INSIGHTS | PERSPECTIVES

NEUROSCIENCE Nocebo effects can make you feel pain Negative expectancies derived from features of commercial drugs elicit nocebo effects

By Luana Colloca ferential nocebo effects between the expen- administration was interrupted (13). These sive and cheaper treatments. Expectancies findings provide evidence that communica- he mysterious phenomenon known of higher pain-related side effects associated tion of treatment discontinuation might, at as the nocebo effect describes nega- with the expensive cream may have triggered least in part, lead to nocebo effects with ag- tive expectancies. This is in contrast to a facilitation of nociception processes at early gravation of symptoms. positive expectancies that trigger pla- subcortical areas and the spinal cord [which In placebo-controlled clinical trials, no- cebo effects (1). In evolutionary terms, are also involved in placebo-induced reduc- cebo effects can influence patients’ clinical nocebo and placebo effects coexist to tion of pain (8)]. The rACC showed a deac- outcomes and treatment adherence. It was Tfavor perceptual mechanisms that anticipate tivation and favored a subsequent activation shown in a clinical trial that atorvastatin in- threat and dangerous events (nocebo effects) of the PAG and spinal cord, resulting in an duced in the same individuals an excess rate and promote appetitive and safety behaviors increase of the nociceptive inputs. This sug- of muscle-related adverse events in the non- (placebo effects). In randomized placebo- gests that the rACC–PAG–spinal cord axis blinded (i.e., patients knew they were taking Downloaded from controlled clinical trials, patients that re- may orchestrate the effects of pricing on no- atorvastatin), nonrandomized 3-year follow- ceive placebos often report cebo hyperalgesia. up phase but not in the initial blinded 5-year side effects (nocebos) that The anticipation of phase when patients and physicians were are similar to those expe- painful stimulation makes unaware of the treatment allocation (atorvas- rienced by patients that healthy study participants tatin or placebo) (14). Furthermore, mislead- receive the investigational perceive nonpainful and ing information about side effects for statins treatment (2). Informa- low-painful stimulations as via public claims has led to treatment discon- http://science.sciencemag.org/ tion provided during the painful and high-painful, tinuation and an increase in fatal strokes and informed consent process respectively (9). Verbally heart attacks (14). and divulgence of adverse induced nocebo effects are Given that nocebo effects contribute to effects contribute to nocebo as strong as those induced perceived side effects and may influence effects in clinical trials (1). through actual exposure clinical outcomes and patients’ adherence to Nocebo (and placebo) ef- to high pain (9). More- medication, we should consider how to avoid fects engage a complex set over, receiving a placebo them in clinical trials and practices (15)—for of neural circuits in the after simulating an effec- example, by tailoring patient-clinician com- central nervous system that tive analgesic treatment, munication to balance truthful information

modulate the perception of touch, pressure, compared to receiving the same placebo about adverse events with expectancies of on October 5, 2017 pain, and temperature (1, 3, 4). Commercial intervention after a treatment perceived as outcome improvement, exploring patients’ features of drugs such as price and labeling ineffective, produces a 49.3% versus 9.7% treatment beliefs and negative therapeutic influence placebos (5, 6). On page 105 of this placebo-induced pain reduction, respectively history, and paying attention to framing (i.e., issue, Tinnermann et al. (7) show that price (10). The relationship between prior unsuc- treatment description) and contextual effects also influences nocebo effects. cessful or successful pain relief interventions (i.e., price). Through an understanding of the Tinnermann et al. evaluated the responses and placebo analgesic effects is linked to a physiological mechanisms, strategies could of healthy participants who received two pla- higher activation of the bilateral posterior in- be developed to reduce nocebo effects. j cebo creams labeled with two distinct prices sula and reduced activation of the right dor- and presented in two boxes that had mar- solateral prefrontal cortex (11). REFERENCES AND NOTES 1. L. Colloca, F. G. Miller, Psychosom. Med. 73, 598 (2011). keting characteristics of expensive or cheap Informing patients that a treatment has 2. A. J. Barsky, R. Saintfort, M. P. Rogers, J. F. Borus, JAMA medication. The creams were described as been stopped, compared to a covert treat- 287, 622 (2002). 3. M. Blasini et al., PAIN Rep. 2, e585 (2017). products that relieve itch but induce local ment interruption, alters the response to 4. I. Tracey, Nat. Med. 16, 1277 (2010). pain sensitization (hyperalgesia). All creams, morphine, diazepam, or deep-brain stimula- 5. R. L. Waber, B. Shiv, Z. Carmon, D. Ariely, JAMA 299, 1016 including controls, were identical and con- tion in postoperative acute pain, anxiety, or (2008). 6. S. Kam-Hansen et al., Sci. Transl. Med. 6, 218ra5 (2014). tained no active ingredients. Nocebo hy- idiopathic Parkinson’s disease, respectively 7. A. Tinnermann et al., Science 358, 105 (2017). peralgesic effects were larger for the “more (12). Patients openly informed about the in- 8. F. Eippert, J. Finsterbusch, U. Bingel, C. Büchel, Science 326, 404 (2009). expensive” cream than for the “cheaper” terruption of each intervention experience 9. L. Colloca, M. Sigaudo, F. Benedetti, Pain 136, 211 (2008). cream. Combined corticospinal imaging a sudden increase of pain, anxiety, or bra- 10. L. Colloca, F. Benedetti, Pain 124, 126 (2006). revealed that the expensive price value in- dykinesia (a manifestation of Parkinson’s 11. S. Kessner et al., JAMA Intern. Med. 173, 1468 (2013). 12. L. Colloca, L. Lopiano, M. Lanotte, F. Benedetti, Lancet creased activity in the prefrontal cortex. disease), whereas patients undergoing a hid- Neurol. 3, 679 (2004). Furthermore, brain regions such as the ros- den interruption do not (12). Neuroimaging 13. U. Bingel et al., Sci. Transl. Med. 3, 70ra14 (2011). A L IN O

14. A. Gupta et al., Lancet 389, 2473 (2017). T tral anterior cingulate cortex (rACC) and the approaches support the clinical observation. 15. L. Colloca, D. Finniss, JAMA 307, 567 (2012). A A N S

periaqueductal gray (PAG) encoded the dif- For example, the action of the analgesic remi- Y fentanil is overridden by activation of the ACKNOWLEDGMENTS This research is funded by the U.S. National Institutes of Health hippocampus that occurs when healthy par- T IO N : BR University of Maryland, School of Nursing and School of (NIDCR, R01DE025946, L.C.). A T R

ticipants that receive heat pain stimulations S

Medicine, Baltimore, C655 West Lombard Street, Suite 729, U

Baltimore, MD 21201, USA. Email: [email protected] are misleadingly told that the remifentanil 10.1126/science.aap8488 IL L

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