• K Arrow, L L Burgoyne, and A M Cyna.
• Women's and Children's Hospital, North Adelaide, SA, Australia.
• Anaesthesia. 2022 Jan 1; 77 Suppl 1: 11-20.

AbstractNocebo refers to non-pharmacological adverse effects of an intervention. Well-intended procedural warnings frequently function as a nocebo. Both nocebo and placebo are integral to the generation of 'real' treatment effects and their associated 'real' side-effects. They are induced or exacerbated by: context; negative expectancy; and negative conditioning surrounding treatment. Since the late 1990s, the neuroscience literature has repeatedly demonstrated that the nocebo effect is mediated by discrete neurobiological mechanisms and specific physiological modulations. Although no single biological mechanism has been found to explain the nocebo effect, nocebo hyperalgesia is thought to initiate from the dorsal lateral prefrontal cortex subsequently triggering the brain's descending pain modulatory system and other pain regulation pathways. Functional magnetic resonance imaging shows that expectation of increased pain is accompanied by increased neural activity in the hippocampus and midcingulate cortex which is not observed when analgesia is expected. Functional magnetic resonance imaging studies have shown that the anterior cingulate cortex is pivotal in the perception of affective pain evoked by nocebo words. Research has also explored neurotransmitters which mediate the nocebo effect. The neuropeptide cholecystokinin appears to play a key role in the modulation of pain by nocebo. Hyperalgesia generated by nocebo also increases the activity of the hypothalamic-pituitary-adrenal axis as indicated by increases in plasma cortisol. The avoidance or mitigation of nocebo needs to be recognised as a core clinical skill in optimising anaesthesia care. Embracing the evidence around nocebo will allow for phrases such as 'bee sting' and 'sharp scratch' to be thought of as clumsy verbal relics of the past. Anaesthesia as a profession has always prided itself on practicing evidence-based medicine, yet for decades anaesthetists and other healthcare staff have communicated in ways counter to the evidence. The premise of every interaction should be 'primum non nocere' (first, do no harm). Whether the context is research or clinical anaesthesia practice, the nocebo can be ignored no longer.© 2022 Association of Anaesthetists.

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