Manipulating placebo analgesia and nocebo hyperalgesia by changing brain excitability.

Harnessing placebo and nocebo effects has significant implications for research and medical practice. Placebo analgesia and nocebo hyperalgesia, the most well-studied placebo and nocebo effects, are thought to initiate from the dorsal lateral prefrontal cortex (DLPFC) and then trigger the brain's descending pain modulatory system and other pain regulation pathways. Combining repeated transcranial direct current stimulation (tDCS), an expectancy manipulation model, and functional MRI, we investigated the modulatory effects of anodal and cathodal tDCS at the right DLPFC on placebo analgesia and nocebo hyperalgesia using a randomized, double-blind and sham-controlled design. We found that compared with sham tDCS, active tDCS could 1) boost placebo and blunt nocebo effects and 2) modulate brain activity and connectivity associated with placebo analgesia and nocebo hyperalgesia. These results provide a basis for mechanistic manipulation of placebo and nocebo effects and may lead to improved clinical outcomes in medical practice.

Consideration in Randomized Placebo-Controlled Trial on Neck Pain to Avoid the Placebo Effect in Analgesic Action.

Background: In neck pain treatment, many therapies are focused on etiology, while it is well-known that placebo analgesia is also present in these therapies. The specific efficacy for etiology may be underestimated by ignoring their actual placebo effect. In this study, a logistic regression analysis is used to explore the risk factors causing different placebo responses in patients with neck pain among two RCTs. The probability of the placebo effect is predicted based on these risk factors. Methods: Trial A and Trial B were similarly designed, randomized, double-/single-blind, placebo-controlled trials in patients treating neck pain with Qishe pill or Shi-style manipulation. Both studies set a placebo pill twice a day or traction for every other day as control. For further analyses on the placebo effect in neck pain management, logistic regression was used to assess subgroup-placebo interactions. The odds ratio assessed a significant influence on the placebo effect. Results: In this pooled analysis, the total number of patients recruited for these two studies was 284, of which 162 patients received placebo treatment (placebo drug or traction for every other day). No statistically significant differences are found at baseline between the participants with placebo effect and non-placebo effect in the gender, age, and disease duration except in VAS and NDI at the initial time. There are numerically more patients with placebo effect in the shorter disease duration subgroup (< 4 months [76%]), higher initial VAS subgroup (>60 mm [90%]), and worse initial NDI subgroup (>24 [72%]) compared with the gender and age subgroup. An ROC curve is established to assess the model-data fit, which shows an area under the curve of 0.755 and a 95% confidence interval of 0.677-0.830. Participants who show placebo effect after 2 weeks have significantly lower VAS scores after 4 weeks, while there is no significant difference in NDI improvement between the two groups after 4 weeks. Conclusion: Neck pain patients with shorter disease duration are more likely to overscore their pain severity, because of their less experience in pain perception, tolerance, and analgesia expectation.

What Do Placebo and Nocebo Effects Have to Do With Health Equity? The Hidden Toll of Nocebo Effects on Racial and Ethnic Minority Patients in Clinical Care.

A placebo effect is a positive clinical response to non-specific elements of treatment with a sham or inert replica of a drug, device, or surgical intervention. There is considerable evidence that placebo effects are driven by expectation of benefit from the intervention. Expectation is shaped by a patient's past experience, observations of the experience of others, and written, verbal, or non-verbal information communicated during treatment. Not surprisingly, expectation in the clinical setting is strongly influenced by the attitude, affect, and communication style of the healthcare provider. While positive expectations can produce beneficial effects, negative information and experiences can lead to negative expectations, and consequently negative or nocebo effects. Key components identified and studied in the placebo and nocebo literature intersect with factors identified as barriers to quality care in the clinical setting for Black patients and other patients of color, including poor patient-clinician communication, medical mistrust, and perceived discrimination. Thus, in the context of discrimination and bias, the absence of placebo and presence of nocebo-generating influences in clinical settings could potentially reinforce racial and ethnic inequities in clinical outcomes and care. Healthcare inequities have consequences that ripple through the medical system, strengthening adverse short- and long-term outcomes. Here, we examine the potential for the presence of nocebo effects and absence of placebo effects to play a role in contributing to negative outcomes related to unequal treatment in the clinical encounter.

The Placebo and Nocebo Responses in Clinical Trials in Inflammatory Bowel Diseases.

Placebo and nocebo responses are mostly discussed in clinical trials with functional bowel disorders. Much less has been investigated and is known in gastrointestinal diseases beyond irritable bowel syndrome (IBS), especially in inflammatory bowel diseases (IBD). For the purpose of this review, we screened the Journal of Interdisciplinary Placebo Studies (JIPS) database with approximately 4,500 genuine placebo research articles and identified nine meta-analyses covering more than 135 randomized and placebo-controlled trials (RCTs) with more than 10,000 patients with Crohn´s disease (CD) and another five meta-analyses with 150 RCTs and more than 10,000 patients with ulcerative colitis (UC). Only three discussed nocebo effects, especially in the context of clinical use of biosimilars to treat inflammation. The articles were critically analyzed with respect to the size of the placebo response in CD and UC, its effects on clinical improvement versus maintenance of remission, and mediators and moderators of the response identified. Finally, we discussed and compared the differences and similarities of the placebo responses in IBD and IBS and the nocebo effect in switching from biologics to biosimilars in IBD management.

