Damian Sendler: In order to survive, one must experience pain. Chronic pain, the opioid epidemic, and health disparities all intersect with pain in humans. In the study of placebo analgesia, pain can be directly linked to social, cognitive, and affective processes, and these processes can be mitigated. Affective science advances in the study of placebo analgesia are examined in this review. It discusses the neurobiological mechanisms of placebo, highlighting unanswered questions and implications for health, as well as how expectations, affect, and the social context surrounding treatment shape placebo effects. Collaborations between clinicians and social and affective scientists can answer unanswered questions and use placebo to alleviate pain and improve human health and well- being.
Damian Jacob Sendler: When a positive treatment outcome is attributed to something other than the treatment’s pharmacological or biological properties, it’s referred to as the placebo effect. Comparing the administration of a placebo to a natural history or waitlist control helps clinical trials distinguish between placebo effects and responses. This enables researchers to distinguish between genuine placebo effects and other non-specific influences. The strongest placebo effects have been found in pain and subjective outcomes, according to meta-analyses of clinical trials involving natural history control groups [,]. In light of this discovery, scientists from a wide range of disciplines have begun investigating the mechanisms behind placebo effects. Additionally, pain or side effects may be measured as a result of inert treatments in order to measure the nocebo effect, the negative counterpart to the placebo effect.
Dr. Sendler: In laboratory experiments, acute pain stimulation (e.g., heat administered through a thermode; Figure 1) can be used to isolate the mechanisms of placebo analgesia and nocebo hyperalgesia by paired with an inert substance that a participant believes is a potent analgesic treatment and then measuring associations between pain and neurobiological responses (Figure 2). Studies have shown that expectations that are based on knowledge taught or learned through experience are critical [,]. As a result, it has been proposed that the placebo effect should be known as a’meaning response’ [] because expectations about treatment are laden with meaning and emotional significance. Additionally, the placebo effect is influenced by the unique psychosocial context of treatment, including the patient–provider interactions that occur. In the following sections, I’ll discuss the latest findings on placebo analgesia’s affective, social, and cognitive influences.
In placebo analgesia, a lot of research has focused on the role of expectation and prediction. People’s implicit and explicit knowledge (e.g., verbal suggestion or instruction) and experience (i.e. conditioning or associative learning) lead to expectations about clinical outcomes, according to models of placebo based on expectancy. It’s possible that a person’s response to conditioning and verbal suggestion differs. Over the course of a few days, for example, a team of researchers administered active treatments to various groups of participants. Tourniquet pain challenge participants received ketorolac tromethamine, Parkinson’s disease patients received subthalamic nucleus stimulation, and healthy volunteers received sumatriptan – which lowers cortisol and raises growth hormone levels. Subsets of participants were informed that they would receive a new treatment that had the opposite effect of the conditioned treatment after this conditioning phase. Researchers administered a placebo to all participants to see if the effects mimicked instructions (i.e., were reversed with the placebo) or were simply the result of conditioning effects (no reversal). Instructions reversed the effects of the placebo on pain and motor performance, but growth hormone and cortisol mirrored conditioning. I This shows that I prior experience and explicit beliefs play a role in placebo effects, and (ii) outcomes may differ in their responsiveness to explicit expectations mediated by verbal instruction. We recently combined this type of instructed reversal with computational models of aversive learning, and found that the striatum and orbitofrontal cortex updated with instructions, while the amygdala learned purely from experience [,]. Next, researchers should investigate whether the dissimilar effects of instructions and learning on placebo effects across different domains are due to the same mechanisms.
Predictive coding can be used to modulate pain in response to both pain-predictive cues and placebo analgesia paradigms. A lot of questions remain, however, including whether and how well cue-based pain modulation paradigms capture the concept of placebo analgesia. A pain-predictive cue tells the brain how strong the next noxious stimulus will be, setting up anticipations for when it will arrive. A brief phasic signal is used for both the cue and the stimulus. As opposed to this, a typical analgesic treatment lasts longer, has a variable onset, and reduces sensitivity to the painful stimulus itself. Morphine patients, for example, aren’t concerned about getting a simple finger prick, or even a shot, as long as they don’t get anything at all. Similar to Kirsch’s distinction between stimulus and response expectations, we refer to cue-based expectations as stimulus expectancies, and placebo-related expectations as treatment expectancies, even though both stimulus and treatment expectancies are likely to induce response expectancies. []. (i.e., expectations for reduced pain).
