Biomarkers of chronic pain: A tool for diagnosis and evaluation of management – Where do we stand?

Abstract

With another milestone in history, as India completes 75 years of independence, long-term pain or chronic pain, as they call it, still nags a vast majority of our population. Even when there is a solitary precipitating event in the genesis of chronic pain (e.g., injury), there remains a combination of factors that affect its duration, intensity, and effects (physical, psychological, social, and emotional).[1] Truly stated by Niculescu et al., blood biomarkers constitute a kind of liquid biopsy,[2] all the more significant in subjective clinical conditions, such as pain. The term “biomarker,” as defined by the National Institutes of Health Biomarkers Definitions Working Group, is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.[3] Current advanced research suggests that genetic expression of cytokines (signaling proteins mediating activation, differentiation, and proliferation of immune cells), positively or negatively, correlates with the experience of chronic pain. They can be pro-inflammatory or anti-inflammatory, and a misaligned balance between the two has been a common finding in most of the studies conducted. Pro-inflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, IL-2, IL-33, CCL3, CXCL1, CCR5, and tumor necrosis factor-alpha, have been found to play significant roles in the amplification of chronic pain states.[4] The anti-inflammatory ones include IL-4, IL-10, and transforming growth factor β1. Whereas the world has taken leaps in research and evaluation of biomarkers, little of such research has been paid heed to at the national level. The role of cytokine in chronic pain states was observed in Germany in 2006.[5] In 2020, Gunn et al. have rightly concluded that abnormal biomarker findings provide objective support for the role of cytokine-mediated inflammation, oxidative stress, abnormally low production of neurotransmitters, and micronutrient deficiencies in the development or worsening of chronic pain.[6] Although a few observations on the incidence and prevalence of chronic pain, the social burden, etc., have been reported from the subcontinent, little research has been done for the same. The recently reported research on the role of biomarkers in chronic pain has been published in 2020. This was a longitudinal observational study by Goel et al. who observed the frequency, patterns, and response to the treatment related to various biomarkers (biological and psychosocial) in patients of chronic nonspecific pain syndrome.[7] Another notable well-designed, double-blind randomized controlled trial by Saxena et al. on an important biomarker, serum brain-derived neurotrophic factor (BDNF), was reported in 2016. BDNF levels were significantly decreased in patients of thoracic postherpetic neuralgia as compared to healthy volunteers. Subsequently, a significant rise in the levels was seen after a multimodal intervention using pregabalin therapy and pulsed radiofrequency of the intercostal nerves.[8] On the international platform, the biopsychosocial model, which accounts for the dynamics and complex interactions among physiological, psychological, and social factors, has replaced the earlier biomedical approach of chronic pain. An evaluation of these interactions is being appreciated to tailor-specific treatment and prevention of chronic pain. The panel of functional pain biomarkers with predictive abilities can be beneficial as it provides practitioners with novel, objective insight into the contributors of pain, paving the way for a truly personalized pain medicine. The Indian subcontinent, with a population as diverse as the entire world, now needs to put the foot down, to accelerate if not overtake in the researches on chronic pain biomarkers. An approach to management based merely on international research and data would have a much-varied outcome in a population diversity almost as extensive as the biodiversity worldwide, a call to the pain physicians to venture into this lapsed, unrecalled domain.