Placebo Hypoalgesia Research Articles

A Computational Framework for Understanding the Impact of Prior Experiences on Pain Perception and Neuropathic Pain.

Pain perception is influenced not only by sensory input from afferent neurons but also by cognitive factors such as prior expectations. It has been suggested that overly precise priors may be a key contributing factor to chronic pain states such as neuropathic pain. However, it remains an open question how overly precise priors in favor of pain might arise. Here, we first verify that a Bayesian approach can describe how statistical integration of prior expectations and sensory input results in pain phenomena such as placebo hypoalgesia, nocebo hyperalgesia, chronic pain, and spontaneous neuropathic pain. Our results indicate that the value of the prior, which is determined by the internal model parameters, may be a key contributor to these phenomena. Next, we apply a hierarchical Bayesian approach to update the parameters of the internal model based on the difference between the predicted and the perceived pain, to reflect that people integrate prior experiences in their future expectations. In contrast with simpler approaches, this hierarchical model structure is able to show for placebo hypoalgesia and nocebo hyperalgesia how these phenomena can arise from prior experiences in the form of a classical conditioning procedure. We also demonstrate the phenomenon of offset analgesia, in which a disproportionally large pain decrease is obtained following a minor reduction in noxious stimulus intensity. Finally, we turn to simulations of neuropathic pain, where our hierarchical model corroborates that persistent non-neuropathic pain is a risk factor for developing neuropathic pain following denervation, and additionally offers an interesting prediction that complete absence of informative painful experiences could be a similar risk factor. Taken together, these results provide insight to how prior experiences may contribute to pain perception, in both experimental and neuropathic pain, which in turn might be informative for improving strategies of pain prevention and relief.

Integration of Prior Expectations and Suppression of Prediction Errors During Expectancy-Induced Pain Modulation: The Influence of Anxiety and Pleasantness.

Pain perception arises from the integration of prior expectations with sensory information. Although recent work has demonstrated that treatment expectancy effects (e.g., placebo hypoalgesia) can be explained by a Bayesian integration framework incorporating the precision level of expectations and sensory inputs, the key factor modulating this integration in stimulus expectancy-induced pain modulation remains unclear. In a stimulus expectancy paradigm combining emotion regulation in healthy male and female adults, we found that participants' voluntary reduction in anticipatory anxiety and pleasantness monotonically reduced the magnitude of pain modulation by negative and positive expectations, respectively, indicating a role of emotion. For both types of expectations, Bayesian model comparisons confirmed that an integration model using the respective emotion of expectations and sensory inputs explained stimulus expectancy effects on pain better than using their respective precision. For negative expectations, the role of anxiety is further supported by our fMRI findings that (1) functional coupling within anxiety-processing brain regions (amygdala and anterior cingulate) reflected the integration of expectations with sensory inputs and (2) anxiety appeared to impair the updating of expectations via suppressed prediction error signals in the anterior cingulate, thus perpetuating negative expectancy effects. Regarding positive expectations, their integration with sensory inputs relied on the functional coupling within brain structures processing positive emotion and inhibiting threat responding (medial orbitofrontal cortex and hippocampus). In summary, different from treatment expectancy, pain modulation by stimulus expectancy emanates from emotion-modulated integration of beliefs with sensory evidence and inadequate belief updating.

Can observational learning reinforce open-label placebo hypoalgesia?