The fact that cue-based pain modulation is additive to placebo and opioid analgesia [has been previously demonstrated] supports the idea that stimulus and treatment expectations engage separate mechanisms. Tonic -opioid release may be involved in placebo analgesia, while cue-based pain modulation is likely to be mediated by phasic dopamine prediction errors that signal the expected value of the upcoming stimulus. []. Naltrexone has no effect on cue-based pain modulation, which is consistent with the hypothesis that dopamine blockade by haloperidol does not affect placebo analgesia. The striatum and prefrontal cortex showed greater coupling in response to treatment expectancies in a placebo analgesia study that directly compared treatment and stimulus expectancies, such that prediction errors were only observed in response to stimulus expectancies []. As a result, we conducted a meta-analysis that found that treatment expectancies elicited activation decreases in the left insula and increased activation of ventral striatum, PAG, rACC, and other regions; stimulus expectancies were associated with activation increases in the cerebellum, inferior parietal lobule, and lateral prefrontal cortex. Researchers should continue to assess whether stimulus and treatment expectations engage the same mechanisms or reflect distinct pain-modulatory processes in order to determine the validity of our paradigms.
Contrary to popular belief, the placebo effect is not solely a function of one’s expectations, and one’s expectations are not limited to the mind alone. Patients seek treatment because they are in pain, and the ritual of treatment can alleviate pain in two ways: I by reducing negative affect and emotions like anxiety, fear, and stress, and (ii) by increasing positive affect through feelings of trust, hope, and support. Treatment rituals can alleviate pain in both ways. Nocebo effects may also be exacerbated by negative emotions such as anxiety or fear of side effects or outcomes [,]. There is some evidence to suggest that mood and affect are intertwined with placebo effects, but there have been only a few studies to test this hypothesis. Do placebos work by decreasing negative emotions and increasing happy ones?
Several studies have shown that placebos can reduce negative feelings []. Among healthy volunteers, a reduction in fear and anxiety was found when placebo analgesia was used in place of a standard treatment. In patients with neuropathic pain, the opposite was found when placebo analgesia was used. Brain imaging studies have also shown that placebo analgesia is linked to emotional processing, as well. The magnitude of placebo analgesia can be predicted based on anticipatory activity in emotion-related brain networks, but not in regions involved with pain or cognitive control [], and placebo effects for pain and anxiety are associated with overlapping activity in the rostral anterior cingulate cortex (rACC), lateral orbitofrontal cortex (OFC), and ventrolateral prefrontal cortex (VLPFC) [], suggesting common mechanisms of action.
Anxiety has also been linked to nocebo hyperalgesia. The anxiolytic diazepam and the cholecystokinin (CCK) antagonist proglumide can both block the nocebo analgesia that results from nocebo administration. Stress-induced hyperalgesia is primarily mediated by CCK, which can also inhibit opioid-related analgesia in the PAG []. An interesting finding is that pre-existing anxiety does not appear to be a risk factor for nocebo effects [,,], suggesting that anxiety affects outcomes only when it arises as a response to the treatment ritual. The nocebo effect for headaches can be reduced by inducing a positive mood, according to recent behavioral research [,]. Compared to the extensive literature on placebo, fewer studies have examined the neural and psychological mechanisms of nocebo. Nocebo effects can be mitigated in clinical practice if more research is done into the specific factors that cause nocebo effects. In [], a thorough review of the role of affect in placebo and nocebo is provided.
When it comes to placebo or nocebo, it’s likely that the psychosocial treatment context, including patient–provider interactions, play a role. In chronic pain, having a good therapeutic alliance is associated with better outcomes. The attitude and behavior of the physician directly influences clinical outcomes, according to studies on the placebo effect. To compare the placebo effects on allergic reactions, research shows that patients with irritable bowel syndrome benefit more from acupuncture treatments administered by doctors who are warm and empathic, as opposed to those treated by doctors on a waitlist or with a neutral approach []. Health care providers’ characteristics may affect patient mood and emotions in a way that increases the effectiveness of the placebo effect, although studies rarely examine how providers affect patients’ feelings directly. Even before interacting with others, social factors can have an impact on one’s expectations and health outcomes. Recent studies have shown that first impressions of healthcare providers based solely on facial features can influence pain and expectations about pain [,]
There are many factors that influence whether a patient experiences placebo or nocebo effects during a clinical encounter, such as the interaction between the patient and the healthcare provider []. Patients’ responses in simulated clinical interactions are influenced by their perceptions of similarity and empathy. All patients will have different interactions with their health care providers, as well as a different social context in which they are receiving treatment. People who have had negative outcomes or discrimination in a healthcare environment have different expectations than people who have had positive experiences, for example, and experienced discrimination is associated with increased stress and reduced physical and mental health [].
