Magne Arve Flaten

Drug-related Information Generates Placebo and Nocebo Responses That Modify the Drug Response

OBJECTIVE Administration of the muscle relaxant carisoprodol and placebo was crossed with information that was agonistic or antagonistic to the effect of carisoprodol. It was investigated whether information alone induced physiological and psychological responses, and whether information modified the response to the drug. METHODS Half of the subjects received capsules containing 525 mg carisoprodol together with information that the drug acted in a specific way (Groups Relaxant/C, Stimulant/C, and No Information/C). The other half of the subjects received lactose (Groups Relaxant/L, Stimulant/L, and No Information/L). Dependent variables were blink reflexes and skin conductance responses, subjective measures of tension and sleepiness, and serum carisoprodol and meprobamate concentrations. Recordings were made between 15 and 130 minutes after administration of the capsules. RESULTS The Stimulant/L group reported more tension compared with the other two groups, and carisoprodol increased tension even more in the Stimulant/C group. The Relaxant/C group displayed higher levels of carisoprodol serum concentration compared with the other groups that received carisoprodol. CONCLUSIONS Reported tension was modulated in the direction suggested by the stimulant information. The effect of carisoprodol on tension was also modulated by stimulant information. Increased carisoprodol absorption in the group that received relaxant information could be a mechanism in the placebo response.

Amygdala and anterior cingulate cortex activation during affective startle modulation : a PET study of fear

The human startle response is modulated by emotional experiences, with startle potentiation associated with negative affect. We used positron emission tomography with 15O‐water to study neural networks associated with startle modulation by phobic fear in a group of subjects with specific snake or spider phobia, but not both, during exposure to pictures of their feared and non‐feared objects, paired and unpaired with acoustic startle stimuli. Measurement of eye electromyographic activity confirmed startle potentiation during the phobic as compared with the non‐phobic condition. Employing a factorial design, we evaluated brain correlates of startle modulation as the interaction between startle and affect, using the double subtraction contrast (phobic startle vs. phobic alone) vs. (non‐phobic startle vs. non‐phobic alone). As a result of startle potentiation, a significant increase in regional cerebral blood flow was found in the left amygdaloid–hippocampal region, and medially in the affective division of the anterior cingulate cortex (ACC). These results provide evidence from functional brain imaging for a modulatory role of the amygdaloid complex on startle reactions in humans. They also point to the involvement of the affective ACC in the processing of startle stimuli during emotionally aversive experiences. The co‐activation of these areas may reflect increased attention to fear‐relevant stimuli. Thus, we suggest that the amygdaloid area and the ACC form part of a neural system dedicated to attention and orientation to danger, and that this network modulates startle during negative affect.

The effect of experimenter gender on autonomic and subjective responses to pain stimuli.

Abstract Several studies have shown that male subjects report lower pain intensity to female compared to male experimenters. The present experiment examined whether experimenter gender also modulated autonomic pain responses. Sixty‐four students (32 females) participated in a 2 Subject gender × 2 Experimenter gender × 15 Pain Tests mixed design. Six experimenters, three females and three males collected data. Heat pain was +48 °C induced to the right volar forearm. Subjective measurements consisted of pain intensity, pain unpleasantness, stress, arousal and mood. Autonomic responses were heart rate variability and skin conductance levels. The results revealed significant interactions between experimenter gender and subject gender on pain intensity and arousal, but there were no interactions in the physiological data. In conclusion, the lower pain report in male subjects to female experimenters is not mediated by changes in autonomic parameters, and the effect of experimenter gender is probably due to psychosocial factors.

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.

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.

Gender Differences in Placebo Analgesia: Event-Related Potentials and Emotional Modulation

Objectives: To examine whether there are gender differences in event-related potential (ERP) responses to painful stimulation after administration of placebo medication; and to investigate whether placebo medication reduces anticipatory stress and if this reduction can explain the placebo analgesic response. Several experimental and clinical studies have shown that males report lower pain compared with females. There are, however, few reports of gender differences in placebo analgesia. Methods: All subjects (n = 33; 17 women) participated in both a natural history and a placebo condition. ERPs were evoked by heat pulses with a peak at 52°C. Results: The results showed that pain unpleasantness and the N2/P2 ERP components were reduced in the placebo condition compared with the natural history condition. Only men displayed placebo responses in pain report and in the P2 component. Anticipatory stress was reduced after placebo administration, and the reduction in anticipatory stress was significantly related to the placebo effect on pain. Regression analyses revealed that the interaction of gender by anticipatory stress was significantly related to the mean placebo response, with men responding with lower stress after placebo medication, and larger placebo responses. Conclusions: A placebo response on pain unpleasantness was observed in men only, and reduced stress after placebo administration was observed in males only. Thus, reduced stress may be a mechanism for placebo responses in pain. ERP = event-related potential; NRS = Numerical Rating Scale.