Previous research has indicated that an open-label placebo can reduce pain in both healthy participants and patients with chronic pain. Because nondeceptive placebos seem to be an effective and more ethical alternative to deceptive placebos, optimizing this kind of treatment is essential. Observational learning was previously shown to induce the deceptive placebo effect; therefore, this study aimed to verify its effectiveness in fortifying the open-label placebo effect. Healthy volunteers (N = 117) were randomly assigned to 4 groups: open-label placebo with observational learning (OLP + OBL), open-label placebo (OLP), deceptive placebo with observational learning (OBL), or control group. Participants underwent baseline and testing measurements, during which they self-reported pain induced by heat stimulation. Between assessments, placebo cream was openly administered in the OLP and OLP + OBL groups. The OLP + OBL group next watched a model experiencing hypoalgesia after cream application. In the OBL group, participants received placebo cream with no information about its effect, and then they watched the model. The placebo effect was successfully evoked in all experimental groups (OLP + OBL, OLP, and OBL), which confirms the effectiveness of both open-label and deceptive placebo interventions for pain reduction. However, the hypoalgesic effect was of similar magnitude in the OLP and OLP + OBL groups, which indicates that observation did not contribute to the effect. The results showed that reinforcing the open-label placebo by observational learning may be redundant, but more research is needed to confirm these findings.

Placebo hypoalgesia induced by operant conditioning: a comparative study on the effects of verbal, token-based, and social rewards and punishers

Operant conditioning was shown to be a mechanism of placebo hypoalgesia; however, only verbal rewards and punishers were applied in the previous study. We aimed to induce placebo hypoalgesia using more clinically relevant consequences: token-based and social. Participants were divided into three experimental groups (with verbal, social, and token-based rewards and punishers); and two control groups (with and without placebo application). During operant conditioning, participants in the experimental groups received thermal stimuli of equal intensity and were rewarded for reporting lower pain and punished for reporting higher pain compared to their pretest pain levels. The control groups did not receive any consequences. Our results revealed placebo hypoalgesia was induced by operant conditioning only in the experimental groups with social and token-based reinforcement, compared to the control groups. The hypoalgesic effect found in the group that received verbal reinforcement did not differ significantly from the control group with the placebo application. Moreover, expectations about upcoming pain intensity were found to be a mediator, and the number of reinforcers received during conditioning was a predictor of placebo hypoalgesia. These findings highlight the potential benefits of incorporating token-based and social consequences for optimizing treatment outcomes in pain management.

Open-label placebo hypoalgesia: what works for whom under which circumstances.

Open-label placebo hypoalgesia: what works for whom under which circumstances.

Placebo Hypoalgesia and Nocebo Hyperalgesia Induced by Observational Learning May Be Difficult to Disentangle in a Laboratory Setting

Observational learning (OBL) (seeing pain/pain treatment in others) can evoke placebo hypoalgesia and nocebo hyperalgesia. Data that compare these effects and illuminates the role of expectations and empathy are scarce. Healthy participants (n = 105) were randomized to: 1) placebo OBL, 2) nocebo OBL, or 3) no-observation control group. OBL consisted of a model simulating pain relief or increase after a sham ointment was applied to one arm. Pain was evoked with thermal stimuli on both arms (ointment, contralateral) at baseline and postobservation. Expectations, pain ratings, and physiological data (eg, skin conductance level) were collected. A 3 × 2 × 2 (Group × Arm × Phase) mixed analyses of variance revealed a 3-way interaction that confirmed that OBL modulates pain: F(2, 93) = 6.08, P = .003, ηp2 = .12. Significant baseline-to-post-observation pain increases were shown in the nocebo OBL group, with a bigger increase for the arm with ointment (both P ≤ .007). In the placebo OBL group, pain was higher for the contralateral relative to the ointment arm (P < .001). Baseline-to-post-observation pain increase was significant for the contralateral arm (P < .001). Expectation mediated these effects. Skin conductance level decreased over time during ointment trials in the nocebo OBL group, suggesting reduced physiological arousal. The findings illustrate that OBL modulates pain through expectations. In the placebo OBL group, the pain did not decrease for the ointment but increased for the contralateral stimuli, which may reflect nocebo learning. Experimental OBL paradigms typically examine relative differences between ointment and contralateral cues. This can complicate disentangling placebo hypoalgesia and nocebo hyperalgesia in laboratory settings. Implications for existing theories are discussed. PerspectiveData that systematically compare placebo hypoalgesia and nocebo hyperalgesia induced by OBL are scarce. The current work illustrates that these effects may be more difficult to disentangle than previously assumed, which could have implications for existing theories on OBL and placebo effects and their translation to clinical practice.

