A role for the microbiota in complex regional pain syndrome?

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.