Positive (placebo) or negative (nocebo) responses to inert or sham treatments are common occurrences in medicine. Both are complex neurobiological phenomena that can be triggered or modulated by a variety of environmental, psychological, and cognitive factors. Now, new research adds another variable to the equation by demonstrating that the purported cost of an inert treatment can influence the nocebo response.
Researchers led by Christian Büchel, University Medical Center Hamburg-Eppendorf, Germany, show that labeling an inert treatment as expensive was associated with stronger nocebo hyperalgesia in healthy volunteers compared to an inert treatment labeled as cheap. Moreover, combined corticospinal imaging, which allows for simultaneous recording in the brain and spinal cord, revealed that interactions primarily between the rostral anterior cingulate cortex (rACC), periaqueductal grey (PAG) and the spinal cord, mediate this effect.
“The work was cleverly designed, and what I particularly liked was that they investigated nocebo effects in the context of side effects induced by a treatment intervention with no active ingredients—that is, a placebo—which is a very practical way to think about the clinical implications of nocebo research,” said Marta Pecina, University of Pittsburgh, US, who was not involved in the study.
The research was published online October 6 in Science, with an accompanying perspective by Luana Colloca, University of Maryland, Baltimore, US.
The placebo effect involves positive expectations of a treatment based on a patient’s perception, prior experiences, and the therapeutic encounter. The nocebo effect involves negative expectations of a treatment based on the same factors. In the pain field, placebo analgesia is a common occurrence in many randomized controlled trials of pain relievers, and one that has been growing steadily in recent decades (Tuttle et al., 2015). The neurobiology of the placebo response has been well studied and involves the endogenous opioid system (e.g., Eippert et al., 2009; also see PRF related webinar).
Previous studies have also shown that commercial features of drugs such as price information, packaging, and labeling can affect the placebo response (Waber et al., 2008; see PRF related news story).
“There have been several studies showing that price information influences the placebo effect, so we were interested to find out if the same was true for the nocebo effect,” said Alexandra Tinnermann, first author of the study.
Inducing expectations
The researchers recruited 49 healthy participants for the new study. In order to induce negative expectations to examine nocebo effects, the investigators told the participants that the aim of the study was to investigate a reported side effect of increased pain sensitivity from two commonly prescribed creams used to treat atopic dermatitis; in reality, both creams contained no active ingredients. One cream was labeled as cheap and the other as expensive, but no actual price was specified for either treatment. In addition, the cheap cream was packaged in a custom-designed box to imply it was a generic medication and the expensive cream in a different box to imply it was a brand medication.
The team asked a separate sample of 66 individuals who did not take part in the nocebo part of the study to estimate the actual price of the two creams based on the packaging. They estimated the price of the more elaborately designed blue box containing the supposedly expensive cream as significantly higher than the price of the unembellished orange and white box containing the cheap cream.
Next, the cheap nocebo cream was applied to skin patches on the forearm in one group (the cheap group), and the expensive cream to skin patches in another group (the expensive group), and left on for 30 minutes. Both groups also received a control cream. After the researchers removed the creams, they applied heat pain stimuli to the skin patches. They told the participants that they would receive the same stimuli on both patches but, in reality, they covertly lowered the temperature on the control patch and raised it on the nocebo patch to reinforce the notion of increased pain sensitivity due to side effects of the creams.
During the subsequent test phase, the investigators again administered nocebo cream and, after removing the cream, applied heat pain stimuli while participants were lying in an MRI scanner. All heat pain stimuli applied during the test phase were identical and corresponded to a 50 rating on the visual analogue pain scale. Skin hyperalgesia was significantly higher in the expensive group compared to the cheap group, suggesting that manipulating expectations about the price of a treatment can enhance the nocebo effect.
A neural signal
The results may appear slightly counterintuitive, as patients generally prefer more expensive treatments and consider them more effective than cheap, generic ones. But according to Tinnermann, “If one assumes that a more expensive treatment causes greater placebo effects because it is a more potent agent, and if we consider this in the context of nocebo, then the more potent agent also may produce more side effects.”
The behavioral findings were complemented by neuroimaging data, which provided an indication of neural representations of nocebo effects. Irrespective of value information, neural activity at the cervical segment of the spinal cord was increased during nocebo treatment.
Since the behavioral nocebo effect was greater in the expensive group, the researchers next sought to determine how these behavioral differences were reflected at the neural level. They discovered greater differences in activation of the PAG in the expensive group compared to the cheap group.
Nocebo effects are described as the opposite of placebo effects, but interestingly, the pattern of PAG activation in the current study was similar to previous observations of PAG activation during placebo conditions (Geuter et al., 2013; Wager et al., 2004). This indicates that, regardless of the direction of expectation (positive for placebo or negative for nocebo), the central nervous system engages this region during pain modulation. A possible reason for this may be the activation of on-or-off cells in the PAG-rostral ventromedial medulla (RVM) pathway, which can either facilitate (on cells) or inhibit (off cells) descending nociceptive transmission to the spinal cord, during nocebo or placebo, respectively (Millan, 2002).
To further interrogate the relationship between value and neural activity, the researchers examined the time course of activation in the spinal cord and the rostral anterior cingulate cortex (rACC) and discovered correlations between behavioral nocebo effects and neuronal coupling of both regions with the PAG. Interestingly, the PAG region interacting with the rACC was located ventrally, whereas the PAG area showing coupling with the spinal cord was located laterally, indicating a functional segregation of the PAG.
Tinnermann and colleagues next used a method known as mediation analysis to determine if the rACC directly mediated the effect of value. Indeed, they found that activity in the rACC, an area known to encode the affective component of pain, directly mediated the effect of price information on the behavioral nocebo response (Fuchs et al., 2014).
Small differences, big effects
The price difference between the cheap and expensive creams was small—only three or four euros—but still enough to produce differences in neural activation and behavioral nocebo effects. “The fact that you can see changes in the brain as well as behavior in response to such a small monetary difference was fascinating,” said Pecina.
Indeed, Tinnermann sees price manipulation as a potential next step for future research. “Does it make a difference if we tell participants the price beforehand? Or if we tell them that the difference in price is 20 or even 200 euros, does this scale to higher nocebo responses?”
Dara Bree is a postdoctoral fellow at Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, US.
Image credit: kasezo/123RF Stock Photo
