogenesis of different types of nociceptive and neuropathic chronic pain. DESIGN: At a workshop in Liverpool, UK (October 2012), experts presented evidence suggesting immunological involvement in chronic pain and recent data supporting the concept that the established immune-modulating drug, polyvalent immunoglobulin G (IgG), either given intravenously (IVIg) or subcutaneously (SCIg), may reduce pain in some peripheral neuropathies and a range of other pain disorders. Workshop's attendees discussed the practicalities of using IVIg and SCIg in these disorders, including indications, cost-effectiveness, and side effects. RESULTS: IgG may reduce pain in a range of nociceptive and neuropathic chronic pain conditions, including diabetes mellitus, Sjögren's syndrome, fibromyalgia, complex regional pain syndrome, post-polio syndrome, and pain secondary to pathological autoantibodies. CONCLUSIONS: IgG is a promising treatment in several chronic pain conditions. IgG is a relatively safe therapeutic strategy, with uncommon and mild side effects but high costs. Randomized, controlled trials and predictive tests are needed to better support the use of IgG for refractory chronic pain.

Widespread pain in patients with complex regional pain syndrome.

OBJECTIVES: Our goal was to ascertain the prevalence of widespread pain in our cohort of patients with complex regional pain syndrome (CRPS). METHODS: We conducted a retrospective analysis of clinical letters and notes. We assessed data from consecutive patients diagnosed with CRPS according to the Budapest criteria, after a referral to one consultant at a tertiary Pain Medicine referral center. RESULTS: Between July 2007 and September 2012, 190 patients (149 females) received a diagnosis of CRPS according to the Budapest criteria, and an additional 26 patients received the diagnosis of CRPS NOS (not otherwise specified). The CRPS patients were an average of 44 years of age, and had a median disease duration of 18 months. Before the CRPS incident trigger, a third had already experienced other than everyday pains in the now CRPS-affected limb. Twenty-one patients (11.1%) experienced widespread pain in clinic, which was often not communicated in the referral letters. The types of triggering traumata and frequencies of Budapest signs and symptoms did not differ between patients with or without widespread pain. All patients considered their widespread pain as an important factor affecting their quality of life; for the majority it was of similar severity to the CRPS pain. Additional patients reported CRPS-concomitant regional pains, most commonly headaches/migraines, lower back pain, and irritable bowel syndrome. DISCUSSION: In this systematic assessment of the incidence of widespread pain in a large cohort of patients with CRPS, important widespread pain affected > 10% of patients. Our data support the inclusion of routine enquiries about additional pains in the clinical assessment of patients with CRPS.