ARTICLE IN PRESS2 B. Whalley et al. / Journal of Psychosomatic Research xx (2008) xxx–xxxplacebo responding can be found under optimal conditions. gloves. Expectancy ratings were taken after the cream wasTo this end, responses to identical placebo treatments were applied but before the pain stimulus.assessed on two occasions. If consistency cannot be found The study was conducted over two identical experimentalwith all other factors held constant, it is unlikely to be found sessions, between 1 and 8 days apart (mean 2.5 days, S.D.=at all. Second, we tested the hypothesis that an individuals 2.0). Each session consisted of two trials. On each trial,response to placebo is reasonably consistent across participants simultaneously received two pain stimuli, eachcontexts. To do this, we measured responses to two to a finger of a different hand. One finger was treated with aplacebos that differed only in name. If consistency in the placebo analgesic cream; the other finger was untreated. Forresponse to placebo can be disrupted by a simple change in one trial, the placebo was labeled “Trivaricaine;” for thename, then the search for a generic placebo responder other, it was labeled “Ibuprofen”, and order of presentationwould be impossible. Third, we tested the extent to which was balanced across the sample. Different fingers were usedacquiescence, absorption, and response expectancy pre- for each trial within a session. For half the trials, placebo wasdicted placebo responding. administered to a finger on the right hand and for half to a Acquiescence and absorption are personality traits. finger on the left hand. After the pain stimulus was applied,Acquiescence has been reported to be associated with pain intensity was recorded. At the end of their final session,placebo responding [7–11], and absorption has been participants completed the two personality measures andreported to be a correlate of imaginative suggestibility were thanked and debriefed.. If there is stability in placebo responding they seemlikely candidates in the search for predictors. In contrast to Measures and pain stimulusacquiescence and absorption, response expectancy, whichhas been identified as a central factor in placebo responding Two identical Forgione-Barber Strain Gauge Pain[17,18], is a context-specific variable. Unlike personality Stimulators were used. The device consists of a doughnut-traits, which are presumed to be relatively stable across shaped weight (900 g) at the end of a movable bar (231 g)situation and time, context-specific variables vary greatly as that pivots vertically from a stand at one end. The subjectsa function of the context in which they are assessed. Because finger is placed in a grooved notch on the top of a 50-mmthey are context-specific, response expectancies might stand so that the bar can be lowered gently onto the finger.predict placebo responding even where it is inconsistent The bar tapered at the point of contact and is approximatelyover time and situation. 2 mm wide. The pain stimulator delivers approximately 2041 g of force to a finger. Two sets of the apparatus were adjusted for the right or left hand, so that the remaining threeMethod fingers could rest on the platform between the stand and the bar attachment.Participants and procedure Measurements of pain and pain expectancy were taken on 11-point scales, with separate ratings taken for each Students and nonfaculty staff at the University of hand. End points were marked from no pain at all (0) toPlymouth were recruited via poster for the study; most of the worst pain you can imagine (10). For pain ratings,the students received partial course credit in return for their participants were asked “How intensely did the lever hurtparticipation, but the remainder of the participants received [with/without] the cream?” and for expectancy measure-no compensation. All participants had to be aged over ments participants were asked “How intensely do you think18 years, and exclusion criteria were any preexisting skin the lever will hurt [with/without] the cream?” For each drugcondition, any previous trauma to the fingers to be tested, or (Trivaricaine and Ibuprofen) and at each time pointany medical condition affecting bones or joints (e.g., (Session 1 and Session 2), we calculated the followingosteoporosis, arthritis). A total of 81 participants were variables for analysis: placebo scores, subtracting the scorerecruited, of whom 71 (88%) completed both test sessions for untreated finger from the score for the treated finger,and are included in the analysis below (six participants did and expectancy scores, subtracting expected pain intensitynot give consent to begin the first trial and four failed to for the untreated finger from expected intensity for thereturn for the second test session). Our sample was 67% treated finger.female, and the mean age was 20.6 years (S.D.=5.4). Acquiescence was measured with the 56-item Bass During the consent procedure, participants were told that Acquiescence scale ; valid responses to each item arethe experiment was to compare the reliability of two “yes,” “no,” and “uncertain.” Bass scale scores are calculatedanalgesic creams: a well-known over-the-counter remedy by summing “yes” responses. Absorption was measured with(“Ibuprofen”) and a medication used in hospitals for the the 34-item Tellegen absorption scale ; valid responsesrelief of pain (“Trivaricaine”). Both creams were placebos are “yes” (1) or “no” (0). Absorption scores in this samplebut were presented in realistic nonbranded chemists (mean=19.1, S.D.=5.9) were near identical to previouspackaging and consisted of white aqueous cream. To college-based samples . Internal reliability for bothadminister the creams, the experimenter donned surgical scales was acceptable: Tellegen α=.80, Bass α=.87.
