Systematic manipulation of experimenters' non-verbal behaviors for the investigation of pain reports and placebo effects.

Objective: Non-verbal behaviors (NBs) of caregivers affect pain reports and placebo effects. However, little experimental research has systematically examined the caregivers' NBs. This study protocol and preparatory study report a systematic manipulation of experimenters' NBs to investigate pain report and placebo effects. Methods: We propose an experiment in which videotaped experimenters (VEs) conduct a pain stimulation and a placebo treatment study. The VEs express one positively enhanced NB and keep the other NBs neutral. Participants will be randomized to either the positive facial expressions (+FE), tone of voice (+TV), body movement (+BM), or neutral NBs (i.e., neutral condition; NC) of the VEs. As a preparatory study for proof of concept, two groups of NB coders from Norway and the USA separately rated the degree of NBs (eye contact, body postures and movements, and tone of voice), and impressions of dominance and being in charge, positivity, and expressivity from each NB video. The NB videos had construct validity and reliability. The +BM and +FE were rated as more dominant and in charge than the +TV and the NC. The +FE and +BM were rated as the most positive and expressive NBs, respectively. Expected results: +FE will have the largest placebo effects on pain and stress levels. However, transmitting the NBs to patients by VEs is challenging. Moreover, controlling for the effects of research assistants present in the testing room is challenging. Discussion: We propose that caregivers' NBs affect pain reports and placebo effects. Moreover, different NBs elicit different impressions, and a better understanding of the role of caregiver NBs requires more rigorous investigations. Lastly, aiming to investigate the caregiver NBs, the varying degrees of micro-NBs and their effects on the formation of impressions should be considered.

A global meta-analysis of depression, anxiety, and stress before and during COVID-19.

OBJECTIVE: This meta-analysis compared negative emotions (NEs) as depression, anxiety, and stress, from before the pandemic to during the pandemic. METHOD: A total of 59 studies (19 before, 37 during-pandemic, and 3 that included both) using the Depression, Anxiety and Stress Scale (DASS) were included. A random effects model estimated the means of NEs before and during the pandemic. RESULTS: Studies from 47 countries involving 193,337 participants were included. Globally, NEs increased during the pandemic, and depression had the largest elevation. In Asia, depression and stress were elevated, whereas in Europe, only depression increased, and in America, no differences in NEs between before and during the pandemic were observed. The later time phase of the pandemic was associated with lower stress globally, and lower stress and anxiety in Europe. Being younger was associated with more stress globally, and being older was associated with higher anxiety in Asia. Students had higher anxiety globally, and higher NEs in all three aspects in Europe compared to the general population. The COVID-19 infection rate was associated with more stress globally, and stress and anxiety in Europe. During the pandemic, females reported higher levels of depression, anxiety, and stress compared to males, most pronounced in Europe. CONCLUSION: NEs increased during the pandemic, with younger and student populations, females and Asians having the highest elevations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Experiencing COVID-19 symptoms without the disease: The role of nocebo in reporting of symptoms.

BACKGROUND: A nocebo effect occurs when inactive factors lead to worsening of symptoms or reduce treatment outcomes. Believing that one is or has been infected with COVID-19 may act as a nocebo. However, not much is known about potential nocebo effects associated with the reporting of COVID-19 symptoms. AIM: An online survey investigated whether certainty of being infected with COVID-19, age, sex, cognitive, emotional and personality factors were associated with perceived severity of COVID-19 symptoms. METHODS: Participants (N=375) filled out an online survey containing 57 questions asking about symptoms resembling COVID-19, certainty of being infected with COVID-19, anxiety, stress and personality dimensions. RESULTS: Certainty of being infected with COVID-19 and anxiety predicted 27% of the variance in reporting of COVID-like symptoms. The mediation analysis showed that both higher certainty of being infected and anxiety independently predicted increased reports of COVID-like symptom. Females had higher anxiety and stress levels, and reported more COVID-like symptoms than males did. Older age was not associated with reporting COVID-like symptoms. CONCLUSIONS: Believing to be infected with COVID-19, along with anxiety, can enhance the severity of COVID-like symptoms. Thus, the nocebo effect was due to both cognitive and emotional factors and was higher in females.

