Systematic Review and Meta-Analysis
Effectiveness of placebo interventions for patients
with nonspecific low back pain: a systematic review
and meta-analysis
Rob H.W. Strijkersa,*, Marco Schreijenberga, Heike Gergera, Bart W. Koesa,b, Alessandro Chiarottoa,c
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Abstract
Little is known about the effectiveness of placebo interventions in patients with nonspecific low back pain (LBP). This systematic
review assessed the magnitude of the effects of placebo interventions as compared to no intervention in randomized controlled trials
(RCTs) including patients with LBP. Embase, MEDLINE (Ovid), and Cochrane CENTRAL databases were searched from inception to
December 5, 2019. Randomized controlled trials comparing placebo intervention vs no intervention in adult patients with
nonspecific LBP were included. Pain intensity, physical functioning, and health-related quality of life measured at short-term,
medium-term, and long-term follow-up were the outcomes of this review. Twenty-one randomized controlled trials were included;
one concerning acute LBP and one subacute LBP, whereas 19 studies reported on chronic LBP. In chronic LBP, placebo
interventions were more effective than no intervention at short-term follow-up for pain intensity (standardized mean difference 5
20.37, 95% confidence interval [CI] 5 20.55 to 20.18, moderate-quality evidence), physical functioning (standardized mean
difference 20.19, 95% CI 5 20.39-0.01, moderate-quality evidence), and physical quality of life (mean difference 5 22.71, 95% CI
5 24.71-0.71, high-quality evidence), respectively. These effects were not significant at medium-term follow-up, and no data were
available at long-term follow-up. These results show placebo interventions are more effective than no intervention at short-term
follow-up in patients with chronic LBP. However, the magnitude of the effects is probably not clinically relevant (approximately 8
points on a 0-100 pain scale). Future research should identify effect modifiers and causal mechanisms explaining the short-term
effects of placebo interventions in patients with chronic LBP.
Keywords: Systematic review, Low back pain, Placebo, No intervention
1. Introduction
Placebo effects capture the imagination of patients, clinicians,
and researchers, but their definitions and clinical relevance have
been a topic of debate for decades. In 1986, Grünbaum theorized
that the observed effects of any intervention may be attributable
to characteristic and contextual factors; he defined placebo as
one of these factors.21,29 From 2001 onward, Hróbjartsson and
Gøtzsche published a series of systematic reviews concerning
placebo interventions in clinical trials for all clinical
conditions.30–33 They included trial designs that included both a
placebo intervention group and a no intervention group (eg,
waiting lists) and were thus able to estimate the magnitude of
Sponsorships or competing interests that may be relevant to content are disclosed
at the end of this article.
a
Department of General Practice, Erasmus MC, University Medical Center
Rotterdam, Rotterdam, The Netherlands, b Center for Muscle and Joint Health,
University of Southern Denmark, Odense, Denmark, c Department of Health
Sciences, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam Movement
Sciences, The Netherlands
*Corresponding author. Address: Department of General Practice, Erasmus MC,
University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The
Netherlands. Tel.: 131107030004. E-mail: r.strijkers@erasmusmc.nl (R.H.W. Strijkers).
Supplemental digital content is available for this article. Direct URL citations appear
in the printed text and are provided in the HTML and PDF versions of this article on
the journal’s Web site (www.painjournalonline.com).
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placebo effects compared with no intervention in trials. In their
most recent update,33 Hróbjartsson and Gøtzsche concluded
that, generally speaking, placebo interventions do not have
important clinical effects, with the sole exception of patientreported outcomes, such as pain (standardized mean difference
[SMD] 5 20.28). Nevertheless, another research team systematically reviewing only randomized controlled trials (RCTs)
conducted in patients with pain complaints (and including articles
from an earlier version of the Hróbjartsson and Gøtzsche literature
search) found that the pooled magnitude of placebo effects is
very small (3.2 points reduction on a scale of 100).36 The
magnitude of the placebo effect can depend on the method of
delivery. Studies using placebo as an intervention have shown
greater effects than studies using placebo as a control. Both
situations are included in our study.
In the field of low back pain (LBP, the most disabling condition
worldwide13,24), conservative interventions are often administered to patients,63 despite evidence suggesting that such
interventions have modest effects(0-9 points on a scale of 0100) at best when compared with placebo.11,55,57 It has been
suggested that sham oral medication could produce clinically
meaningful change in pain scores in patients with LBP without a
specific nociceptive source for their complaints (eg, LBP24),52
thus contradicting earlier evidence regarding the magnitude of
placebo interventions for pain.31 However, studies with a no
intervention group were not included in this systematic review,
which makes it impossible to actually estimate the magnitude of
the placebo effect vs no intervention in LBP. Comparison of
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placebo intervention vs no intervention is important to correct for
phenomena such as regression to the mean and natural history
of the disease, which do not represent true placebo effects.