Baseline heart rate variability predicts placebo hypoalgesia in men, but not women.

Placebo hypoalgesic effects vary greatly across individuals, making them challenging to control for in clinical trials and difficult to use in treatment. We investigated the potential of resting vagally-mediated heart rate variability (vmHRV) to help predict the magnitude of placebo responsiveness. In two independent studies (total N = 77), we administered a placebo paradigm after measuring baseline HRV. In Study I, we delivered heat pain to the forearm, on skin patches treated with "real" and "control" cream (identical inactive creams). In Study II, electrical pulses to the forearm were modulated by sham transcutaneous electrical nerve stimulation. We combined data from both studies to evaluate the relationship between vagally-mediated HRV (vmHRV) parameters and the placebo response size, while also assessing sex differences in this relationship. This revealed a positive association between vmHRV and the degree of pain relief, and this effect was driven by men. These results not only reveal new insights into the (sex-specific) mechanisms of placebo hypoalgesia, but also suggest that measuring vmHRV may be helpful in predicting placebo responsiveness. Given that placebo hypoalgesic effects contribute substantially to treatment outcomes, such a non-invasive and easily obtained predictor would be valuable in the context of personalized medicine.

Choice Enhances Placebo Hypoalgesia More in Weaker Placebo Contexts: A Partial Reinforcement Study

Providing individuals with choice over treatment has been found to enhance placebo hypoalgesia. However, this choice effect is not always present. The current study tested whether the strength of the placebo context influenced the effect of choice on placebo hypoalgesia. Using an established electrocutaneous pain paradigm, the choice effect was compared when placebo hypoalgesia was induced by Continuous Reinforcement (CRF) (strong placebo context) versus partial reinforcement (PRF) (weak placebo context). Healthy volunteers (N = 133) were randomized to receive either choice over treatment administration or no choice and then to placebo conditioning under either CRF (placebo always followed by surreptitious pain reduction during training) or PRF (placebo only followed by surreptitious pain reduction on half of the training trials). At the test, placebo hypoalgesia was greater and more resistant to extinction overall for those with choice. Importantly, however, the choice effect in enhancing the magnitude of placebo hypoalgesia was stronger after PRF than CRF. These results indicate that choice may have greater placebo-enhancing power in weaker placebo contexts. Therefore, choice may be a cheap and effective tool for improving clinical outcomes by facilitating placebo hypoalgesia when the existing treatment context is insufficient to produce placebo hypoalgesia itself. PerspectiveThis study demonstrates that the enhancing effect of choice on placebo hypoalgesia is greater in a weaker placebo context. As such, offering choice could be an ethical way to effectively improve pain outcomes when placebo effects cannot be readily produced by the treatment context.

Learning pain from others: a systematic review and meta-analysis of studies on placebo hypoalgesia and nocebo hyperalgesia induced by observational learning.

Observing someone experience pain relief or exacerbation after an intervention may induce placebo hypoalgesia or nocebo hyperalgesia. Understanding the factors that contribute to these effects could help in the development of strategies for optimizing treatment of chronic pain conditions. We systematically reviewed and meta-analyzed the literature on placebo hypoalgesia and nocebo hyperalgesia induced by observational learning (OL). A systematic literature search was conducted in the databases PubMed, PsycINFO, Web of Science, ScienceDirect, PsycARTICLES, Scopus, and Academic Search Ultimate. Twenty-one studies were included in the systematic review, 17 of which were suitable for meta-analysis (18 experiments; n = 764 healthy individuals). The primary end point was the standardized mean difference (SMD) for pain following placebo cues associated during OL with low vs high pain. Observational learning had a small-to-medium effect on pain ratings (SMD 0.44; 95% confidence interval [CI] 0.21-0.68; P < 0.01) and a large effect on pain expectancy (SMD 1.11; 95% CI 0.49-2.04; P < 0.01). The type of observation (in-person vs videotaped) modulated the magnitude of placebo hypoalgesia/nocebo hyperalgesia (P < 0.01), whereas placebo type did not (P = 0.23). Finally, OL was more effective when observers' empathic concern (but no other empathy-related factors) was higher (r = 0.14; 95% CI 0.01-0.27; P = 0.03). Overall, the meta-analysis demonstrates that OL can shape placebo hypoalgesia and nocebo hyperalgesia. More research is needed to identify predictors of these effects and to study them in clinical populations. In the future, OL could be an important tool to help maximize placebo hypoalgesia in clinical settings.

