Differential Effectiveness of Placebo Treatments A Systematic Review of Migraine Prophylaxis

Research
Original Investigation
Differential Effectiveness of Placebo Treatments

A Systematic Review of Migraine Prophylaxis
Karin Meissner, MD; Margrit Fssler, MD; Gerta Rcker, PhD; Jos Kleijnen, PhD; Asbjorn Hrbjartsson, PhD;
Antonius Schneider, MD; Gerd Antes, MD; Klaus Linde, MD
Editor's Note page 1951
IMPORTANCE When analyzing results of randomized clinical trials, the treatment with the
greatest specific effect compared with its placebo control is considered to be the most
effective one. Although systematic variations of improvements in placebo control groups
would have important implications for the interpretation of placebo-controlled trials, the
knowledge base on the subject is weak.
Supplemental content at
jamainternalmedicine.com
OBJECTIVE To investigate whether different types of placebo treatments are associated with
different responses using the studies of migraine prophylaxis for this analysis.
DESIGN, SETTING, AND PARTICIPANTS We searched relevant sources through February 2012
and contacted the authors to identify randomized clinical trials on the prophylaxis of migraine
with an observation period of at least 8 weeks after randomization that compared an
experimental treatment with a placebo control group. We calculated pooled random-effects
estimates according to the type of placebo for the proportions of treatment response. We
performed meta-regression analyses to identify sources of heterogeneity. In a network
meta-analysis, direct and indirect comparisons within and across trials were combined.
Additional analyses were performed for continuous outcomes.
EXPOSURE Active migraine treatment and the placebo control conditions.
MAIN OUTCOMES AND MEASURES Proportion of treatment responders, defined as having an
attack frequency reduction of at least 50%. Other available outcomes in order of preference
included a reduction of 50% or greater in migraine days, the number of headache days, or
headache score or a significant improvement as assessed by the patients or their physicians.
RESULTS Of the 102 eligible trials, 23 could not be included in the meta-analyses owing to
insufficient data. Sham acupuncture (proportion of responders, 0.38 [95% CI, 0.30-0.47])
and sham surgery (0.58 [0.37-0.77]) were associated with a more pronounced reduction of
migraine frequency than oral pharmacological placebos (0.22 [0.17-0.28]) and were the only
significant predictors of response in placebo groups in multivariable analyses (P = .005 and
P = .001, respectively). Network meta-analysis confirmed that more patients reported
response in sham acupuncture groups than in oral pharmacological placebo groups (odds
ratio, 1.88 [95% CI, 1.30-2.72]). Corresponding analyses for continuous outcomes showed
similar findings.
CONCLUSIONS AND RELEVANCE Sham acupuncture and sham surgery are associated with
higher responder ratios than oral pharmacological placebos. Clinicians who treat patients
with migraine should be aware that a relevant part of the overall effect they observe in
practice might be due to nonspecific effects and that the size of such effects might differ
between treatment modalities.
Author Affiliations: Author
affiliations are listed at the end of this
article.
JAMA Intern Med. 2013;173(21):1941-1951. doi:10.1001/jamainternmed.2013.10391

Published online October 14, 2013.
Corresponding Author: Karin

Meissner, MD, Institute of Medical
Psychology,
Ludwig-Maximilians-University
Munich, Goethestrasse 31, 80336
Munich, Germany (karin.meissner
@med.lmu.de).
1941
Copyright 2013 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a University of Illinois - Chicago User on 01/31/2014
Research Original Investigation
Effectiveness of Placebo Treatments
lacebo controls are important when evaluating the effectiveness of medical treatments. They separate specific and nonspecific effects (including placebo effects, regression to the mean, natural course of the disease, etc)
and reduce bias by enabling blinding of participants (and, if
possible, of providers and outcome assessors). Although placebo-controlled trials may not be possible for ethical or technical reasons in certain instances, they are an important tool
when investigating whether a treatment truly works, in the
sense that the postulated mechanism of action makes a clinically relevant difference.
Placebo controls are crucial in many evaluations of health
care. However, for theoretical reasons and based on empirical
evidence, responses to placebo treatments can be quite variable depending on several factors, such as the type of placebo
treatment,1-3 how such treatments are provided (eg, in an enthusiastic or a neutral manner),4 and whether informed consent is obtained.5 Although these issues might be of little relevance for some conditions, they could be of major importance
for those conditions in which cognitive and emotional processes
play a central role, such as chronic pain or depression or when
the symptoms evaluated are mostly of a subjective nature.
Differential responses to different types of placebo controls would challenge the classic interpretation of randomized clinical trials that the treatment with the greatest specific effect compared with its placebo control is also the most
effective one.6 Rather, a direct comparison of the different types
of treatments would be necessary to find out the best treatment option for a certain disease. Otherwise, a complex intervention with a small specific effect but a large placebo effect, for example, would be considered of little value while still
Figure 1. The Efficacy Paradox Demonstrated by a Hypothetical 4-Arm
Study to Compare Specific and Placebo Effects of Different Types of
Treatments
Regression to the mean/
spontaneous changes
Placebo effects
Specific effects
70
Not significant
60
Significant
Improvement, %
50
40
30
20
10
0
Treatment 1
Placebo 1
Treatment 2
Placebo 2
Study Arm
Patients are randomized to 1 of 4 arms, each 2 of which represent a