Thus, the current knowledge about actual magnitude of
placebo effects in LBP is still limited. As the literature search
of Hróbjartsson and Gøtzsche is now over 10 years old and
because uncertainty remains about the effectiveness of
placebo interventions for LBP, it is time to gain further insight
into the magnitude of placebo effects in the LBP field. The main
objective of this systematic review is to assess the magnitude
of effects of placebo interventions in comparison with no
intervention for patients with LBP.
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2.3. Outcomes of interest
Pain intensity, physical functioning, and health-related quality of
life (HRQoL; ie, core outcome domains for LBP8) measured at
short-term (up to 3 months), medium-term (4-12 months), and
long-term (1 or 2 years) follow-up were the primary outcomes of
this review. If an RCT did not include at least one of these
outcomes, the article was excluded. In case of multiple shortterm outcomes, the outcome closest to 1-month follow-up was
used for the primary analysis.
2.4. Selection of studies
The study protocol for this systematic review was written a priori
and was registered on February 4, 2019 (PROSPERO Registration number CRD42019127465). The guidance of the Cochrane
Back and Neck Review Group was followed for the methods.19
The PRISMA statement was adopted for the reporting of this
systematic review.44
Two reviewers (M.S. and A.C.) independently screened titles and
abstracts of the articles found in the literature search to decide
which articles to retrieve in full text. The same 2 reviewers read the
full-text articles to include all relevant studies according to the
selection criteria, as mentioned above. A consensus meeting was
held to discuss studies about which there was disagreement
between the reviewers. In case of disagreement, a third
independent reviewer (B.W.K.) made the final decision whether
or not to include the study.
2.1. Databases and search strategy
2.5. Data extraction
Embase, MEDLINE (Ovid), and Cochrane CENTRAL databases
were searched from inception up to December 5, 2019. The
search strategies for this systematic review were based on the
strategy used in Hróbjartsson and Gøtzsche’s 2010 Cochrane
review,33 with “low back pain” as an additional search key term.
The new search strategy was developed in collaboration with an
experienced information specialist. Elements of the search were
“back pain,” “placebo,” and “randomized controlled trial” and
corresponding synonyms (Appendix A, supplemental digital
content available at http://links.lww.com/PAIN/B345). No language restrictions were adopted for the search. Furthermore, the
references of all included studies of the most recent update of the
Cochrane review by Hróbjartsson and Gøtzsche were searched
manually for additional studies.33
Data extraction on outcomes was performed in duplicate by 2
reviewers (R.H.W.S. and H.G.), whereas data extraction on
characteristics of included studies and their patients was performed
by one reviewer (R.H.W.S.) and double checked by a second one
(M.S.). Standardized extraction forms were used (Appendix B,
supplemental digital content available at http://links.lww.com/PAIN/
B345). These characteristics included study design, sample size,
baseline patients’ characteristics (eg, age, sex, pain duration, pain
intensity, physical functioning, chronicity [acute: ,6 weeks, subacute: 6 , 12 weeks, and chronic .12 weeks]), interventions’
characteristics, follow-up time, primary outcomes, results for
outcomes at all follow-ups (mean, SD, and sample size), and
funding source. We performed the meta-analysis in RevMan (Review
Manager v5.3, The Nordic Cochrane Centre, Copenhagen, DK).
Whenever possible means and SDs were extracted directly from
the article or derived from available values (medians, IQR, 95%
confidence interval [CI], ranges, etc) using appropriate estimation
formulas.61 We used GetData Graph Digitizer version 2.26.0.20 to
retrieve data from article figures and graphs in case no written data
were available. If articles reported change from baseline, the
endpoint mean was calculated and SD of the baseline was used as
suggested by the Cochrane Handbook v6, chapter 6.5.2.8. In case
of multiple placebo groups (eg,enhanced and nonenhanced
placebo interventions), the results of the placebo groups were
combined by taking the weighted mean and SDs of the 2 groups.12
2. Methods
2.2. Eligibility criteria
Inclusion criteria were as follows:
(1) randomized controlled trials with a three-group design (active
intervention group, placebo group, and no intervention
groups) or at least a comparison of a placebo intervention vs
no intervention (in a 2-group design);
(2) studies recruiting adult patients (.18 years old) with nonspecific LBP; in trials with a mixed population (eg, LBP and
neck pain patients), at least 75% of participants had LBP for
the trial to be eligible;
(3) the study has evaluated the effectiveness of a placebo
intervention; and
(4) the study is available as a full-text article.