Caffeine-associated stimuli elicit conditioned responses : an experimental model of the placebo effect

Rationale: A neutral stimulus repeatedly paired with administration of a drug may elicit a conditioned response. This process, termed pharmacological classical conditioning, may be important in the understanding of placebo effects. Objective: The unconditioned response to caffeine is increased physiological and psychological arousal. The present study investigated whether stimuli associated with the use of caffeine, i.e. the smell and taste of coffee, elicited a conditioned increase in arousal. It was also investigated whether conditioned arousal modulated the unconditioned arousal induced by caffeine. Methods: Twenty subjects who drank at least two cups of coffee per day were exposed to four conditions in a within-subjects design, where the subjects received coffee or orange juice crossed with placebo or 2 mg/kg caffeine. Dependent variables were skin conductance responses and startle reflexes to 85 dB noise bursts, skin conductance levels, blood pressure, heart rate, and subjective measures of arousal. Results: Both caffeine (caffeinated juice) and caffeine-associated stimuli (decaffeinated coffee) increased subjective and physiological arousal. When caffeine and caffeine-associated stimuli were presented together (caffeinated coffee), a non-significant tendency towards an additive effect of the conditioned arousal on the unconditioned arousal to caffeine was seen in some dependent variables. Conclusions: Presentation of caffeine-associated stimuli to caffeine-users elicited conditioned responses similar to the unconditioned drug response. Thus, presentation of caffeine-associated stimuli could be used as an experimental model of placebo effects.

The roles of physiological and subjective stress in the effectiveness of a placebo on experimentally induced pain.

Objective: To examine whether reduction of negative emotions and associated autonomic activity could explain placebo analgesia, and to test the effect of experimenter gender on the placebo analgesic response. Methods: Sixty-three (n = 32 females) students participated in a within-subjects design where subjects were tested on two separate days, one day for the experimental condition (placebo) and one day for the natural history condition. In the experimental condition, the participants received capsules containing lactose with information that the capsules were a high dose of a potent painkiller. In the natural history condition, the procedures were identical except that the placebo capsules were not administrated. The experimenters were blinded to the fact that all participants received placebo. Pain was induced by a thermode holding +46°C with duration of 240 seconds to the forearm. Electrocardiogram was measured to obtain data for analysis of heart rate variability. Subjective measurements consisted of pain intensity, pain unpleasantness, stress, arousal, and mood. Results: The results showed a placebo effect on pain intensity and a concomitant reduction in subjective stress and cardiac activity. Stepwise regressions revealed that reduced subjective stress was the only predictor for the placebo analgesic response. Contrary to our hypothesis, male subjects displayed increased placebo analgesia when a male acted as experimenter. Conclusions: The results indicate that reduced negative emotional activation could be a mechanism in placebo analgesia and that experimenter gender is probably not systematically related to placebo analgesia. ECG = electrocardiogram; HRV = heart rate variability.

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

Summary The relation of fear of pain to placebo analgesia was investigated. Fear of pain was associated with reduced placebo analgesia in subjective reports and event‐related potentials. Abstract 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.

Is fear of pain related to placebo analgesia

OBJECTIVE Verbal information that a painkiller has been administered generates an expectation of pain relief which in turn decreases pain. This expectation-based pain reduction is termed placebo analgesia. We hypothesized that fear of pain would be related to higher stress and pain intensity and to reduced placebo analgesia. METHODS Sixty-three students (30 females) participated in a Two-Condition (placebo, natural history)xFive-Test (one pretest, four post-tests) within-subjects design. Heat pain was induced by a 30x30-mm contact thermode to the medial volar forearm. Each pain test lasted for 4 min at a temperature of 46 degrees C. Stress, arousal, and pain intensity and pain unpleasantness were rated on 100-mm visual analogue scales. RESULTS Fear of pain was related to higher anticipatory stress and to higher stress and pain intensity during pain. Fear of pain was also related to reduced placebo analgesic responding. CONCLUSION Fear of pain was positively related to stress both during pain and in the anticipation of pain, and negatively related to placebo analgesia. Previous research has indicated a role for increased stress in the nocebo response, and the present findings suggest that decreased stress may strengthen the placebo response.