Language Matters: Avoiding Placebo’s Evil Twin, Nocebo

Debnath Chatterjee MD, Myron Yaster MD, John E. Fiadjoe MD

I first heard about nocebo (“the evil twin of placebo”) at a lecture on the subject by John Fiadjoe at a SPA meeting. It, like so many of his lectures, was a revelation and changed my clinical practice (So, Ira Cohen and Kim Battle, if you are reading this, score one for SPA CME accreditation!).  Indeed, over the past 6 months I’ve made a lot of use my understanding of nocebo effects in my role as a volunteer Covid vaccinator. In the past, I would have used the negative expression and said to both adults and children: “this may sting a little, like a bee bite”.  Instead, I used a positive, therapeutic alternative and said: “you may or may not feel anything at all”. In fact, when I was done injecting, most adults and children would ask: “you mean you’re done? I didn’t feel anything at all”.  To the adults I would then say, “Of course you didn’t feel anything, I’m an anesthesiologist!”  Because of their expertise and interest in this subject, I asked John and Dabe Chatterjee, to co-write today’s PAAD with me.  Myron Yaster MD

Original article

Arrow K, Burgoyne LL, Cyna AM. Implications of nocebo in anaesthetic care. Anaesthesia 2022, 77 (suppl.1), 11-20. PMID: 35001386.

While the beneficial effects of placebo are well established, today’s PAAD is a narrative review published in Anaesthesia that highlights placebo’s evil twin, nocebo, which refers to the non-pharmacological adverse effects of an intervention. The term nocebo is derived from the Latin word noceo, which means “I shall harm”. Nocebo effects arise from negative expectations, and results in harmful and dangerous outcomes in many clinical contexts, including patient care, informed consent process, and clinical trials.1 (Figure 1) Even well-intended procedural warnings can function as a nocebo. For example, warning patients that intravenous cannulation was going to feel like a ‘bee sting’ did not appear to be beneficial and might have been counterproductive.2 In another double-blind randomized controlled trial of 140 women receiving spinal anesthesia for Caesarean section or epidural analgesia for labor, participants who were warned of a ‘big bee sting’ before local anesthetic infiltration had higher pain scores than those informed that the area was being numbed.3 Similarly, a direct suggestion of drug side effects or listing all the possible complications from a procedure can become self-fulfilling.

              While the precise neurobiological mechanisms that explain the nocebo effect are not known, placebo analgesia and nocebo hyperalgesia are thought to initiate from the dorsal lateral prefrontal cortex and subsequently trigger the brain’s descending pain modulatory pathways.1 Nocebo effects have been shown to be mediated by the neuropeptide cholecystokinin and blocked by proglumide, a mixed cholecystokinin type A and type B receptor antagonists. Additionally, nocebo hyperalgesia has also been associated with increased activity of the hypothalamic-pituitary-adrenal axis, which is blocked by diazepam, suggesting a role of anxiety.4

                   So, what are the implications of this recent nocebo research on our anesthetic practice? Communications that elicit negative expectations have the potential to harm. Therefore, “calibrated and nuanced language is required during procedural disclosure to communicate truthful information that positively influences the patient’s affective state, while minimizing negative responses”.5 Tables 2 and 3 from today’s article lists examples of nocebo communications that can be reframed for a therapeutic benefit (reprinted below). Similarly, today’s article supports one of my (Myron) personal beliefs, namely, overwhelming patients with a generic list of anesthetic risks on the day of surgery can be potentially harmful by increasing anxiety and may increase the likelihood of an adverse outcome such as pain or nausea.6 Indeed, in a survey of parents consenting for an anesthetic for their child, nearly 50% of the parents would rather not receive any risk information on the day of surgery. “Most parents simply preferred reassurance that the anesthesiologist would do everything to ensure their child’s safety and comfort.”7 Therefore, our risk discussions must be individualized considering the patient’s/parent’s concerns and their request for more information.

What do you think? Please let us know and we’ll post in the reader’s response page.

References

1.      Colloca L, Barsky AJ. Placebo and nocebo effects. New Engl J Med.2020. 382,

2.      Dutt-Gupta J, Brown T, Cyna AM. Effect of communication on pain during intravenous cannulation: a randomized controlled trial. Br J Anaesth. 2007;99(6): 871-5.

3.      Varelmann D, Pancaro C, Cappiello E, Camann W. Nocebo-induced hyperalgesia during local anesthetic inject. Anesth Analg. 2010: 110:868-70.

4.      Benedetti F, Amanzio M, Vighetti S, et al. The biochemical and neuroendocrine bases of the hyperalgesia nocebo effect. Journal of Neuroscience. 2006; 26:12014-22.

5.      Kraus BS. “This may hurt”: predictors in procedural disclosures may do harm. BMJ. 2015;6350:h649.

6.      Cyna AM, Simmons SW. Guidelines on informed consent in anaesthesia: unrealistic, unethical, untenable. British Journal of Anaesthesia. 2017;119: 1086-9.

7.      Morrison C, Munk R, Lo JJS, et al. Parental understanding of their child’s risk of anesthesia. British Journal of Anaesthesia. 2019;123: e5-6.