From Mechanism to Cure: Renewing the Goal to Eliminate the Disease of Pain

Abstract

Objective: Persistent pain causes untold misery worldwide and is a leading cause of disability. Despite its astonishing prevalence, pain is undertreated, at least in part because existing therapeutics are ineffective or cause intolerable side effects. In this review, we cover new findings about the neurobiology of pain and argue that all but the most transient forms of pain needed to avoid tissue damage should be approached as a disease where a cure can be the goal of all treatment plans, even if attaining this goal is not yet always possible.

Design: We reviewed the literature to highlight recent advances in the area of the neurobiology of pain.

Results: We discuss barriers that are currently hindering the achievement of this goal, as well as the development of new therapeutic strategies. We also discuss innovations in the field that are creating new opportunities to treat and even reverse persistent pain, some of which are in late-phase clinical trials.

Conclusion: We conclude that the confluence of new basic science discoveries and development of new technologies are creating a path toward pain therapeutics that should offer significant hope of a cure for patients and practitioners alike. Classification of Evidence. Our review points to new areas of inquiry for the pain field to advance the goal of developing new therapeutics to treat chronic pain.

Figure 1

Clustering of neuropathic pain patients into three major subtypes. The EuroPain consortium identified three major types of neuropathic pain patients using a clustering analysis algorithm. These are defined by their dominant sensory feature, sensory loss (cluster 1), irritable nociceptor/thermal hyperalgesia (cluster 2), and mechanical hyperalgesia (cluster 3), but there are other dominant features found in these clusters that give further clues into mechanisms involved in neuropathic pain in these patients. PAG = periaqueductal grey.

Figure 2

Major areas of the ascending pain system and locations of plasticity. The diagram shows the basic anatomy of the ascending pain pathway with examples of locations where plasticity can occur, driving persistent pain. For instance, inflammation or injury to nociceptors can cause changes in the excitability and/or phenotype of these cells, causing them to fire action potentials to low-threshold stimuli and/or in the absence of any apparent stimulus (ectopic activity).

Figure 3

The irritable nociceptor, molecular mechanisms. The diagram shows channels and modulatory proteins involved in pain transduction, signal propagation, and transmitter release in the spinal dorsal horn. The top panel shows these in the normal state, and the bottom panel shows how changes in these proteins can lead to an irritable nociceptor phenotype. Such changes include increased expression or activity in transducers like TRPV1 or P2X channels, increases in G-protein coupled receptor (GPCRs) like EP receptors, and enhanced signaling in nociceptor terminals. Increases in the expression of voltage-gated sodium channels (Na_vs) and decreased expression of potassium channels can also shift the balance toward excitation in these nociceptors. Finally, changes in expression of inhibitory and excitatory proteins in the central terminals of nociceptors can also enhance the irritability of these cells. CNS = central nervous system.

Figure 4

Mechanisms driving pain and three opportunities to reverse chronic or persistent pain. The cycle at the top left shows many mechanisms that can lead to persistent pain. One way that treatments can reverse persistent pain would be to directly target those mechanisms that caused the pain to become persistent to effectively reverse the cycle. Another way would be to employ endogenous resolution mechanisms, like resolvins, to reverse persistent pain in a manner that is not dependent on its cause. Finally, treatments that can take persistent pain to a new, acceptable set point could also be engineered. These might include employing viral vectors to introduce optogenetic control of nociceptor activity in persistent pain conditions.

Figure 5

Optogenetic control of nociceptors in vivo using implantable LED devices. The diagram shows a neuropathic pain patient with the irritable nerve at the site indicated with the large arrow. The implantable LED device is placed along the nerve and the DRG is transduced with a vector to allow for expression of halorhodopsin which causes Cl- influx to the cell in response to light. The combination of the implantable LED and the expressed halorhodopsin allows for termination of the pain signal at the site of the LED through a strong inhibitory current produced by the exogenous channel.