Endogenous opioids contribute to the feeling of pain relief in humans

Endogenous opioids mediate the pleasurable responses to positively reinforcing stimuli such as palatable food. Yet, the reduction or omission of a negative experience can also be rewarding (negative reinforcement). As such, pain relief leads to negative reinforcement and evokes a pleasant feeling in humans. Although it has been shown that the feeling of pleasure associated with positive reinforcement is at least partly mediated through endogenous opioids, it is currently unknown whether similar neurochemical mechanisms are involved in the pleasant feeling evoked by pain relief. In this study, 27 healthy participants completed 2 identical experimental sessions, 1 with placebo and 1 with naltrexone, an endogenous opioid antagonist. Pain relief was induced by superficial cooling after heat stimulation of capsaicin-sensitized skin. Participants rated the relief and pleasantness in response to the cooling. Endogenous opioid blockade by naltrexone decreased relief and pleasantness ratings compared with placebo (P = 0.0027). This study provides evidence that endogenous opioids play a role in mediating the pleasant feeling of pain relief in humans. Clinically, the rewarding nature of pain relief and its underlying mechanisms require consideration because of their potential reinforcing effects on behaviors that might be beneficial short-term but maladaptive long-term.