Factors associated with use of opioid rescue medication after surgery.

BACKGROUND: Opioid exposure after surgery increases risk of persistent opioid use. Here, we characterize at-home use of opioid rescue medication during 1-2 days after outpatient surgery (N=270) in a postoperative opioid-sparing context at a Norwegian hospital. METHODS: The postsurgical pain management plan included non-steroidal anti-inflammatory drugs and up to six pills of 5 mg oxycodone as rescue analgesics. In this observational study we assessed risk factors for taking rescue opioids after surgery, by comparing patients who did, with those who did not. RESULTS: Only 35% (N=228) of patients reported taking rescue opioids 1-2 days after discharge. Patients taking rescue opioids after surgery (opioid-takers) differed from non-takers by prevalence of preoperative chronic pain (>3 months; 74% vs 48%), higher pain severity and interference before and after surgery, reporting lower ability to cope with postsurgical pain, higher nervousness about the surgery, being younger, and having received more opioid analgesics in the recovery room. Exploratory predictive modeling identified opioid administration in the recovery room as the most important predictor of at-home rescue medication use. Follow-up after >4 months indicated low acute pain levels (mean±SD = 1.1±1.8), with only four patients (2%, N=217) reporting opioid analgesic use. CONCLUSION: Factors related to at-home rescue medication use closely mirrored known risk factors for persistent opioid use after surgery, such as prior chronic pain, prior substance use, affective disturbances, and pain severity before surgery. These findings are potential targets in patient-centered care. Nevertheless, and reassuringly, findings are consistent with the idea that opioid-sparing postsurgical care can prevent large-scale chronic opioid use.

Opioid antagonism in humans: a primer on optimal dose and timing for central mu-opioid receptor blockade.

Non-human animal studies outline precise mechanisms of central mu-opioid regulation of pain, stress, affiliation and reward processing. In humans, pharmacological blockade with non-selective opioid antagonists such as naloxone and naltrexone is typically used to assess involvement of the mu-opioid system in such processing. However, robust estimates of the opioid receptor blockade achieved by opioid antagonists are missing. Dose and timing schedules are highly variable and often based on single studies. Here, we provide a detailed analysis of central opioid receptor blockade after opioid antagonism based on existing positron emission tomography data. We also create models for estimating opioid receptor blockade with intravenous naloxone and oral naltrexone. We find that common doses of intravenous naloxone (0.10-0.15 mg/kg) and oral naltrexone (50 mg) are more than sufficient to produce full blockade of central MOR (>90% receptor occupancy) for the duration of a typical experimental session (~60 min), presumably due to initial super saturation of receptors. Simulations indicate that these doses also produce high KOR blockade (78-100%) and some DOR blockade (10% with naltrexone and 48-74% with naloxone). Lower doses (e.g., 0.01 mg/kg intravenous naloxone) are estimated to produce less DOR and KOR blockade while still achieving a high level of MOR blockade for ~30 min. The models and simulations form the basis of two novel web applications for detailed planning and evaluation of experiments with opioid antagonists. These tools and recommendations enable selection of appropriate antagonists, doses and assessment time points, and determination of the achieved receptor blockade in previous studies.

Stress recovery with social support: A dyadic stress and support task.

How does social support bolster resilience? Here, we present a new dyadic paradigm to study causal mechanisms of acute and ecologically valid social support in the laboratory. The Dyadic Stress and Support Task (DSST) consists of a psychosocial stress phase and a recovery phase. During DSST stress, a pair of participants take turns to perform public speaking and mental arithmetic in front of a panel. Unable to see or touch each other, they witness each other's performance and feedback. During DSST recovery, the pair either interact freely with each other for 5 min (social support condition) or interact separately with an experimenter (non-support condition). To establish the validity of the DSST, we tested 21 pairs of long-term close friends in a pilot study. Primary outcome measures were ratings of affective state and bodily arousal (VAS scales 0-100). Secondary outcome measures were heart rate and salivary cortisol. DSST stress successfully induced subjective Stress Activation, increased Negative Affect and decreased Positive Affect. We also observed increased heart rate and salivary cortisol. After DSST recovery, Stress Activation and Negative Affect ratings were reduced in both groups. Positive Affect was completely restored to pre-stress baseline levels in the Social support group, while remaining significantly lower in the Non-support group. The DSST successfully induced stress and negative affect and captured stress recovery in both groups. Free-form interaction with the friend enhanced recovery of affective state, supporting the validity of spontaneous interaction between friends as a model of social support.

