A study examining psychological factors that predict the magnitude of placebo hypoalgesia and individual responsiveness found significant placebo effects in patients with temporomandibular disorder and healthy participants.


Placebo effects are a form of endogenous opioids-based descending pain modulation that have potential to serve as an alternative to opioids and other pharmacological treatments for pain. “However, not everyone responds to placebo treatments and manipulation procedures,” explains Yang Wang, PhD. “Placebo responding rates in clinical trials and experimental studies vary widely, which raises the question: who responds to placebos? Addressing this issue can deepen our understanding of placebo mechanisms and may help clinicians individualize treatment in the context of precision medicine.”

Interactions Between Psychological Factors Often Goes Overlooked

Previous studies have examined various psychological factors and their impact on placebo hypoalgesia. “However, investigators might overlook the fact that psychological factors often interact with each another,” explains Dr. Wang. “For example, people with neurotic traits more commonly suffer from mood disorders. As such, we need to identify higher psychological dimensions from validated psychological surveys so we can see how the negative and positive valence systems, the social process system, pain-related factors, and personality traits underlie distinct aspects of behavioral placebo effects.”

Dr. Wang, PhD, and colleagues had a study published in Pain that aimed to identify psychological factors that could predict the magnitude of placebo hypoalgesia and individual responsiveness. “We used the Research Domain of Criteria, a proposed framework National Institute of Mental Health, to identify higher domains of psychological characteristics that can influence placebo effects,” Dr. Wang says. A total of 397 patients with temporomandibular disorder (TMD) and 397 healthy control participants were included in the analysis. Placebo effects were induced in both the TMD and healthy participant groups using classical conditioning with heat thermal painful stimuli that was tailored to each person’s pain sensitivities.

Negative Valence System Plays Key Role in Placebo Effects

According to the results, significant placebo effects were seen in patients with TMD and in healthy participants. Across the TMD and healthy control groups, emotional distress and pain-related fear and catastrophizing emerged as significant predictors of a smaller magnitude of placebo hypoalgesia (Figure). Higher levels of emotional distress predicted slower extinction rates in both TMD and healthy control participants.

“The presence of chronic pain interacted with the positive valence system in influencing pain relief expectations,” says Dr. Wang. “When compared with healthy participants, patients with chronic pain were more sensitive to rewards, and higher reward sensitivity was associated with greater expectations of pain relief. These results suggest it might still be too early to consider a general psychological placebo analgesic mechanism across patients and healthy individuals.”

The findings also suggest the negative valence system plays an important role in impairing the formation of placebo effects. “Higher levels of emotional distress can impair placebo effects,” Dr. Wang says. “Simply put, people who are more depressed, anxious, and stressed were less likely to respond to placebos. However, since the effect size was not large, other factors can further address differences in placebo responses.”

Placebo Effects Have Potential to Translate to Chronic Pain Treatment

The findings highlight the critical roles of emotional distress and pain-related fear and catastrophizing in reducing the magnitude of placebo effects in patients with pain and in healthy participants. “Pain is a subjective experience that greatly relies on psychological factors,” says Dr. Wang. “Awareness of the power of placebo effects is a key first step towards a synergic patient-clinician interaction. Our study demonstrated that chronic pain patients have a similar magnitude of placebo analgesic effects as healthy participants. This is encouraging because it suggests placebo effects have the potential to translate to chronic pain treatments.”

More research is needed to determine whether psychological determinants can be used to predict placebo responsiveness in patients with pain. “Future research can combine psychological approaches with in-depth phenotyping of sociodemographic aspects, biological signatures, and brain neural responses,” says Dr. Wang. “Studying these aspects may provide tangible mechanistic findings that can translate to clinical practice and advance the science of pain. Our hope is to provide clinicians with a larger arsenal of therapeutic options for personalized pain management.”