double-blind substudy with an active treatment arm and a corresponding
placebo arm. Regression to the mean and spontaneous changes are assumed to
be equal in all groups. Treatment arm 2 has a smaller specific effect than
treatment arm 1, but its total (specific + placebo) effect is larger because it is
associated with a larger placebo effect. Adapted from Walach.6
1942
being more effective than a simple drug application with a moderate specific effect but only a small placebo effect. This paradox has been termed the efficacy paradox (Figure 1).6
Although systematic variations of improvements in placebo control groups would have important implications for
the interpretation of placebo-controlled trials, the knowledge
base on the subject is weak. Trials with a direct comparison
of different types of placebo treatments are relatively rare,
dispersed over a variety of conditions, and difficult to
identify.3 For these reasons, systematic reviews making indirect comparisons are warranted. In this review, we collected
randomized clinical trials on the prophylaxis of migraine that
included a placebo control group. We focused on migraine
because this disease has high prevalence and economic relevance, a variety of treatment strategies have been investigated, and diagnostic criteria and outcome measures are relatively well defined. An influence of contextual factors on
clinical outcomes also seems plausible on theoretical
grounds. The primary aim of this review was to determine
whether different types of placebo treatments are associated
with different effect sizes.
Methods
Literature Search
We searched MEDLINE, EMBASE, the Cochrane Controlled
Trials Register, and PsychINFO (from inception to February
2012) using a combination of keywords and text words related to migraine and placebo controls, combined with validated filters for controlled clinical trials.7 The search strategy
for MEDLINE is shown in the Supplement (eTable 1).
Study Selection
We included randomized placebo-controlled trials of the prophylactic treatment of migraine in adults with observation periods of at least 8 weeks after randomization. Studies had to
report at least 1 clinical outcome related to migraine (eg, response, frequency, pain intensity, headache scores, or analgesic use). Migraine had to be diagnosed according to the International Headache Society criteria, or criteria for migraine
diagnosis had to be in close agreement with the International
Headache Society classification. We excluded crossover studies except when the results of the first administration were
given separately. We also excluded studies in which migraine
was associated with other neurological disorders, studies of
daily or converted migraine, studies with single-blind placebo run-in periods, studies with changes in prophylactic migraine treatment (except for titration of study medication
therapy), and studies with experimental cointerventions (except for acute migraine attacks).
We screened all abstracts identified by the literature search
and removed irrelevant hits (eg, duplicate studies, studies that
were not randomized clinical trials, studies of conditions other
than migraine, and treatment of acute migraine). All other articles were obtained in full text and checked by 2 reviewers
(K.M. and M.F.) for eligibility according to our selection criteria. Disagreements were resolved by discussion.
JAMA Internal Medicine November 25, 2013 Volume 173, Number 21
Original Investigation Research
Data Collection
The 2 reviewers extracted information on patients, methods,
interventions, outcomes, and results using a pretested standard form. In particular, we extracted the bibliographic details of the study; exact diagnoses and headache classifications used; number and type of centers; age and sex of the
patients; duration of disease; number of patients undergoing
randomization, treatment, and analysis; special inclusion criteria; resistance to previous treatment; number of and reasons for dropouts; duration of baseline, treatment, and follow-up periods; type, duration, and frequency of experimental
and sham treatments; description of other groups (if any); handling of acute migraine attacks; cointerventions; informed consent procedure; definition of primary outcomes; adverse
events; success of blinding; type of analysis (ie, intent to treat
or per protocol); and randomization ratio of placebo to active
treatment (eg, 1:1, 1:2).
Outcome Measures
9480 Records identified

9460 Through database searching
20 Through other sources
3594 Duplicates removed
5886 Records screened for eligibility
5466 Clearly irrelevant
420 Full-text articles assessed for eligibility
302 Excluded
44 Diagnoses did not fit
163 Designs did not fit
69 Interventions did not fit
26 Various reasons
102 Studies (reported in 118 articles) included
The primary outcome measure was the proportion of responders. We preferably defined responders as patients with a reduction in attack frequency of at least 50%. If these data were
not available, we used (in descending order of preference) patients with at least a 50% reduction in the number of migraine days, with at least a 50% reduction in the number of
headache days, with at least a 50% reduction in headache
scores, and with significant improvement as assessed by the
patients or their physicians. As a secondary outcome measure, we preferably extracted the frequency of migraine attacks (means and SDs) per month at baseline and follow-up or
(in descending order of preference) the number of migraine
days per month, number of headache days per month, migraine index, headache index, headache scores, headache intensity, or frequency of analgesic use. The following time windows were applied: 8 weeks or 2 months after randomization,
3 to 4 months after randomization, 5 to 6 months after randomization, and more than 6 months after randomization. The
analysis considered preferably the data 3 to 4 months after randomization; otherwise, the presented data closest to 3 to 4
months were used. All outcomes relied on patient reports,
mainly collected in headache diaries. If a study contained multiple treatment groups that differed only in the dosage, we
pooled the values.
Risk of Bias Assessment

Risk of bias was assessed using the risk of bias tool of the Cochrane Collaboration.8 We considered adequate sequence generation, allocation concealment, patient blinding, addressing
incomplete outcome data at 4 months and at 5 to 12 months
after randomization, and absence of selective reporting. At least
2 reviewers K.M., M.F., or K.L.) independently judged whether
the risk of bias for each criterion was considered low, high, or
unclear. Disagreements were resolved by discussion.
Statistical Analysis
The proportion of responders in the placebo and active treatment groups with the associated 95% confidence intervals and
the relative risk between the percentage of responders in the
Figure 2. Flowchart
23 Had insufficient data