ARTICLE IN PRESS B. Whalley et al. / Journal of Psychosomatic Research xx (2008) xxx–xxx 3Table 1 Table 3Means and (S.D.s) for pain intensity scores (N=71) Correlations of placebo and expectancy scores Time 1 Time 2 Placebo scoresPlaceboname Untreated Treated Untreated Treated Time 1 Time 2Trivaricaine 6.56 (1.80) 5.32 (1.89) 6.83 (1.78) 5.46 (1.95) Expectancy scores Trivaricaine Ibuprofen Trivaricaine IbuprofenIbuprofen 6.61 (1.75) 5.69 (1.86) 6.68 (1.73) 5.78 (2.03) Trivaricaine Time 1 .25 ⁎ .20 .14 .12 Ibuprofen Time 1 .47 ⁎⁎ .18 .36 ⁎⁎ .15 Trivaricaine Time 2 .59 ⁎⁎ .22 .47 ⁎⁎ .33 ⁎⁎Data analysis Ibuprofen Time 2 .27 ⁎ .61 ⁎⁎ .68 ⁎⁎ .58 ⁎⁎ ⁎ P≤.05. Statistical analyses were performed with SPSS 14. A ⁎⁎ P≤.01.within-subject analysis of variance (ANOVA) was used totest for the presence of a placebo effect and differences in itsmagnitude as a function placebo name and experimental indicated that the delay between test sessions did notsession. Because the intertrial interval varied widely, we significantly affect the reliability of placebo responses.tested whether the length of interval had effect by enteringinterval is a covariate in the above ANOVA. Pearson Were responses temporally consistent?correlations were calculated to assess consistency ofindividual differences in the placebo effect and the prediction First, we tested whether a person who responded to aof the placebo effect by personality variables initial placebo at Time 1 was more likely to respond to the sameresponse-expectancy ratings. The mediating effect of placebo at Time 2. Large correlations between placeboexpectancy ratings was analyzed with multiple regression scores for the same placebo at Times 1 and 2 indicate aanalyses in which prior placebo effect ratings were strong temporal relationship for responses to the samecontrolled statistically. placebo at different times (Trivaricaine r =.60, P≤.001; Ibuprofen r =.77, P≤.001).Results Were responses consistent across contexts?Did the creams generate a placebo effect? We tested whether a person who responded to one placebo would be more likely to respond to a second, Mean pain ratings with and without placebo on each trial differently labeled placebo. Given the high correlationsare presented in Table 1. We carried out repeated-measures between responses to the same placebo across sessions, weANOVA (drug label, session, and treatment) to evaluate the combined scores for each placebo, creating a mean placeboeffects of the creams as placebos. A significant main effect Trivaricaine score and a mean placebo Ibuprofen score.was found for placebo treatment [F(1,70)=43.61, P≤.001, There was no significant relationship between mean scoresη2=.38, S.M.D.=0.60], indicating that the placebo creams for the two placebos: r =.10, P N.41. An analysis usinghad a moderate beneficial effect when compared with no individual scores from each trial (e.g., correlating response tocream. No other significant main effects or interactions were Trivaricaine at Time 1 or Time 2 with response to Ibuprofenfound, suggesting that the two labels were equally effective at Time 1 or 2) produced similar results.and they were equally effective at Sessions 1 and 2. Re-peating this analysis with intersession interval as a covariate Did our personality measures correlate with the placebo effect?Table 2Correlations of personality measures with placebo and expectancy scores Correlations between the personality measures used and Tellegen absorption a Bass acquiescence a placebo and expectancy responses are shown in Table 2. No correlations were found with placebo responses, althoughPlacebo responses Trivaricaine Time 1 .06 −.05 one correlation was found between Time 1 Trivaricaine Trivaricaine Time 2 .02 .02 expectancy and absorption. No further correlations were Ibuprofen Time 1 −.06 −.02 found with placebo or expectancy scores when collapsing Ibuprofen Time 2 −.06 −.04 across drug, session, looking at trials in the order ofExpectancy scores administration, or when correlating the maximum placebo Trivaricaine Time 1 .28 ⁎ .13 Trivaricaine Time 2 .10 .10 response exhibited in any of the trials. A follow-up Ibuprofen Time 1 .03 .07 analysis, testing for a moderating effect of personality on Ibuprofen Time 2 .01 .01 responses across context, indicated that neither acquies- ⁎ Pb.05. cence nor absorption affected consistency of response a Intercorrelation between the Tellegen and Bass scales was .44. across contexts.