Placebo Effects on Stress, but Not on Pain Reports. A Multi-Experiment Study.

BACKGROUND: Contextual factors, such as participant/experimenter sex may moderate the placebo effects. We tested whether the participant and experimenter sex modulated placebo effects on experimentally induced pain and associated stress. OBJECTIVE: To investigate if (i) participant sex and (ii) experimenter sex influence placebo analgesia and subjective and physiological stress in two experiments employing a within-subjects and a mixed design, respectively. Placebo effects were investigated in pain reports, stress, and blood pressure. METHODS: Participants received painful stimulations and a placebo cream. In Experiment One (N = 59) participants underwent a placebo condition (PC) and a natural history condition (NHC) in random order. A placebo cream was applied in the PC and then the heat stimulation temperature was surreptitiously lowered. Identical stimulations were administered in the NHC, but with no cream, no information, and no lowered temperature. In Experiment Two, participants (N = 93) were randomly assigned to three groups receiving either a placebo cream with surreptitiously lowered intensity of electric stimuli (Placebo, PG), a placebo cream (Cream-Control, CCG) without changing the stimuli, or lowered intensity, but with no cream (Pain-Control, PCG) in a mixed design. All participants in both experiments received the same stimuli in the post-test as in the pre-test. Four experimenters (two females) in Experiment One, and five experimenters (two females) in Experiment Two conducted the studies. RESULTS: No placebo effect was seen on pain. However, there were placebo effects on stress, moderated by participant and experimenter sex: in Experiment One males in the PC had lower diastolic blood pressure (DBP) compared to males in the NHC. Participants in the PC had lower DBP compared to the NHC when tested by a female. In Experiment Two, participants expected more cream effectiveness when a female experimenter administered it, and reported lower stress in the PG compared to the PCG when tested by females. CONCLUSION: Our findings highlight a distinction between placebo effects on pain and on associated stress. Secondly, female experimenters recorded lower physiological and subjective stress, higher effectiveness expectations, and lower pain from both sexes compared to male experimenters. Possible reasons for the failure to find a pain placebo effect are discussed.

What Psychological Factors Make Individuals Believe They Are Infected by Coronavirus 2019?

Background: We previously showed, by means of an online-based survey, that the belief of being infected by coronavirus disease 2019 (COVID-19) acted as a nocebo and predicted higher perception of symptoms similar to COVID-19 symptoms. However, there is little known about the psychological mechanisms that give rise to beliefs such as certainty of being infected by COVID-19, and this was investigated in the present study. Objective: Using the same data from the previous online survey with the same research team, we further investigated whether certainty of being infected by COVID-19 is associated with age, sex, health anxiety, and/or personality traits. Methods: Respondents (N = 375) filled out an online survey with 57 questions about symptoms similar to COVID-19, certainty of being infected by COVID-19, anxiety, stress, health anxiety, and personality dimensions (based on the five-factor model of personality). Results: Higher levels of conscientiousness and health anxiety were independently associated with certainty of being infected by COVID-19. The model predicted 29% of the variance in certainty of being infected by COVID-19. Conclusion: Being conscientious and worried about health issues were associated with the belief of being infected by COVID-19. Such finding may have implications for health care personnel who provide COVID-19 testing or consulting services to general population, as individuals high in these traits may over-report COVID-like symptoms. Theoretically, these findings point to psychological factors that may increase nocebo and possibly placebo effects. Clinically, the findings suggest that individuals high in conscientiousness and health anxiety may be more likely to over-report their bodily experiences.

Placebo Analgesia, Nocebo Hyperalgesia, and the Cardiovascular System: A Qualitative Systematic Review.