79 Studies included in 1 meta-analysis
56 Proportion of response
17 Pretreatment-to-posttreatment changes
38 Posttreatment values
This flowchart depicts the selection of the 79 studies.
placebo and active treatment groups (responder ratio [RR])

were calculated for each study, and results were pooled using
random-effects models. To evaluate the effects of different
types of placebo treatments, we performed stratified analyses (for descriptive purposes) and meta-regression analyses
using the inverse variance method (Freeman-Tukey arcsine
transformation). In explorative analyses, we investigated the
effects of 15 covariates on outcome separately and then in a
multivariable meta-regression analysis (Supplement [eTables
3 and 4]). Because a strong overlap between the factors type
of placebo treatment and type of blinding was present, we
tested 2 models for multivariable analyses, in each of which
only one of these factors was involved. Responder data in the
active treatment groups, placebo control groups, and notreatment groups were then subjected to a network analysis
using a fixed-effects method based on logistic regression to enable indirect comparisons between studies while preserving
within-group randomization.9-12
Secondary analyses were performed on continuous outcomes. The changes from baseline to after treatment (pretreatment to posttreatment changes) were analyzed by calculating standardized mean differences in the placebo and
active treatment groups with the associated 95% CIs. Posttreatment data were analyzed by calculating standardized
mean differences between placebo and active treatment
groups with the associated 95% CIs. For both types of continuous outcomes, individual study results were pooled
using the inverse variance method and a random-effects
model. Network analyses were performed by adapting the
1943
Table 1. Basic Results for the 26 Studies Providing Proportion of Responders and RRs for Oral Pharmacological
Placebo Treatmenta
Placebo
No. of
Responders/
Total No. of
Patients
Source
Adly et al,17 1992
Andersson et al,22 1983
Proportion
(95% CI)
1/16
0.06 (0.00-0.30)
4/37
0.11 (0.03-0.25)
Responder/
Total No. of
Patients
Proportion (95%
CI)
RR (95% CI)
6/16
0.38 (0.15-0.65)
6.00 (0.81-44.35)
2.72 (0.94-7.87)
10/34
0.29 (0.15-0.47)
159/363
0.44 (0.39-0.49)
2.02 (1.41- 2.90)
0.38 (0.27-0.49)
67/238
0.28 (0.23-0.34)
0.75 (0.53-1.06)
0.32 (0.13-0.57)
10/14
0.71 (0.42-0.92)
2.26 (1.08-4.74)
Brandes et al,28 2004
26/120 0.22 (0.15-0.30)
Cady et al,31 2009
30/80
6/19
Carasso and Yehuda,32

1984
Active Treatment
Carrieri et al,33 1985
3/14
0.21 (0.05-0.51)
11/14
0.79 (0.49-0.95)
3.67 (1.30-10.37)
Cruz et al,36 1985
0/10
0.00 (0.00-0.31)
9/20
0.45 (0.23-0.68)
9.73 (0.63-151.44)
de Tommaso et al,37
2007
0/15
0.00 (0.00-0.22)
16/30
0.53 (0.34-0.72)
16.77 (1.08-261.36)
Diener et al,39 1996
17/55
0.31 (0.19-0.45)
63/159
0.40 (0.32-0.48)
1.28 (0.83-1.99)
31/146 0.21 (0.15-0.29)
162/429
0.38 (0.33-0.43)
1.78 (1.27-2.49)
12/34
0.35 (0.20-0.54)
4.24 (1.31-13.72)
Edwards et al,46 2003
3/36
0.08 (0.02-0.22)
Freitag et al,50 2002
28/116 0.24 (0.17-0.33)
36/123
0.29 (0.21-0.38)
1.21 (0.79-1.85)
Goadsby et al,53 2009
29/65
0.45 (0.32-0.57)
36/59
0.61 (0.47-0.73)
1.37 (0.97-1.92)
Hivik et al,59 2010

(study 1)
12/38
0.32 (0.18-0.49)
27/73
0.37 (0.26-0.49)
1.17 (0.67-2.04)
80/154 0.52 (0.44-0.60)
60/160
0.38 (0.30-0.45)
0.72 (0.56-0.93)
59
Hivik et al,
(study 2)
2010
Holroyd et al,60 2010
22/55
0.40 (0.27-0.54)
18/53
0.34 (0.22-0.48)
0.85 (0.52-1.39)
Louis,66 1981
4/29
0.14 (0.04-0.32)
18/29
0.62 (0.42-0.79)
4.50 (1.73-11.67)
Mei et al,68 2004
8/57
0.14 (0.06-0.26)
22/58
0.38 (0.26-0.52)
2.70 (1.31-5.56)
Mendenopoulos et al,69
1985
0/11
0.00 (0.00-0.28)
5/9
0.56 (0.21-0.86)
13.32 (0.84-211.36)
4/30
0.13 (0.04-0.31)
1.55 (0.49-4.94)
Orholm et al,72 1986
6/29
0.21 (0.08-0.40)
169/370
0.46 (0.41-0.51)
2.06 (1.44-2.94)
0.34 (0.24-0.46)
55/140
0.39 (0.31-0.48)
1.15 (0.79-1.68)
20/66
0.30 (0.20-0.43)
28/66
0.42 (0.30-0.55)
1.40 (0.88-2.22)
Storey et al,86 2001
2/21
0.10 (0.01-0.30)
5/19
0.26 (0.09-0.51)
2.76 (0.61-12.61)
Vahedi et al,90 2002
9/27
0.33 (0.17-0.54)
8/26
0.31 (0.14-0.52)
0.92 (0.42-2.02)
Silberstein et al,81 2004
26/117 0.22 (0.15-0.31)
Silberstein et al,80 2006
25/73
Somerville and
Herrmann,84 1978
92
Weber and Reinmuth,