The mechanisms of placebo are well understood, but not everyone responds to placebos in the same way, or at the same rate. Social determinants of health are likely to play a significant role in understanding individual differences in health. Pain treatment for non-white people in the United States is often inadequate, despite the fact that they experience more pain in clinical and laboratory settings [,]. Even healthcare practitioners have false beliefs about the pain that Black people experience because of their skin color []. [White] perceivers are slower to identify pain in Black faces than in white faces, and they are less likely to prescribe pain treatment for the same level of pain in Black than in white faces. Racism and discrimination may also directly influence pain perception in racial and ethnic minority patients, as demonstrated by a recent fMRI study that found that African Americans reported greater pain and heat-related activation in the ventromedial prefrontal cortex (VMPFC), and these associations were larger in participants who had experienced higher levels of discrimination.
Damian Sendler
They may have a direct impact on placebo responses, but research suggests that leveraging the patient–provider interaction could help reduce disparities. There is less trust in doctors for people from racialized groups who have been traumatized and unfairly treated, whereas reported satisfaction is higher when patients see doctors from their own background It has been shown that concordance between the researcher and participant reduces pain in Black participants, but not Hispanic or non-Hispanic white participants [], and the protective effect of concordance was greatest for participants who reported higher levels of experienced discrimination and worry about it. []. In a study of acute pain, Black/African American participants’ higher levels of experienced discrimination were linked to higher levels of pain and stronger brain responses to pain, while perceived similarity was linked to lower expected pain and stronger placebo analgesia across multiple studies. A possible explanation for these results is that non-Hispanic Black participants have lower MOR binding when subjected to painful stimulation []. Researchers studying placebo and nocebo effects should collaborate with those studying health disparities in order to better understand how these effects vary across sociocultural groups, while also taking a cultural neuroscience perspective into consideration. There are more views on the path to racial equality in pain science [].
Damian Jacob Markiewicz Sendler: One step closer to understanding patient–provider interactions is being taken by a new study on the analgesic effects of acupuncture. Neuronal responses in fibromyalgia patients undergoing experimental acute pain and clinicians were simultaneously measured using hyperscanning fMRI scans. Both facial and neural coherence of the patient-provider relationship were measured during electroacupuncture sessions in which real or sham electroacupuncture was used to treat patients’ pain. Real and sham electroacupuncture had similar analgesic effects, indicating that the study provides more insight into placebo effects than into acupuncture per se. The strength of the patient-provider relationship, the provider’s estimated treatment effectiveness, the degree to which patients and providers mirrored each other’s facial expressions during pain anticipation, and other aspects of the patient-provider concordance during pain anticipation were all found to be associated with patient analgesia. An exciting new study shows that therapeutic rapport and acute pain relief are linked in chronic pain. Future research should expand this method to other patient populations and measure interpersonal processes in the context of active treatments that are distinct from placebos.
The potency of placebo analgesia shows that pain is modulated by the combination of expectation, affect, and the social context surrounding treatment. Are these mechanisms specific to pain and how do they work? In the same way that other placebo effects influence expectations, mood, and the unique psychosocial context of the clinic, placebo analgesia is likely to engage similar psychological processes. Clinical outcomes may have similar neural mechanisms that support these psychological processes, but the downstream mediators of placebo effects are likely to be different. Only a few studies have examined placebo effects in relation to other treatments, but more research is being done to determine whether the pain-processing brain mechanisms (which show reductions with placebo) are specific to pain. This section focuses on the brain mechanisms of placebo analgesia and the evidence for pain specificity.
