Cold allodynia is correlated to paroxysmal and evoked mechanical pain in complex regional pain syndrome (CRPS).

OBJECTIVES: Mechanisms of complex regional pain syndrome (CRPS) are still debated. Identifying subgroups of patients have been attempted in the hope of linking clinical findings to possible mechanisms. The aim of the present study was to investigate whether subgroups of CRPS (based on quantitative sensory testing (QST)-results) differed with respect to different characteristics of pain like spontaneous ongoing or paroxysmal pain and mechanical dynamic allodynia. METHODS: 61 CRPS-patients (type 1 and 2) were examined clinically and with QST, in affected and contralateral extremity, with assessment of thresholds for warmth, cold and heat-and cold pain. RESULTS: 43 patients (20 men, 23 men) were diagnosed with CRPS 1 (70.5%) and 18 patients (8 women and 10 men) with CRPS 2 (29.5%). Three subgroups were defined based on thermal thresholds; A (thermal allodynia 22.9%), B (thermal hyposensitivity 37.3%), C (thermal allodynia and hyposensitivity 39.3%). Paroxysmal pain was more prevalent in patients with thermal allodynia (merging group A + C, 25/38-65.8%) compared to patients without thermal allodynia (group B, 5/23-21.7%) (p-value=0.00085). CONCLUSIONS: We suggest that cold allodynia is based on hyper-excitability of very superficial skin nociceptors. The correlation between paroxysmal pain, allodynia to light touch and cold allodynia suggests that activity in those peripheral nociceptors can drive both, paroxysmal pain and spinal sensitization leading to stroke evoked allodynia. Mechanistically, the physical cold stimulus can unmask disease-related hyperexcitability by closure of temperature-sensitive potassium channels or induction of resurgent currents. Small fiber degeneration alone may not be the crucial mechanism in CRPS, nor explain pain.

The challenge of recognizing severe pain and autonomic abnormalities for early diagnosis of CRPS.

OBJECTIVES: Complex regional pain syndrome (CRPS) is a disabling usually post-traumatic pain condition. International guidelines emphasize early diagnosis for treatment and improved outcome. Early intense and persistent pain along with features of autonomic dysfunction in the first week's post-injury are early warning signs for development of CRPS. We have previously reported a delayed diagnosis of CRPS. The main purpose of the present study was to investigate possible causes of a delayed diagnosis, with a special focus of recognition of risk factors. METHODS: A total of 52 CRPS 1 (without detectable nerve damage) and CRPS 2 (with evidence of nerve lesion) patients were included in the study. When examined at OUS-Rikshospitalet, we retrospectively asked the patients on the development of pain and autonomic abnormalities from the time of the eliciting injury, performed a thorough clinical investigation with an emphasis on signs of autonomic failure and compared symptoms and clinical findings with such information in previous medical records. We also evaluated symptoms and signs according to the type of injury they had suffered. RESULTS: Of a total of 52 patients (30 women and 22 men, mean age 39.0 years at the time of injury), 34 patients had CRPS type 1 (65.4%) and 18 CRPS type 2 (34.6%), 25 patients with pain in the upper and 27 in the lower extremity. A total of 35 patients (67.3%) were diagnosed with CRPS (following mean 2.1 years) prior to the investigation at OUS-Rikshospitalet (mean 4.86 years following injury). Mean time from injury to diagnosis was 33.5 months (SD 30.6) (2.8 years) for all patients. In retrospect, all 17 patients first diagnosed at OUS met the CRPS diagnosis at an earlier stage. All patients retrospectively reported intense pain (numeric rating scale > 7) from the time of injury with a large discrepancy to previous medical records which only stated intense pain in 29.4% of patients with CRPS type 1 and 44.4% of patients with CRPS type 2 within the first four months. While the patients reported an early onset of autonomic dysfunction, present in 67.3 and 94.2% of the patients within one week and one month, respectively, reports of autonomic abnormalities within the first four months was far less (maximum in 51.7% of patients with CRPS type 1 and in 60% in CRPS 2). In 10 patients with CRPS type 1, no symptom nor sign of autonomic abnormalities was reported. CONCLUSIONS: We still find a significant delay in the diagnosis of CRPS. There is a large discrepancy between both self-reporting of intense, disproportionate pain, as well as symptoms of autonomic abnormalities from the time of injury, and documentation in previous medical records. Our findings suggest a lack of awareness of risk factors for the development of CRPS, such as early intense pain and autonomic abnormalities without recovery, contributing to delayed diagnosis. The present results suggest causes of delayed CRPS-diagnosis. An increased attention to early warning signs/risk factors may improve diagnosis of CRPS.