Background: Placebo/nocebo effects involve the autonomic nervous system, including cardiac activity, but studies have reported inconsistent findings on how cardiac activity is modulated following a placebo/nocebo effect. However, no systematic review has been conducted to provide a clear picture of cardiac placebo responses. Objective: The main goal of the present study is to review the effects of placebo analgesia and nocebo hyperalgesia on cardiac activity as measured by blood pressure, heart rate, and heart rate variability. Methods: Using several Boolean keyword combinations, the PubMed, EMBASE, PsycINFO, Cochrane Review Library, and ISI Web of Knowledge databases were searched until January 5, 2020, to find studies that analyzed blood pressure, heart rate, or heart rate variability indexes following a placebo analgesic/nocebo hyperalgesic effect. Results: Nineteen studies were found, with some reporting more than one index of cardiac activity; eight studies were on blood pressure, 14 studies on heart rate, and six on heart rate variability. No reliable association between placebo/nocebo effects and blood pressure or heart rate was found. However, placebo effects reduced, and nocebo effects increased low-frequency heart rate variability, and heart rate variability significantly predicted placebo effects in two studies. Conclusion: Placebo/nocebo effects can have reliable effects on heart rate variability, but not on heart rate and blood pressure.

A Qualitative Systematic Review of Effects of Provider Characteristics and Nonverbal Behavior on Pain, and Placebo and Nocebo Effects.

Background: Previous research has indicated that the sex, status, and nonverbal behaviors of experimenters or clinicians can contribute to reported pain, and placebo and nocebo effects in patients or research participants. However, no systematic review has been published. Objective: The aim of this study was to investigate the effects of experimenter/clinician characteristics and nonverbal behavior on pain, placebo, and nocebo effects. Methods: Using EmBase, Web of Knowledge, and PubMed databases, several literature searches were conducted to find studies that investigated the effects of the experimenter's/clinician's sex, status, and nonverbal behaviors on pain, placebo, and nocebo effects. Results: Thirty-four studies were included, 20 on the effects of characteristics of the experimenter/clinician, 11 on the role of nonverbal behaviors, and 3 on the effects of both nonverbal behaviors and characteristics of experimenters/clinicians on pain and placebo/nocebo effects. There was a tendency for experimenters/clinicians to induce lower pain report in participants of the opposite sex. Furthermore, higher confidence, competence, and professionalism of experimenters/clinicians resulted in lower pain report and higher placebo effects, whereas lower status of experimenters/clinicians such as lower confidence, competence, and professionalism generated higher reported pain and lower placebo effects. Positive nonverbal behaviors (e.g., smiling, strong tone of voice, more eye contact, more leaning toward the patient/participant, and more body gestures) contributed to lower reported pain and higher placebo effects, whereas negative nonverbal behaviors (i.e., no smile, monotonous tone of voice, no eye contact, leaning backward from the participant/patient, and no body gestures) contributed to higher reported pain and nocebo effects. Conclusion: Characteristics and nonverbal behaviors of experimenters/clinicians contribute to the elicitation and modulation of pain, placebo, and nocebo effects.

The Influence of Placebo Analgesia Manipulations on Pain Report, the Nociceptive Flexion Reflex, and Autonomic Responses to Pain.

Expectations for pain relief and experience/conditioning are psychological factors that contribute to placebo analgesia, yet few studies have studied the physiological mechanisms underlying their effects. This study randomized 133 participants to 4 groups: an expectation only (E-only) group, a conditioning only (C-only) group, an expectation plus conditioning (E+C) group, and a natural history (NH) control group. Painful electric stimulations were delivered before and after an inert cream was applied to the site of stimulation. Pain-related outcomes (pain ratings, nociceptive flexion reflex [NFR], skin conductance response, and heart rate acceleration) were recorded after each stimulation. NFR (a measure of spinal nociception) assessed if placebo analgesia inhibited spinal processing of pain. E+C was the only manipulation that significantly inhibited pain and skin conductance response. Surprisingly, NFR was facilitated in the E+C and E-only groups. No effects were noted for C-only. Mediation analysis suggested 2 descending processes were engaged during E+C that influenced spinal nociception: 1) descending facilitation and 2) descending inhibition that was also responsible for pain reduction. These results suggest that E+C manipulations produce the strongest analgesia and have a complex influence on spinal nociception involving both inhibitory and facilitatory processes. PERSPECTIVE: This study assessed whether placebo analgesia manipulations that include expectations, conditioning, or both modulate the NFR (measure of spinal nociception). Only the manipulation that involved expectations and conditioning inhibited pain, but both expectation manipulations facilitated NFR. This suggests a complex modulation of spinal neurons by placebo manipulations.