Mental health and use of health care services in opioid-exposed school-aged children compared to foster children.

Given the concerns raised regarding the effects of prenatal exposure to methadone and buprenorphine on the developmental outcomes of the children, this study assessed mental health and use of services in a national sample of school-aged children (N = 78) born to women enrolled in opioid maintenance treatment during pregnancy, compared with a group of foster children (N = 140). The majority of the opioid-exposed children lived with their birth parent(s) at the time of assessment (N = 62), while 16 lived in foster homes. Caregivers completed the Strengths and Difficulties Questionnaire (SDQ) and the Reactive Attachment Disorder scale. Teachers completed the SDQ. Three kinds of services were included in measuring service use: school-based education services, child mental health services, and hospital-based habilitation services. The main finding of the study is that children prenatally exposed to methadone or buprenorphine living with their family of origin had significantly better mental health status than their foster-placed counterparts and that of the comparison group of foster children. In addition, the exposed children living at home had less child welfare involvement, and only half of them were using any of the three services measured. The odds for using services increased significantly in accordance with increasing mental health problems, independent of group affiliation, indicating a need-based access to services. In line with other studies, we found that the odds for using one or more services was 2.3 times greater for boys than for girls. Our results contribute to a more-nuanced understanding of the developmental outcomes of prenatal exposure to methadone and buprenorphine, and factors associated with increased service use in groups of at-risk children.

Children born to women in opioid maintenance treatment: A longitudinal study of child behavioral problems and parenting stress.

In the wake of the "opioid epidemic", there is considerable concern regarding potential harmful long-term effects of prenatal opioid exposure. Opioid misuse and addiction confer increased exposure to lifestyle stressors and health burdens. Accordingly, it is challenging to disentangle effects of prenatal opioid exposure per se from factors related to maternal stress. In this study, we followed 36 women enrolled in comprehensive opioid maintenance treatment (OMT) program and their children alongside 36 age-matched mother-child dyads from a community sample (COMP) from pregnancy until child-age 8 years. Across five sessions, we used a battery of well-established questionnaires to investigate trajectories of parenting stress and mental health symptoms as well as child behavior problems. The 8-year retention was relatively high (OMT: 72%, COMP: 67%), and the OMT sample remarkably stable and well-functioning, with minimal concomitant illicit drug use. Mixed effects regressions showed significantly different trajectories of child behavior problems (F = 3.8, p = 0.024) and parenting stress (F = 3.1, p = 0.016) in the two groups. Differences in experienced stress were largely explained by more distress specifically related to the parenting role in the OMT group (F = 9.7, p = 0.003). The OMT sample also reported higher psychological distress (F = 15.6, p < 0.001) than the comparison group, but notably few participants presented with problems that warranted clinical intervention. The results underscore the benefits of tailored follow-up of children prenatally exposed to opioids and their families beyond infancy and toddlerhood. Long-term direct effects of prenatal opioid exposure on behavior problems are likely modest, given an otherwise stable caregiving environment conducive to healthy development.

The Role of Mu-Opioids for Reward and Threat Processing in Humans: Bridging the Gap from Preclinical to Clinical Opioid Drug Studies.

PURPOSE OF REVIEW: Opioid receptors are widely expressed in the human brain. A number of features commonly associated with drug use disorder, such as difficulties in emotional learning, emotion regulation and anhedonia, have been linked to endogenous opioid signalling. Whereas chronic substance use and misuse are thought to alter the function of the mu-opioid system, the specific mechanisms are not well understood. We argue that understanding exogenous and endogenous opioid effects in the healthy human brain is an essential foundation for bridging preclinical and clinical findings related to opioid misuse. Here, we will examine psychopharmacological evidence to outline the role of the mu-opioid receptor (MOR) system in the processing of threat and reward, and discuss how disruption of these processes by chronic opioid use might alter emotional learning and reward responsiveness. RECENT FINDINGS: In healthy people, studies using opioid antagonist drugs indicate that the brain's endogenous opioids downregulate fear reactivity and upregulate learning from safety. At the same time, endogenous opioids increase the liking of and motivation to engage with high reward value cues. Studies of acute opioid agonist effects indicate that with non-sedative doses, drugs such as morphine and buprenorphine can mimic endogenous opioid effects on liking and wanting. Disruption of endogenous opioid signalling due to prolonged opioid exposure is associated with some degree of anhedonia to non-drug rewards; however, new results leave open the possibility that this is not directly opioid-mediated. SUMMARY: The available human psychopharmacological evidence indicates that the healthy mu-opioid system contributes to the regulation of reward and threat processing. Overall, endogenous opioids can subtly increase liking and wanting responses to a wide variety of rewards, from sweet tastes to feelings of being connected to close others. For threat-related processing, human evidence suggests that endogenous opioids inhibit fear conditioning and reduce the sensitivity to aversive stimuli, although inconsistencies remain. The size of effects reported in healthy humans are however modest, clearly indicating that MORs play out their role in close concert with other neurotransmitter systems. Relevant candidate systems for future research include dopamine, serotonin and endocannabinoid signalling. Nevertheless, it is possible that endogenous opioid fine-tuning of reward and threat processing, when unbalanced by e.g. opioid misuse, could over time develop into symptoms associated with opioid use disorder, such as anhedonia and depression/anxiety.

