Is the Placebo Powerless?- An Analysis of Clinical Trials Comparing Placebo with No Treatment

doi:10.1056/NEJM200105243442106

A correction has been published: N Engl J Med 2001;345(4):304.

Volume 344:1594-1602		May 24, 2001		Number 21

Is the Placebo Powerless?— An Analysis of Clinical Trials Comparing Placebo with No Treatment

Asbjorn Hrobjartsson, M.D., and Peter C. Gotzsche, M.D.

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ABSTRACT

Background Placebo treatments have been reported to help patientswith many diseases, but the quality of the evidence supportingthis finding has not been rigorously evaluated.

Methods We conducted a systematic review of clinical trialsin which patients were randomly assigned to either placebo orno treatment. A placebo could be pharmacologic (e.g., a tablet),physical (e.g., a manipulation), or psychological (e.g., a conversation).

Results We identified 130 trials that met our inclusion criteria.After the exclusion of 16 trials without relevant data on outcomes,there were 32 with binary outcomes (involving 3795 patients,with a median of 51 patients per trial) and 82 with continuousoutcomes (involving 4730 patients, with a median of 27 patientsper trial). As compared with no treatment, placebo had no significanteffect on binary outcomes, regardless of whether these outcomeswere subjective or objective. For the trials with continuousoutcomes, placebo had a beneficial effect, but the effect decreasedwith increasing sample size, indicating a possible bias relatedto the effects of small trials. The pooled standardized meandifference was significant for the trials with subjective outcomesbut not for those with objective outcomes. In 27 trials involvingthe treatment of pain, placebo had a beneficial effect, as indicatedby a reduction in the intensity of pain of 6.5 mm on a 100-mmvisual-analogue scale.

Conclusions We found little evidence in general that placeboshad powerful clinical effects. Although placebos had no significanteffects on objective or binary outcomes, they had possible smallbenefits in studies with continuous subjective outcomes andfor the treatment of pain. Outside the setting of clinical trials,there is no justification for the use of placebos.

Placebos have been reported to improve subjective and objectiveoutcomes in up to 30 to 40 percent of patients with a wide rangeof clinical conditions, such as pain, asthma, high blood pressure,and even myocardial infarction.¹^,²^,³ In his 1955 article "ThePowerful Placebo," Beecher concluded, "It is evident that placeboshave a high degree of therapeutic effectiveness in treatingsubjective responses, decided improvement, interpreted underthe unknowns technique as a real therapeutic effect, being producedin 35.2±2.2% of cases."¹

Beecher's article and the 35 percent figure are often citedas evidence that a placebo can be an important medical treatment.The vast majority of reports on placebos, including Beecher'sarticle, have estimated the effect of placebo as the differencefrom base line in the condition of patients in the placebo groupof a randomized trial after treatment. With this approach, theeffect of placebo cannot be distinguished from the natural courseof the disease, regression to the mean, and the effects of otherfactors.⁴^,⁵^,⁶ The reported large effects of placebo could therefore,at least in part, be artifacts of inadequate research methods.

Despite the reservations of many physicians,⁷ the clinical useof placebo has been advocated in editorials and articles inleading journals.³^,⁸^,⁹ To understand better the effects of placeboas a treatment, we conducted a systematic review of clinicaltrials in which patients with various clinical conditions wererandomly assigned to placebo or to no treatment. We were primarilyinterested in the clinical effect of placebo as a treatmentfor disease, rather than the role of placebo as a comparisontreatment in clinical trials. A secondary aim was to study whetherthe effect of placebo differed for subjective and objectiveoutcomes.

Methods

Definition of Placebo

Placebo is difficult to define satisfactorily.⁵ In clinicaltrials, placebos are generally control treatments with a similarappearance to the study treatments but without their specificactivity. We therefore defined placebo practically as an interventionlabeled as such in the report of a clinical trial.

Literature Search

We searched Medline, EMBASE, PsycLIT, Biological Abstracts,and the Cochrane Controlled Trials Register for trials publishedbefore the end of 1998. The search was developed iterativelyfor synonyms of "placebo," "no treatment," and "randomized clinicaltrial" (the exact search strategy is available as SupplementaryAppendix 1 with the full text of this article at http://www.nejm.organd was based on a published protocol¹⁰). We systematicallyread the reference lists of included trials and selected booksand review articles. We also asked researchers in the fieldto provide lists of relevant trials.