Yoga and massage are associated with small experimental placebo effects in chronic orofacial pain.

Complementary and Integrative Health Approaches (CIHA), including but not limited to, natural products and Mind and Body Practices (MBPs), are promising non-pharmacological adjuvants to the arsenal of pain management therapeutics. We aim to establish possible relationships between use of CIHA and the capacity of descending pain modulatory system in the form of occurrence and magnitude of placebo effects in a laboratory setting. This cross-sectional study investigated the relationship between self-reported use of CIHA, pain disability, and experimentally induced placebo hypoalgesia in chronic pain participants suffering from Temporomandibular Disorders (TMD). In the 361 enrolled TMD participants, placebo hypoalgesia was measured using a well-established paradigm with verbal suggestions and conditioning cues paired with distinct heat painful stimulations. Pain disability was measured with the Graded Chronic Pain Scale, and use of CIHA were recorded with a checklist as part of the medical history. Use of physically oriented MBPs (e.g., yoga and massage) was associated with reduced placebo effects (F1,2110.44 = 23.15, p < 0.001, Cohen's d = 0.171). Further, linear regressions indicated that greater number of physically oriented MBPs predicted smaller placebo effects (β = -0.17, p = 0.002), and less likelihood of being a placebo responder (OR = 0.70, p = 0.004). Use of psychologically oriented MBPs and natural product were not associated with placebo effects magnitude and responsiveness. Our findings suggest that use of physically oriented CIHA was associated with experimental placebo effects possibly through an optimized capability to recognize distinct somatosensorial stimulations. Future research is needed to understand the mechanisms underlying placebo-induced pain modulation in CIHA users. Chronic pain participants who use physically oriented mind-body practices, such as yoga and massage, demonstrated attenuated experimentally induced placebo hypoalgesia in comparison with those who do not use them. This finding disentangled the relationship between use of complementary and integrative approaches and placebo effects, providing the potential therapeutic perspective of endogenous pain modulation in chronic pain management.

Parabrachial Projections to PAG-RVM Axis May Promote Placebo Hypoalgesia and Nocebo Hyperalgesia.

Pain is a hallmark of many ailments and represents an important signal of health and well being. Therefore, understanding how nociceptive signals are transmitted and the pathways that promote pain perception and modulation is fundamental to health care. Pain modulation can occur not only via

Who are the placebo responders? A cross-sectional cohort study for psychological determinants.

A number of studies have demonstrated substantial individual differences in placebo effects. We aimed to identify individual psychological factors that potentially predicted the magnitude of placebo hypoalgesia and individual responsiveness. The Research Domain Criteria framework and a classical conditioning with suggestions paradigm were adopted as experimental models to study placebo phenotypes in a cohort of 397 chronic pain participants with a primary diagnosis of temporomandibular disorder (TMD) and 397 healthy control (HC) participants. The magnitude of placebo hypoalgesia was operationalized as the average difference in pain ratings between the placebo and control conditions. The individual placebo responsiveness was identified as the status of placebo responders and nonresponders based on a permutation test. We observed significant placebo effects in both TMD and HC participants. A greater level of emotional distress was a significant predictor of smaller magnitude (slope b = -0.07) and slower extinction rate (slope b = 0.51) of placebo effects in both TMD and HC participants. Greater reward seeking was linked to greater postconditioning expectations (ie, reinforced expectations) in TMD (slope b = 0.16), but there was no such a prediction in HC participants. These findings highlight that negative valence systems might play a role in impairing placebo effects, with a larger impact in chronic pain participants than in healthy participants, suggesting that individuals reporting emotional distress and maladaptive cognitive appraisals of pain may benefit less from placebo effects.