Psychiatric studies of placebo analgesia isolate psychological factors that influence pain response to inert therapy. As a result, in clinical trials, treatments are compared against placebos in an attempt to isolate the effects that are solely caused by a treatment. It is assumed that placebo and treatment effects are additive and independent of each other in this subtraction logic. In a classic 2 2 factorial design, we and others have directly tested these assumptions using a balanced placebo design [], in which treatment instructions – which manipulate expectations – are crossed with actual drug delivery. A treatment that is active is administered to participants who expect a drug and those who do not, while a treatment that is inert is administered to participants who expect a drug and those who do not. A direct comparison of drug effects, placebo/instruction effect interactions, and clinical outcomes can be done using this method. Placebo and the -opioid analgesic remifentanil had additive effects on subjective pain [,] but pure drug effects on heat responses in pain-related regions [,], regardless of instruction, were observed in previous studies. Different patterns of placebo–drug combinations are likely with various doses, pain measures, and analgesics, which is important to note. With the peripherally acting lidocaine analgesic, expectancy–drug interactions have been observed [], and cannabidiol has shown additive effects on conditioned pain modulation and interactive effects on offset analgesia, pain threshold, and pain tolerance. Progress can be made in understanding the psychological factors that underlie placebos and combining them with active treatments in a way that improves patient outcomes and may even reduce the need for pharmacological treatments through further research using the balanced placebo design.
However, thanks to recent advances in neuroimaging analysis and machine learning, we are now able to create accurate pain classifiers and determine the specificity of a given pain experience. To be more specific, the NPS [] is an fMRI-based brain pattern (Figure 2) that predicts whether or not a statistical brain map (i.e., a standard fMRI analysis result) represents pain, and which of two conditions is more painful. One of the most reliable and accurate methods for predicting acute pain in new studies [] and different types of noxious stimuli [] has been developed. Opioid analgesics strongly influence the NPS []. It’s not clear if it’s as effective as a placebo.
A meta-analysis of 20 fMRI studies using placebo analgesia found this to be effective []. With an activation rate of >95 percent in all studies and across the entire participant pool, NPS differences between painful stimulation and baseline had a significant impact on participants’ responses. Subjective pain ratings were moderately influenced by placebo effects in most studies. To be fair to placebo analgesia, NPS reductions were small even when limited to those who responded to placebo (i.e., individuals who reported large reductions in pain with placebo). Emifentanil (a -opioid analgesic) and placebo were directly compared in two studies included in the meta-analysis. Remifentanil’s effect on the NPS was ten times greater than the placebo effect, despite their analgesic potency being similar.
Damien Sendler: Nonnociceptive networks may play a role in the placebo effect on acute pain, according to these findings A subsequent meta-analysis [] found that the insula, habenula, and cerebellum, as well as the ventral attention and somatomotor networks, were the only areas to show consistent reductions across subjects. Strangely enough, the majority of pain-related regions showed inconsistent effects across studies, instead correlating with participants’ individual tolerance for the placebo effect. The DLPFC and rACC were among the regions previously thought to show increases with placebo analgesia, but multiple studies found significant heterogeneity. There is evidence that these modulatory regions may be sensitive to the various contextual factors discussed earlier, such as expectation and the emotional state of the patient, because these factors differed between studies.
The extent to which placebo analgesia studies generalize to different modalities is an important question. Research on placebo analgesia as well as research on placebo and expectancy effects across different modalities can be considered.
Pain-related brain responses have been studied in a number of recent studies comparing noxious stimuli with salient stimuli from other sensory modalities [,,,]. To distinguish between painful and nonnociceptive stimuli, brain activity patterns were matched according to subjective intensity/salience, and all nociceptive regions except the ACC showed stronger activity for painful stimuli in comparison to equally salient touch, sound, or vision. Painful heat and unpleasant sounds were matched on the basis of physiological arousal (a proxy for salience), and brain responses in the posterior parietal operculum distinguished painful stimuli from salient auditory stimuli. Despite the fact that the salience network is activated by pain, some brain responses are specific to pain.
Are placebo analgesia’s specificities the same as those of narcotics? It’s necessary to compare placebo analgesia with other treatments to determine whether the neural and psychological mechanisms of pain modulation are specific to the treatment or if they support placebo effects more broadly. Studies comparing placebo effects in different contexts have been few and far between. A placebo analgesia study in which participants were instructed that a treatment would not only reduce pain but also have an effect on another modality – either to improve motor performance [] or to reduce anxiety [] – was conducted. A standard placebo-analgesia conditioning manipulation was then performed on the participants in the key conditions, in which noxious stimuli were secretly reduced. Both the primary and secondary modality of pain were evaluated in terms of subjective and objective measures. Subjects in each study experienced placebo analgesia and effects in the secondary modality despite never having been conditioned there. For the secondary domain (i.e., improved motor performance [] or altered P2 and N2 amplitudes []), placebo effects were only observed when instructions were paired with placebo conditioning, while placebo effects on subjective outcomes (fatigue [] and unpleasantness ratings []) were observed whether or not subjects underwent conditioning.