Influence of catechol-O-methyltransferase Val158Met on fear of pain and placebo analgesia.

Higher levels of fear have been shown to partly explain individual differences in placebo analgesic responding. The catechol-O-methyltransferase (COMT) rs4680 Val158Met polymorphism has been associated with both increased placebo analgesia and increased fear-related behavior, in what appears to be inconsistent findings in the literature. The aim of the study was therefore to investigate placebo analgesia and fear-related processes with regard to the COMT genotype, to sort out whether the Met-allele is associated with increased placebo analgesia or increased fear of pain (FOP). A 3 Group (Emla, placebo and natural history) by 5 Test (2 pretest, 3 posttests) mixed design was used (N = 223). A contact heat-evoked stimulator was used to induce pain, and FOP was quantified with the Fear of Pain Questionnaire-III. Saliva was obtained for genotyping. As expected, we observed a significant interaction of test by group (P < 0.01), with lower pain report in the placebo group compared with the natural history group (P < 0.01). There was a main effect of the COMT genotype on fear of medical pain (P = 0.032), and Met-allele carriers reported significantly higher fear of medical pain compared with the Val-allele (P = 0.044). We observed no effect of the COMT genotype on mean pain-level report or placebo analgesia. Thus, we conclude that the Met-allele seems to be associated with the negative emotional process of fear, but not with placebo analgesia.

Developing a model for measuring fear of pain in Norwegian samples: The Fear of Pain Questionnaire Norway.

BACKGROUND: Fear of pain is highly correlated with pain report and physiological measures of arousal when pain is inflicted. The Fear of Pain Questionnaire III (FPQ-III) and The Fear of Pain Questionnaire Short Form (FPQ-SF) are self-report inventories developed for assessment of fear of pain (FOP). A previous study assessed the fit of the FPQ-III and the FPQ-SF in a Norwegian non-clinical sample and proved poor fit of both models. This inspired the idea of testing the possibility of a Norwegian FOP-model. AIMS AND METHODS: A Norwegian FOP-model was examined by Exploratory Factor Analysis (EFA) in a sample of 1112 healthy volunteers. Then, the model fit of the FPQ-III, FPQ-SF and the Norwegian FOP-model (FPQ-NOR) were compared by Confirmatory Factor Analysis (CFA). Sex neutrality was explored by examining model fit, validity and reliability of the 3 models amongst male and female subgroups. RESULTS: The EFA suggested either a 4-, a 5- or a 6-factor Norwegian FOP model. The eigenvalue criterion supported the suggested 6-factor model, which also explained most of the variance and was most interpretable. A CFA confirmed that the 6-factor model was better than the two 4- and 5-factor models. Furthermore, the CFA used to test the fit of the FPQ-NOR, the FPQ-III and the FPQ-SF showed that the FPQ-NOR had the best fit of the 3 models, both in the whole sample and in sex sub-groups. CONCLUSION: A 6-factor model for explaining and measuring FOP in Norwegian samples was identified and termed the FPQ-NOR. This new model constituted six factors and 27 items, conceptualized as Minor, Severe, Injection, Fracture, Dental, and Cut Pain. The FPQ-NOR had the best fit overall and in male- and female subgroups, probably due to cross-cultural differences in FOP. IMPLICATIONS: This study highlights the importance on exploratory analysis of FOP-instruments when applied to different countries or cultures. As the FPQ-III is widely used in both research and clinical settings, it is important to ensure that the models construct validity is high. Country specific validation of FOP in both clinical and non-clinical samples is recommended.

