INSIGHTS | PERSPECTIVES
By Luana Colloca
The mysterious phenomenon known as the nocebo effect describes nega- tive expectancies. This is in contrast to positive expectancies that trigger pla- cebo effects (1). In evolutionary terms, nocebo and placebo effects coexist to
favor perceptual mechanisms that anticipate
threat and dangerous events (nocebo effects)
and promote appetitive and safety behaviors
(placebo effects). In randomized placebo-controlled clinical trials, patients that receive placebos often report
side effects (nocebos) that
are similar to those experienced by patients that
receive the investigational
treatment (2). Information provided during the
informed consent process
and divulgence of adverse
effects contribute to nocebo
effects in clinical trials (1).
Nocebo (and placebo) effects engage a complex set
of neural circuits in the
central nervous system that
modulate the perception of touch, pressure,
pain, and temperature (1, 3, 4). Commercial
features of drugs such as price and labeling
influence placebos ( 5, 6). On page 105 of this
issue, Tinnermann et al. ( 7) show that price
also influences nocebo effects.
Tinnermann et al. evaluated the responses
of healthy participants who received two placebo creams labeled with two distinct prices
and presented in two boxes that had marketing characteristics of expensive or cheap
medication. The creams were described as
products that relieve itch but induce local
pain sensitization (hyperalgesia). All creams,
including controls, were identical and contained no active ingredients. Nocebo hyperalgesic effects were larger for the “more
expensive” cream than for the “cheaper”
cream. Combined corticospinal imaging
revealed that the expensive price value increased activity in the prefrontal cortex.
Furthermore, brain regions such as the ros-
tral anterior cingulate cortex (rACC) and the
periaqueductal gray (PAG) encoded the dif-
ferential nocebo effects between the expen-
sive and cheaper treatments. Expectancies
of higher pain-related side effects associated
with the expensive cream may have triggered
a facilitation of nociception processes at early
subcortical areas and the spinal cord [which
are also involved in placebo-induced reduc-
tion of pain ( 8)]. The rACC showed a deac-
tivation and favored a subsequent activation
of the PAG and spinal cord, resulting in an
increase of the nociceptive inputs. This sug-
gests that the rACC–PAG–spinal cord axis
may orchestrate the effects of pricing on no-
The anticipation of
painful stimulation makes
healthy study participants
perceive nonpainful and
low-painful stimulations as
painful and high-painful,
respectively ( 9). Verbally
induced nocebo effects are
as strong as those induced
through actual exposure
to high pain ( 9). Moreover, receiving a placebo
after simulating an effective analgesic treatment,
( 10). The relationship between prior unsuccessful or successful pain relief interventions
and placebo analgesic effects is linked to a
higher activation of the bilateral posterior insula and reduced activation of the right dorsolateral prefrontal cortex ( 11).
Informing patients that a treatment has
been stopped, compared to a covert treatment interruption, alters the response to
morphine, diazepam, or deep-brain stimulation in postoperative acute pain, anxiety, or
idiopathic Parkinson’s disease, respectively
( 12). Patients openly informed about the interruption of each intervention experience
a sudden increase of pain, anxiety, or bradykinesia (a manifestation of Parkinson’s
disease), whereas patients undergoing a hidden interruption do not ( 12). Neuroimaging
approaches support the clinical observation.
For example, the action of the analgesic remi-
fentanil is overridden by activation of the
hippocampus that occurs when healthy par-
ticipants that receive heat pain stimulations
are misleadingly told that the remifentanil
administration was interrupted ( 13). These
findings provide evidence that communica-
tion of treatment discontinuation might, at
least in part, lead to nocebo effects with ag-
gravation of symptoms.
In placebo-controlled clinical trials, nocebo effects can influence patients’ clinical
outcomes and treatment adherence. It was
shown in a clinical trial that atorvastatin induced in the same individuals an excess rate
of muscle-related adverse events in the non-blinded (i.e., patients knew they were taking
atorvastatin), nonrandomized 3-year follow-up phase but not in the initial blinded 5-year
phase when patients and physicians were
unaware of the treatment allocation (
atorvastatin or placebo) ( 14). Furthermore, misleading information about side effects for statins
via public claims has led to treatment discontinuation and an increase in fatal strokes and
heart attacks ( 14).
Given that nocebo effects contribute to
perceived side effects and may influence
clinical outcomes and patients’ adherence to
medication, we should consider how to avoid
them in clinical trials and practices ( 15)—for
example, by tailoring patient-clinician communication to balance truthful information
about adverse events with expectancies of
outcome improvement, exploring patients’
treatment beliefs and negative therapeutic
history, and paying attention to framing (i.e.,
treatment description) and contextual effects
(i.e., price). Through an understanding of the
physiological mechanisms, strategies could
be developed to reduce nocebo effects. j
REFERENCES AND NOTES
1. L. Colloca, F. G. Miller, Psychosom. Med. 73, 598 (2011).
2. A. J. Barsky, R. Saintfort, M. P. Rogers, J. F. Borus, JAMA
287, 622 (2002).
3. M. Blasini et al ., PAIN Rep. 2, e585 (2017).
4. I. Tracey, Nat. Med. 16,1277(2010).
5. R. L. Waber, B. Shiv, Z. Carmon, D. Ariely, JAMA 299, 1016
6. S. Kam-Hansen etal. , Sci. Transl.Med. 6, 218ra5 (2014).
7. A. Tinnermann et al ., Science 358, 105 (2017).
8. F. Eippert, J. Finsterbusch, U. Bingel, C. Büchel, Science
326, 404 (2009).
9. L. Colloca, M. Sigaudo, F. Benedetti, Pain136, 211 (2008).
10. L. Colloca, F. Benedetti,Pain 124, 126 (2006).
11. S. Kessner et al ., JAMA Intern. Med. 173, 1468 (2013).
12. L. Colloca, L. Lopiano, M. Lanotte, F. Benedetti, Lancet
Neurol. 3, 679 (2004).
13. U. Bingel et al., Sci. Transl. Med. 3, 70ra14 (2011).
14. A.Gupta et al., Lancet 389,2473(2017).
15. L.Colloca, D.Finniss, JAMA 307,567(2012).
This research is funded by the U.S. National Institutes of Health
(NIDCR, R01DE025946, L.C.).
Nocebo effects can make you feel pain
Negative expectancies derived from features of commercial drugs elicit nocebo effects
University of Maryland, School of Nursing and School of
Medicine, Baltimore, C655 West Lombard Street, Suite 729,
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