SCN10A Mutation in a Patient with Erythromelalgia Enhances C-Fiber Activity Dependent Slowing.

Gain-of-function mutations in the tetrodotoxin (TTX) sensitive voltage-gated sodium channel (Nav) Nav1.7 have been identified as a key mechanism underlying chronic pain in inherited erythromelalgia. Mutations in TTX resistant channels, such as Nav1.8 or Nav1.9, were recently connected with inherited chronic pain syndromes. Here, we investigated the effects of the p.M650K mutation in Nav1.8 in a 53 year old patient with erythromelalgia by microneurography and patch-clamp techniques. Recordings of the patient's peripheral nerve fibers showed increased activity dependent slowing (ADS) in CMi and less spontaneous firing compared to a control group of erythromelalgia patients without Nav mutations. To evaluate the impact of the p.M650K mutation on neuronal firing and channel gating, we performed current and voltage-clamp recordings on transfected sensory neurons (DRGs) and neuroblastoma cells. The p.M650K mutation shifted steady-state fast inactivation of Nav1.8 to more hyperpolarized potentials and did not significantly alter any other tested gating behaviors. The AP half-width was significantly broader and the stimulated action potential firing rate was reduced for M650K transfected DRGs compared to WT. We discuss the potential link between enhanced steady state fast inactivation, broader action potential width and the potential physiological consequences.

Exonic mutations in SCN9A (NaV1.7) are found in a minority of patients with erythromelalgia.

Background and aim "Gain-of-function" mutations in voltage-gated sodium channel NaV1.7 have been linked to erythromelalgia (EM), characterized by painful hot and red hands and feet. We investigated the proportion of patients with EM that carry a mutation in NaV1.7 or in other pain-related genes and studied possible clinical differences. Methods In this study, 48 patients with EM were screened for mutations in a total of 29 candidate genes, including all sodium channel subunits, transient receptor potential channels (TRPA1, TRPV1, TRPM8), neurotrophic factors (NGF, NGFR, BDNF, GDNF, NTRK1 and WNK1) and other known pain-related genes (CACNG2, KCNS1, COMT, P2RX3, TAC1, TACR1), using a combination of next generation sequencing and classical Sanger sequencing. Results In 7/48 patients protein-modifying mutations of NaV1.7 (P187L, I228M, I848T (n = 4) and N1245S) were identified. Patients with the I848T mutation could be identified clinically based on early onset and severity of the disease. In contrast, there were no clinical characteristics that differentiated the other patients with NaV1.7 mutation from those patients without. We also found more than twenty rare protein-modifying genetic variants in the genes coding for sodium channels (NaV1.8, NaV1.9, NaV1.6, NaV1.5, NaV2.1, SCN1B, SCN3B), transient receptor potential channel (TRPA1, TRPV1), and other pain-related targets (WNK1 and NGFR). Conclusion We conclude that functionally characterized mutations of NaV1.7 (I848T) are present only in a minority of patient with EM. Albeit the majority of patients (27/48) carried rare protein-modifying mutations the vast majority of those will most probably not be causally linked to their disease. Implications The key question remaining to be solved is the possible role of rare variants of NaV1.8, NaV1.9, or beta-subunits in provoking chronic pain conditions or even EM.