The Fear of Pain Questionnaire-III and the Fear of Pain Questionnaire-Short Form: a confirmatory factor analysis.

BACKGROUND: The Fear of Pain Questionnaire-III (FPQ-III) is a widely used instrument to assess the fear of pain (FOP) in clinical and nonclinical samples. The FPQ-III has 30 items and is divided into three subscales: Severe Pain, Minor Pain and Medical Pain. Due to findings of poor fit of the original three-factor FPQ-III model, the Fear of Pain Questionnaire-Short Form (FPQ-SF) four-factor model has been suggested as an alternative. The FPQ-SF is a revised version of the FPQ-III, reduced to 20 items and subdivided into four subscales: Severe Pain, Minor Pain, Injection Pain and Dental Pain. AIMS AND METHODS: The purpose of the study was to investigate the model fit, reliability and validity of the FPQ-III and the FPQ-SF in a Norwegian nonclinical sample, using confirmatory factor analysis (CFA). The second aim was to explore the model fit of the two scales in male and female subgroups separately, since previous studies have uncovered differences in how well the questionnaires measure FOP across sex; thus, the questionnaires might not be sex neutral. It has been argued that the FPQ-SF model is better because of the higher fit to the data across sex. To explore model fit across sex within the questionnaires, the model fit, validity and reliability were compared across sex using CFA. RESULTS: The results revealed that both models' original factor structures had poor fit. However, the FPQ-SF had a better fit overall, compared to the FPQ-III. The model fit of the two models differed across sex, with better fit for males on the FPQ-III and for females on the FPQ-SF. CONCLUSION: The FPQ-SF is a better questionnaire than the FPQ-III for measurement of FOP in Norwegian samples and across sex subgroups. However, the FPQ-III is a better questionnaire for males than for females, whereas the FPQ-SF is a better questionnaire for females than for males. The findings are discussed and directions for future investigations outlined.

A systematic review of sex differences in the placebo and the nocebo effect.

OBJECTIVES: The present review investigated whether there are systematic sex differences in the placebo and the nocebo effect. METHODS: A literature search was conducted in multiple electronic databases. Studies were included if the study compared a group or condition where a placebo was administered to a natural history group or similar cohort. RESULTS: Eighteen studies were identified - 12 on placebo effects and 6 on nocebo effects. Chi-square tests revealed that 1) males responded more strongly to placebo treatment, and females responded more strongly to nocebo treatment, and 2) males responded with larger placebo effects induced by verbal information, and females responded with larger nocebo effects induced by conditioning procedures. CONCLUSION: This review indicates that there are sex differences in the placebo and nocebo effects, probably caused by sex differences in stress, anxiety, and the endogenous opioid system.

The Placebo Analgesic Effect in Healthy Individuals and Patients: A Meta-Analysis.

OBJECTIVE: The present meta-analysis investigates whether the magnitude of placebo analgesia is different in patients compared with healthy individuals and whether placebo analgesia is different in experimentally induced pain compared with clinical pain in patients. METHODS: A literature search in Web of Science (ISI) on the terms "placebo analgesia" and "placebo analgesic" was conducted. The search resulted in 71 studies, including 4239 participants. Fifty-five studies included healthy individuals and 16 studies included patients. Of the 16 studies with patients, five studies investigated clinical pain and 11 studies investigated experimentally induced pain. RESULTS: The average effect size was 1.24 for healthy individuals and 1.49 for patients. In the studies with patients, the average effect sizes of placebo treatment were 1.73 for experimentally induced pain and 1.05 for clinical pain. A χ test revealed that there were relatively more studies with patients compared with healthy volunteers in which there was a clinically significant reduction in pain (p = .040). CONCLUSIONS: The findings suggest that patients benefited from placebo treatment to a greater degree than healthy individuals did and that studies on healthy individuals may underestimate the magnitude of the placebo analgesic effect in patients. Patients' clinical pain and experimentally induced pain respond to placebo to the same degree.

Pain-related negative emotions and placebo analgesia.

