Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities

Abstract

Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.

Genetic influences on brain activation and large-scale functional connectivity during nociceptive processing: a twin study

“…Even comparing non-painful and painful stimuli shows marked differences whereby the former resembles a network formation akin to resting-state (Zheng et al, 2020). The cluster of edges identified in the present study captures variance associated with additive genetics supporting the search for a genetically informed neural pain signature (Davis et al, 2020). Future studies should compare resting-state and pain-evoked functional connectivity and estimate the extent of their shared genetics and the neural targets of their shared and non-shared genes.…”

“…One major reason for the urgency of improving our understanding of the neural representations of pain is the opioid crisis, where opioid-based analgesics have created a wave of addiction, leading to overdoses and deaths. One review and a recent consensus paper by leading pain clinicians and scientists (Davis et al, 2020; Tracey, Woolf, & Andrews, 2019) explicitly ask for pain biomarkers– verifiable in preclinical models and patients. Stratification biomarkers may increase the probability of success in pharmacological clinical trials by as much as 21% in phase III clinical trials in all disease areas (Davis et al, 2020).…”

“…One review and a recent consensus paper by leading pain clinicians and scientists (Davis et al, 2020; Tracey, Woolf, & Andrews, 2019) explicitly ask for pain biomarkers– verifiable in preclinical models and patients. Stratification biomarkers may increase the probability of success in pharmacological clinical trials by as much as 21% in phase III clinical trials in all disease areas (Davis et al, 2020). Our results may help determine if clinical pain is manifested in genetically inferred nociceptive regions, and hopefully lead to beneficial sub-grouping and patient stratification.…”

A Deep Brain Stimulation Trial Period for Treating Chronic Pain

“…There remains a large gap in characterizing such power-band based biomarkers of naturalistic, spontaneous chronic pain; an sEEG trial can fill this gap. Ultimately, by combining recording with simultaneous stimulation in these areas, an sEEG trial period could inform adaptive DBS algorithms (for a thorough discussion of brain-based pain biomarkers see [ 42 , 54 ]).…”

Dissociation Between Individual Differences in Self-Reported Pain Intensity and Underlying Brain Activation

“…The search for an objective biomarker for pain intensity has been driven by a legitimate need to adequately assess pain in individuals who are unable to adequately communicate their firstperson experience of pain to a third person 26 , as well as to understand changes in such markers over time in response to disease or treatment [27][28][29][30] . However, there is also substantial pressure to use such markers to confirm the veracity of a patient's report of pain for legal and financial reasons 26,27,30,31 .…”