When one suffers less, all suffer less: Individual pain ratings are more effective than group ratings in producing placebo hypoalgesia.

BackgroundPlacebo hypoalgesia can be induced by observing a person (model) whose pain relief is the result of the use of an inert substance or procedure. This study examined whether verbal modelling, that is, showing pain ratings provided by other people, is sufficient to induce placebo hypoalgesia.MethodsParticipants from the experimental groups were acquainted with pain ratings (presented on VASs) derived from a single person (groups 1 and 3) or a group of people (groups 2 and 4) that were allegedly subjected to the same painful procedure. The ratings of pain stimuli that were allegedly applied with placebo were lower than the ratings of stimuli applied without placebo. In two of the experimental groups (group 3 and 4), participants also watched a video recording showing individuals who allegedly provided pain ratings; however, they did not observe them undergoing pain stimulation. The control group did not undergo any manipulation. Then, the participants received a series of the same thermal pain stimuli that were applied either with or without placebo and rated their intensity.ResultsPlacebo hypoalgesia was induced only in participants presented with pain ratings provided by a single person, regardless of whether this person was previously seen. However, the pain ratings presented to the participants generally decreased individual pain sensations, regardless of whether they came from a group of people or a single person.ConclusionsVerbal modelling can produce placebo hypoalgesia and reduce pain sensations. It may be effectively used in clinical practice to modify patients' responses to pain treatment.SignificanceThis study shows that knowledge about pain ratings provided by another person is sufficient to induce placebo hypoalgesia; thus, neither direct nor indirect observation of a person experiencing pain is necessary to induce this effect. Pain ratings derived from a group of people can decrease pain sensations but they do not produce placebo hypoalgesia.

Direct Verbal Suggestibility as a Predictor of Placebo Hypoalgesia Responsiveness.

Reliably identifying good placebo responders has pronounced implications for basic research on, and clinical applications of, the placebo response. Multiple studies point to direct verbal suggestibility as a potentially valuable predictor of individual differences in placebo responsiveness, but previous research has produced conflicting results on this association. In two double-blind studies, we examined whether behavioral direct verbal suggestibility measures involving a correction for compliance would be associated with individual differences in responsiveness to conditioned and unconditioned placebo hypoalgesia using an established placebo analgesia paradigm. In study 1 (n = 57; mean [standard deviation] age = 23.7 [8.1] years; 77% women), we used behavioral hypnotic suggestibility as a predictor of placebo hypoalgesia induced through conditioning and verbal suggestion, whereas in study 2 (n = 78; mean [standard deviation] = 26.1 [7.4] years; 65% women), we measured nonhypnotic suggestibility and placebo hypoalgesia induced through verbal suggestion without conditioning. In study 1, the placebo hypoalgesia procedure yielded a moderate placebo response (g = 0.63 [95% confidence interval = 0.32 to 0.97]), but the response magnitude did not significantly correlate with hypnotic suggestibility (rs = 0.11 [-0.17 to 0.37]). In study 2, the placebo procedure did not yield a significant placebo response across the full sample (g = 0.11 [-0.11 to 0.33]), but the magnitude of individual placebo responsiveness significantly correlated with nonhypnotic suggestibility (rs = 0.27 [0.03 to 0.48]). These results suggest that the extent to which direct verbal suggestibility captures variability in placebo responsiveness depends on the use of conditioning and highlights the utility of suggestibility as a potential contributing factor to placebo responding when placebo hypoalgesia is induced through verbal suggestions.

Order does matter: the combined effects of classical conditioning and verbal suggestions on placebo hypoalgesia and nocebo hyperalgesia.