Selection of Studies

We included studies if patients were assigned randomly to aplacebo group or an untreated group (often there was also athird group that received active treatment). We excluded studiesif randomization was clearly not concealed — that is,if group assignment were predictable¹¹ (e.g., patients wereassigned to treatment groups according to the day of the month).We also excluded studies if participants were paid or were healthyvolunteers, if the person who assessed objective outcomes wasaware of group assignments, if the dropout rate exceeded 50percent, or if it was very likely that the alleged placebo hada clinical effect not associated with the treatment ritual alone(e.g., movement techniques for postoperative pain). All potentiallyeligible trial reports were read in full by both authors. Disagreementsconcerning eligibility were resolved by discussion.

Extraction of Data

Data were extracted from the report of each trial with the useof forms tested in pilot studies. We contacted the authors ofthe included studies when reported outcome data were inadequatefor meta-analysis. We noted how the randomization was conductedand whether the therapist responsible for the administrationof placebo (as distinct from the observer) was unaware of groupassignments. Furthermore, we noted the purpose of the trial,the dropout rate, whether the placebo was given in additionto the standard treatment, and whether the main outcome wasclearly indicated.

We noted whether the placebo was pharmacologic (e.g., a tablet),physical (e.g., a manipulation), or psychological (e.g., a conversation);whether clinical problems reported by the patients could havebeen observed by others (i.e., whether the symptoms were observableoutcomes such as cough); and whether objective outcomes werelaboratory data, were derived from examinations that requiredthe cooperation of the patients (i.e., objective outcomes suchas forced expiratory volume), or did not require such cooperation(e.g., edema).

Both reviewers independently selected outcomes by referringonly to the methods sections of articles; any disagreementswere resolved by discussion. As the primary outcome, we selectedthe main objective or subjective outcome of each trial (preferablya characteristic symptom). If a main outcome was not indicated,we used the outcome that we felt was most relevant to patients.Binary outcomes (e.g., the proportions of smokers and nonsmokers)were preferred to continuous ones (e.g., the mean number ofcigarettes smoked). Data recorded immediately after the endof treatment were preferred to follow-up data, although end-of-treatmentdata were not always available. For crossover trials, we extracteddata from the first treatment period only; if that was not possible,we used the summary data as if they had been derived from aparallel-group trial (i.e., using the between-group standarddeviations and total number of participants for both groups).

Synthesis of Data

For each trial with binary outcomes, we calculated the relativerisk of an unwanted outcome, defined as the ratio of the numberof patients with an unwanted outcome to the total number ofpatients in the placebo group, divided by the same ratio inthe untreated group. Thus, a relative risk below 1.0 indicatesa beneficial effect of placebo.

For trials with continuous outcomes, we calculated the standardizedmean difference, which was defined as the difference betweenthe mean value for an unwanted outcome in the placebo groupand the corresponding mean value in the untreated group dividedby the pooled standard deviation.¹² A value of –1 signifiesthat the mean in the placebo group was 1 SD below the mean inthe untreated group, indicating a beneficial effect of placebo.

We calculated the pooled relative risk of an unwanted outcomefor trials with binary outcomes and the pooled standardizedmean difference for those with continuous outcomes.¹³ Becauseof the different clinical conditions and settings, we expectedthat the data sets would be heterogeneous — that is, thatthe effects of individual trials would vary more than expectedby chance alone. The variance and statistical significance ofthe differences were therefore assessed with the use of random-effectcalculations.¹³ We calculated the pooled effects for subjectiveand objective outcomes and for specific clinical problems thathad been investigated in at least three trials by differentresearch groups.¹⁴

We performed preplanned analyses of subgroups to see whetherour findings were sensitive to the type of placebo or the typeof outcome involved. Furthermore, for each trial, we plottedthe effect against the inverse of its standard error (whichincreases with the number of trial participants). Since thevariation in the estimated effect decreases with increasingsample size, the plot is expected to resemble a symmetricalfunnel. If there is significant asymmetry in such funnel plots,it is usually caused by small trials' reporting greater effects,on average, than large trials, which can reflect publicationbias¹⁵ or other biases. We also performed several preplannedsensitivity analyses to determine whether our findings weresensitive to variations in the quality of the trials.

In trials with continuous outcomes, we used F tests to checkwhether the standard deviations of the placebo group and theuntreated group were significantly different.¹⁶ We regardedthe distributions of either group as non-Gaussian if 1.64 SDexceeded the mean for positive outcomes.¹⁷ Chi-square testswere used to test for heterogeneity on the basis of the DerSimonianand Laird Q statistic.¹³^,¹⁸ Results are reported with 95 percentconfidence intervals. All P values are two-tailed.

