Updates & Features
The Neurobiology of the Placebo Effect
– The 1st PainSolve Webinar
Psychological and Neurobiological Mechanisms of Placebo and Nocebo Responses
PainSolve Editorial Team
We are delighted to have had Prof. Ulrike Bingel (University Hospital Essen, Germany) host our inaugural PainSolve webinar on the 12th December 2018, titled, ‘Psychological and Neurobiological Mechanisms of Placebo and Nocebo Responses.’ Prof. Bingel presented pivotal studies that have moulded today’s understanding of the neurobiology and clinical relevance of the placebo and nocebo effects, with a focus on placebo analgesia.
Prof. Bingel’s Presentation
Prof. Bingel began with a brief history of the placebo effect, describing its emergence through observations made by Henry Beecher during the Second World War.1 Since then, a variety of studies have shown that the placebo effect has a clinically significant role in pain management,2 symptom improvement3 and has long-lasting effects.4
Both pharmacological and functional imaging experiments have helped to uncover the roles of endogenous neurotransmission and spinal cord in placebo analgesia.5,6,7 However, a 2018 meta-analysis by Prof. Bingel, Tor Wager and colleagues, shows that changes in nociceptive processing do not sufficiently explain placebo analgesia indicating the involvement of brain areas responsible for the emotional and cognitive-evaluation of pain in placebo analgesia.8 The final section highlighted clinically focused studies, considering how the placebo effect impacts clinical trials and in-clinic treatment, for example by simply changing the medication label.9
In both the morning and the afternoon sessions, webinar attendees showed great interest during the discussion through intriguing and probing questions for Prof. Bingel. The first question delved into specific patient–physician communication that may take advantage of the placebo effect to maximise drug efficacy. Prof. Bingel asserted that drug development and marketing divisions within pharmaceutical companies should work much more closely, and that patient information leaflets or video tutorials providing helpful and positive information to patients around medications would be beneficial. From a clinician’s perspective, they need to alleviate anxieties, assess prior treatment experiences, implement social learning mechanisms and provide adequate drug information during patient–physician interactions. These interactions aim to improve low expectancies and/or prevent negative preconditioning, which may trigger the nocebo effect and prevent maximum therapeutic benefits. The discussion then transitioned to how higher costs due to longer patient–physician communications may cause political hurdles in healthcare systems, potentially preventing implementation of these changes. We hope to fulfil the interest generated here in the future webinar by Prof. Bingel on this topic at the beginning of 2019!
Further discussion highlighted our lack of understanding into the heterogeneity of placebo responses between patients, which Prof. Bingel describes as the ‘holy grail’ in placebo research. We are currently unable to explain why some patients, who have previously had poor treatment experiences, almost always react negatively and why some react positively when a new treatment option is presented. Prof. Bingel later suggested that there could be value in the assessment of prior treatments in clinical trials to allow subgroup analysis to understand how conditioning affects placebo analgesic responses. One explanation for this heterogeneity could come from the Hall 2012 study, where irritable bowel syndrome patients with a certain catechol-O-methyltransferase polymorphism (met/met) were significantly more responsive to placebo responses.10 Prof. Bingel suggests that patients should not be excluded from studies due to their genetic profile. However, she does mention that these data give us an insight into the understanding the interindividual heterogeneity in the placebo analgesic responses.
One of the final discussion points brought up the idea of providing a pill that looks different to the previously given pill, and assessing whether this could potentially overcome previous negative expectations. A study that involved changing the route of administration did not lead to an improvement in the analgesic effect, suggesting that changes such as these are not sufficient to prevent negative preconditioning.11 Despite this, Prof. Bingel believes that if the context is correct for the introduction of a new route of administration, then the placebo effect may be harnessed or the nocebo effect limited to maximise therapeutic benefits.
- Beecher HK. Ann Surg 1946; 123(1): 96–105
- Vase L, et al. Pain 2009; 145(1–2): 36–44
- Leuchter AF, et al. Br J Psychiatry 2014; 205(6): 443–449
- Quessy SN, et al. Pain 2008; 138(3): 479–483
- Wager TD, et al. Nat Rev Neurosci 2015; 16(7): 403–418
- Eippert F, et al. Neuron 2009; 63(4): 533–43
- Eippert F, et al. Science 2009; 326(5951): 404
- Zunhanner M, et al. JAMA Neurol 2018; 75(11): 1321–1330
- Kam-Hansen S, et al. Sci Transl Med 2014; 6(218): 218ra5
- Hall KT, et al. PLoS One 2012; 7(10): e48135
- Zunhammer M, et al. Sci Transl Med 2017; 9(393): pii: eaal2999