Enhanced affect/cognition-related brain responses during visceral placebo analgesia in irritable bowel syndrome patients Hsing-Feng Lee b,d , Jen-Chuen Hsieh a,c,d , Ching-Liang Lu a,b,d,⇑ , Tzu-Chen Yeh a,c,d , Cheng-Hao Tu c , Chou-Ming Cheng c , David M. Niddam a,c,d , Han-Chieh Lin b,d , Fa-Yauh Lee b,d , Full-Young Chang b,d a Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan b Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan c Integrated brain Research laboratory, Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan d School of Medicine, National Yang-Ming University, Taipei, Taiwan Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. article info Article history: Received 17 January 2011 Received in revised form 23 February 2012 Accepted 20 March 2012 Keywords: Placebo analgesia Visceral pain Irritable bowel syndrome Functional brain imaging abstract Placebo analgesia is a psychosocial context effect that is rarely studied in visceral pain. Patients with irritable bowel syndrome (IBS) exhibit visceral hyperalgesia and heightened affective/cognitive brain region activation during visceral stimuli. Psychological factors alter the pain and brain activation pattern, and these changes are more pronounced in IBS patients. Expectation constitutes the major neuropsycho- logical mechanism in the placebo effect. This study confirmed the heightened affective/cognitive brain responses in IBS patients during visceral placebo analgesia using a placebo model with expectation, which was enhanced by suggestion and conditioning. Seventeen IBS patients and 17 age-/sex-matched controls were enrolled. Psychophysical inventories (Hospital Anxiety and Depression Scale [HADS], visual analogue scale, and short-form McGill questionnaire) were completed. Brain activity during placebo intervention and anticipation was assessed in response to rectal distension using 3T-functional magnetic resonance imaging. Suggestion-/conditioning-enhanced placebo was used to convince controls/patients of the efficacy of a newly developed intravenous drug (saline, in actuality) for the relief of rectal disten- sion-induced visceral pain. A comparable visceral placebo analgesia was observed in IBS patients and control subjects. IBS patients demonstrated a higher HADS-anxiety score, which was predictive of a weak placebo effect. Suggestion-/conditioning-enhanced placebo evoked more activity in affective/cognitive brain regions (insula, midcingulate cortex, and ventrolateral prefrontal cortex [VLPFC]) in IBS patients than in healthy controls. VLPFC was also more active during anticipation in IBS patients. In conclusion, IBS patients and control subjects achieved comparable placebo analgesia during experimentally induced rectal pain. The visceral placebo analgesia produced heightened activity in affective/cognitive brain regions in IBS patients. Ó 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. 1. Introduction Placebo analgesia is the most well-studied placebo effect. Placebo analgesia is a psychobiological phenomenon that is attrib- uted to the ‘‘suggestion’’ of clinical improvement and Pavlovian conditioning. Placebo analgesia is mediated through opioidergic and dopaminergic pathways [42]. In the opioidergic pathway, pain inhibition signals that originate in the cerebral cortex project to the hypothalamus, periaqueductal gray, and rostroventromedial medulla before terminating in the spinal cord [41,45]. The dopaminergic pathway, which is responsible for reward expecta- tion, originates in the ventral tegmental area and projects to the nucleus accumbens (NAcc) [38]. These pathways were obtained from ‘‘somatic’’ pain models in healthy volunteers. Visceral and somatic pain are fundamentally different in several aspects. Visceral pain is more poorly localized and is more unpleasant than perceived intensity-matched somatic pain [7]. Brain-imaging studies demonstrate that cortical specialization in the sensory-discriminative and affective/cognitive areas of the cor- tex may account for the observed perceptual differences between somatic and visceral pain [4]. Irritable bowel syndrome (IBS) is a dis- order of chronic ‘‘visceral’’ pain in the absence of detectable disease [1]. Clinical trials of chronic visceral pain treatment in IBS patients have revealed a placebo efficacy of approximately 50% [11,35]. The mechanisms underlying the placebo response remain unclear. 0304-3959/$36.00 Ó 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.pain.2012.03.018 ⇑ Corresponding author at: Institute of Brain Science, National Yang-Ming University, Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan. Tel.: +886 2 2875 2111x3385; fax: +886 2 2873 9318. E-mail addresses: cllu@ym.edu.tw, cllu@vghtpe.gov.tw (C.-L. Lu). PAIN Ò 153 (2012) 1301–1310 www.elsevier.com/locate/pain