Results

Selection and Characteristics of Studies

We identified 727 potentially eligible trials. We subsequentlyexcluded 597 trials for the following reasons: 404 were nonclinicalor nonrandomized, 129 were missing a placebo group or an untreatedgroup, 29 were reported in more than one publication, 11 hadclearly unblinded assessment of objective outcomes, and 24 metother criteria for exclusion, such as dropout rates over 50percent. No relevant outcome data were available for 16 of theremaining 130 trials. The analysis therefore included 114 trials.¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷^,²⁸^,²⁹^,³⁰^,³¹^,³²^,³³^,³⁴^,³⁵^,³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹^,⁵⁰^,⁵¹^,⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸^,⁵⁹^,⁶⁰^,⁶¹^,⁶²^,⁶³^,⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸^,⁶⁹^,⁷⁰^,⁷¹^,⁷²^,⁷³^,⁷⁴^,⁷⁵^,⁷⁶^,⁷⁷^,⁷⁸^,⁷⁹^,⁸⁰^,⁸¹^,⁸²^,⁸³^,⁸⁴^,⁸⁵^,⁸⁶^,⁸⁷^,⁸⁸^,⁸⁹^,⁹⁰^,⁹¹^,⁹²^,⁹³^,⁹⁴^,⁹⁵^,⁹⁶^,⁹⁷^,⁹⁸^,⁹⁹^,¹⁰⁰^,¹⁰¹^,¹⁰²^,¹⁰³^,¹⁰⁴^,¹⁰⁵^,¹⁰⁶^,¹⁰⁷^,¹⁰⁸^,¹⁰⁹^,¹¹⁰^,¹¹¹^,¹¹²^,¹¹³^,¹¹⁴^,¹¹⁵^,¹¹⁶^,¹¹⁷^,¹¹⁸^,¹¹⁹^,¹²⁰^,¹²¹^,¹²²^,¹²³^,¹²⁴^,¹²⁵^,¹²⁶^,¹²⁷^,¹²⁸^,¹²⁹^,¹³⁰^,¹³¹^,¹³²

There were 10 crossover trials, of which 7 (which included atotal of 182 patients) were handled as parallel trials. In 112trials, there was a third group assigned to active treatmentin addition to the placebo and the untreated groups. In 88 ofthese, determining the effect of placebo was not mentioned asan objective of the study. The trial reports were publishedin five languages between 1946 and 1998. The outcomes were binaryin 32 trials¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷^,²⁸^,²⁹^,³⁰^,³¹^,³²^,³³^,³⁴^,³⁵^,³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹^,⁵⁰and continuous in 82.⁵¹^,⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸^,⁵⁹^,⁶⁰^,⁶¹^,⁶²^,⁶³^,⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸^,⁶⁹^,⁷⁰^,⁷¹^,⁷²^,⁷³^,⁷⁴^,⁷⁵^,⁷⁶^,⁷⁷^,⁷⁸^,⁷⁹^,⁸⁰^,⁸¹^,⁸²^,⁸³^,⁸⁴^,⁸⁵^,⁸⁶^,⁸⁷^,⁸⁸^,⁸⁹^,⁹⁰^,⁹¹^,⁹²^,⁹³^,⁹⁴^,⁹⁵^,⁹⁶^,⁹⁷^,⁹⁸^,⁹⁹^,¹⁰⁰^,¹⁰¹^,¹⁰²^,¹⁰³^,¹⁰⁴^,¹⁰⁵^,¹⁰⁶^,¹⁰⁷^,¹⁰⁸^,¹⁰⁹^,¹¹⁰^,¹¹¹^,¹¹²^,¹¹³^,¹¹⁴^,¹¹⁵^,¹¹⁶^,¹¹⁷^,¹¹⁸^,¹¹⁹^,¹²⁰^,¹²¹^,¹²²^,¹²³^,¹²⁴^,¹²⁵^,¹²⁶^,¹²⁷^,¹²⁸^,¹²⁹^,¹³⁰^,¹³¹^,¹³²In 76 trials, the outcome in the data we extracted was identifiedas a main outcome by the authors of the trials. If only patientsin the placebo and untreated groups were counted, the trialswith binary outcomes included 3795 patients with a median of51 patients per trial (interquartile range, 26 to 72), and thetrials with continuous outcomes included 4730 patients witha median of 27 patients per trial (interquartile range, 20 to52).

The typical pharmacologic placebo was a lactose tablet. Thetypical physical placebo was a procedure performed with a machinethat was turned off (e.g., sham transcutaneous electrical nervestimulation). The typical psychological placebo was a nondirectional,neutral discussion between the patient and the treatment provider,referred to as an "attention placebo." No treatment typicallyentailed observation only or standard therapy; in the lattercase, all patients in the trial received standard therapy, andthe placebo was additional.