The authors have chosen to only include RCTs as they provide
the least biased estimates on the effectiveness of interventions for
clinical practice.64 Following Hróbjartsson and Gøtzsche,33 we
defined a placebo intervention as any intervention labelled in the
trial report as being a placebo or an analogous term, such as
sham, fake, dummy, or nonspecific or unspecific treatment.
Randomized controlled trials in which the placebo group and no
treatment group received the same underlying treatment (eg,
“usual care”) were included. Studies focusing on nocebo
treatments or effects were excluded.
2.6. Risk of bias assessment
Two reviewers (R.H.W.S. and M.S.) independently scored the risk
of bias (RoB) of included studies using the revised Cochrane riskof-bias tool for randomized trials, version of August 22, 2019.28
This RoB tool consists of 23 items in 5 subdomains that can be
answered with “yes,” “probably yes,” “probably no,” “no,” or “no
information.” This results in a trial overall RoB judgement that may
be “low,” “high,” or “some concerns.” A consensus meeting was
held to discuss studies about which there was disagreement
between the reviewers. In case a consensus was not reached, a
third independent reviewer (A.C.) made the final decision
concerning the risk of bias assessment.
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2.7. Meta-analysis and interpretation of results
Between-group MDs were calculated for continuous or ordinal
outcomes measured with the same instruments; SMDs were
estimated if different instruments were used to assess the same
outcome (eg, Roland–Morris Disability Questionnaire and Oswestry Disability Index to measure physical functioning). Statistical
pooling was performed if there was clinical (sufficiently homogeneous study population) and methodological homogeneity
(comparison, outcome, and assessment time points) across
trials. Random-effects models rather than a fixed-effects model
was used on the assumption that the included studies differed to
some extent with respect to clinical and other factors.
To assess the presence of between-study heterogeneity of
effect sizes, t2 was calculated to get an estimate of the variance
between the effect sizes from individual studies.26 For the primary
outcome a value of t2 5 0.04 was considered as low
heterogeneity, 0.09 as moderate, and 0.16 as high heterogeneity.3 In addition, the I2 statistic was used which can be interpreted
as the percentage of heterogeneity attributable to between-study
variation rather than a random error.27 Meta-analyses were
performed in Review Manager (RevMan) 5.3. If at least 10 studies
were included in a meta-analysis, a funnel plot was created to
explore whether there was asymmetry among the trial results
(which may indicate publication bias). Separate analyses were
conducted for patients with (sub)acute or chronic LBP, consistently with the method guideline for systematic reviews of the
Cochrane Back and Neck Group.19 Subgroup analyses were also
considered for different placebo interventions (eg, open-label
placebo, placebo acupuncture, and placebo tape). A sensitivity
analysis was conducted, excluding studies rated as having a high
RoB. For all analyses, a 2-sided P , 0.05 was used to indicate
statistical significance, ie, whether placebo interventions were
more effective than no intervention. Based on recent studies
estimating the smallest worthwhile effect for conservative
interventions vs no intervention in patients with LBP,9,17 a 20%
between-group difference was a priori established as a clinically
relevant effect.
2.8. Evidence synthesis
The Grading of Recommendations Assessment, Development, and Evaluation22 approach was subsequently used to
rate the quality of evidence of pooled estimates into “high,”
“moderate,” “low,” or “very low” as suggested by the
Cochrane Back and Neck Group.19 For each specific
outcome, evidence was downgraded one or more levels for
each of the 5 Grading of Recommendations Assessment,
Development, and Evaluation components that was met
across all studies measuring that particular outcome:
limitations, inconsistency, indirectness, imprecision, and
publication bias. 19,22 The following rules were used for
downgrading quality of evidence:
(1) Limitations: one level if 50% to 75% of included trials scored
“low or some concerns” on RoB and 2 levels if less than 50%
of included trials scored “low or some concerns” on RoB.
(2) Inconsistency: one level if the value for the I2 statistic was
between 40% and 75%.
(3) Indirectness: one level if a study did not specifically mention
the target population (adult patients with nonspecific LBP) or if
it was unclear whether the intervention could be indeed
considered a placebo and whether the control was indeed a
no intervention with respect to the placebo.
(4) Imprecision: one level if the total sample for a specific outcome
was ,100 patients and 2 levels if the total sample for a specific
outcome was ,50 patients.
(5) Publication bias: one level if the funnel plot indicates
publication bias may be present.