A randomized placebo-controlled intranasal oxytocin study on first impressions and reactions to social rejection.

Oxytocin is central to pair-bonding in non-human animals. We assessed effects of intranasal oxytocin on bond formation between two opposite-sex strangers. In a double-blind placebo-controlled design, 50 pairs of one man and one woman received oxytocin or placebo spray intranasally. After treatment, they played a social interaction game, followed by tasks designed to measure first impressions of the opposite-sex co-participant, and a virtual ball-tossing game (cyberball), designed to measure reactions to rejection by the co-participant. We found no evidence that intranasal oxytocin can improve first impressions of an opposite-sex stranger, and some Bayesian support against this hypothesis. For rejection sensitivity, we observed a sex-and-context-dependent drug effect on post-ostracism mood ratings, consistent with recent studies indicating that interindividual variation and social context can interact with intranasal oxytocin effects. Further research is needed to determine the generalisability of these findings, i.e. if oxytocin can improve first impressions in humans under different conditions.

'Defrosting' music chills with naltrexone: The role of endogenous opioids for the intensity of musical pleasure.

The endogenous opioid system has been implicated during experiences of pleasure (i.e., from food or sex). Music can elicit intense emotional and bodily sensations of pleasure, called 'Chills'. We investigated the effects of an opioid antagonist (50 mg naltrexone) or placebo (40 µg d3-vitamin) while listening to self-selected music or other 'control' music selected by another participant. We used a novel technique of continuous measurement of pleasantness with an eye tracker system, where participants shifted their eyes along a visual analogue scale, in the semblance of a thermometer so that, as the music unfolded, gaze positions indicated the self-reported hedonic experience. Simultaneously, we obtained pupil diameters. Self-reported pleasure remained unchanged by naltrexone, which - however - selectively decreased pupillary diameters during 'Chills'. Hence, the endogenous µ-opioid signaling is not necessary for subjective enjoyment of music but an opioid blockade dampens pupil responses to peak pleasure, consistent with decreased arousal to the music.

Assessment of Anhedonia in Adults With and Without Mental Illness: A Systematic Review and Meta-analysis.

Importance: Anhedonia, a reduced capacity for pleasure, is described for many psychiatric and neurologic conditions. However, a decade after the Research Domain Criteria launch, whether anhedonia severity differs between diagnoses is still unclear. Reference values for hedonic capacity in healthy humans are also needed. Objective: To generate and compare reference values for anhedonia levels in adults with and without mental illness. Data Sources: Web of Science, Scopus, PubMed, and Google Scholar were used to list all articles from January 1, 1995 to July 2, 2019, citing the scale development report of a widely used anhedonia questionnaire, the Snaith-Hamilton Pleasure Scale (SHAPS). Searches were conducted from April 5 to 11, 2018, and on July 2, 2019. Study Selection: Studies including healthy patients and those with a verified diagnosis, assessed at baseline or in a no-treatment condition with the complete 14-item SHAPS, were included in this preregistered meta-analysis. Data Extraction and Synthesis: Random-effects models were used to calculate mean SHAPS scores and 95% CIs separately for healthy participants and patients with current major depressive disorder (MDD), past/remitted MDD, bipolar disorder, schizophrenia, substance use disorders, Parkinson disease, and chronic pain. SHAPS scores were compared between groups using meta-regression, and traditional effect size meta-analyses were conducted to estimate differences in SHAPS scores between healthy and patient samples. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Main Outcomes and Measures: Self-reported anhedonia as measured by 2 different formats of the SHAPS (possible ranges, 0-14 and 14-56 points), with higher values on both scales indicating greater anhedonia symptoms. Results: In the available literature (168 articles; 16 494 participants; 8058 [49%] female participants; aged 13-72 years), patients with current MDD, schizophrenia, substance use disorder, Parkinson disease, and chronic pain scored higher on the SHAPS than healthy participants. Within the patient groups, those with current MDD scored considerably higher than all other groups. Patients with remitted MDD scored within the healthy range (g = 0.1). This pattern replicated across SHAPS scoring methods and was consistent across point estimate and effect size analyses. Conclusions and Relevance: The findings of this meta-analysis indicate that the severity of anhedonia may differ across disorders associated with anhedonia. Whereas anhedonia in MDD affects multiple pleasure domains, patients with other conditions may experience decreased enjoyment of only a minority of life's many rewards. These findings have implications for psychiatric taxonomy development, where dimensional approaches are gaining attention. Moreover, the SHAPS reference values presented herein may be useful for researchers and clinicians assessing the efficacy of anhedonia treatments.