The results for the individual trials are available as Supplementary Appendix 2and Supplementary Appendix 3 with the full text ofthis article at http://www.nejm.org. The trials investigated40 clinical conditions: hypertension, asthma, anemia, hyperglycemia,hypercholesterolemia, seasickness, Raynaud's disease, alcoholabuse, smoking, obesity, poor oral hygiene, herpes simplex infection,bacterial infection, common cold, pain, nausea, ileus, infertility,cervical dilatation, labor, menopause, prostatism, depression,schizophrenia, insomnia, anxiety, phobia, compulsive nail biting,mental handicap, marital discord, stress related to dental treatment,orgasmic difficulties, fecal soiling, enuresis, epilepsy, Parkinson'sdisease, Alzheimer's disease, attention-deficit–hyperactivitydisorder, carpal tunnel syndrome, and undiagnosed ailments.

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Supplementary Appendix 2. Trials with Binary Outcomes.

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Supplementary Appendix 3. Trials with Continuous Outcomes.

Binary Outcomes

As compared with no treatment, placebo did not have a significanteffect on binary outcomes (overall pooled relative risk of anunwanted outcome with placebo, 0.95; 95 percent confidence interval,0.88 to 1.02). The pooled relative risk was 0.95 for trialswith subjective outcomes (95 percent confidence interval, 0.86to 1.05) and 0.91 for trials with objective outcomes (95 percentconfidence interval, 0.80 to 1.04) (Table 1).

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Table 1. Effect of Placebo in Trials with Binary or Continuous Outcomes.

There was significant heterogeneity among the trials with binaryoutcomes (P=0.003), indicating that the variation in the effectof placebo among trials was larger than would be expected toresult from chance alone. The heterogeneity was not due to smalltrials' showing more pronounced effects of placebo than largetrials (P=0.56).¹⁵

Three clinical problems had been investigated in at least threeindependent trials with binary outcomes: nausea, relapse afterthe cessation of smoking, and depression. Placebo had no significanteffect on these outcomes, but the confidence intervals werewide (Table 2).

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Table 2. Effect of Placebo on Specific Clinical Problems.

Continuous Outcomes

The overall pooled standardized mean difference was –0.28(95 percent confidence interval, –0.38 to –0.19).Thus, there was a beneficial effect of placebo, because thepooled mean of the placebo groups was 0.28 SD lower than thepooled mean of the untreated groups (P<0.001). The pooledstandardized mean difference was significant for trials withsubjective outcomes (–0.36; 95 percent confidence interval,–0.47 to –0.25) but not for trials with objectiveoutcomes (–0.12; 95 percent confidence interval, –0.27to 0.03) (Table 1).

There was significant heterogeneity among the trials with continuousoutcomes (P<0.001). The magnitude of the effect of placebodecreased with increasing sample size (P=0.05), indicating apossible bias related to the effects of small trials.

Pain, obesity, asthma, hypertension, insomnia, and anxiety wereeach investigated in at least three independent trials. Onlythe 27 trials involving the treatment of pain (including a totalof 1602 patients) showed a significant effect of placebo ascompared with no treatment (pooled standardized mean difference,–0.27; 95 percent confidence interval, –0.40 to–0.15). There was no significant effect of placebo onthe other conditions, although the confidence intervals werewide (Table 2).

Expressing the standardized mean differences in terms of clinicaloutcomes indicates that the effect of placebo on pain correspondsto a reduction in the mean intensity of pain of 6.5 mm (95 percentconfidence interval, 3.6 to 9.6) on a 100-mm visual-analoguescale. The nonsignificant effect of placebo on obesity correspondsto a reduction in mean weight of 3.2 percent (95 percent confidenceinterval, 7.4 to –1.2 percent); on hypertension, a reductionin mean diastolic blood pressure of 3.2 mm Hg (95 percent confidenceinterval, 7.8 to –1.3); and on insomnia, a decrease inthe mean time required to fall asleep of 10 minutes (95 percentconfidence interval, 25 to –5). For asthma and anxiety,the measurement scales were too variable to allow clinical interpretationof the results.

Small trials involving the treatment of pain did not have significantlygreater effects than large trials (P=0.20), but the power ofthe test was low.¹⁵ There was no significant heterogeneity amongthe nine sets of data on specific clinical problems (P>0.10),but the power of these analyses was also low.

