Fear-induced hyperalgesia in quiescent inflammatory bowel disease

Recurring pain is a debilitating symptom in inflammatory bowel disease (IBD), often persisting beyond acute gut inflammation with unclear underlying mechanisms. Altered emotional reactivity to pain has been proposed as a key contributor to pain persistence, but experimental evidence is scarce. This study investigated whether pain-related fear learning shapes the perception of acute experimental pain in quiescent IBD. Implementing a 2-day differential fear conditioning paradigm, we assessed the acquisition and extinction of conditioned fear in response to nociceptive (thermal pain) and non-nociceptive (aversive tones) unconditioned stimuli (US) in IBD patients and healthy controls. After overnight consolidation, US re-exposure was evaluated, focusing on pain intensity and unpleasantness ratings. Compared with healthy volunteers, IBD patients exhibited significantly enhanced pain intensity and unpleasantness upon re-exposure to pain, correlating with the magnitude of pain-related fear learning the day before. The relationship between fear learning and pain intensity was fully mediated by pain unpleasantness, suggesting a key role of the emotional valence of pain. Notably, behavioral measures of fear acquisition and extinction were unaltered in patients, pointing toward pain-related central adaptations rather than exaggerated fear acquisition as the underlying mechanism. These findings identify fear-induced hyperalgesia as a potential central mechanism contributing to persistent pain in IBD and highlight the importance of targeting conditioned fear in future personalized interventions to fill the current therapeutic gap in IBD-related pain.