Anhedonia in chronic pain and prescription opioid misuse.

BACKGROUND: Both acute and chronic pain can disrupt reward processing. Moreover, prolonged prescription opioid use and depressed mood are common in chronic pain samples. Despite the prevalence of these risk factors for anhedonia, little is known about anhedonia in chronic pain populations. METHODS: We conducted a large-scale, systematic study of anhedonia in chronic pain, focusing on its relationship with opioid use/misuse, pain severity, and depression. Chronic pain patients across four distinct samples (N = 488) completed the Snaith-Hamilton Pleasure Scale (SHAPS), measures of opioid use, pain severity and depression, as well as the Current Opioid Misuse Measure (COMM). We used a meta-analytic approach to determine reference levels of anhedonia in healthy samples spanning a variety of countries and diverse age groups, extracting SHAPS scores from 58 published studies totaling 2664 psychiatrically healthy participants. RESULTS: Compared to healthy samples, chronic pain patients showed higher levels of anhedonia, with ~25% of patients scoring above the standard anhedonia cut-off. This difference was not primarily driven by depression levels, which explained less than 25% of variance in anhedonia scores. Neither opioid use duration, dose, nor pain severity alone was significantly associated with anhedonia. Yet, there was a clear effect of opioid misuse, with opioid misusers (COMM ⩾13) reporting greater anhedonia than non-misusers. Opioid misuse remained a significant predictor of anhedonia even after controlling for pain severity, depression and opioid dose. CONCLUSIONS: Study results suggest that both chronic pain and opioid misuse contribute to anhedonia, which may, in turn, drive further pain and misuse.

Effects of opioid receptor stimulation and blockade on touch pleasantness: a double-blind randomised trial.

The µ-opioid receptor (MOR) system has long been thought to underpin the rewarding properties of pleasant touch. Numerous non-human animal studies implicate MORs in social behaviours involving touch, but little is currently known about MOR involvement in human touch reward. Here, we employed a bi-directional pharmacological double-blind crossover design to assess the role of the human MOR system for touch pleasantness and motivation. Forty-nine male volunteers received 10 mg per-oral morphine, 50 mg per-oral naltrexone and placebo before being brushed on their forearm at three different velocities (0.3, 3 and 30 cm/s). In a touch liking task, pleasantness ratings were recorded after each 15 s brushing trial. In a touch wanting task, participants actively manipulated trial duration through key presses. As expected, 3 cm/s was the preferred velocity, producing significantly higher pleasantness ratings and wanting scores than the other stimuli. Contrary to our hypothesis, MOR drug manipulations did not significantly affect either touch pleasantness or wanting. The null effects were supported by post hoc Bayesian analyses indicating that the models with no drug effect were more than 25 times more likely than the alternative models given the data. We conclude that µ-opioid signalling is unlikely to underpin non-affiliative touch reward in humans.

Intact responses to non-drug rewards in long-term opioid maintenance treatment.