1972
Pooled random effects
0/11
0.00 (0.00-0.28)
390/1418 0.22 (0.17-0.28)
5/8
0.62 (0.24-0.91)
14.88 (0.95-234.19)
1023/2546
0.41 (0.37-0.45)
1.62 (1.29-2.03)
method originally developed for logistic regression9-12 for

continuous outcomes.13
We assessed heterogeneity between trials using the I2
statistic.14 All analyses were performed with the R packages
meta15 and metafor.16
Results
A total of 102 studies (reported in 118 publications) met the inclusion criteria. At least 1 outcome could be included in the
meta-analyses from 79 studies (Figure 2).
Characteristics of Included Studies

The individual characteristics of the 79 studies17-93 included
in the meta-analyses are given in the Supplement (eTable 2).
Dichotomous and/or continuous data were retrieved from 56
and 55 studies, respectively, and 32 studies provided both types
1944
Abbreviation: RR, responder ratio.

a
Heterogeneity (I2) for the placebo

group is 81.3%; for the active
treatment group, 66.3%; and for
the RR, 72.6% (all P < .001).
of data. The 79 trials had randomly allocated a total of 9278

patients to an experimental treatment, a placebo treatment,
no treatment, or an active control treatment. The mean age of
study patients was 39 years, they experienced migraine for a
mean of 18 years, and most of the study participants (79.8%)
were female. Twenty-four studies had a clearly predefined outcome measure and 21 had a partly predefined primary outcome measure (such as predefinition of the outcome but not
of the time point). Fifty-one trials were double blind; 26, single
blind; and 2, not specified. In 49 trials, the randomization ratio (placebo to active treatment) was 1:1; in 30 trials, 1:2 or less.
In 35 studies, the placebo treatment was an orally administered placebo for a pharmacological drug; in 13 studies, sham
acupuncture (typically superficial needling at nonacupuncture points); in 10 studies, a pharmacological sham injection;
in 8 studies, an orally administered placebo for an herbal remedy, a homeopathic remedy, or a vitamin supplement; in 8 studies, a sham cognitive-behavioral treatment; in 3 studies, a sham
Table 2. Basic Results for the 8 Studies Providing Proportion of Responders and RRs for Herbal, Vitamin, and
Homeopathic Placebo Treatmenta
Placebo Group
No. of
Responders/
Total No. of
Patients
Source
Grossmann and
Schmidramsl,54 2001
65
Lipton et al,
2004
Proportion
(95% CI)
14/110 0.13 (0.07-0.20)
Active Treatment Group

No. of
Responders/
Total No. of
Patients
Proportion
(95% CI)
RR (95% CI)
27/108
0.25 (0.17-0.34)
1.96 (1.09-3.54)
4/27
0.15 (0.04-0.34)
14/33
0.42 (0.25-0.61)
2.86 (1.07-7.69)
1.37 (1.01-1.86)
31/77
0.40 (0.29-0.52)
86/156
0.55 (0.47-0.63)
Maizels et al,67 2004
11/25
0.44 (0.24-0.65)
10/24
0.42 (0.22-0.63)
0.95 (0.50-1.81)
Peikert et al,74 1996
7/38
0.18 (0.08-0.34)
14/43
0.33 (0.19-0.49)
1.77 (0.80-3.92)
Pfaffenrath et al,77 1996
10/34
0.29 (0.15-0.47)
10/35
0.29 (0.15-0.46)
0.97 (0.46-2.03)
Abbreviation: RR, responder ratio.
Pfaffenrath et al,76 2002
11/35
0.31 (0.17-0.49)
25/112
0.22 (0.15-0.31)
0.71 (0.39-1.29)
6/33
0.18 (0.07-0.35)
7/35
0.20 (0.08-0.37)
1.10 (0.41-2.93)
193/546
0.33 (0.23-0.44)
1.28 (0.97-1.70)
87
Straumsheim et al,
2000
94/379 0.26 (0.17-0.35)

group is 74.2% (P < .001); for the
active treatment group, 84.4%
(P < .001); and for the RR, 34.4%
(P = .15).
Table 3. Basic Results for the 6 Studies Providing Proportion of Responders and RRs for Pharmacological
Placebo Injectiona
Placebo Group
No. of
Responders/
Total No. of
Patients
Source
Anand et al,21 2006
47
0.00 (0.00-0.21)
RR (95% CI)
0.75 (0.48-0.93) 25.00 (1.61-338.38)
63/207
0.30 (0.24-0.37)
0.96 (0.72-1.28)
5/20
0.25 (0.09-0.49)
12/40
0.30 (0.17-0.47)
1.20 (0.49-2.94)
Guyuron et al,55 2005
8/19
0.42 (0.20-0.67)
NAb
NAb
NAb
11/60
0.18 (0.10-0.30)
12/64
0.19 (0.10-0.30)
1.02 (0.49-2.14)
10/41
0.24 (0.12-0.40)
19/42
0.45 (0.30-0.61)
1.85 (0.98-3.49)
118/369
0.37 (0.24-0.50)
1.30 (0.80-2.10)
75
Petri et al,
2009
79
Silberstein et al,
2000
67/211 0.32 (0.26-0.39)
12/16
Proportion
(95% CI)
Evers et al,48 2004
Elkind et al,
2006
0/16
Proportion
(95% CI)

