Predicting transition to chronic pain

Abstract

Purpose of review: Most individuals who develop pain following an inciting event will return to a healthy state as the injury heals. However, a small percentage continue to suffer, that is, transition to chronic pain. Chronic pain may persist for years and is accompanied by cognitive abnormalities, as well as diminished quality of life. In animals, persistent pain is characterized by peripheral and spinal cord reorganization, and recent evidence in humans also indicates cortical reorganization. Yet, despite more than 30 years of research, there is little agreement on the neural mechanisms that mediate the transition from acute to chronic pain.

Recent findings: In a longitudinal brain-imaging study, individuals who developed an intense back pain episode were followed over a 1-year period, during which pain and brain parameters were collected repeatedly. A smaller number of healthy individuals and chronic back pain patients were also studied concomitantly, as positive and negative controls. At the time of entry into the study, strength of synchrony between the medial prefrontal cortex and nucleus accumbens (i.e. functional connectivity) was predictive (>80% accuracy) of individuals who subsequently transition to chronicity 1 year later.

Summary: Properties of the brain's emotional learning circuitry predict the transition to chronic pain. The involvement of this circuitry in pain remains mostly unexplored. Future human and animal model studies are necessary to unravel underlying mechanisms driving pain chronicity, with the potential of advancing novel therapeutics for preventing pain chronification.

FIGURE 1

Brain circuitry predicting pain chronification. (a) Medial prefrontal cortex (mPFC) activity reflects intensity of back pain in two separate groups of patients. Adapted with permission from [30]. (b) Functional connectivity of nucleus accumbens (NAc) in healthy individuals and in chronic low back pain (CBP) patients, during a thermal pain task. In healthy individuals connectivity is mainly to insula, whereas in CBP it preferentially connects to mPFC. Scatter plot shows that mPFC–NAc connectivity strength in CBP reflects magnitude of back pain. Adapted with permission from [31]. (c) Left panel: Change in back pain over 1 year in subacute back pain (SBP) patients. SBP was subdivided to recovering (SBPr, grey triangles) and persisting (SBPp, black squares). Ordinate is mean ± SD pain intensity assessed by visual analog scale (VAS; 0–100). Horizontal bars represent the range of time from visit 1 for SBPp (black), SBPr (grey), and healthy controls (blue). Red lines are the mean. Right panel: Top: whole-brain functional connectivity contrast for NAc (green) between recovering and persistent SBP (SBPp > SBPr) identifies mPFC. Bar graph: mean and SD of mPFC–NAc connectivity strength. Receiver operator curves and probability of discrimination D are shown for predicting SBPp and SBPr groups, at three time points from initial brain scans. Note visit 2 is 3 months, and visits 3 and 4 are 6 and 12 months from initial scan. Thus, predicting future pain chronicity seems to improve at longer times from scan. (d) Odds ratio (OR) for predicting SBPp and SBPr based on functional connectivity at different time intervals. Series 2/1 is OR for prediction based on visits 1 and 2, series 3/1 is based on visits 1,2, and 3, whereas series 4/1 is based on visits 1, 2, 3, 4. In all cases, the longer the time interval the better is the prediction. Adapted with permission from [32▪▪].

FIGURE 2

A model regarding brain circuitry involved in the transition from acute to chronic pain. Nociceptive information, perhaps distorted by peripheral and spinal cord sensitization processes, impinges on limbic circuitry. The interaction of limbic circuitry with prefrontal processes determines the level at which a certain pain condition transitions to a more emotional state. The limbic circuitry also provides learning/modulation signals to the rest of the cortex inducing functional and anatomical distortions that reflect the suffering and coping strategies. Adapted from [50]. LPFC, lateral prefrontal cortex; mPFC, medial prefrontal cortex; ACC, anterior cingulate cortex; NAc, nucleus accumbens; Amyg, amygdala; Hippo, hippocampus.