Autonomic Arousal as a Mechanism of the Persistence of Nocebo Hyperalgesia

Placebo and nocebo mechanisms can lead to clinically significant modulation of pain. Although learning is considered to be the broad mechanism underlying placebo analgesia as well as nocebo hyperalgesia, critical differences have emerged in their specific mechanisms. One of the most interesting of these is that whereas placebo analgesia seems to be relatively short-lived, nocebo hyperalgesia appears more resistant to extinction, often persisting indefinitely. The current study examined why nocebo hyperalgesia persists longer than placebo analgesia. Sixty healthy volunteers were randomized to receive placebo conditioning, nocebo conditioning, or no conditioning using an experimental pain model with surreptitious decreases (placebo group) and increases (nocebo group) in pain stimulation paired with sham treatment during training. Pain was then assessed in a test phase with and without the sham treatment at equal pain stimulation. The conditioning procedure successfully induced placebo analgesia as well as nocebo hyperalgesia in the relevant groups, with nocebo hyperalgesia outlasting placebo analgesia, confirming nocebo hyperalgesia's resistance to extinction. Most interestingly, nocebo treatment led to heightened anticipatory anxiety ratings and autonomic arousal. Further, autonomic arousal completely mediated the effect of nocebo versus placebo training on extinction, suggesting that heightened autonomic arousal may be an important mechanism in the persistence of nocebo hyperalgesia. Perspective: Heightened anticipatory anxiety in the form of elevated autonomic arousal may explain why nocebo hyperalgesia persists relative to placebo analgesia. As such, interventions that reduce anticipatory anxiety could reduce the burden of persistent nocebo hyperalgesia. (C) 2017 by the American Pain Society.