ARTICLE IN PRESS4 B. Whalley et al. / Journal of Psychosomatic Research xx (2008) xxx–xxxDid response-expectancy predict the placebo effect? and response expectancies independently predicting variance in outcome . To evaluate initial response expectancies prior to any Another possibility is that response to placebo is due toexperience with either placebo cream, we calculated each implicit, as well as explicit, response expectancies. Work inparticipants initial placebo response and initial expectancy other fields has alerted researchers to the extent to whichresponse, ignoring the name of the label. Initial placebo nonconscious processing can influence behavior withoutresponse and expectancy response were significantly provoking verbal reports [29,30], and this has also beencorrelated (r=.33, P≤.01). Table 3 shows the relationship found in the effect of conditioning on placebo response .between placebo response and expectancy for Trivaricaine It follows that verbal reports of expectancies may notand Ibuprofen in both sessions. Subsequent expectancies exhaustively measure the extent to which people process andwere significantly associated with prior placebo effects, respond to features of a given placebo. Future researchsuggesting that peoples response expectancies were altered should explore this possibility.by previous experience. However, expectancies for Triva- We found a strong association between experiencedcaine [t(70)=1.10, ns] and Ibuprofen [t(70)=−.07, ns] did not placebo effects and subsequent expectancies, suggesting thatchange between Sessions 1 and 2. the experience of placebo effects altered participants expectations for future responding. This may account for larger observed correlations between expectancies andDiscussion placebo responses in later trials. A practical implication of these data is that initial We found that with contextual factors held constant, response to a placebo, as might be obtained during the run-responses to placebo were highly reliable indicating that, in phase of a clinical trial, is likely to be the best way ofunder these circumstances, there is temporal stability in identifying placebo responders. Placebo washouts areplacebo responding. However, participants responses to two controversial, and they have been criticized both becausedifferently labeled placebos were not consistent, indicating they are ineffective and because they may have unexpectedthat even very small changes in the context of presentation consequences on trial samples [31,32], although as Lee et al.can affect individual differences in the placebo response and  have recently noted, they continue to be widely used.confirming Gelfands early prediction that placebo correlates Our data suggest that a general rejection of placebo washoutmay vary according to the “entire placebo situation” . periods may be premature. We note that much of the data onThese data suggest that the search for a generic placebo wash-out periods has come from trials of selective serotoninresponder—one who responds consistently to placebo across reuptake inhibitors (SSRIs) antidepressants for which a largedifferent situations—can never be successful, and our failure component of the “active” treatment is in fact placebo-to find general associations between placebo responses and mediated , and under these conditions, washing outpersonality measures is therefore unsurprising. placebo responders would reduce effect sizes in both arms of There may not be one placebo response but several. It the trial. Ironically, placebo washout periods may bewould seem that there are multiple mechanisms involved and effective only in trials of medications that do not generatethey differ as a function of the context in which the placebo large placebo effects.is presented [23–26]. For example, spirituality has been Expectancy predicts placebo responding to some degreefound to be a consistent predictor of a placebo when the and, although it is correlated with prior experience, it isplacebo is contextualized as a spiritual therapy , and partially independent. However, some caveats are in order.optimism has been found to predict for a positive but not a First, unlike the present study, placebo-controlled clinical trialsnegative placebo . Conceptualizing placebos as a contain double-blind instructions and participants are aware“meaning response”  that acts through multiple mechan- that they might receive placebo. In contrast, the instructions inisms—including motivation as well as expectancy and our study were similar to those in comparative drug trialsconditioning—may aid our understanding of these context- without placebo controls. Second, our population wasspecific effects. primarily female and we cannot be sure that the results Response expectancies are context-specific, and this generalize to males as well. Third, we used an experimentalmakes them more reliable predictors of placebo response pain stimulus. Thus, we cannot be certain that our results willthan the generic trait measures included in this study. The generalize to clinical contexts. Future studies of consistency ofbest measure of the influence of expectancy is the association response in clinical patients might employ a variant of thebetween initial expectancies and the initial response to open-hidden paradigm , avoiding the ethical problems ofplacebo. This reveals a modest association, suggesting that, withholding analgesics from patients in pain. Fourth, data onat best, expectancy only partially explains the placebo effect. placebo analgesics might not generalize to other types ofThese data suggest that there may be other context-specific placebos. For these reasons, tests of consistency of placebocharacteristics of the person that determine the response to a responding should also be conducted with other types ofplacebo. Recent studies of placebos in therapeutic contexts placebos known to be effective, for example anxiolytics orhave found just such a pattern, with context-specific traits treatments for Parkinsons disease . Additionally, the
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