Damian Jacob Sendler
A placebo-related expectation can be transferred across modalities, but experiential learning may be required to reinforce expectations based on instructions. Research into the possibility that a placebo could reduce emotional distress as well as physical pain found that even in the absence of conditioning, participants who received a “effective painkiller” experienced less pain from noxious heat and less negative affect when viewing images of rejection than those who received the control condition. Many people show different responses to different placebo interventions within a single modality [], which may be due to their differing expectations about different treatments. This type of cross-modal reaction has been predicted in studies of placebo generalization and transfer, which together suggest that placebo effects can generalize across modalities. Individuals’ differing expectations of different outcomes under basic conditions, on the other hand, may influence the degree to which expectations transfer in natural circumstances.
What is the degree of cross-modality conservation in the brain mechanisms of placebo? Petrovic and colleagues [] compared brain imaging data from a study of placebo analgesia [] with a study of placebo anxiolytics [] in which participants viewed emotional images when they believed they had received an anxiolytic therapy. It has previously been shown that the right lateral OFC, which has been linked to value processing and affective regulation in other studies, has a significant placebo effect on subjective outcomes in both studies. The right VLPFC and the adjacent lateral OFC have been implicated in placebo analgesia [,], emotion regulation [], and social exclusion [], and they may play a general role in regulating negative affect [] and defensive responses [] based on lesion models. Despite this, the lateral OFC was not identified in placebo analgesia meta-analyses [,]. In a recent study, Koban and colleagues directly compared placebo effects on pain and negative feelings when participants viewed images of rejected partners []. Each domain was affected by activation in the right DLPFC, but the responses were distinct both in location and when tested with a classifier. Studies using transcranial magnetic stimulation (TMS) and Alzheimer’s disease prefrontal deterioration (Alzheimer’s disease) have shown that the DLPFC plays a causal role in placebo analgesia []. A large body of research has shown that the DLPFC plays an important role in higher-order cognition and goal-directed behavior [], and these findings are consistent with these findings.
Cross-modal expectancy effects can be better understood through studies of cue-based expectations. Cue-based expectancy effects on painful and nonpainful stimuli have been studied in several recent studies [,] which analyzed the specificity of brain responses. Comparing pain to other unpleasant outcomes (disgusting odors [] or images that were unpleasant) was found to be comparable in terms of unpleasantness. Before stimulation, modality-specific predictive cues were shown, and results from the opposite modality were occasionally followed by tests to see if they induce cross-modal modulation (i.e., pain cues were followed by odors or images). Both domain-specific and domain-independent expectancy effects were mediated by the anterior insula in these studies (i.e. predictions about pain only modulated subjective pain, and predictions about odors or images only modulated responses to nonpainful stimuli). Both studies found that the posterior insula processes pain-specific information in the same way that predictive coding does []. It appears that even if one brain region (the anterior insula) is linked to unpleasantness in various ways (such as placebo effects on physical and social pain), it still performs in a mode-specific manner, as the DLPFC does. From these findings, it is possible to extrapolate that placebo effects may use similar circuits across modalities to support expectations, learning, and affect, but the downstream mechanisms are likely to differ for different clinical outcomes.
Experimental studies of placebo separately manipulate and measure cognitive processes and neural mechanisms that contribute to clinical placebo effects, including learning, instruction, affect, and social interactions, but rarely consider interactions between these various aspects of placebo.. Patients’ expectations may be altered or their anxiety reduced by caring providers, for example. Expectations about pain can influence mood, affect, and emotion in a variety of ways.
Does the placebo effect have a wide range of applications? We may be able to predict whether a person is a “placebo responder” based on biological factors, which should be stable over time within individuals. To the contrary, it may be more likely that placebo responses are influenced by the interaction between the individual and the context in which they are administered.
Clinical populations and clinical trials can be compared to experimental models of placebo analgesia. Experiments on acute pain are not good models for chronic pain because they focus on acute noxious stimuli and do not take into account mechanisms of expectancy-based modulation, such as placebo. It is imperative that basic researchers and clinicians work together to investigate whether and how placebo mechanisms influence outcomes for individual patients, specific pain conditions, and specific treatment contexts.
