A role for the microbiota in complex regional pain syndrome?

Abstract

Complex regional pain syndrome (CRPS) is a debilitating neuroinflammatory condition of unknown etiology. Symptoms include excruciating pain and trophic changes in the limbs as defined by the Budapest criteria. The severity and functional recovery of CRPS, unlike most pain conditions, is quantifiable using a variation of the Budapest criteria known as the CRPS severity score. Like many chronic pain conditions, CRPS is difficult to treat once pain has been present for more than 12 months. However, previous work has demonstrated that a subset of patients with new-onset CRPS (~50%) improve if treated within one year, while the rest have minimal to no symptom improvement. Unfortunately, this leads to permanent disability and often requires invasive and costly treatments such as spinal cord stimulation or long-term opioid therapy. Because the etiology is unknown, treatment is multimodal, and often supportive. Biomarkers that predict severity or resolution of symptoms would significantly change treatment but have not yet been identified. Interestingly, there are case reports of remission or resolution of CRPS symptoms with the use of antibiotics known to affect the gut flora. Mouse studies have demonstrated that modulation of the gut microbiome is anti-nociceptive in visceral, inflammatory and neuropathic pain models. We hypothesize that the variable clinical potential for recovery and response to therapy in CRPS may be secondary to or reflected in changes in the gut microbiota. We suggest that the microbiota may mediate or reflect clinical status via the metabolome, activation of the immune system and/or microglial activation. We hypothesize that the gut microbiome is a potential mediator in development and persistence of CRPS symptoms and propose that the clinical condition of CRPS could provide a unique opportunity to identify biomarkers of the microbiota and potential therapies to prevent pain chronification.

Keywords: Chronic pain; Complex regional pain syndrome; Gut microbiome; Gut microbiota; Metabolomics.

Fig. 1

The Budapest Criteria. Complex Regional Pain Syndrome (CRPS) is a diagnosis of exclusion. The accepted criteria for the diagnosis of CRPS is based on observed signs in two or more categories and reported symptoms in three or more of the listed categories (Harden et al., 2010).

Fig. 2

Potential Mechanisms of CRPS. Several hypothesized mechanisms of the development and persistence of Complex Regional Pain Syndrome (CRPS). Microbiota in the gut prime the immune system to produce antibodies (including auto-antibodies) and release metabolites (such as short chain fatty acids) and cytokines (for example, IL-1). After a peripheral injury, local auto-antibodies and cytokines are released to initiate an inappropriate inflammatory response resulting in severe pain. Microbiota-produced metabolites and/or cytokines may cross the blood brain barrier to result in microglial activation and thus pain chronification. Created with BioRender.com.