No. of
Responders/
Total No. of
Patients
101/367 0.23 (0.14-0.34)
electromagnetic device; and in 2 studies, sham surgery (skin

incision in the groin43 and exposure of cranial nerves and
muscles at trigger sites56). In 4 studies, only the placebo arms
were analyzed owing to different types of treatments in the placebo and active treatment groups.44,55,85,89 Four studies included a no-treatment group.24,49,52,64 One acupuncture
study40 included a group that received guideline-oriented standard drug therapy.
Most studies had considerable weaknesses in relation to
the details of sequence generation (51 studies with a high or
unclear risk of bias), allocation concealment (68 studies with
a high or unclear risk of bias), and blinding (48 studies with a
high or unclear risk of bias). In 39 studies, the dropout rates at
4 months were substantial (>15%) and could have led to distortions. Although study results were often presented in a suboptimal manner, we considered the risk of selective reporting
in most studies (n = 70) to be low.
Results of Included Studies

The overall pooled proportion of responders in the active
treatment groups was 0.42 (95% CI, 0.38-0.45), whereas it
was 0.26 (0.22-0.30) in the placebo groups. On average,
active treatment was significantly more effective than placebo treatment (RR, 1.40 [95% CI, 1.23-1.59]). Heterogeneity
between trials was substantial (for placebo and active treatjamainternalmedicine.com
Abbreviations: NA, not applicable;

RR, responder ratio.
a

group is 73.3% (P = .002); for the
(P < .001); and for the RR, 56.2%
(P = .06).
Indicates study with different types

of placebo and active treatments;
only the placebo data were included
in the analyses.
ment groups, I 2 = 80.8% and 80.7%, respectively [both

P < .001]; for placebo vs active treatment groups, I2 = 60.5%
[P < .001]).
Stratified analyses according to type of placebo treatment showed wide variations in the proportions of responders in the placebo groups (Tables 1, 2, 3, 4, and 5). On average, sham surgery and sham acupuncture (Table 4) were
associated with the greatest responder proportions (0.58
[95% CI, 0.37-0.77] and 0.38 [0.30-0.47], respectively),
whereas oral pharmacological placebos (Table 1) were associated with clearly smaller ones (0.22 [95% CI, 0.17-0.28]).
The pooled proportions of responders for other placebo
treatments ranged from 0.23 to 0.27 (Tables 2, 3, and 5). Subgroup analyses according to the type of placebo confirmed
significant differences between different types of placebo
treatments (Q = 22.02 [P = .001]), with substantial heterogeneity across trials (I2 = 80.8% [P < .001]). The proportions of
responders in the sham acupuncture and sham surgery subgroups were significantly greater than those in the subgroup
of oral pharmacological placebos (P = .004 and P = .03,
respectively).
In addition to type of placebo treatment, separate subgroup analyses revealed that studies with sample sizes larger
than 100 patients, patients unresponsive to previous prophylactic treatments, parallel-group design, and single blinding
1945
Table 4. Basic Results for the 12 Studies Providing Proportion of Responders and RRs for Sham Surgery and
Sham Acupuncturea
Placebo Group
No. of
Responders/
Total No. of
Patients
Source
Proportion
(95% CI)

No. of
Responders/
Total No. of
Patients
Proportion
(95% CI)
RR (95% CI)
Sham Surgery
Guyuron et al,56 2009
15/26
NA
0.58 (0.37-0.77)
NA
41/49
0.84 (0.70-0.93)
1.45 (1.02-2.06)
NA
NA
NA
Sham Acupuncture
Alecrim-Andrade et
al,18 2005
8/32
0.25 (0.11-0.43)
16/32
0.50 (0.32-0.68)
2.00 (1.00-4.00)
Alecrim-Andrade et
al,20 2006
3/15
0.20 (0.04-0.48)
4/16
0.25 (0.07-0.52)
1.25 (0.33-4.68)
Alecrim-Andrade et
al,19 2008
4/18
0.22 (0.06-0.48)
5/19
0.26 (0.09-0.51)
1.18 (0.38-3.72)
13/21
0.62 (0.38-0.820)
8/23
0.35 (0.16-0.57)
0.56 (0.29-1.08)
Ceccherelli et al,34
1987
5/15
0.33 (0.12-0.62)
13/15
0.87 (0.60-0.98)
2.60 (1.24-5.46)
159/327
0.49 (0.43-0.54)
163/304
0.54 (0.48-0.59)
1.10 (0.95-1.28)
3/10
0.30 (0.07-0.65)
11/20
0.55 (0.32-0.77)
1.83 (0.66-5.12)
Baust and
Strtzbecher,23 1978
Henry,58 1985
Kubiena et al,62 1992
3/15
0.20 (0.04-0.48)
4/15
0.27 (0.08-0.55)
1.33 (0.36-4.97)
Linde et al,64 2005
43/81
0.53 (0.42-0.64)
78/145
0.54 (0.45-0.62)
1.01 (0.79-1.31)
Weinschtz et al,93
1994 (study 1)
8/20
0.40 (0.19-0.64)
13/20
0.65 (0.41-0.85)
1.62 (0.87-3.04)
93
8/21
0.38 (0.18-0.62)
15/20
0.75 (0.51-0.91)
1.97 (1.08-3.59)
257/575
0.38 (0.30-0.47)
330/629
0.51 (0.42-0.59)
1.29 (1.02-1.61)
Weinschtz et al,
1994 (study 2)
Abbreviations: NA, not applicable;

