Towards a theory of chronic pain

Abstract

In this review, we integrate recent human and animal studies from the viewpoint of chronic pain. First, we briefly review the impact of chronic pain on society and address current pitfalls of its definition and clinical management. Second, we examine pain mechanisms via nociceptive information transmission cephalad and its impact and interaction with the cortex. Third, we present recent discoveries on the active role of the cortex in chronic pain, with findings indicating that the human cortex continuously reorganizes as it lives in chronic pain. We also introduce data emphasizing that distinct chronic pain conditions impact on the cortex in unique patterns. Fourth, animal studies regarding nociceptive transmission, recent evidence for supraspinal reorganization during pain, the necessity of descending modulation for maintenance of neuropathic behavior, and the impact of cortical manipulations on neuropathic pain is also reviewed. We further expound on the notion that chronic pain can be reformulated within the context of learning and memory, and demonstrate the relevance of the idea in the design of novel pharmacotherapies. Lastly, we integrate the human and animal data into a unified working model outlining the mechanism by which acute pain transitions into a chronic state. It incorporates knowledge of underlying brain structures and their reorganization, and also includes specific variations as a function of pain persistence and injury type, thereby providing mechanistic descriptions of several unique chronic pain conditions within a single model.

Figure 1

Group average brain activity for pain in 6 different chronic pain populations or conditions. In all cases activity for continuous rating of pain contrasted with rating equivalent visual bar magnitudes is shown. Thermal pain activity is for n=16 healthy controls. CBP spontaneous pain is for n=13 Chronic Back Pain patients. In Post Herpetic Neuralgia (PHN), n=11, allodynia pain is for tactile stimuli that evoke pain, and for spontaneous pain. In osteoarthritis (OA, n=14) activity is shown for mechanical stimulation of the painful knee joint. In pelvic pain (PP, n=3) activity is shown for spontaneous pain.

Figure 2

Brain regions modulated by rating perceived pain for some of the conditions shown in Figure 1. Abbreviations are the same as in Figure 1.

Figure 3

A simplified working diagram of the main theoretical construct upon which this review is based. The afferent inputs and their segregation in the spinal cord, brainstem and thalamus is from (Braz et al., 2005); cortical connectivity is derived from Price (Price, 2000) and Apkarian et al. (Apkarian et al., 2005); and based on our fMRI studies of clinical pain patient populations. The cartoon is basically an expansion of a diagram originally proposed by (Melzack and Casey, 1968). The interaction between basal ganglia (Gl Pal), amygdala (Amyg), and medial prefrontal cortex (mPFC) constitutes the emotional, motivational and hedonic components that we hypothesize influence the quality of perceived pain and also modulate nociceptive processing at the spinal cord level through descending pathways. Blue pathways engage motivation, hedonics and affect. Red pathways are more involved in sensory coding, including inputs to the thalamus, primary and secondary somatosensory cortices (s1 and s2), and insula. The interaction between mPFC and dorsolateral prefrontal cortex (DLPFC) is mutually inhibitory. We hypothesize that blue pathways are strengthened in chronic neuropathic pain and red pathways are more involved in acute pain. The specific interactions between ascending and descending modulations would determine the specific brain activity patterns identified in distinct chronic pain conditions, which would reflect peripheral as well as learned central reorganization. The descending pathway indicated through the periaqueductal gray (PAG) in fact comprises of a multipliscity of descending projections.