Chronic pain is defined as a pain sensation that persists or recurs for over 3 months (1). Over 30% of the global population currently suffers from chronic pain, making it a major public health issue (2). Unlike acute pain, chronic pain is long-lasting and can persist for years or even longer, imposing a substantial burden on individuals and the economy (3, 4). Therefore, identifying risk and protective factors for chronic pain is crucial for its prevention and treatment.

Polyunsaturated fatty acids (PUFAs) are essential fatty acids (FAs) that cannot be synthesized by the body and must be obtained through dietary intake (5). PUFAs are key components of cell membranes and play a crucial role in cell structure and function (6). Additionally, PUFAs are involved in regulating inflammatory response, antithrombotic processes, lipid metabolism, and other physiological functions (7–9). Observational studies have shown an association between PUFA intake and the occurrence and severity of chronic pain (10–13). Omega-3 FAs can reduce inflammatory markers in chondrocytes, exerting anti-inflammatory and analgesic effects, whereas omega-6 FAs can promote inflammation and induce pain (14). However, a five-year randomized controlled study conducted in the United States found that omega-3 FA supplementation did not improve knee pain caused by osteoarthritis (15). Therefore, the causal relationship between PUFAs and chronic pain remains unclear.

Mendelian randomization (MR) utilizes genetic variation as an instrumental variable to infer causal relationships between exposure and disease outcome (16). By following the Mendelian inheritance law of “random distribution of parental alleles to offspring” during gamete formation, genetic variation is not influenced by traditional confounding factors such as socioeconomic status, environmental exposure, and behavioral factors. Thus, MR overcomes the limitations of traditional epidemiological studies, which can be affected by confounding factors and reverse causality (17). In this study, we aimed to investigate the causal relationship and its directionality between circulating PUFA concentrations and pain in different body sites using a two-sample MR analysis with large-scale open-access genome-wide association study (GWAS) pooled data.

We used MR to systematically assess the causal relationship and its direction between four PUFAs and omega-6:3 ratios and pain in eight body parts. The results revealed a negative correlation between the concentration of omega-3 FAs and DHA and the occurrence of abdominal and pelvic pain. Conversely, a positive correlation was observed between the omega-6:3 ratio and abdominal and pelvic pain. Furthermore, we observed a negative association between omega-3 FA concentration and lower back pain and/or sciatica. However, no causal relationship was found between circulating PUFA concentrations and pain in other body sites.

Omega-3 fatty acids have been found to have anti-inflammatory and analgesic effects, while Omega-6 fatty acids promote inflammation (27). Research has demonstrated that omega-3 fatty acids can influence cellular signaling pathways by altering the composition and function of cell membranes, thus reducing inflammatory responses (28). Specifically, DHA, one of the Omega-3 fatty acids, can reduce inflammation by inhibiting the synthesis of the inflammatory mediator prostaglandin E2 and combating oxidative stress (29, 30). Additionally, studies have shown that higher ratios of Omega-6 to Omega-3 fatty acids are associated with an increased risk of cardiovascular disease, autoimmune diseases, and cancer (31, 32). Therefore, maintaining a proper balance of omega-3 and Omega-6 fatty acid intake is crucial for maintaining good health. In theory, this evidence supports that higher circulating concentrations of omega-3 FAs and DHA, along with lower levels of the omega-6 to omega-3 ratio, may reduce the risk of abdominal and pelvic pain.

Several observational studies have explored the association between PUFAs and chronic pain (33–37). In a randomized controlled study, the infusion of omega-3 FAs demonstrated efficacy in alleviating pain caused by rheumatoid arthritis (38). Another study indicated that dietary supplementation with omega-3 FAs and DHA could reduce the incidence and progression of pain in the older population (39). However, omega-6 FAs may contribute to inflammation, as significantly elevated levels of omega-6 FA metabolites were reported in women with irritable bowel syndrome (40). Similarly, another study found a higher omega-6:3 ratio to be associated with orofacial pain, headache, and low back pain (41). In a randomized controlled study, joint pain in patients with inflammatory bowel disease was effectively ameliorated by correcting the omega-6:3 ratio (42). Our MR study produced consistent results, demonstrating that higher omega-6:3 ratios elevate the risk of abdominal pain, whereas higher circulating omega-3 FAs and DHA concentrations alleviate abdominal pain. However, no causal link was observed with joint pain.

Although observational studies have shown an association between PUFAs and chronic pain, only a few MR studies have been conducted. To the best of our knowledge, only one MR study has investigated the relationship between omega-3 FAs and low back pain risk, revealing that genetically increasing circulating omega-3 FA concentrations can reduce this risk (43). However, our findings do not support this conclusion. In our MR study, only the weighted median and weighted mode methods indicated a causal relationship between circulating omega-3 FA concentrations and low back pain, as measured using the IVW method [OR 95% CI: 0.948 (0.894, 1.005), p = 0.073], but no causal relationship was found between them. Notably, the sample size of our study was nearly twice that of the aforementioned MR study. Moreover, our study data was derived from different patient populations, sourced from the UK biobank and Finland genome project (Finn Gen), effectively avoiding sample duplication. Additionally, our findings remained robust across multiple analytical approaches, exhibiting no heterogeneity or pleiotropy. Although this MR study represents the largest and most comprehensive investigation to date in terms of sample size, FA types, and pain locations, future studies will require larger datasets from genomic association studies to obtain more accurate and reliable results.

This study possesses several advantages. First, this is the most comprehensive MR study to date exploring the relationship between PUFAs and pain. We included four different types of PUFAs and the omega-6:3 ratio while investigating causal associations with pain in eight body parts. This comprehensive approach enhances the coverage and credibility of our results. Second, compared with observational studies, MR studies overcome the effects of confounding variables and reverse causality. Third, we selected SNPs that satisfied the MR hypothesis as IVs, all of which exhibited strong associations with PUFAs. Lastly, all SNPs were derived from European populations, thereby minimizing the possibility of population stratification bias.

Nonetheless, this study has some limitations. First, it relied on publicly available pooled data from GWASs, which restricted our ability to analyze other subtypes of PUFAs (e.g., alpha-linolenic, eicosapentaenoic, and arachidonic acids) in investigating the relationship between PUFAs and pain. Second, despite the utilization of a large GWAS database, our study might have been unable to detect small causal relationships. Third, this study can only establish the relationship between genes and phenotypes but cannot elucidate the biological mechanism of these relationships. Therefore, the occurrence and development of complex phenotypes cannot be fully explained. Lastly, the study population primarily consisted of individuals of European ancestry, limiting the generalizability to other ethnic populations.

This MR study suggests that higher circulating omega-3 FA and DHA concentrations and lower omega-6:3 ratios are associated with a decreased risk of abdominal and pelvic pain. Maintaining an appropriate omega-6:3 ratio is crucial for the prevention and management of abdominal and pelvic pain. Furthermore, higher circulating omega-3 FA concentrations may reduce the risk of lower back pain and/or sciatica. However, no causal relationship was found between circulating PUFA concentrations and pain in other body parts, including pain related to the face, throat and chest, joints, limbs, low back pain, and gynecological sites. These findings contribute to the targeted prevention and treatment of chronic pain through the use of PUFAs.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number (s) can be found in the article/Supplementary material.

YD: Writing – review & editing, Conceptualization, Writing – original draft. YC: Conceptualization, Writing – review & editing, Data curation, Software. RG: Writing – review & editing, Supervision, Validation. RJ: Writing – review & editing, Project administration, Resources, Visualization. CZ: Data curation, Software, Writing – review & editing, Visualization.

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.