Autonomic arousal as a mechanism of the persistence of nocebo hyperalgesia

Abstract

Placebo and nocebo mechanisms can lead to clinically significant modulation of pain. Whilst learning is considered to be the broad mechanism underlying both placebo analgesia and nocebo hyperalgesia, critical differences have emerged in their specific mechanisms. One of the most interesting of these is that while 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 randomised 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 both placebo analgesia and 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 is an important mechanism in the persistence of nocebo hyperalgesia.