3. Results
3.1. Characteristics and included studies
The literature search revealed 7803 potentially relevant articles,
and 21 RCTs were included in the review (Fig. 1). Of the 21
studies, one reported on subjects with acute LBP,58 one reported
on subacute LBP,16 and the remaining 19 studies reported on
patients with chronic LBP.2,4–7,14,35,37–43,45,46,50,54,62 Study
characteristics of all 21 included RCTs are shown in Table 1.
3.2. Risk of bias analysis
Three studies were identified as having an overall high risk of
bias.14,41,54 All of the studies had a high risk of bias on
measurement of the outcome, which is inherent to the study
setup. The risk of bias analysis for each individual study is
presented in Figure 2.
3.3. Primary endpoints
3.3.1. Chronic low back pain
3.3.1.1. Pain intensity
There was moderate-quality evidence (19 RCTs, N 5 1443) that
placebo interventions reduced back pain intensity compared with
no intervention at short-term follow-up (SMD 20.37, 95% CI
20.55 to 20.18, P , 0.0001, t2 5 0.11) (refer to Figure 3). This
between-group difference translates to approximately 8 points on
a 0 to 100 pain scale, corresponding to approximately 14% major
improvement in the placebo group, which did not reach the
predefined 20% improvement for clinical relevance. Sensitivity
analyses excluding RCTs with a high risk of bias showed a smaller
but still statistically significant effect in favor of placebo
interventions (SMD 20.27, 95% CI 20.47 to 20.06, P 5
0.0003). There was low-quality evidence (3 RCTs, N 5 154) that
placebo interventions are not significantly better than no intervention for back pain reduction at medium-term follow-up
(SMD 20.26, 95% CI 20.59-0.06, P 5 0.11 t2 5 0.00) (refer to
Figure 3). Sensitivity analyses excluding high risk of bias studies
confirmed this finding (SMD 20.19 95% CI 20.56 to 0.18, P 5
0.31). No long-term follow-up data were available.
3.3.1.2. Physical functioning
There was moderate-quality evidence (11 RCTs, N 5 775) that
placebo interventions improved physical functioning compared with
no intervention at short-term follow-up (SMD 20.19, 95% CI 20.39 to
20.01, P 5 0.07 t2 5 0.06) (refer to Figure 4). This difference
corresponds to approximately 1.3 points between-group difference
on the 0 to 24 Roland–Morris Disability Questionnaire, which is not
considered to be a clinically relevant effect. Sensitivity analysis
excluding high risk of bias studies confirmed this finding (SMD
20.17 95% CI 20.32 to 20.02, P 5 0.03). Only one study reported on
medium-term outcomes for physical functioning, showing no
statistical difference between placebo intervention and no intervention
(MD 22.60 95% CI 29.09 to 3.89 P 5 0.43 [scale 0-24]). No study
reported on long-term outcomes.
Copyright © 2021 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
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Figure 1. PRISMA 2009 flow diagram. LBP, lower back pain.
3.3.1.3. Health-related quality of life
There was high-quality evidence (3 RCTs, N 5 267) that placebo
interventions improved quality of life on the physical component
summary score of the SF-36 compared with no intervention on
short-term follow-up (MD 2.71, 95% CI 0.71-4.71, P 5 0.008, t2
5 0.34 [scale 0-100]) (refer to Figure 5). There was high-quality
evidence (3 RCTs, N 5 267) that placebo intervention does not
improve quality of life on the mental component summary score of
the SF-36 compared with no intervention on short-term follow-up
(MD 20.49, 95% CI 23.49 to 2.51, P 5 0.75, t2 5 2.85 [scale 0100]) (refer to Figure 5). No study data were available for mediumterm or long-term follow-up.
3.3.2. (sub)Acute low back pain
No meta-analysis for acute LBP was performed because of
lack of studies on any of the primary endpoints. One study
reported on physical functioning.58 There was no statistical
difference between placebo intervention and no treatment (MD
7.0; 95% CI 20.13 to 14.13, P 5 0.05 [scale 0-24]). Another
study reported on pain intensity in short-term follow-up.16
Short-term pain intensity was not different between placebo
intervention and no treatment (MD 7.0; 95% CI 26.02 to
20.02; P 5 0.29 [scale 0-100]).