In most experimental studies in which verbal suggestion and classical conditioning are implemented together to induce placebo effects, the former precedes the latter. In naturally occurring situations, however, the information concerning pain does not always precede but often follows the pain experience. Moreover, this information is not always congruent with experience. This study investigates whether the chronology of verbal suggestion and conditioning, as well as their congruence, affects placebo hypoalgesia and nocebo hyperalgesia. The effects induced in 15 groups were compared. The participants in 8 experimental groups were presented with verbal suggestions that were either congruent or incongruent with classical conditioning. The verbal suggestions were provided either before or after conditioning. In 2 other experimental groups, placebo conditioning or nocebo conditioning was implemented without any verbal suggestion; in 2 groups, verbal suggestion of hypoalgesia or hyperalgesia without conditioning was applied. The control groups without any suggestions or conditioning were also included. Placebo hypoalgesia induced by congruent procedures was significantly stronger when the suggestion of hypoalgesia preceded rather than followed conditioning. The order of the congruent procedures did not affect the magnitude of nocebo hyperalgesia. In the groups in which incongruent procedures were implemented, placebo hypoalgesia or nocebo hyperalgesia was in line with the direction of the last-used procedure, regardless of whether it was conditioning or verbal suggestion. The results show that not the type of the procedure (verbal suggestion or conditioning), but the direction of the last-used procedure shapes pain-related expectancies and determines placebo effects.

Placebo hypoalgesia: racial differences.

No large-cohort studies that examine potential racial effects on placebo hypoalgesic effects exist. To fill this void, we studied placebo effects in healthy and chronic pain participants self-identified as either African American/black (AA/black) or white. We enrolled 372 study participants, 186 with a diagnosis of temporomandibular disorder (TMD) and 186 race-, sex-, and age-matched healthy participants to participate in a placebo experiment. Using a well-established paradigm of classical conditioning with verbal suggestions, each individual pain sensitivity was measured to calibrate the temperatures for high- and low-pain stimuli in the conditioning protocol. These 2 temperatures were then paired with a red and green screen, respectively, and participants were told that the analgesic intervention would activate during the green screens to reduce pain. Participants then rated the painfulness of each stimulus on a visual analog scale ranging from 0 to 100. Racial influences were tested on conditioning strength, reinforced expectations, and placebo hypoalgesia. We found that white participants reported greater conditioning effects, reinforced relief expectations, and placebo effects when compared with their AA/black counterparts. Racial effects on placebo were observed in TMD, although negligible, short-lasting, and mediated by conditioning strength. Secondary analyses on the effect of experimenter-participant race and sex concordance indicated that same experimenter-participant race induced greater placebo hypoalgesia in TMDs while different sex induced greater placebo hypoalgesia in healthy participants. This is the first and largest study to analyze racial effects on placebo hypoalgesia and has implications for both clinical research and treatment outcomes.

The neural processes of acquiring placebo effects through observation

Learning through social observation is critical for humans. The present study investigates the neural processes underlying the acquisition of placebo effects through observational learning. We created a new functional magnetic resonance imaging (fMRI) paradigm where participants (n ​= ​38, healthy, both sexes) observed a demonstrator experiencing pain relief by a placebo treatment cream and experiencing pain without a treatment (control cream), and subsequently performed the same procedure themselves.Participants demonstrated placebo hypoalgesia while they performed the procedure themselves, confirming that observational learning can lead to placebo effects. During the observational learning phase, fMRI analysis showed a modulation of the amygdalae, periaqueductal grey, temporoparietal junctions (TPJ), and dorsolateral prefrontal cortex (DLPFC). Connectivity between the DLPFC and TPJ during the observational learning task was modulated by the placebo treatment and predicted subsequent placebo effects. Mediation analysis further confirmed that the DLPFC-TPJ connectivity formally mediated the effect of the observed treatment condition on subsequent placebo effects. Additionally, pre-recorded resting state connectivity between the DLPFC and TPJ also predicted observationally-learned placebo effects. Our findings provide an understanding of the neural processes during the acquisition of placebo effects through observation and indicate a critical role for DLPFC-TPJ integration processes during observational learning of therapeutic outcomes.