Placebo and Nocebo Effects Across Symptoms: From Pain to Fatigue, Dyspnea, Nausea, and Itch.

Placebo and nocebo effects are, respectively, the helpful and harmful treatment effects that do not arise from active treatment components. These effects have thus far been researched most often in pain. It is not yet clear to what extent these findings from pain can be generalized to other somatic symptoms. This review investigates placebo and nocebo effects in four other highly prevalent symptoms: dyspnea, fatigue, nausea, and itch. The role of learning mechanisms (verbal suggestions, conditioning) in placebo and nocebo effects on various outcomes (self-reported, behavioral, and physiological) of these different somatic symptoms is explored. A search of experimental studies indicated that, as in pain, the combination of verbal suggestion and conditioning is generally more effective than suggestion alone for evoking placebo and nocebo effects. However, conditioning appears more and verbal suggestions less relevant in symptoms other than pain, with the exception of placebo effects on fatigue and nocebo effects on itch. Physiological measures, such as heart rate, lung function, or gastric activity, are rarely affected even when self-reported symptoms are. Neurobiological correlates are rarely investigated, and few commonalities appear across symptoms. Expectations generally predict placebo and nocebo effects for dyspnea and itch but seem less involved in fatigue and nausea. Individual characteristics do not consistently predict placebo or nocebo effects across symptoms or studies. In sum, many conclusions deriving from placebo and nocebo pain studies do appear to apply to other somatic symptoms, but a number of important differences exist. Understanding what type of learning mechanisms for which symptom are most likely to trigger placebo and nocebo effects is crucial for generalizing knowledge for research and therapies across symptoms and can help clinicians to optimize placebo effects in practice.

Placebo Manipulations Reverse Pain Potentiation by Unpleasant Affective Stimuli.

According to the motivational priming hypothesis, unpleasant stimuli activate the motivational defense system, which in turn promotes congruent affective states such as negative emotions and pain. The question arises to what degree this bottom-up impact of emotions on pain is susceptible to a manipulation of top-down-driven expectations. To this end, we investigated whether verbal instructions implying pain potentiation vs. reduction (placebo or nocebo expectations)-later on confirmed by corresponding experiences (placebo or nocebo conditioning)-might alter behavioral and neurophysiological correlates of pain modulation by unpleasant pictures. We compared two groups, which underwent three experimental phases: first, participants were either instructed that watching unpleasant affective pictures would increase pain (nocebo group) or that watching unpleasant pictures would decrease pain (placebo group) relative to neutral pictures. During the following placebo/nocebo-conditioning phase, pictures were presented together with electrical pain stimuli of different intensities, reinforcing the instructions. In the subsequent test phase, all pictures were presented again combined with identical pain stimuli. Electroencephalogram was recorded in order to analyze neurophysiological responses of pain (somatosensory evoked potential) and picture processing [visually evoked late positive potential (LPP)], in addition to pain ratings. In the test phase, ratings of pain stimuli administered while watching unpleasant relative to neutral pictures were significantly higher in the nocebo group, thus confirming the motivational priming effect for pain perception. In the placebo group, this effect was reversed such that unpleasant compared with neutral pictures led to significantly lower pain ratings. Similarly, somatosensory evoked potentials were decreased during unpleasant compared with neutral pictures, in the placebo group only. LPPs of the placebo group failed to discriminate between unpleasant and neutral pictures, while the LPPs of the nocebo group showed a clear differentiation. We conclude that the placebo manipulation already affected the processing of the emotional stimuli and, in consequence, the processing of the pain stimuli. In summary, the study revealed that the modulation of pain by emotions, albeit a reliable and well-established finding, is further tuned by reinforced expectations-known to induce placebo/nocebo effects-which should be addressed in future research and considered in clinical applications.

Choose Your Words Wisely: The Impact of Message Framing on Patients' Responses to Treatment Advice.

Other people's words can have a powerful influence on how we interpret our environment, what we expect and experience, what we value, how we feel, what we choose, and how we behave. Placebo (and nocebo) effects are a dramatic example of this. The way in which healthcare professionals discuss, describe, and inform patients about the characteristic effects of a given disease and it prevention, diagnosis and treatment influence patients' feelings and expectations which in turn affects their psychobiological responses to, and subjective experiences and outcomes of the disease and its treatment effects. The effect of clinicians' words on patients' responses to treatments and procedures, both active and inert or sham is nothing less than incredible. The way in which information about treatment effects is delivered to patients can even reverse the clinically proven effects of an active treatment, or increase the adverse effects of it. In this chapter, we begin by presenting the data on the impact of message framing on affect and expectations of health care in experimental situations followed by the evidence that indicates how various patient, disease and clinician related factors modify framing effects in the clinic. Finally we discuss how framing effects affect clinical practice. They can be leveraged to enhance placebo effects and minimize nocebo effects. They can provide strategies to assist shared-decision making in the face of complex uncertainty. Going forward, automation of health care and artificial intelligence may change the delivery of health care but patients will continue to be humans seeking health gains while avoiding health losses and how the information is presented will always be susceptible to framing effects.