Individuals undergoing treatment for a symptom like pain expect that the treatment will reduce the pain. Many studies show that healthy volunteers or patients in pain report less pain after inactive treatment, if they believe that active medication has been administrated. The reduction of pain can be partly blocked by systemic administration of naloxone, an opioid antagonist. There is reduced central nervous system activation to painful stimuli in individuals who have been given a placebo and told it is a painkiller. These findings suggest that the expectation of pain relief generates central nervous system opioid activity that inhibits pain transmission to the cerebral cortex. Expectations may thus lead to changes in central nervous system activity that reduces pain. It is proposed that expectations activate a homeostatic system that corrects perturbations to the system via negative feedback. The nocebo effect is the opposite of the placebo effect, and is due to induction of negative emotions. Part of the treatment of many symptoms and diseases is due to autonomic adjustments controlled by the central nervous system. The involvement of emotional processes in placebo effects could have important consequences for interpretation of data from randomized controlled trials.

Expectations of increased and decreased pain explain the effect of conditioned pain modulation in females.

OBJECTIVE: Chronic pain is believed to be related to a dysfunction of descending pain modulatory mechanisms. Functioning of descending pain modulation can be assessed by various methods, including conditioned pain modulation (CPM). CPM refers to the inhibition of one source of pain by a second noxious stimulus, termed the conditioning stimulus. This procedure can activate an endogenous pain inhibitory mechanism that inhibits early nociceptive processing. Chronic pain and anxiety disorders are more prevalent among females and it has been hypothesized that females react with more negative emotions towards unpleasant stimuli and this might be part of the explanation of greater pain sensitivity in females. The present study investigated whether expectations modulate the effect of conditioning stimulation on pain, subjective stress, and heart rate. In addition, we investigated whether the modulation of CPM by expectations differed between males and females. METHODS: Seventy-two subjects (including 36 women) received six noxious heat stimuli to the forearm. During three of these stimuli, a conditioning stimulus (cold-water bath) was applied to the contralateral arm in order to activate CPM. One third of the subjects were told that this would reduce pain (analgesia group), one-third that it would increase pain (hyperalgesia group), and one third received no information about its effect (no info group). RESULTS: Information that conditioning stimulation decreased or enhanced pain had the corresponding effect in females, but not in males. Conditioning stimulation increased stress, but not heart rate in females in the hyperalgesia group. A higher expectation of analgesia and lower stress during conditioning stimulation was associated with larger inhibitory CPM. CONCLUSION: These results suggest that reduced inhibitory CPM can be due to contextually induced cognitive and emotional factors and not necessarily a dysfunction of descending inhibitory pathways.

Induced fear reduces the effectiveness of a placebo intervention on pain.

Fear was induced by the anticipation of electric shock in order to investigate whether fear reduced the effectiveness of a placebo intervention on reported pain and the acoustic startle reflex. Thirty-three subjects participated in a 3 Condition (Natural History [NH], Placebo [P], Placebo+Fear [PF])×3 Test (Pretest, Posttest 1, Posttest 2) within-subject design, tested on 3 separate days. Measures of fear were fear of pain (FOP), measured by the Fear of Pain Questionnaire (FPQ-III); fear-potentiated startle; and a self-report measure that assessed the effectiveness of the fear induction procedure. In the pain intensity data, there was a trend towards a placebo effect. This trend was abolished by induced fear, and was most pronounced in subjects who were highest in measures of fear. The placebo manipulation also caused a reduction in startle reflex amplitude. This effect was abolished by induced fear, and was strongest amongst high FOP subjects. In conclusion, induced fear abolished placebo analgesia, and this effect was strongest in subjects who had high scores on measures of fear.

The placebo effect: advances from different methodological approaches.

There is accumulating evidence from different methodological approaches that the placebo effect is a neurobiological phenomenon. Behavioral, psychophysiological, and neuroimaging results have largely contributed to accepting the placebo response as real. A major aspect of recent and future advances in placebo research is to demonstrate linkages between behavior, brain, and bodily responses. This article provides an overview of the processes involved in the formation of placebo responses by combining research findings from behavioral, psychophysiological, and neuroimaging methods. The integration of these different methodological approaches is a key objective, motivating our scientific pursuits toward a placebo research that can inform and guide important future scientific knowledge.

