Chronic opioid exposure may disrupt intestinal permeability through multiple mechanisms, potentially leading to increased inflammation, bacterial translocation, and systemic immune activation, according to a new study.
In the comprehensive review, published in The American Journal of Gastroenterology, investigators from Mayo Clinic examined the interplay between opioids, intestinal barriers, and the gut microbiome. They reported that opioids altered tight junction protein expression, disrupted toll-like receptor signaling, and induced changes in gut microbiota composition.
Among the key findings were:
- Morphine altered the function and organization of tight junctions between gut epithelial cells by disrupting the localized expression of occludin and zona occludens 1 proteins.
- Opioid-induced changes in intestinal permeability were toll-like receptor (TLR)-dependent and interleukin (IL)-17A–dependent.
- Morphine exposure increased expression of both TLR and IL-17A in the small intestine.
- Opioid use led to significant alterations in gut microbiota, including reduced ratio of Bacteroidetes to Firmicutes and elevated abundance of Staphylococcus and Enterococcus genuses.
- Morphine enhanced bacterial translocation from the gut lumen into peritoneal organs and the circulatory system.
The investigators also examined the potential of peripherally acting μ-opioid receptor antagonists (PAMORAs), such as methylnaltrexone, naloxegol, naldemedine, and alvimopan, in treating opioid-induced bowel dysfunction. These agents acted peripherally on μ-opioid receptors in the gastrointestinal tract with minimal central nervous system penetration.
A post hoc analysis of 12 placebo-controlled, randomized clinical trials showed that patients with noncancer pain or advanced disease treated with methylnaltrexone had a 60% reduction in the risk of mortality compared with those receiving placebo.
The investigators noted that the effects of opioids on intestinal function extended beyond slowing gastrointestinal transit. They described the interplay between opioid signaling, toll-like receptors, and the gut microbiome in disrupting intestinal barrier function.
This review synthesized data from numerous preclinical and clinical studies examining the effects of opioids on intestinal permeability, gut microbiota, and related physiological processes. The investigators conducted a literature review, focusing on both basic science research and clinical trials investigating opioid-induced bowel dysfunction and the efficacy of PAMORAs.
The study presented a mechanistic explanation of how opioids disrupted intestinal barrier function and summarized clinical data on the efficacy of PAMORAs in treating opioid-induced constipation.
Four PAMORAs were reported as U.S. Food and Drug Administration (FDA)-approved for various indications related to opioid-induced bowel dysfunction. Additionally, the review mentioned lubiprostone, a chloride channel activator, as another FDA-approved medication for treating opioid-induced constipation. A meta-analysis of approximately 7,800 patients found that PAMORAs significantly improved symptoms of opioid-induced constipation.
The investigators noted several areas of uncertainty, including the need for validated treatment algorithms and guidelines for managing opioid-induced constipation, as well as potential peripheral effects of PAMORAs that required further investigation.
This study was financially supported by Salix Pharmaceuticals, with the lead author disclosed service on scientific advisory boards for several pharmaceutical companies, while the co-author reported no conflicts of interest.