Unlocking Pain Relief: How Epigenetics Shapes Holistic Lifestyle Strategies for Chronic Pain Sufferers

The Comprehensive Pain Management editorial series explored various facets surrounding chronic pain, with the ambitious goal of contributing to the ongoing paradigm shift in the healthcare sector from a biomedical and structural viewpoint to a wider, patient-centered perspective on health and illness.1-4

The editorials released in the series concentrated on profiling and phenotyping individuals with chronic pain based on their clinical presentation,5 emphasizing the significance of multimodal approaches that encompass education and behavioral techniques.6 They underscored the critical role of lifestyle influences such as sleep,3 physical activity,7 stress,2 and nutrition.8 This editorial series was an essential initiative, encapsulating the most pertinent findings from recent research on the subject, and marks a significant advancement towards improved management of individuals suffering from chronic pain.

The final editorial will elaborate on the biological mechanisms that might underpin chronic pain and establish the biological substrate linking persistent pain with lifestyle factors. Epigenetic mechanisms hold particular intrigue for this inquiry. Epigenetics comprises a collection of mechanisms capable of modulating gene expression and biological functions.9 The majority of the human epigenome remains relatively constant throughout life, with exceptions during the epigenetic reprogramming that transpires during embryonic development.10 Nonetheless, epigenetic alterations at certain loci in the genome can respond to environmental challenges and lifestyle factors such as smoking, negative childhood experiences, sleep disruptions, diet, and physical activity.11 This renders them suitable biomarkers for numerous diseases, as well as complex traits like chronic pain.

Epigenetics in health and disease

Cancer was the initial illness where epigenetics, particularly DNA methylation (the process of adding methyl groups to cytosines in the DNA, often resulting in gene silencing), was investigated systematically. Over recent decades, widespread DNA hypo-methylation coupled with localized hyper-methylation of tumor suppressor gene promoters has emerged as one of the defining characteristics of cancer development and progression.12 This laid the groundwork for the extensive discipline of epigenetics in human health and disease. Research rapidly broadened to encompass other conditions, including neurological disorders, autoimmune diseases, and metabolic syndromes.10

Another pertinent field where epigenetics has made substantial contributions is aging, particularly with regard to biological age.13 Biological age is intended to assess the overall health of an individual’s biological functions relative to their chronological age. Biological age relies on a combination of physiological markers, considered indicative of one’s bodily capabilities and well-being, and is thought to reflect one’s true aging process.

Although the term biological age has been utilized since the beginning of the century, its contemporary understanding and application in forecasting health and lifespan became more apparent with advancements in epigenetics and the invention of so-called epigenetic clocks.14 Epigenetic clocks consist of mathematical models that estimate biological age by analyzing DNA methylation levels at a selection of genomic loci (typically between 300 to approximately 1000 loci are utilized in the models). They have been validated across numerous studies and can now serve as dependable biomarkers of an individual’s health status.15 A recent investigation compared epigenetic clocks to other promising markers of biological age such as telomere length, transcriptomics, proteomics, and metabolomics biomarkers, concluding that the epigenetic clock offered the most precise estimation of biological age.16

Epigenetic clocks have garnered significant interest due to their precision and potential to predict morbidity and mortality, representing a pivotal development in aging research.15 Moreover, epigenetic clocks can be utilized beyond the aging field and function as biomarkers for numerous diseases and complex traits such as chronic pain, as well as to assess the impact of environmental and lifestyle factors. In conjunction with DNA methylation of specific functional genomic regions, they can indeed serve as the primary outcome measure in trials examining the effects of smoking, physical activity, stress, sleep, and diet on health.

The connection between epigenetics and lifestyle factors

DNA methylation has consistently demonstrated a correlation with various health dimensions and diseases and is already employed as a biomarker for smoking, obesity, and type 2 diabetes.17-19 Smoking serves as a particularly significant illustration. Among the lifestyle factors investigated thus far, smoking provokes arguably the most profound effect. DNA methylation is consistently found to be altered at thousands of methylation sites in current smokers. Many of these modifications – though not all – revert to baseline within 1 to 5 years following smoking cessation.