Disruption of non-drug reward processing in addiction could stem from long-term drug use, addiction-related psychosocial stress, or a combination of these. It remains unclear whether long-term opioid maintenance treatment (OMT) disrupts reward processing. Here, we measured subjective and objective reward responsiveness in 26 previously heroin-addicted mothers in >7 years stable OMT with minimal psychosocial stress and illicit drug use. The comparison group was 30 healthy age-matched mothers (COMP). Objective reward responsiveness was assessed in a two-alternative forced-choice task with skewed rewards. Results were also compared to performance from an additional 968 healthy volunteers (meta-analytic approach). We further compared subprocesses of reward-based decisions across groups using computational modelling with a Bayesian drift diffusion model of decision making. Self-reported responsiveness to non-drug rewards was high for both groups (means: OMT = 6.59, COMP = 6.67, p = 0.84, BF10 = 0.29), yielding moderate evidence against subjective anhedonia in this OMT group. Importantly, the mothers in OMT also displayed robust reward responsiveness in the behavioral task (t19 = 2.72, p = 0.013, BF10 = 3.98; d = 0.61). Monetary reward changed their task behavior to the same extent as the local comparison group (reward bias OMT = 0.12, COMP = 0.12, p = 0.96, BF10 = 0.18) and in line with data from 968 healthy controls previously tested. Computational modelling revealed that long-term OMT did not even change decision subprocesses underpinning reward behavior. We conclude that reduced sensitivity to rewards and anhedonia are not necessary consequences of prolonged opioid use.

The role of the opioid system in decision making and cognitive control: A review.

The opioid system regulates affective processing, including pain, pleasure, and reward. Restricting the role of this system to hedonic modulation may be an underestimation, however. Opioid receptors are distributed widely in the human brain, including the more "cognitive" regions in the frontal and parietal lobes. Nonhuman animal research points to opioid modulation of cognitive and decision-making processes. We review emerging evidence on whether acute opioid drug modulation in healthy humans can influence cognitive function, such as how we choose between actions of different values and how we control our behavior in the face of distracting information. Specifically, we review studies employing opioid agonists or antagonists together with experimental paradigms of reward-based decision making, impulsivity, executive functioning, attention, inhibition, and effort. Although this field is still in its infancy, the emerging picture suggests that the mu-opioid system can influence higher-level cognitive function via modulation of valuation, motivation, and control circuits dense in mu-opioid receptors, including orbitofrontal cortex, basal ganglia, amygdalae, anterior cingulate cortex, and prefrontal cortex. The framework that we put forward proposes that opioids influence decision making and cognitive control by increasing the subjective value of reward and reducing aversive arousal. We highlight potential mechanisms that might underlie the effects of mu-opioid signaling on decision making and cognitive control and provide directions for future research.

Morphine reduced perceived anger from neutral and implicit emotional expressions.

The µ-opioid system modulates responses to pain and psychosocial stress and mediates non-social and social reward. In humans, the µ-opioid agonist morphine can increase overt attention to the eye-region and visual exploration of faces with neutral expressions. However, little is known about how the human µ-opioid system influences sensitivity to and appraisal of subtle and explicit cues of social threats and reward. Here, we examined the effects of selective µ-opioid stimulation on perception of anger and happiness in faces with explicit, neutral or implicit emotion expressions. Sixty-three healthy adults (32 females) attended two sessions where they received either placebo or 10 mg per oral morphine in randomised order under double-blind conditions. Based on the known µ-opioid reduction of pain and discomfort, as well as reports suggesting that the non-specific partial agonist buprenorphine or the non-specific antagonist naltrexone affect appraisal of social emotional stimuli, we hypothesised that morphine would reduce threat sensitivity and enhance perception of happy facial expressions. While overall perception of others' happiness was unaffected by morphine treatment, morphine reduced perception of anger in stimuli with neutral and implicit expressions without affecting perception of explicit anger. This effect was statistically unrelated to gender, subjective drug effects, mood and autism trait measures. The finding that a low dose of µ-agonist reduced the propensity to perceive anger in photos with subtle facial expressions is consistent with the notion that µ-opioids mediate social confidence and reduce sensitivity to threat cues.

Opioid Modulation of Value-Based Decision-Making in Healthy Humans.

Modifying behavior to maximize reward is integral to adaptive decision-making. In rodents, the µ-opioid receptor (MOR) system encodes motivation and preference for high-value rewards. Yet it remains unclear whether and how human MORs contribute to value-based decision-making. We reasoned that if the human MOR system modulates value-based choice, this would be reflected by opposite effects of agonist and antagonist drugs. In a double-blind pharmacological cross-over study, 30 healthy men received morphine (10 mg), placebo, and the opioid antagonist naltrexone (50 mg). They completed a two-alternative decision-making task known to induce a considerable bias towards the most frequently rewarded response option. To quantify MOR involvement in this bias, we fitted accuracy and reaction time data with the drift-diffusion model (DDM) of decision-making. The DDM analysis revealed the expected bidirectional drug effects for two decision subprocesses. MOR stimulation with morphine increased the preference for the stimulus with high-reward probability (shift in starting point). Compared to placebo, morphine also increased, and naltrexone reduced, the efficiency of evidence accumulation. Since neither drug affected motor-coordination, speed-accuracy trade-off, or subjective state (indeed participants were still blinded after the third session), we interpret the MOR effects on evidence accumulation efficiency as a consequence of changes in effort exerted in the task. Together, these findings support a role for the human MOR system in value-based choice by tuning decision-making towards high-value rewards across stimulus domains.