RR, responder ratio.
a

group is 60.2% (P = .005); for the
(P < .001); and for the RR, 39.4%
(P = .08).
Table 5. Basic Results for the 4 Studies Providing Proportion of Responders and RRs for Sham Electromagnetic
Device and Sham CBTa
Placebo Group
No. of
Responders/
Total No. of
Patients
Source
Proportion
(95% CI)

No. of
Responders/
Total No. of
Patients
Proportion
(95% CI)
RR (95% CI)
Sham Electromagnetic Device

Dowson et al,44 1985
6/23 0.26 (0.10-0.48)
NAb
NAb
NAb
NA
NA
NA
NA
NA
Abbreviations: CBT,
cognitive-behavioral treatment; NA,
not applicable; RR, responder ratio.
a

group is 0% (P = .87); for the active
treatment group, 4.8%% (P = .35);
and for the RR, 0% (P = .72).
Indicates study with different types

of placebo and active treatments;
only the placebo data were included
in the analyses.
Sham CBT
Blanchard et al,24 1990
9/30 0.30 (0.15-0.49)
32/82
0.39 (0.28-0.50)
1.30 (0.71-2.39)
14/56 0.25 (0.14-0.38)
4/19
0.21 (0.06-0.46)
0.84 (0.06-2.25)
2/6
0.33 (0.04-0.78)
1.67 (0.21-13.43)
38/107
0.35 (0.26-0.45)
1.18 (0.71-1.95)
71
Mullinix et al,
1978
1/5
0.20 (0.01-0.72)
24/91 0.27 (0.19-0.36)
were associated with significantly greater placebo RRs (Supplement [eTable 3]). Explorative multivariable analyses showed
the placebo treatments of sham surgery and sham acupuncture to be the only independent predictors of placebo RRs in
model 1 (Supplement [eTable 4]). In model 2, blinding emerged
as the only independent predictor of placebo RRs, with singleblinded studies associated with greater RRs.
Forty trials with dichotomous outcomes were included in
a network meta-analysis, which allowed comparisons among
sham acupuncture, oral pharmacological placebos, sham cognitive-behavioral treatment, their corresponding active treatments, and no treatment (Figure 3). Results are summarized
in Figure 4. Sham acupuncture was associated with greater effects than were oral pharmacological placebos and no treat1946
ment (odds ratio, 1.88 [95% CI, 1.30-2.72] and 4.57 [2.34-8.92],
respectively). Meta-analyses of continuous outcomes and the
corresponding network meta-analyses broadly confirmed the
findings for the dichotomous data (Supplement [eTables 5
through 8]).
Discussion
In the studies included in this review, the amount of reduction in migraine frequency varied systematically between different types of placebo. We found consistent evidence across
analyses that sham acupuncture was associated with a more
pronounced frequency reduction than were oral pharmaco-
Figure 3. Network Based on Studies Providing Proportions of Response
Figure 4. Results of the Network Meta-analysis Based

on Responder Ratios
Pharmacological
placebo
Treatment
Pharmacological placebo
pill compared with:
26
Pharmacological
drug
Sham
acupuncture

11
Acupuncture
Linde et al,64 2005

No treatment

Sham
Cognitive-behavioral
cognitive-behavioral
treatment
3
treatment
Numbers and solid lines indicate studies with direct comparisons between
active treatment and placebo groups; dashed lines, studies with direct
comparisons with an additional group. Three-armed studies are displayed as
triangles (the sources are given in the figure).
logical placebos. Sham surgery also appeared to be more effective, but data on this subject were sparse. Oral placebos for
herbs, vitamins, or homeopathic drugs; injected placebos for
pharmacological drugs; a sham electromagnetic device; and
sham cognitive-behavioral treatment were associated with effects similar to oral pharmacological placebos.
By focusing on a single condition with well-defined diagnostic criteria and outcome measures, we were able to confirm and extend earlier findings that suggested physical placebo treatments in general and acupuncture in particular were
associated with greater effects than were pharmacological placebo treatments.1,94,95 Experimental placebo research in the
past decades has provided ample evidence that treatments
without active ingredients can relieve pain and other symptoms, and the underlying mechanisms are increasingly
understood.96 The context and meaning of a placebo treatment are more important than the placebo vehicle itself.4,97
However, the context and meaning of surgery, for example, differ considerably from those of an oral drug. Patients may develop greater expectations about treatments such as acupuncture and surgery because of the more elaborate and impressive
treatment rituals.98 The higher level of attention and physical contact may also play a role.99 The most probable explanation for the apparently greater effectiveness of sham acupuncture and possibly sham surgery compared with placebo
pills is thus their systematic association with contextual factors that are known to enhance placebo effects. Part of the enhanced placebo effect, however, may also result from the physiological effects of skin injury during sham acupuncture and
sham surgery.100,101
Our results suggest that the response to sham acupuncture and sham surgery can be as great as the mean response
to active drugs. The other placebo treatments in our data set
OR (SE)
[95% CI]
Sham acupuncture
Sham CBT
Pharmacological drug
Acupuncture
CBT
No treatment
Sham acupuncture
compared with:
0.53 (0.19)
0.99 (0.67)
0.56 (0.08)
0.39 (0.19)
0.79 (0.62)
2.43 (0.38)
[0.37-0.77]
[0.27-3.67]
[0.48-0.65]
[0.27-0.56]
[0.23-2.70]
[1.16-5.09]
Sham CBT
Acupuncture
CBT
No treatment
Sham CBT compared with:
Sham acupuncture
Acupuncture
CBT
No treatment
compared with:
1.88 (0.19)
1.86 (0.66)
1.05 (0.17)
0.73 (0.12)
1.49 (0.60)
4.57 (0.34)
[1.30-2.72]
[0.52-6.64]
[0.75-1.47]
[0.58-0.92]
[0.46-4.87]
[2.34-8.92]
1.01 (0.67)
0.54 (0.65)
0.57 (0.67)
0.39 (0.65)
0.80 (0.35)
2.46 (0.55)
[0.27-3.77]
[0.15-1.93]
[0.15-2.09]
[0.11-1.40]
[0.41-1.60]
[0.83-7.28]
Pharmacological placebo 1.79 (0.08)

