Composite Pain Biomarker Signatures for Objective Assessment and Effective Treatment

Abstract

Pain is a subjective sensory experience that can, mostly, be reported but cannot be directly measured or quantified. Nevertheless, a suite of biomarkers related to mechanisms, neural activity, and susceptibility offer the possibility-especially when used in combination-to produce objective pain-related indicators with the specificity and sensitivity required for diagnosis and for evaluation of risk of developing pain and of analgesic efficacy. Such composite biomarkers will also provide improved understanding of pain pathophysiology.

Figure 1a, b.. Mechanisms of acute and chronic pain:

The normal physiological response to an acute noxious stimulus is depicted in black with the involvement of Aδ, and C fiber nociceptors transducing the input from the periphery to the superficial laminae of the dorsal horn of the spinal cord where they can be modulated. From the spinal cord, signals are relayed via regions in the brain stem to the brain where pain emerges as a perception and the sensory and emotional context and learning is applied to interpret and aid future avoidance of the stimulus. The major classes of chronic pain and the processes which are believed to lead to chronic pain in susceptible individuals are depicted in red. During inflammation, while the stimulus e.g. activated immune cells or a skin incision is present, there exists a status of peripheral sensitization (PS) characterized by erythema and tenderness to innocuous stimuli, typically heat. PS goes away once the peripheral pathology resolves. Stimuli activating nociceptors that are noxious, repeated and sustained e.g. following nerve injury, induce the process of central sensitization (CS) in the dorsal horn spinal cord. Initially CS is protective and enables the organism to avoid further injury due to a heightened awareness of its surroundings but at some point CS becomes pathological. CS produces pain in non-inflamed tissue by co-opting novel inputs e.g. Aβ fibers, thus mechanical pain is typical of CS and heat pain is more typical of peripheral sensitization. Recently it has been shown that a subset of corticospinal neurons (CSNs) known to originate in the primary and secondary somatosensory cortex and to directly innervate the spinal dorsal horn via CST axons can directly modulate normal and pathological tactile sensory processing in the spinal cord. Facilitation and descending inhibition are processes that occur due to different regions of the brain and brainstem inhibiting or activating (or even disinhibiting) nociceptive inputs to the spinal cord. The effect can be seen on both mechanical and heat sensations in different forms of chronic pain and an imbalance in this system (less inhibition, more facilitation) is a key mechanism, as are changes in the brain’s neurochemistry, structure and functional activity. Shown in green are the current methodologies that are used to define biomarkers at the particular levels of nociceptive and pain processing that apply to acute and chronic pain

Figure 1a, b.. Mechanisms of acute and chronic pain:

The normal physiological response to an acute noxious stimulus is depicted in black with the involvement of Aδ, and C fiber nociceptors transducing the input from the periphery to the superficial laminae of the dorsal horn of the spinal cord where they can be modulated. From the spinal cord, signals are relayed via regions in the brain stem to the brain where pain emerges as a perception and the sensory and emotional context and learning is applied to interpret and aid future avoidance of the stimulus. The major classes of chronic pain and the processes which are believed to lead to chronic pain in susceptible individuals are depicted in red. During inflammation, while the stimulus e.g. activated immune cells or a skin incision is present, there exists a status of peripheral sensitization (PS) characterized by erythema and tenderness to innocuous stimuli, typically heat. PS goes away once the peripheral pathology resolves. Stimuli activating nociceptors that are noxious, repeated and sustained e.g. following nerve injury, induce the process of central sensitization (CS) in the dorsal horn spinal cord. Initially CS is protective and enables the organism to avoid further injury due to a heightened awareness of its surroundings but at some point CS becomes pathological. CS produces pain in non-inflamed tissue by co-opting novel inputs e.g. Aβ fibers, thus mechanical pain is typical of CS and heat pain is more typical of peripheral sensitization. Recently it has been shown that a subset of corticospinal neurons (CSNs) known to originate in the primary and secondary somatosensory cortex and to directly innervate the spinal dorsal horn via CST axons can directly modulate normal and pathological tactile sensory processing in the spinal cord. Facilitation and descending inhibition are processes that occur due to different regions of the brain and brainstem inhibiting or activating (or even disinhibiting) nociceptive inputs to the spinal cord. The effect can be seen on both mechanical and heat sensations in different forms of chronic pain and an imbalance in this system (less inhibition, more facilitation) is a key mechanism, as are changes in the brain’s neurochemistry, structure and functional activity. Shown in green are the current methodologies that are used to define biomarkers at the particular levels of nociceptive and pain processing that apply to acute and chronic pain

Figure 2a.

Categories for Measuring Pain.

Figure 2b.. How we currently ‘measure pain’ in humans:

This falls into the following broad categories: (i) self-reports using rating scales/descriptors/questionnaires to exogenous stimuli or any ongoing and spontaneous pain; (ii) observed measures of pain-like behavior; (iii) indirect measures of physiology/autonomic changes. (ii) currently is subjective and may suffer from cultural and social biases/influences as well as a lack of sensitivity and specificity but artificial intelligence/machine learning methods may remove the subjectivity and identify more sensitive components, (iii) are indirect assessments and make significant assumptions when relating these physiological measures to the underlying subjective state.

Figure 2c.. How we currently ‘measure pain’ in animals:

Preclinical pain-related categories are shown with increasing complexity from top to bottom. The vast majority of testing still involves use of exogenously applied thermal and mechanical stimuli (typically to the plantar surface of the hind paws of rodents) and reflexive output measures. Other measures of behavior based on choice (avoidance of an activity or avoidance of an aversive condition) and complex measures of physiological function are being increasingly introduced. Finally, we anticipate that human observation on animal behavior will be supplanted by computer-based machine-learning approaches to identify specific pain-related behaviors, such as facial grimace.

Figure 3.. A need for pain biomarkers:

There are numerous situations that would benefit from the availability of specific, sensitive and accurate biomarkers for pain. Each of these are in themselves complex areas of biological science and medicine that require different combinations of the features of biomarkers listed in Table 1 relative to each other. For example, while routine patient management would benefit from use of safety and monitoring biomarkers, it would arguably be of greater benefit for non-verbal patients and neonates for a pharmacodynamic response biomarker. The consequences of false negative findings from a pain biomarker, include: (1) trust issues between doctor-patient, employee-patient or family-patient; (2) denial of medical treatment; (3) mental health, stress, spousal/family issues; (4) financial/insurance and employment issues; (5) privacy/legal (medical malpractice issues). The consequences of false positive findings, include: (1) unnecessary, costly, harmful analgesic treatment in non-communicative patients; (2) human, infrastructure, financial and time resources; (3) misunderstanding as a substitute for self-report. These are serious issues to be considered in the development of any pain biomarker, as has been discussed (Davis et al., 2017).

Figure 4.. Cross species validation of biomarker evaluation:

Nerve growth factor (NGF) has potential as a mechanistic pain biomarker in inflammatory conditions since its relationship to chronic inflammatory pain translates both across species and from genetics to therapy. However, for NGF to constitute such a biomarker its specificity and sensitivity will need to be evaluated and met.

Figure 5.. Machine learning in biomarker development.

Illustration of Neurological Pain Signature and Pain-Analgesia Signature for Analgesic drug development as ‘biomarkers’ currently being developed using machine learning tools and data from human neuroimaging studies.

Figure 6.

A Composite Biomarker Signatures for Pain.