Widespread hyperalgesia in irritable bowel syndrome is dynamically maintained by tonic visceral impulse input and placebo/nocebo factors: evidence from human psychophysics, animal models, and neuroimaging

Abstract

Irritable bowel syndrome (IBS) is a highly prevalent gastrointestinal disorder that is often accompanied by both visceral and somatic hyperalgesia (enhanced pain from colorectal and somatic stimuli). Neural mechanisms of both types of hyperalgesia have been analyzed by neuroimaging studies of IBS patients and animal analog studies of "IBS-like" rats with delayed rectal and somatic hypersensitivity. Results from these studies suggest that pains associated with both visceral and widespread secondary cutaneous hyperalgesia are dynamically maintained by tonic impulse input from the non-inflamed colon and/or rectum and by brain-to-spinal cord facilitation. Enhanced visceral and somatic pains are accompanied by enhanced pain-related brain activity in IBS patients as compared to normal control subjects; placebos can normalize both their hyperalgesia and enhanced brain activity. That pain in IBS which is likely to be at least partly maintained by peripheral impulse input from the colon/rectum is supported by results showing that local rectal-colonic anesthesia normalizes visceral and somatic hyperalgesia in IBS patients and visceral and somatic hypersensitivity in "IBS-like" rats. Yet these forms of hyperalgesia are also highly modifiable by placebo and nocebo factors (e.g., expectations of relief or distress, respectively). Our working hypothesis is that synergistic interactions occur between placebo/nocebo factors and enhanced afferent processing so as to enhance, maintain, or reduce hyperalgesia in IBS. This explanatory model may be relevant to other persistent pain conditions.

Fig. 1

IBS patients’ and normal control subjects’ VAS pain intensity ratings of rectal distention pressures of 35 and 55 mm Hg (left panel) and of thermal stimulation of the foot (right panel). Note that patients with IBS rate pain intensity from rectal distension and cutaneous heat stimuli (P<0.001). Values are represented as means±standard deviation, n=12 IBS patients, 17 controls. Based on data from Verne GN, Robinson ME, Price DD: Hypersensitivity to visceral and cutaneous pain in the irritable bowel syndrome. Pain 93:7–14, 2001.

Fig. 2

(Left panel) VAS pain intensity ratings during rectal distention (35 mm Hg). Three separate trials were performed: baseline or natural history (natural), rectal placebo, and rectal lidocaine. This study was conducted with a standard clinical trial design without suggestions for analgesia (10 IBS patients). (Right panel) VAS pain intensity ratings of cutaneous heat pain in the same IBS patients, showing a similar reversal of heat hyperalgesia by lidocaine.

Fig. 3

Comparison of the placebo effect of a clinical trial and that of a second study wherein a verbal suggestion for analgesia was added. Note the larger placebo effect for the latter. Based on data from Vase L, Robinson ME, Verne GN, Price DD: The contributions of suggestion, desire, and expectation to placebo effects in irritable bowel syndrome patients: An empirical investigation. Pain 105:17–25, 2003.34

Fig. 4

In a fMRI study, brain activity of irritable bowel syndrome (IBS) patients was measured in response to rectal distension by a balloon barostat (Price et al., 2007). A large placebo effect was produced by suggestions and accompanied by large reductions in neural activity in known pain-related areas, such as thalamus, S-1, S-2, insula, and anterior cingulate cortex (ACC). These large reductions occurred during the period of stimulation and well before subjects provided pain ratings, thereby reflecting effects unlikely to result from report biases. Based on data from Price, D.D., Craggs, J.G., Verne, G.N., Perlstein, W.M., Robinson, M.E., 2007. Placebo analgesia is accompanied by large reductions in pain-related brain activity in irritable bowel syndrome patients, Pain 127, 63–72.