Sensitivity Analyses

The number of trials compared in the sensitivity analyses wasin most cases nine or more, and they included more than 1000patients. There was no difference in the effect of placebo betweensubcategories of objective and subjective binary outcomes (Table 3).The effect of placebo among subcategories of continuousoutcomes did not differ significantly, except for a negativeeffect of placebo in four trials with laboratory data⁶⁶^,⁶⁷^,⁷⁵^,⁷⁶(Table 3). For both continuous and binary outcomes, there wereno significant differences among the various types of placebos(Table 4).

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Table 3. Effect of Placebo in Trials with Specific Types of Outcomes.

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Table 4. Effect of Three Types of Placebo.

The effect of placebo on continuous or binary outcomes was notinfluenced by the dropout rate ( $<=$ 15 percent vs. > 15 percent)or by whether the observers were aware of group assignments,but only two trials with binary objective outcomes (involving316 patients) included observers who were clearly unaware ofthe group assignments³⁹^,⁴⁰ (data not shown). The effects ofplacebo were also unrelated to whether the care providers wereunaware of the treatment type (placebo or experimental), whetherplacebos were given in addition to standard treatments, whetherthe effect of placebo was an explicit research objective, orwhether we had identified the main outcome on the basis of clinicalrelevance (data not shown). The size of the effect in trialswith clearly concealed randomization did not differ from thatin other trials, but only four trials with continuous outcomes⁸⁴^,⁹⁵^,⁹⁷^,¹⁰⁷(involving 523 patients) and one with binary outcomes⁴⁰ (involving54 patients) reported clearly concealed randomization (datanot shown). For continuous outcomes, the effect was not influencedby non-Gaussian distributions in the placebo or the untreatedgroups (data not shown).

Discussion

We did not detect a significant effect of placebo as comparedwith no treatment in pooled data from trials with subjectiveor objective binary or continuous objective outcomes. We did,however, find a significant difference between placebo and notreatment in trials with continuous subjective outcomes andin trials involving the treatment of pain.

Several types of bias may have affected our findings. Blindedevaluation of subjective outcomes was not possible in the trialswe reviewed. Patients in an untreated group would know theywere not being treated, and patients in a placebo group wouldthink they had received treatment. It is difficult to distinguishbetween reporting bias and a true effect of placebo on subjectiveoutcomes, since a patient may tend to try to please the investigatorand report improvement when none has occurred. The fact thatplacebos had no significant effect on objective continuous outcomessuggests that reporting bias may have been a factor in the trialswith subjective outcomes.

If patients in the untreated groups sought treatment outsidethe trials more often than patients in the placebo groups, theeffects of placebo might be less apparent. Very few trials providedinformation on concomitant treatment. The risk of bias is expectedto be larger in trials in which placebo is the only treatmentand is not given in addition to standard therapy. We did not,however, find a difference in effect between the two types oftrials.

There was some evidence that placebos had greater effects insmall trials with continuous outcomes than in large trials.This could indicate that some small trials with negative outcomeshave not been published or that we did not identify them.¹⁵It is difficult to identify relevant trials in this field; anothersystematic search for trials involving placebo groups versusuntreated groups found only 12 studies.¹³³ We identified 114trials from which the outcomes could be extracted, but 88 ofthese trials investigated the effect of active treatment ina third group of patients and did not explicitly study the effectof placebo. Because the publication of such trials is not directlyassociated with the effect of placebo, it is unlikely that theexistence of unpublished trials could explain the higher effectsreported in small studies.

Poor methodology in small trials could also explain the largeeffects of placebo. It surprised us that we found no associationbetween measures of the quality of a trial and placebo effects.However, the statistical power of our sensitivity analyses mayhave been too low. Furthermore, it is possible that small trialstended to investigate clinical conditions in which placebostruly had greater effects. Thus, although we found an effectof placebos on subjective continuous outcomes, the inverse relationbetween trial size and effect size implies that the estimatesof pooled effect should be interpreted cautiously.

It can also be difficult to interpret whether a pooled standardizedmean difference is large enough to be clinically meaningful.Some individual trials reported clinically relevant effectswith standardized mean differences of less than –0.6,⁹¹but such "outlier" values may be spurious. If the possible biaseswe have discussed are disregarded, the pooled effect of placeboon pain corresponds to one third of the effect of nonsteroidalantiinflammatory drugs, as compared with placebo, in double-blindtrials.¹³⁴ It is uncertain whether such an effect is importantfor patients.

Our study has other limitations. We did extensive analyses ofpredefined subgroups according to the type of placebo, disease,and outcome without identifying a subgroup of trials in whichthe effect of placebo was large. However, we cannot excludethe possibility that, in the pooling of heterogeneous trials,the existence of such a subgroup was obscured. Our conclusionsare also limited to the clinical conditions and outcomes thatwere investigated. It should be noted that few trials reportedon the quality of life or patients' well-being.

