Hypothesis / aims of study
Chronic pain conditions are increasingly recognized for their heterogeneity, often exhibiting significant overlap with various bio-psychological factors. Fibromyalgia (FM), irritable bowel syndrome (IBS), vulvodynia, myalgic encephalomyelitis/chronic fatigue syndrome, interstitial cystitis/painful bladder syndrome, chronic pelvic pain, endometriosis, chronic tension-type headache, migraine headache, and chronic lower back pain stand among the most prevalent pain disorders. The confluence of these pain disorders has been designated as chronic overlapping pain conditions (COPCs) [1]. Frequently, etiological factors of COPCs remain elusive, leaving patients without a satisfactory explanation or a clear terminology with which to articulate their condition to others.
The methylenetetrahydrofolate reductase (MTHFR) gene, responsible for encoding an enzyme involved in metabolism, has garnered attention due to its association with decreased responsiveness to antidepressants and pain medication. MTHFR facilitates a key chemical reaction involving folate (vitamin B9), rendering it more bioavailable in the bloodstream. Its role is critical in the conversion of homocysteine to methionine, an essential amino acid utilized in protein synthesis and other vital biochemical processes [2]. Individuals harboring MTHFR mutations have reported heightened pain sensitivity, neuropathic pain, cardiovascular complications including heart attacks, strokes, and blood clots, as well as obstetric complications such as miscarriages and neurological genetic defects during pregnancy. Additionally, symptoms such as depression, anxiety, and fatigue have been noted [2]. However, comprehensive understanding regarding the spectrum of symptoms, diagnostic approaches, and optimal management strategies remains limited.
Given the potential implications of MTHFR mutation in chronic pain, this study sought to elucidate the prevalence of COPCs and associated symptoms within the MTHFR population in comparison to the general population.
Study design, materials and methods
For participant selection, our group utilized our institution’s health records and diagnosis codes associated with the MTHFR gene mutation. Inclusion criteria required the presence of the MTHFR mutation, while no exclusion criteria were applied. Initial screening identified seventy-seven individuals with this mutation who had received care from our providers.
Upon identification, each participant was mailed an information sheet outlining the study and a survey that asked about the participants history of anxiety, TMJ, migraines, generalized body pain/ joint pain, palpitations, pelvic pain, miscarriages, dysmenorrhea, depression and peripheral nerve pain. Data from the survey responses were collected to discern the prevalence and spectrum of symptoms associated with the presence of the MTHFR gene mutation. Wilson’s procedure with continuity correction was utilized to calculate 95% confidence intervals for the percent of respondents with each symptom/diagnosis. The National Health Interview Survey and National Comorbidity Survey were utilized to identify the percentage of individuals in the United States with each symptom/diagnosis.
Results
Of the seventy-seven individuals mailed surveys, three decided to opt out of the survey, and 20 returned the survey. The most frequent symptom was anxiety with 15 (75%) (95%CI 51%-90%) of participants reporting this. 12 (60%) (95%CI 36%-80%) reported TMJ, 11 (55%) (95%CI 32%-76%) reported migraines, 11 (55%) (95%CI 32%-76%) reported general body pain or joint pain, 9 (45%) (95%CI 24%-68%) reported palpitations, 9 (45%) (95%CI 24%-68%) reported abdominal pain, 8 (40%) (95%CI 20%-64%) reported miscarriages, 8 (40%) (95%CI 20%-64%) reported pain with menses, 8 (40%) (95%CI 20%-64%) reported depression, and 8 (40%) (95%CI 20%-64%) reported peripheral nerve pain.
United States population data reports that 19.1% of individuals have anxiety, 12.0% have TMJ, 15.3% have migraines, 20.9% have generalized body pain/joint pain, 16.0% have palpitations, 15.0% have pelvic pain, 15.3% have miscarriages, 71.1% have pain with menses, 8.3% have depression and 6.0% have peripheral nerve pain.
All of the measures mentioned that were investigated, besides pain with menses, were statistically increased in our survey population of MTHFR mutation patients compared to that of the general United States population. Pain with menses was statistically decreased in our survey population of MTHFR mutation participants compared to that of the general United States population (Table 1).
Interpretation of results
In survey respondents we noted a significant increase in the percentage of patients reporting anxiety, TMJ, migraines, generalized body pain/joint pain, palpitations, pelvic pain, miscarriages, depression and peripheral nerve pain when compared to the general United States population. A reduction in pain with menses was also noted in this group. This may signify the increase in pain and related diagnoses that was previously elucidated to in the MTHFR mutation patient population. Although the etiology of many of the conditions listed above are believed to be multifactorial there may be a unifying cause to an increased propensity for pain conditions in this select population. The reasons why this may be occurring are still not well understood. MTHFR mutations may affect folate metabolism pathways in these patients and hinder the ability to maintain nerve fibers over time, causing subsequent irregular pain signaling. Disturbance of these pathways may have a role in chronic overlapping pain syndromes and the related diagnoses surveyed in this study.