The µ-opioid system promotes visual attention to faces and eyes.

Paying attention to others' faces and eyes is a cornerstone of human social behavior. The µ-opioid receptor (MOR) system, central to social reward-processing in rodents and primates, has been proposed to mediate the capacity for affiliative reward in humans. We assessed the role of the human MOR system in visual exploration of faces and eyes of conspecifics. Thirty healthy males received a novel, bidirectional battery of psychopharmacological treatment (an MOR agonist, a non-selective opioid antagonist, or placebo, on three separate days). Eye-movements were recorded while participants viewed facial photographs. We predicted that the MOR system would promote visual exploration of faces, and hypothesized that MOR agonism would increase, whereas antagonism decrease overt attention to the information-rich eye region. The expected linear effect of MOR manipulation on visual attention to the stimuli was observed, such that MOR agonism increased while antagonism decreased visual exploration of faces and overt attention to the eyes. The observed effects suggest that the human MOR system promotes overt visual attention to socially significant cues, in line with theories linking reward value to gaze control and target selection. Enhanced attention to others' faces and eyes represents a putative behavioral mechanism through which the human MOR system promotes social interest.

Sweet taste pleasantness is modulated by morphine and naltrexone.

BACKGROUND: Rodent models highlight the key role of µ-opioid receptor (MOR) signaling in palatable food consumption. In humans, however, the effects of MOR stimulation on eating and food liking remain unclear. OBJECTIVES: Here, we tested sweet pleasantness experience in humans following MOR drug manipulations. We hypothesized that behaviors regulated by the endogenous MOR system would be enhanced by MOR agonism and decreased by antagonism. In line with rodent findings, we expected the strongest drug effects for the sweetest (high-calorie) sucrose stimuli. As very sweet stimuli are considered aversive by many people (called sweet dislikers), we also assessed whether MOR manipulations affect pleasantness ratings of sucrose-water stimuli differently depending on subjective and objective value. METHODS: In a bidirectional psychopharmacological cross-over study, 49 healthy men underwent a sweet taste paradigm following double-blind administration of the MOR agonist morphine, placebo, and the opioid antagonist naltrexone. RESULTS: As hypothesized, MOR stimulation with morphine increased pleasantness of the sweetest of five sucrose solutions, without enhancing pleasantness of the lower-sucrose solutions. For opioid antagonism, an opposite pattern was observed for the sweetest drink only. The observed drug effects on pleasantness of the sweetest drink did not differ between sweet likers and dislikers. CONCLUSIONS: The bidirectional effect of agonist and antagonist treatment aligns with rodent findings showing that MOR manipulations most strongly affect the highest-calorie foods. We speculate that the MOR system promotes survival in part by increasing concordance between the objective (caloric) and subjective (hedonic) value of food stimuli, so that feeding behavior becomes more focused on the richest food available.

Placebo improves pleasure and pain through opposite modulation of sensory processing.

Placebo analgesia is often conceptualized as a reward mechanism. However, by targeting only negative experiences, such as pain, placebo research may tell only half the story. We compared placebo improvement of painful touch (analgesia) with placebo improvement of pleasant touch (hyperhedonia) using functional MRI and a crossover design. Somatosensory processing was decreased during placebo analgesia and increased during placebo hyperhedonia. Both placebo responses were associated with similar patterns of activation increase in circuitry involved in emotion appraisal, including the pregenual anterior cingulate, medial orbitofrontal cortex, amygdala, accumbens, and midbrain structures. Importantly, placebo-induced coupling between the ventromedial prefrontal cortex and periaqueductal gray correlated with somatosensory decreases to painful touch and somatosensory increases to pleasant touch. These findings suggest that placebo analgesia and hyperhedonia are mediated by activation of shared emotion appraisal neurocircuitry, which down- or up-regulates early sensory processing, depending on whether the expectation is reduced pain or increased pleasure.