We reviewed the effect of placebos but not the effect of thepatient–provider relationship. We could not rule out apsychological therapeutic effect of this relationship, whichmay be largely independent of any placebo intervention.²⁰

Moreover, the use of placebos in blinded, randomized trialsis a precaution directed against many forms of bias and notonly a way of controlling for the effects of placebo. Patientswho are aware of their treatment assignment may differ fromunaware patients in their way of reporting beneficial and harmfuleffects of treatment, in their tendency to seek additional treatmentoutside the study, and in their risk of dropping out of thestudy. Furthermore, staff members who are aware of treatmentassignments may differ in their use of alternative forms ofcare and in their assessment of outcomes. Thus, even if therewas no true effect of placebo, one would expect to find differencesbetween placebo and untreated groups because of bias associatedwith a lack of double-blinding.

We were unable to detect any such significant difference intrials with subjective or objective binary or continuous objectiveoutcomes. This surprising finding can possibly be explainedby our selection of trials. Since our goal was to study theclinical effect of placebos, we reduced the influence of observerbias and bias due to dropouts by excluding trials with clearlyunblinded objective outcomes and by attempting to analyze post-treatmentdata instead of follow-up data. In addition, since most trialswe included did not primarily address the effect of a placebobut, rather, evaluated that of an active treatment, our studymay have underestimated bias associated with the interests ofthe investigators. Since the design of our review precludesestimation of the overall influence of bias due to a lack ofdouble-blinding, our results do not imply that control groupsthat receive no treatment can be substituted for control groupsthat receive placebo without creating a risk of bias. This resultis in accordance with an empirical study of 33 meta-analyses,which found that randomized trials that were not double-blindedyielded larger estimates than blinded trials, with odds ratiosthat were exaggerated by 17 percent.¹¹

In conclusion, we found little evidence that placebos in generalhave powerful clinical effects. Placebos had no significantpooled effect on subjective or objective binary or continuousobjective outcomes. We found significant effects of placeboon continuous subjective outcomes and for the treatment of painbut also bias related to larger effects in small trials. Theuse of placebo outside the aegis of a controlled, properly designedclinical trial cannot be recommended.

Supported by a grant from the Faculty of Health Sciences atthe University of Copenhagen.

We are indebted to Henrik R. Wulff, Jos Kleijnen, and Iain Chalmersfor valuable comments on previous versions of the manuscript;to Gunvor Kienle, Andrew Vickers, Harald Walach, Clive Adams,and Iain Chalmers for lists of relevant trials; and to the numerousplacebo-trial researchers for access to additional data.

Source Information

From the Department of Medical Philosophy and Clinical Theory, University of Copenhagen, Panum Institute, and the Nordic Cochrane Centre, Rigshospitalet — both in Copenhagen, Denmark.

Address reprint requests to Dr. Hróbjartsson at the Department of Medical Philosophy and Clinical Theory, University of Copenhagen, Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark, or at a.hrobjartsson{at}cochrane.dk.

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Appendix

Supplementary Appendix 1. Search Strategy

Medline, EMBASE, PsycLIT, Biological Abstracts, and the CochraneControlled Trials Register were searched.

Search history for Medline Advanced SilverPlatter version, from1966 to 1998

PLACEBO* for MOCK* or SHAM* or FAKE* or VEHICLE* or DUMM* orATTENTION* CONTROL* or PSEUDO* TREAT* or UN?SPECIFIC* or NON?SPECIFIC*

and

NO??TREAT* or NO TREAT* or NON TREAT* or UN?TREAT* or UN TREAT*or MINIM* TREAT* or USUAL?TREAT* or USUAL TREAT* or

NO INTERV* or NON INTERV* or NO??INTERV* or NO CONTACT* OR NONCONTACT* or NO??CONTACT?* or USUAL CONTACT* OR USUAL CARE* or

NO PILL* or NON PILL* or NO??PILL* or NO TABLET* or NON TABLET*or NO??TABLET* or NO MEDIC* or NON MEDIC* or NO??MEDIC* or UNMEDIC* or UN?MEDIC* or MINIM* MEDIC* or

NO??SURGER* or NO OPERAT* or NON OPERAT* or NO??OPERAT* OR NOSURGER* OR NON SURGER* OR NO??SURGER* or

(NO THERAP* or NO??THERAP* or NON THERAP* or MINIM* THERAP*or USUAL* THERAP*) in AB or (NO THERAP* or NO??THERAP* or NONTHERAP* or MINIM* THERAP* or USUAL* THERAP*) in T1