Variability in placebo analgesia and the role of fear of pain--an ERP study.

Fear of pain (FOP) and its effect on placebo analgesia was investigated. It was hypothesized that FOP should interfere with placebo-mediated pain inhibition and result in weaker placebo responding in pain intensity, pain unpleasantness, stress, and event-related potentials to contact heat pain. Thirty-three subjects participated in a balanced 2 condition (natural history, placebo)×3 test (pretest, posttest 1, posttest 2) within-subject design, tested on 2 separate days. FOP was measured by the Fear of Pain Questionnaire and subjective stress by the Short Adjective Check List. Placebo effects were found on reported pain unpleasantness and N2 and P2 amplitudes. FOP was related to reduced placebo responding in pain unpleasantness, but this was only evident for the subjects who received the placebo condition on day 1. Subjects who received the placebo condition on day 1 experienced more pretest stress than those who received the placebo condition on day 2 (ie, reversed condition order), and this explained the interaction effect on placebo responding. FOP was related to reduced placebo responding on P2 amplitude, whereas placebo responding on N2 amplitude was unaffected by FOP. Higher placebo responses on N2 and P2 amplitudes were both related to higher placebo analgesic magnitude in pain unpleasantness. In conclusion, increased FOP was found to reduce subjective and electrophysiological placebo analgesic responses.

The relation of emotions to placebo responses.

The hypothesis put forth is that expectations of treatment effects reduce negative emotions and thereby reduce symptoms, e.g. pain. Negative emotions increase pain, and it is hypothesized that placebos reduce pain by reducing negative emotions, i.e. feelings of nervousness, fear and anxiety. Placebo analgesia has been shown to be mediated via opioid activity, and relaxation increases opioid activity. The placebo acquires its relaxing effect due to verbal information that pain will be reduced, or due to associations between the placebo and the reduction in pain after effective treatment. Thus, the placebo signals that unpleasantness will be less after administration of the placebo. This involves negative reinforcement which is due to activation of a dopaminergic system that has been found to be activated during placebo analgesia and is involved in positive emotions. The nocebo effect of increased pain is, consistent with this model, because of increased fear and anxiety. The new aspect of the presented model is the hypothesis that expectations reduce negative emotions, and that negative reinforcement that involves the dopaminergic reinforcement system should be a contributor to placebo responses.

Interaction between expectancies and drug effects: an experimental investigation of placebo analgesia with caffeine as an active placebo.

RATIONALE: In a randomised placebo-controlled clinical trial it is assumed that psychosocial effects of the treatment, regression to the mean and spontaneous remission are identical in the drug and placebo group. Consequently, any difference between the groups can be ascribed to the pharmacological effects. Previous studies suggest that side effects of drugs can enhance expectancies of treatment effects in the drug group compared to the placebo group, and thereby increase placebo responses in the drug group compared to the placebo group. OBJECTIVES: The hypothesis that side effects of drugs can enhance expectancies and placebo responses was tested. METHOD: Painful laser stimuli were delivered to 20 healthy subjects before and after administration of a drink with 0 or 4 mg/kg caffeine. The drink was administered either with information that it contained a painkiller or that it was a placebo. Laser-evoked potentials and reports of pain, expectancy, arousal and stress were measured. RESULTS: Four milligrammes per kilogramme of caffeine reduced pain. Information that a painkiller was administered increased the analgesic effect of caffeine compared to caffeine administered with no drug information. This effect was mediated by expectancies. Information and expectancies had no effect on pain intensity when 0 mg/kg was administered. CONCLUSION: The analgesic effect of caffeine was increased by information that a painkiller was administered. This was due to an interaction of the pharmacological action of the drug and expectancies. Hence, psychosocial effects accompanying a treatment can differ when an active drug is administered compared to a placebo.