Sham acupuncture
0.95 (0.17)
Sham CBT
1.77 (0.67)
Acupuncture
0.70 (0.17)
CBT
1.42 (0.62)
No treatment
4.35 (0.37)
Acupuncture compared with:
Sham acupuncture
1.37 (0.12)
Sham CBT
2.54 (0.65)
1.44 (0.17)
CBT
2.05 (0.60)
No treatment
6.25 (0.34)
CBT compared with:
Sham acupuncture
0.67 (0.60)
Sham CBT
1.24 (0.35)
0.70 (0.62)
Acupuncture
0.49 (0.60)
No treatment
3.06 (0.50)
[1.55-2.08]
[0.68-1.33]
[0.48-6.53]
[0.50-0.98]
[0.42-4.79]
[2.10-8.99]
Favors
comparison
Favors
treatment
[1.78-3.73]
[1.09-1.73]
[0.72-9.04]
[1.02-2.02]
[0.63-6.62]
[3.24-12.07]
[0.37-4.28]
[0.21-2.18]
[0.63-2.47]
[0.21-2.37]
[0.15-1.58]
[1.15-8.09]
0.2
0.5 1.0 2.0
5.0
OR (95% CI)
Results are displayed in text and graphically. CBT indicates cognitive-behavioral

treatment; OR, odds ratio.
showed RRs comparable to those of oral pharmacological placebos. The finding that studies with pharmacological sham injections as placebo controls did not show greater effects than
oral placebo pills is in contrast to the results of 2 earlier
meta-analyses2,102 reporting an enhanced placebo effect of injected vs oral placebos for the treatment of acute migraine attacks. The discrepancy with the literature may be due in part
to the fact that, in our review, the placebo injections controlled for botulinum toxin, which induces persistent physical change due to muscle relaxation, whereas in the other reviews the placebo treatment controlled for analgesics without
1947
such adverse effects. The absence of physical changes in placebo-treated patients in botulinum toxin studies may have led
to the unblinding of patients and physicians, thereby decreasing the placebo effect. The absence of a difference between the
responses to a sham electromagnetic device and oral pharmacological placebos is in agreement with a recent metaanalysis that detected no difference between the placebo response for oral pharmacological placebos and repetitive
transcranial magnetic stimulation.103
The multivariable analyses indicated that the placebo response was greater in single-blinded than in double-blinded
designs (Supplement [eTable 4, model 2]). This response most
probably results from a strong overlap of the factors blinding
and type of treatment in that the placebo treatments associated with the greatest improvements (ie, sham acupuncture
and sham surgery) can usually only be performed in a singleblinded manner. In contrast to what would be expected, single
blinding apparently did not decrease the placebo response.
Our data cannot prove that the differences in migraine frequency reduction are caused by the different types of placebos and their associated context and meaning. In the first part
of our analyses, we compared the outcome of control groups
of separate trials receiving different types of placebo treatments. This comparison of uncontrolled case series is prone
to biases. Although we investigated a variety of covariates, we
cannot rule out the risk of spurious positive associations due
to the high number of covariates and the possibility that we
missed an important factor. Although our main results could
be confirmed by network analyses, the connections in our networks did not allow us to include all studies of our data set,
and the heterogeneity of patients, settings, and treatment modalities further limit the conclusiveness of the network metaanalyses. One potential explanation for our findings could be
ARTICLE INFORMATION
Submitted for Publication: December 13, 2012;
final revision received May 16, 2013; accepted May
19, 2013.
Published Online: October 14, 2013.
doi:10.1001/jamainternmed.2013.10391.
Author Affiliations: Institute of General Practice,
Klinikum rechts der Isar, Technische Universitt
Mnchen, Munich, Germany (Meissner, Fssler,
Schneider, Linde); Institute of Medical Psychology,
Ludwig-Maximilians-University Munich, Munich,
Germany (Meissner); Institute of Biomedical Ethics,
University of Zurich, Zurich, Switzerland (Fssler);
Department for Medical Biometry and Medical
Informatics, University of Freiburg, Freiburg,
Germany (Rcker, Antes); Kleijnen Systematic
Reviews Ltd, Unit 6, York, England (Kleijnen);
School for Public Health and Primary Care,
Maastricht University, Maastricht, the Netherlands
(Kleijnen); Nordic Cochrane Centre, Rigshospitalet,
Copenhagen, Denmark (Hrbjartsson).
Author Contributions: Drs Meissner and Linde had
full access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Meissner, Fssler,
Kleijnen, Hrbjartsson, Antes, Linde.
Acquisition of data: Meissner, Fssler, Linde.
1948
differential response bias.104 The use of patient diaries in migraine trials probably reduces the risk of response bias but does
not eliminate it. Regression to the mean and spontaneous improvements also could vary between subgroups of studies. Our
data suggest that baseline headache frequency was slightly
lower in acupuncture trials compared with pharmacological
trials, making larger regression to the mean less likely. However, this reduced frequency could also imply that patients in
acupuncture trials were easier to treat.
Conclusions
Our results suggest that some types of placebo treatments can
be, on average, associated with greater improvements than others. Although our study cannot prove that this association is
causal, the results support the notion that some placebo treatments can trigger clinically relevant responses. Our findings
warrant further studies testing different types of placebo as well
as active treatments directly against each other. We also suggest that treatment options whose contexts vary strongly
should be investigated in placebo-controlled trials and headto-head comparisons. Otherwise, treatments with small specific effects greater than those of their sham controls are withheld from patients even though they work better than standard
treatment. Clinicians who treat patients with migraine should
be aware that a relevant part of the overall effect they observe in practice might be the result of nonspecific effects and
that the size of such effects might differ between treatment
modalities. In other words, the method of treatment delivery
might have an important influence on outcome. Although our
analyses focused on migraine, the same conclusion could well
be true for other conditions.
Analysis and interpretation of data: Meissner,