Neural and behavioral changes driven by observationally-induced hypoalgesia

Observing successful pain treatment in others can induce anticipatory neural processes that, in turn, relieve pain. Previous studies have suggested that social learning and observation influence placebo hypoalgesia. Here, we used electroencephalography (EEG) to determine the neurophysiological changes associated with pain relief acquired through the observation. Thirty-one participants observed a demonstrator undergo painful heat stimulations paired with a “control” cream and non-painful ones paired with a “treatment” cream, which actually were both Vanicreams. After their observation, the participants then received the same creams and stimulations. We found that the treatment cream led to lower self-reported pain intensity ratings than the control cream. Anticipatory treatment cues elicited smaller P2 in electrodes F1, Fz, FC1, and FCz than the control condition. The P2 component localization indicated a higher current density in the right middle frontal gyrus, a region associated with attentional engagement. In placebo responders, the sensorimotor cortex activity captured in electrodes C3, Cz, and C4 indicated that hypoalgesia was positively correlated with resting state peak alpha frequency (PAF). These results suggest that observationally-induced placebo hypoalgesia may be driven by anticipatory mechanisms that modulate frontal attentional processes. Furthermore, resting state PAF could serve as a predictor of observationally-induced hypoalgesia.

OPRM1 rs1799971, COMT rs4680, and FAAH rs324420 genes interact with placebo procedures to induce hypoalgesia.

Genetics studies on the placebo hypoalgesic effect highlight a promising link between single nucleotide polymorphisms (SNPs) in the dopamine, opioid, and endocannabinoid genes and placebo hypoalgesia. However, epistasis and replication studies are missing. In this study, we expanded on previous findings related to the 3 SNPs in the opioid receptor mu subunit (OPRM1 rs1799971), catechol-O-methyltransferase (COMT rs4680), and fatty acid amide hydrolase (FAAH rs324420) genes associated with placebo hypoalgesia and tested the effect of a 3-way interaction on placebo hypoalgesia. Using 2 well-established placebo procedures (verbal suggestion and learning paradigm), we induced significant placebo hypoalgesic effects in 160 healthy participants. We found that individuals with OPRM1 AA combined with FAAH Pro/Pro and those carrying COMT met/met together with FAAH Pro/Pro showed significant placebo effects. Participants with COMT met/val alleles showed significant placebo effects independently of OPRM1 and FAAH allele combinations. Finally, the model that included the placebo procedure and genotypes predicted placebo responsiveness with a higher accuracy (area under the curve, AUC = 0.773) as compared to the SNPs alone indicating that genetic variants can only partially explain the placebo responder status. Our results suggest that the endogenous mu-opioid system with a larger activation in response to pain in the met/val allele carriers as well as the synergism between endogenous mu-opioid system and cannabinoids might play the most relevant role in driving hypoalgesic responses. Future epistasis studies with larger sample sizes will help us to fully understand the complexity of placebo effects and explain the mechanisms that underlie placebo responsiveness.

Placebo Responses in Chronic Pain: State of Research and Clinical Implications

Placebo hypoalgesia has been found to play an important role in every health care by modulating patients' responses to pharmacologically active analgesic treatments. It may be seen as reflecting the capacity for endogenous pain modulation. Enhancing the efficacy of analgesic treatments by boosting endogenous pain modulation might be particularly relevant for chronic pain patients. Research into placebo hypoalgesic responses to chronic pain is sparse, however. In healthy subjects, placebo hypoalgesia is induced by expectations of pain relief through verbal information and learning experiences. Here we review the existing evidence on placebo hypoalgesia to chronic pain. To our knowledge, placebo hypoalgesia to chronic pain has been investigated experimentally in chronic back and chronic musculoskeletal pain, neuropathic pain after thoracotomy, and episodic migraine. Results point towards a maintenance of placebo hypoalgesic responses in chronic pain populations, thus highlighting the potential benefit of boosting placebo hypoalgesic responses in the treatment of chronic pain. Strategies on boosting placebo hypoalgesic responses in every day healthcare are presented.