Placebo interventions are often claimed to substantially improve patient-reported
and observer-reported outcomes in many clinical conditions, but most
reports on effects of placebos are based on studies that have not
randomised patients to placebo or no treatment. Two previous versions
of this review from 2001 and 2004 found that placebo interventions
in general did not have clinically important effects, but that there
were possible beneficial effects on patient-reported outcomes, especially
pain. Since then several relevant trials have been published.Our
primary aims were to assess the effect of placebo interventions in
general across all clinical conditions, and to investigate the effects
of placebo interventions on specific clinical conditions. Our secondary
aims were to assess whether the effect of placebo treatments differed
for patient-reported and observer-reported outcomes, and to explore
other reasons for variations in effect.We searched the Cochrane Central
Register of Controlled Trials (CENTRAL, The Cochrane Library Issue
4, 2007), MEDLINE (1966 to March 2008), EMBASE (1980 to March 2008),
PsycINFO (1887 to March 2008) and Biological Abstracts (1986 to March
2008). We contacted experts on placebo research, and read references
in the included trials.We included randomised placebo trials with
a no-treatment control group investigating any health problem.Two
authors independently assessed trial quality and extracted data.
We contacted study authors for additional information. Trials with
binary data were summarised using relative risk (a value of less
than 1 indicates a beneficial effect of placebo), and trials with
continuous outcomes were summarised using standardised mean difference
(a negative value indicates a beneficial effect of placebo).Outcome
data were available in 202 out of 234 included trials, investigating
60 clinical conditions. We regarded the risk of bias as low in only
16 trials (8\%), five of which had binary outcomes.In 44 studies
with binary outcomes (6041 patients), there was moderate heterogeneity
(P < 0.001; I(2) 45\%) but no clear difference in effects between
small and large trials (symmetrical funnel plot). The overall pooled
effect of placebo was a relative risk of 0.93 (95\% confidence interval
(CI) 0.88 to 0.99). The pooled relative risk for patient-reported
outcomes was 0.93 (95\% CI 0.86 to 1.00) and for observer-reported
outcomes 0.93 (95\% CI 0.85 to 1.02). We found no statistically significant
effect of placebo interventions in four clinical conditions that
had been investigated in three trials or more: pain, nausea, smoking,
and depression, but confidence intervals were wide. The effect on
pain varied considerably, even among trials with low risk of bias.In
158 trials with continuous outcomes (10,525 patients), there was
moderate heterogeneity (P < 0.001; I(2) 42\%), and considerable variation
in effects between small and large trials (asymmetrical funnel plot).
It is therefore a questionable procedure to pool all the trials,
and we did so mainly as a basis for exploring causes for heterogeneity.
We found an overall effect of placebo treatments, standardised mean
difference (SMD) -0.23 (95\% CI -0.28 to -0.17). The SMD for patient-reported
outcomes was -0.26 (95\% CI -0.32 to -0.19), and for observer-reported
outcomes, SMD -0.13 (95\% CI -0.24 to -0.02). We found an effect
on pain, SMD -0.28 (95\% CI -0.36 to -0.19)); nausea, SMD -0.25 (-0.46
to -0.04)), asthma (-0.35 (-0.70 to -0.01)), and phobia (SMD -0.63
(95\% CI -1.17 to -0.08)). The effect on pain was very variable,
also among trials with low risk of bias. Four similarly-designed
acupuncture trials conducted by an overlapping group of authors reported
large effects (SMD -0.68 (-0.85 to -0.50)) whereas three other pain
trials reported low or no effect (SMD -0.13 (-0.28 to 0.03)). The
pooled effect on nausea was small, but consistent. The effects on
phobia and asthma were very uncertain due to high risk of bias. There
was no statistically significant effect of placebo interventions
in the seven other clinical conditions investigated in three trials
or more: smoking, dementia, depression, obesity, hypertension, insomnia
and anxiety, but confidence intervals were wide.Meta-regression analyses
showed that larger effects of placebo interventions were associated
with physical placebo interventions (e.g. sham acupuncture), patient-involved
outcomes (patient-reported outcomes and observer-reported outcomes
involving patient cooperation), small trials, and trials with the
explicit purpose of studying placebo. Larger effects of placebo were
also found in trials that did not inform patients about the possible
placebo intervention.We did not find that placebo interventions have
important clinical effects in general. However, in certain settings
placebo interventions can influence patient-reported outcomes, especially
pain and nausea, though it is difficult to distinguish patient-reported
effects of placebo from biased reporting. The effect on pain varied,
even among trials with low risk of bias, from negligible to clinically
important. Variations in the effect of placebo were partly explained
by variations in how trials were conducted and how patients were
informed.