Causal relationship between plasma metabolites and chronic regional pain: a Mendelian randomization study

Chronic pain imposes an enormous economic and personal health burden worldwide, with more than one-third of the population affected. However, no studies have systematically analyzed the potential role of plasma metabolites in chronic pain. This study aimed to perform an exploratory, hypothesis-generating Mendelian randomization (MR) analysis to identify candidate metabolite-pain relationships.

Pooled genome-wide association study (GWAS) data for 1400 plasma metabolites from previous research was used as exposures and genetic data from the UK Biobank related to eight chronic regional pains were used as outcomes, including headache, facial pain, neck and shoulder pain, back pain, hip pain, stomachache, knee pain, and general pain. Instrumental variables (IVs) for metabolites were selected at a significance threshold of p < 1 × 10^-5 to ensure sufficient statistical power, with an F-statistic >10 to minimize weak instrument bias. Causal associations between genetically predicted plasma metabolites and chronic regional pain were analyzed using the inverse variance weighting (IVW) method as the primary MR approach. Horizontal pleiotropy tests and sensitivity analyses were performed for each pain phenotype using MR-PRESSO and leave-one-out analyses. In addition, four complementary MR methods-weighted median, sample mode, weighted mode, and MR Egger-were applied to strengthen robustness of the findings. Finally, reverse MR analyses were performed to further refine the results.

MR analyses identified 122 plasma metabolites associated with eight chronic pain conditions, yielding a total of 126 associations with evidence suggestive of causality, with six metabolites implicated in more than one pain condition. Among these conditions, 63 were identified as protective factors for chronic regional pain and 63 as risk factors. Sensitivity analyses and heterogeneity tests supported the robustness of these findings. Reverse MR analysis indicated that neck and shoulder pain was associated with a decreased AMP-to-N-palmitoyl-sphingosine ratio.

This exploratory, hypothesis-generating MR study identifies candidate plasma metabolites and metabolic pathways potentially involved in chronic pain susceptibility across multiple anatomical sites. These findings provide a foundation for future experimental and clinical studies to further investigate metabolite-related mechanisms and potential therapeutic targets.