Toward a Mechanism-Based Approach to Pain Diagnosis

Abstract

The last few decades have witnessed a huge leap forward in our understanding of the mechanistic underpinnings of pain, both in normal states where it helps protect from injury, and in pathological states where pain evolves from a symptom reflecting tissue injury to become the disease itself. However, despite these scientific advances, chronic pain remains extremely challenging to manage clinically. While the number of potential treatment targets has grown substantially and a strong case has been made for a mechanism-based and individualized approach to pain therapy, arguably clinicians are not much more advanced now than 20 years ago, in their capacity to either diagnose or effectively treat their patients. The gulf between pain research and pain management is as wide as ever. We are still currently unable to apply an evidence-based approach to chronic pain management that reflects mechanistic understanding, and instead, clinical practice remains an empirical and often unsatisfactory journey for patients, whose individual response to treatment cannot be predicted. Here we take a common and difficult to treat pain condition, chronic low back pain, and use its presentation in clinical practice as a framework to highlight what is known about pathophysiological pain mechanisms and how we could potentially detect these to drive rational treatment choice. We discuss how present methods of assessment and management still fall well short, however, of any mechanism-based or precision-medicine approach. Nevertheless, substantial improvements in chronic pain management could be possible if a more strategic and coordinated approach were to evolve, one designed to identify the specific mechanisms driving the presenting pain phenotype. We present an analysis of such an approach, highlighting the major problems in identifying mechanisms in patients, and develop a framework for a pain diagnostic ladder that may prove useful in the future, consisting of successive identification of three steps: pain state, pain mechanism and molecular target. Such an approach could serve as the foundation for a new era of individualized/precision pain medicine. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) and American Pain Society (APS) Pain Taxonomy (AAPT) includes pain mechanisms as one of the 5 dimensions that need to be considered when making a diagnostic classification. The diagnostic ladder proposed in this article is both consistent with and an extension of the AAPT.

Pre-surgery physiotherapy and pain thresholds in patients with degenerative lumbar spine disorders

“…The nociceptors have a high threshold, and are one type of primary sensory neuron (47). Typically, the activation is due to mechanical stimuli, but can also be due to thermal or chemical stimuli (47,48). The stimuli activate the nociceptor by changing the membrane-bound transduction, which causes action potentials to propagate (48).…”

“…Typically, the activation is due to mechanical stimuli, but can also be due to thermal or chemical stimuli (47,48). The stimuli activate the nociceptor by changing the membrane-bound transduction, which causes action potentials to propagate (48). The action potential is conducted from the peripheral terminal along either thinly myelinated A delta axons, or unmyelinated C fibre axons to the dorsal root ganglion.…”

“…Evidence of tissue damage in the area in which pain is experienced is needed to confirm that a nociceptive pain state exists. Further criteria may be obtained from image report and mechanical pathology or normal movement causing increased pain are also signs of nociceptive pain (48).…”

Translational studies identify long-term impact of prior neonatal pain experience

“…In particular, we aim for a mechanism based approach [197] for understanding both altered baseline thresholds in adulthood and altered responses to future surgical injury, and evaluate potential preventive analgesic interventions (Fig. 3).…”

Mechanism-based cancer-pain therapy

“…Vardeh at al [50] have recently proposed a concept for pain assessment for all aetiologies which forms a hierarchy comprising pain state (e.g. inflammatory or neuropathic), pain mechanism (e.g.…”