Fssler, Rcker, Kleijnen, Hrbjartsson, Schneider,
Linde.
Drafting of the manuscript: Meissner, Rcker.
Critical revision of the manuscript for important
intellectual content: Fssler, Rcker, Kleijnen,
Hrbjartsson, Schneider, Antes, Linde.
Statistical analysis: Meissner, Rcker, Kleijnen.
Obtaining funding: Meissner, Kleijnen, Linde.
Administrative, technical, or material support:
Schneider, Fssler, Antes.
Study supervision: Kleijnen, Antes, Linde.
Conflicts of Interest Disclosures: None reported.
Funding/Support: This study was supported by
grant 01KG0924 from the German Ministry of
Education and Research.
Role of the Sponsor: The funding source had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
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Editor's Note
All Placebos Are Not Created Equally

Rita F. Redberg, MD
The importance of the placebo effect is well known, and the

use of the placebo in medicine dates back several centuries. A
placebo was defined in 1811 as any medicine adapted more to
please than to benefit the patient (http://triplehelixblog
.com/2012/07/harnessing-the
Related articles pages 1941
and 2006
-placebo-the-human-side-of
-medicine/). I take this 200
-year-old definition to mean placebo can be powerful for subjective outcomes, such as pain measurements, and less important for objectively measured outcomes. Much of what we treat
every day in medicine centers on improving subjective (patientcentered) outcomes. Meissner et al document the importance
of the right comparator group in their systematic review on migraine prophylaxis therapy. As might be expected, the sham acupuncture and sham surgery control groups had a greater reduction of migraine frequency than the oral pharmacological
placebo groups. Thus, in evaluating therapy for migraine prophylaxis, we learn from this review that like treatments should
be compared, such as surgery treatment with sham surgery treatment and pill with sham pill. This important lesson extends far
beyond migraine prophylaxis treatment.
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Differential Effectiveness of Placebo Treatments

JAMA Intern Med. 2013;173(21):1941-1951. doi:10.1001/jamainternmed.2013.10391

Corresponding Author: Karin

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Research Original Investigation

Effectiveness of Placebo Treatments

Patients are randomized to 1 of 4 arms, each 2 of which represent a

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Effectiveness of Placebo Treatments

Original Investigation Research

9480 Records identified

Risk of Bias Assessment

23 Had insufficient data

This flowchart depicts the selection of the 79 studies.

placebo and active treatment groups (responder ratio [RR])

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Research Original Investigation

Effectiveness of Placebo Treatments

2.02 (1.41- 2.90)

Brandes et al,28 2004

26/120 0.22 (0.15-0.30)

Cady et al,31 2009

Carasso and Yehuda,32

Carrieri et al,33 1985

Cruz et al,36 1985

Diener et al,39 1996

Diener et al,42 2004

31/146 0.21 (0.15-0.29)

Edwards et al,46 2003

Freitag et al,50 2002

28/116 0.24 (0.17-0.33)

Goadsby et al,53 2009

Hivik et al,59 2010

80/154 0.52 (0.44-0.60)

Holroyd et al,60 2010

Mei et al,68 2004

Orholm et al,72 1986

Storey et al,86 2001

Vahedi et al,90 2002

Silberstein et al,81 2004

26/117 0.22 (0.15-0.31)

Silberstein et al,80 2006

Weber and Reinmuth,

Pooled random effects

390/1418 0.22 (0.17-0.28)

method originally developed for logistic regression9-12 for

Characteristics of Included Studies

Abbreviation: RR, responder ratio.

Heterogeneity (I2) for the placebo

of data. The 79 trials had randomly allocated a total of 9278

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Effectiveness of Placebo Treatments

Original Investigation Research

14/110 0.13 (0.07-0.20)

Active Treatment Group

Maizels et al,67 2004