Senso-Immunologic Prospects for Complex Regional Pain Syndrome Treatment

Complex regional pain syndrome (CRPS) is a chronic pain syndrome that occurs in tissue injuries as the result of surgery, trauma, or ischemia. The clinical features of this severely painful condition include redness and swelling of the affected skin. Intriguingly, it was recently suggested that transient receptor potential ankyrin 1 (TRPA1) is involved in chronic post-ischemia pain, a CRPS model. TRPA1 is a non-selective cation channel expressed in calcitonin gene-related peptide (CGRP)-positive primary nociceptors that becomes highly activated in ischemic conditions, leading to the generation of pain. In this review, we summarize the history of TRPA1 and its involvement in pain sensation, inflammation, and CRPS. Furthermore, bone atrophy is also thought to be a characteristic clinical sign of CRPS. The altered bone microstructure of CRPS patients is thought to be caused by aggravated bone resorption via enhanced osteoclast differentiation and activation. Although TRPA1 could be a target for pain treatment in CRPS patients, we also discuss the paradoxical situation in this review. Nociceptor activation decreases the risk of bone destruction via CGRP secretion from free nerve endings. Thus, TRPA1 inhibition could cause severe bone atrophy. However, the suitable therapeutic strategy is controversial because the pathologic mechanisms of bone atrophy in CRPS are unclear. Therefore, we propose focusing on the remission of abnormal bone turnover observed in CRPS using a recently developed concept: senso-immunology.

Ketamine for Non-Neuropathic Pain

Chronic pain is one of the leading causes of years lost to disability, as most of the time it is refractory to conventional treatment. Recent advances in understanding the pain mechanisms have favored the use of ketamine as a rescue agent in refractory chronic pain conditions, as it has potential modulating effect on both sensory-discriminative and affective motivational components of pain. Preclinical studies also suggested the antinociceptive effect of sub anesthetic dose of ketamine against central and peripheral neuropathic pain conditions and non-neuropathic pain conditions such as inflammatory and nociceptive pain states. Subanesthetic infusion of ketamine along with adjuvants such as midazolam and clonidine is found to reduce the psychomimetic and cardiovascular side effects of ketamine. Even though the consensus guidelines for intravenous use of ketamine for chronic pain advocate the use of ketamine only for complex regional pain syndrome, various other clinical studies suggested its role in other refractory painful conditions. Hence the present topic focuses specifically on the effect of ketamine on non-neuropathic pain conditions such as complex regional pain syndrome, fibromyalgia, headache, ischemic limb pain, etc. Many studies had shown that ketamine not only reduces the pain scores but also the analgesic medications, which further improves the well-being and quality of life.

Normal manual straight ahead pointing in Complex Regional Pain Syndrome

There is evidence to suggest that people with Complex Regional Pain Syndrome (CRPS) can have altered body representations and spatial cognition. One way of studying these cognitive functions is through manual straight ahead (MSA) pointing, in which participants are required to point straight ahead of their perceived body midline without visual feedback of the hand. We therefore compared endpoint errors from MSA pointing between people with CRPS (n = 17) and matched controls (n = 18), and examined the effect of the arm used (Side of Body; affected/non-dominant, non-affected/dominant). For all participants, pointing errors were biased towards the hand being used. We found moderate evidence of no difference between Groups on endpoint errors, and moderate evidence of no interaction with Side of Body. The differences in variability between Groups were non-significant/inconclusive. Correlational analyses showed no evidence of a relationship between MSA endpoint errors and clinical parameters (e.g. CRPS severity, duration, pain) or questionnaire measures (e.g. body representation, “neglect-like symptoms”, upper limb disability). This study is consistent with earlier findings of no difference between people with CRPS and controls on MSA endpoint errors, and is the first to provide statistical evidence of similar performance of these two groups. Our results do not support a relationship between clinical or self-reported measures (e.g. “neglect-like symptoms”) and any directional biases in MSA. Our findings may have implications for understanding neurocognitive changes in CRPS.