The connectionbetween DNA methylation and other lifestyle influences is not extensively examined and remains to be completely clarified. Nevertheless, initial results appear to be hopeful. Consistent physical exercise has been demonstrated to induce methylation alterations in muscular and fat tissues, especially in genes related to energy metabolism and inflammation, such as the PPARGC1A gene.20 Interestingly, a two-year study that incorporated physical activity and a nutritious diet among 219 post-menopausal women revealed a substantial decrease in the epigenetic clock, indicating that a wholesome lifestyle can indeed decelerate biological aging.21

Epigenetic modifications in genes that control the stress mechanism appear crucial in establishing variations in gene expression and stress resilience during adulthood.22 Negative experiences during childhood also modify DNA methylation in genes that modulate the stress response in children, who subsequently exhibit a higher likelihood of psychiatric illnesses in later life.23 Early childhood trauma (but not events occurring in adulthood) was linked with decreased DNA methylation near the FKBP5 gene, and corresponded with an increased risk of developing post-traumatic stress disorder and chronic pain.24,25

Epigenetic changes in chronic pain

Grasping and managing chronic pain continues to pose a challenge for researchers and healthcare providers globally. It has been established that chronic pain not only diminishes a patient’s life quality but also reduces overall lifespan across all causes of mortality.26 Importantly, the risk of death vanishes when accounting for lifestyle aspects.26 This, alongside other studies indicating that the majority of individuals experiencing chronic pain report diminished physical activity, inadequate diet, poor sleep, and heightened stress, has naturally shifted the focus onto the significance of lifestyle factors in chronic pain.27 In the domain of pain, epigenetics is still at an early stage. A recent comprehensive review28 indicated that chronic pain is also linked to several alterations in DNA methylation of various genes and gene as well as micro-RNA expression. These genes oversee immune activity, inflammatory markers, transporters of glutamate and glycine, brain-derived neurotrophic factor, leptin, and histone deacetylases.28,29 Notably, none of these genes are associated with the musculoskeletal system.

Epigenetic clocks have also been utilized in populations suffering from chronic pain. Thus far, findings are somewhat contradictory, but sample sizes tend to be small, ranging from 8 to 25 participants per group, which presents a clear limitation. One investigation, however, examined epigenetic age acceleration in a group of nearly 4000 individuals, with more than a thousand participants experiencing high-impact pain. Epigenetic age was notably accelerated in subjects with high-impact pain compared to both those with low-impact pain and healthy individuals.30

Collectively, these findings imply that chronic pain is associated with modifications in numerous biological systems – spanning metabolic, immune, and neural functions, to the stress response, as evidenced by the broad alterations in DNA methylation identified in these individuals.

As these corresponding mechanisms can be affected by lifestyle factors such as physical exercise, nutrition, and adverse experiences during childhood, recent advancements in epigenetics bolster the notion for lifestyle modifications in individuals with chronic pain and furnish a biological basis to examine the efficacy of such interventions in these patients.

The significance of recognizing objective biomarkers

Chronic pain is fundamentally subjective, and to this day, diagnosis largely relies on patient self-reporting. This situation presents issues for various reasons. The lack of objective assessments escalates the potential for misdiagnosis, as symptoms of chronic pain overlap with numerous other autoimmune or neurological disorders. Patients frequently undergo prolonged processes of elimination for other conditions before they receive a diagnosis, which extends suffering and may deteriorate clinical outcomes. Furthermore, clinical diagnoses alone fail to provide insight into the underlying mechanisms, thus restricting the development of specialized therapies.

Investigating epigenetic mechanisms would enhance our comprehension of chronic pain pathophysiology and, similar to developments in other areas, has the potential to facilitate diagnosis and classification of intricate clinical presentations through the identification of biomarkers. DNA methylation patterns might actually emerge prior to any observable clinical symptoms, and analyzing the epigenome holds the potential to detect diseases at early stages and assist in disease risk forecasting. This would enable early clinical or lifestyle interventions to avert or postpone disease onset. Epigenetic alterations can additionally serve as targets for personalized treatment approaches, ranging from lifestyle modifications to novel bioengineering applications, while also evaluating treatment responses and monitoring disease progression (Fig. 1).

By refining diagnosis and pinpointing precise personalized treatment at early stages, epigenetic biomarkers can not only enhance care for individuals with chronic pain but also alleviate the overall burden on healthcare systems by bypassing lengthy and expensive diagnostic processes and ineffective therapeutic approaches.