One of the most poorly understood forms of chronic pain is complex regional pain syndrome (CRPS), characterized by an intense, disproportionate, burning pain, usually in a limb, often developing after an injury, surgery, or stroke. The autonomic nerves are involved as the skin frequently changes in temperature, color, sweating, and sensitivity. 

It is a rare disease, and as I have described previously, suffers from a lack of diagnostic accuracy and effective treatment.

“CRPS remains challenging to treat, with patients often experiencing prolonged suffering before receiving appropriate care.” 

– Amir Minerbi, MD, Director Institute for Pain Medicine, Rambam Health Campus Haifa, Israel

While it seems to be due, in part, to autonomic dysregulation, immune and inflammatory causes may play a role, and the diagnosis of CRPS rests on a patient’s signs and symptoms. A search for blood-borne biomarkers has found some candidate cytokines, but the cytokine’s assays sensitivity and specificity are too low to act as screening, let alone diagnostic tools. A new study in Anesthesiology looks at the gut microbiome as a potential biomarker. 

Patients were recruited through clinics, personal outreach, and local media and screened for eligibility using an agreed-upon set of signs and symptoms, the Budapest criteria. 

The criteria include:

• Continuing, disproportionate pain
• Presence of symptoms and signs of autonomic dysregulation. Specifically hypersensitivity, vasomotor changes (temperature or skin color changes), sudomotor changes (swelling or changes in sweat creation), changes in muscle strength or tone, and trophic changes in hair, nails, or skin. 

Participants were scored using the CRPS Severity Score (CSS), which quantifies the presence of the Budapest criteria’s signs and symptoms on a yes-no basis. With a total score of 16, higher scores indicate greater CRPS severity. It is a standard measure used to track symptoms’ severity over time. 

In addition to these more specialized tests, the participants underwent a series of surveys about the quality of physical and emotional life and, of course, our old friend, a food frequency questionnaire. A sample of 100 Israeli individuals, half diagnosed with CRPS and half age, gender, and ethnicity-matched pain-free controls, was used as a machine learning program training set. A similar group of 20 Canadian individuals served as the testing cohort providing a more generalized, international sample. All provided stool samples from which DNA was extracted characterizing their gut microbiome. 

The cohorts had minor differences in smoking status, education, and employment. Perhaps the most significant unmatched variable was the use of pain meds by the CRPS patients. As might be anticipated, CRPS patients, compared to controls, had higher CRPS severity scores (mean of 12), greater pain, anxiety, and depression, and a poorer quality of sleep. More critically, the researchers did not detect any significant differences in diet between the two groups, although dietary differences, by their nature, are sometimes hard to quantify. [1] 

Microbial Clues and Metabolic Echoes

Compared to pain-free individuals, CRPS patients harbored a markedly different community of gut bacteria. Particular species that play key roles in maintaining a healthy microbial ecosystem were notably diminished, while others emerged in higher numbers, painting a picture of a gut environment subtly but meaningfully different and, perhaps, “out of balance.”

In CRPS patients, key gut bacteria involved in succinate and propionic acid metabolism were significantly depleted, while species producing butyrate and lactic acid were elevated – a shift in fermentation pathways. These compositional changes echoed through the body as altered levels of short-chain fatty acids (SCFAs), chemical messengers with known anti-inflammatory and pain-modulating properties. In CRPS patients, levels of these metabolites were consistently lower in both stool and blood, suggesting a tangible loss of beneficial microbial function. Could the alterations in the microbiome alter the biochemical dialogue within the body, making CRPS not only a dysregulation of autonomic nerves but partially a disorder of microbial miscommunication? 

Of greater interest, especially for those with CRPS, the altered microbiome was diagnostically informative. The training set identified a striking pattern of microbiome change that was accurate in identifying CRPS cases (90% sensitivity) and the matched controls (88% specificity). The findings against the Canadian test cohort were essentially the same. 

As with all screening tests, the real value of sensitivity and specificity is determined by the prevalence of the disease in the screening population. Microbiome testing would make more sense in identifying those individuals with chronic pain in the more ambiguous range of the Budapest criteria. In the study, 50% of individuals with some, but not all, hallmarks of a formal diagnosis of CRPS were classified as CRPS patients based on their microbiome. 

Most importantly, the dietary intake of patients and controls were comparable, suggesting that the changes identified were not due to diet. The caveat here is the pain medicines taken by the CRPS patients are an unwitting confounder, as medications can also alter our microbiome.

As with any good study, it raises more questions than it answers. The causal role of the gut in chronic pain disorders is “unfolding.” It is certainly unclear whether these changes are a predisposing factor, a secondary result of CRPS, or an artifact of pain management. As my colleague Dr. Bloom points out, acetaminophen is often a component of opioid medications and is known to alter the gut microbiome.

This study adds an intriguing layer to our thinking about CRPS: gut microbes may play a role in modulating symptoms and defining the disease. A distinct microbial signature, mirrored in reduced anti-inflammatory metabolites, opens the diagnostic door to reducing years of uncertainty. While what we see might be a cause, consequence, or collateral damage, it seems the gut has more say, and we’re just beginning to listen.

[1] CRPS patients in the Canadian test cohort consumed more eggs and fewer vegetables than their Israeli counterparts – you may temper your conclusions accordingly. 

Source: Altered gut microbiome composition and function in individuals with complex regional pain syndrome Anesthesiology DOI: 10.1097/ALN.0000000000005435