WAITING LIST* or WAITING?LIST* or ((NATURAL or SPONTANEOUS)NEAR1 (COURSE or DEVELOPMENT or HISTORY)) or

((TWO or "2" or THREE or "3" or FOUR or "4" or FIVE or "5" orSIX or "6" or SEVEN or "7") NEAR1 (GROUPS or TREATMENT GROUPS))NEAR (CONTROL or CONTROLS)

and

DOUBLE-BLIND-METHOD or SINGLE-BLIND-METHOD or RANDOM-ALLOCATIONor RANDOMIZED-CONTROLLED-TRIALS/ALL SUBHEADINGS or CLINICAL-TRIALS/ALLSUBHEADINGS or

(CLINICAL-TRIAL or RANDOMIZED-CONTROLLED-TRIAL or CONTROLLED-CLINICAL-TRIAL)in PT or

RANDOM* or (CLINICAL near TRIAL*) or DOUBLE* BLIND* or SINGLE*BLIND*

and

HUMAN in TG

Comment:

The central search term "no" was initially an unsearchable stopword in Medline. With the help of the staff at Radcliffe ScienceLibrary in Oxford in the United Kingdom, we contacted the NationalLibrary of Medicine in the United States and the status of "no"was changed to that of a normal search word.

Search strategy for EMBASE CD SilverPlatter version, from 1980to 1998

PLACEBO* or MOCK* or SHAM* or FAKE* or VEHICLE* or DUMM* orATTENTION* CONTROL* or PSEUDO* TREAT* OR UN?specific* or NON?SPECIFIC*

and

NO??TREAT* or NO TREAT* or NON TREAT* or UN?TREAT* or UN TREAT*or MINIM* TREAT* or USUAL?TREAT* or USUAL TREAT* or WITHOUTTREAT* or WITHOUT?TREAT* or

NO INTERV* or NON INTERV* or NO??INTERV* or NO CONTACT* OR NONCONTACT* or NO??CONTACT* or USUAL CONTACT*or USUAL CARE* or

(NO THERAP* or NO??THERAP* or NON THERAP* or MINIM* THERAP*or USUAL* THERAP*) in AB or (NO THERAP* or NO??THERAP* or NONTHERAP* or MINIM* THERAP* or USUAL* THERAP*) in T1 or

NO PILL* or NON PILL* or NO??PILL* or NO TABLET* or NON TABLET*or NO??TABLET* or

WAITING LIST* or WAITING?LIST* or ((NATURAL or SPONTANEOUS)NEAR1 (COURSE or DEVELOPMENT or HISTORY)) or

NO MEDIC* or NON MEDIC* or NO??MEDIC* or UN MEDIC* or UN?MEDIC*or MINIM* MEDIC* or

NO OPERAT* or NON OPERAT* or NO??OPERAT* or NO SURGER* or NONSURGER* or NO??SURGER* or

((TWO or "2" or THREE or "3" or FOUR or "4" or FIVE or "5" orSIX or "6" or SEVEN or "7") NEAR1 (GROUPS or TREATMENT GROUPS))NEAR (CONTROL or CONTROLS)

and

CLINICAL-TRIAL or RANDOMIZED-CONTROLLED-TRIAL or RANDOMIZATIONor DOUBLE-BLIND-PROCEDURE or SINGLE-BLIND-PROCEDURE or CONTROLLED-STUDYor MAJOR-CLINICAL-STUDY or CLINICAL-ARTICLE or

RANDOM* or (CLINICAL near TRIAL*) or DOUBLE* BLIND* or SINGLE*BLIND*

and

HUMAN- in DE

Search Strategy for PsycLIT SilverPlatter version up to 1998

PLACEBO* or MOCK* or SHAM* or FAKE* or VEHICLE* or DUMM* orPSEUDO* TREAT* or ATTENTION* CONTROL* OR UNSPECIFIC* OR NON?SPECIFIC*

and

NO??TREAT* or NO TREAT* or NON TREAT* or UN?TREAT* or UN TREAT*or MINIM* TREAT* or WITHOUT TREAT* or

NO??INTERV* or NO INTERV* OR NON INTERV* or UN?INTERV* or UNINTERV* or MINIM* INTERV* or WITHOUT INTERV* or

NO??MEDIC* or NO MEDIC* or NON MEDIC* or UN?MEDIC* or UN MEDIC*or MINIM* MEDIC* or WITHOUT MEDIC* or NO??PILL* or NO PILL*or NON PILL* or

NO??OPERAT* or NO OPERAT* or NON OPERAT* or UN?OPERAT* or UNOPERAT* or MINIM* OPERAT* or WITHOUT OPERAT* or NO??SURGER*or NO SURGER* or NON SURGER* or MINIM* SURGER* or WITHOUT SURGER*or

WAITING?LIST* or WAITING LIST or VISITATION* or ((NATURAL orSPONTANEOUS) NEAR1 (COURSE* or DEVELOPMENT* or HISTORY*)) or

((TWO or "2" or THREE or "3" or FOUR or "4" or FIVE or "5" orSIX or "6" or SEVEN or "7") NEAR1 (GROUPS or TREATMENT GROUPS))NEAR (CONTROL or CONTROLS)

and

not ANIMAL in (PO or DE)

Comment:

Neither the indexation of clinical trials nor the reportingin abstracts in PsycLIT was helpful for the reliable identificationof randomized trials. With the purpose of minimizing the numberof missed randomized trials, any search terms aimed at identifyingclinical trials were omitted. In a later filtering process,abstracts were read in full.

Search strategy for Biological Abstracts on CD SilverPlatterversion, from 1986 to 1998

PLACEBO* or MOCK* or SHAM* or FAKE* or VEHICLE* or DUMM* orATTENTION* CONTROL* or PSEUDO* CONTROL* or UN?SPECIFIC* or NON?SPECIFIC*

and

NO??TREAT* or NO TREAT* or NON TREAT* or UN?TREAT* or UN TREAT*or MINIM* TREAT* or USUAL?TREAT* or USUAL TREAT* or WITHOUTTREAT* or WITHOUT?TREAT* or

NO INTERV* or NON INTERV* or NO??INTERV* or NO CONTACT* or NONCONTACT* or NO??CONTACT?* or

NO CONTACT* or NON CONTACT* or NO??CONTACT* or USUAL CONTACT*or USUAL CARE* or

NO PILL* or NON PILL* or NO??PILL or NO TABLET* or NON TABLET*or NO??TABLET* or

(NO THERAP* or NO??THERAP* or NON THERAP* or MINIM* THERAP*or USUAL* THERAP*) in TI or

(NO THERAP* or NO??THERAP* or NON THERAP* or MINIM* THERAP*or USUAL* THERAP*) in AB or

NO MEDIC* or NON MEDIC* or NO??MEDIC* or UN MEDIC* or UN?MEDIC*or MINIM* MEDIC* or

NO OPERAT* or NON OPERAT* or NO??OPERAT* or NO SURGER* or NONSURGER* or NO??SURGER* or

WAITING LIST* or WAITING?LIST* or ((NATURAL or SPONTANEOUS)NEAR1 (COURSE or DEVELOPMENT or HISTORY)) or

((TWO or "2" or THREE or "3" or FOUR or "4" or FIVE or "5" orSIX or "6" or SEVEN or "7") NEAR1 (GROUPS or TREATMENT GROUPS))NEAR (CONTROL or CONTROLS)

and

RANDOM* or (CLINICAL near TRIAL*) or DOUBLE* BLIND* or SINGLE*BLIND*

and

HUMAN- in OR or HUMAN in DE or HUMANS in ST

Search Strategy for Cochrane Controlled Trials Register version1998/3

PLACEBO* or MOCK* or SHAM* or FAKE* or VEHICLE* or DUMM* orATTENTION*CONTROL* or PSEUDO*TREAT* or UN?SPECIFIC* or NON?SPECIFIC*

and

not (MEDLINE or EMBASE)

References were downloaded to a ProCite file. A second searchwas conducted in ProCite with a simplified search strategy basedon "no treatment" expressions:

"no treat*" or "no-treat*" or "non treat*" or "non-treat*" or"untreat*" or "no interv*" or "no-interv*" or "non interv*"or "non-interv*" or "no contact*" or "no-contact*" or "non contact*"or "non-contact*" or "usual care*" or "no tablet*" or "no-tablet*"or "non tablet*" or "non-tablet*" or "no pill*" or "no-pill*"or "non pill*" or "non-pill*" or "waiting list*" or "waitinglist*"or "waiting-list*" or "natural course" or "natural development"or "natural history" or "spontaneous course" or "spontaneousdevelopment" or "spontaneous history" or "no medic*" or "nonmedic*" or "non-medic*" or "no surger" or "non surger*" or "non-surger*"or "no operat*" or "non operat*" or "non-operat*"

Comment:

It was not possible to search for words containing less thanthree letters in the Cochrane Controlled Trials Register. Thismade searches for the essential term "no" impossible. The two-phasesearch strategy described above was therefore implemented.

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