3.4. Subgroup analysis
Subgroup analysis of open-label placebo RCTs as compared to
placebo control intervention RCTs showed a similar effect on shortterm pain intensity (SMD 20.33 vs SMD 20.37, appendix C,
supplemental digital content available at http://links.lww.com/PAIN/
B345, Fig. 1). There was high-quality evidence (3 RCTs, N 5 335)
that placebo acupuncture intervention improved back pain intensity
compared with no intervention at short-term follow-up (SMD 20.37,
95% CI 20.64 to 20.10, P 5 0.007). There was very low-quality
evidence (2 RCTs, N 5 80) that placebo taping does not improve
back pain compared with no intervention at short-term follow-up
(SMD 0.09, 95% CI 20.52 to 0.70, P 5 0.77). There was high-quality
evidence (2 RCTs, N 5 345) that placebo injection intervention does
not improve back pain compared with no intervention at short-term
follow-up (SMD 0.03, 95% CI 20.18 to 0.24, P 5 0.77). There was
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2796
First author, journal, Population total
Percentage
year of publication sample participants
female
(N) mean age in y (SD) participants
Duration of complaints Placebo
acute (<6 wk),
intervention
subacute (6-12 wk), or group
chronic (>12 wk)
Comparison
control group
No. of treatments.
Total duration of
treatment.
Pain outcome Physical functioning Quality of life
measures
outcome measures outcome
measures
Follow-up
available
Placebo N 5 27
Age placebo: 33.22
(13.29)
Control N 5 27
Age control: 29.85
(12.09)
Placebo 63%
Control 68%
Chronic
Placebo spinal
manipulative
therapy
No intervention
N56
2 wk
NRS
ODI
NA
2 wk
Borges et al.,4
2014
Placebo N 5 15
Age: 39.6 (9.6)*
Control N 5 14
Age: 39.6 (9.6)*
Placebo 73.3%
Control 64.3%
Chronic
Sham laser
therapy
No intervention
N 5 12
6 wk
NRS
NA
NA
6 wk
Brinkhaus et al.,5
2006
Placebo N 5 70
Age placebo: 58.2 (9.4)
Control N 5 74
Age control: 58.9 (9.5)
Placebo 75.3%
Control 68.4%
Chronic
Sham
acupuncture
Waiting list
N 5 12
8 wk
VAS pain
FFbH-R
SF-36, MCS, and
PCS
8 wk
Carvalho et al.,6
2016
Placebo N 5 41
Placebo 70.7%
Age placebo: 44.4 (13.2) Control 71.4%
Control N 5 42
Age control: 44.1 (13.7)
Chronic
Open-label
placebo pills
Treatment as usual N 5 2dd2
3 wk
NRS
RMDQ
NA
3 wk
Celenay et al.,7
2019
Placebo N 5 21
Placebo 81%
Median (range)
Control 71%
Age placebo: 48 (39-63)
Control N 5 21
Median(Range)
Age control: 55 (24-65)
Chronic
Sham massage
therapy
Standard treatment N 5 15
3 wk
VAS pain
ODI
SF-36, MCS, and
PCS
3 wk
Eardley et al.,14
2013
Placebo N 5 21
Placebo 67%
Age placebo: 48.1 (10.6) Control 64.7%
Control N 5 17
Age control: 44.6 (10.3)
Chronic
Sham
physiotherapy
Waiting list
N55
5 wk
VAS pain
RMDQ
SF-36, MCS, and
PCS
5 wk
Farasyn et al.,16
2006
Placebo N 5 20
Age placebo: 43 (12)
Control N 5 20
Age control: 40 (12)
Sub-acute
Sham
endermology
treatment
Waiting list
N51
30 min
VAS pain
ODI
NA
1 wk
Imamura et al.,35
2016
Placebo N 5 125
Placebo 70.4%
Age placebo: 47.91
Control 63.78%
(8.52)
Control N 5 127
Age control: 48.01 (9.48
Chronic
Sham infusion
therapy
Standard treatment N 5 3
3 wk
VAS pain
RMDQ
NA
3 mo
·
Bialosky et al.,2
2014
R.H.W. Strijkers et al. 162 (2021) 2792–2804
Placebo 55%
Control 56%
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Table 1
Table 1Characteristics of eligible studies (n 5 21).
Chronic
Open-label
placebo pills
No. of treatments.
Total duration of
treatment.
Pain outcome Physical functioning Quality of life
measures
outcome measures outcome
measures
Follow-up
available
Treatment as usual N 5 21
21 d
NRS
ODI
NA
3 wk
VAS pain
ODI
NA
4 wk
Brief Pain
Inventory
subscore 1
NA
NA
3 wk
Kleine-Borgmann
et al.,37 2019
Placebo N 5 67
Age placebo: 60.2
(15.15)
Control N 5 60
Age control: 58.37
(13.97)
Köroglu et al.,38
2017
Placebo N 5 20
Placebo 60%
Age placebo: 50.3 (11.5) Control 40%
Control N 5 20
Age control: 47.9 (15.2)
Chronic
Placebo taping
Treatment as usual N 5 10
2 wk
Placebo 58%
Leichtfried et al.,39 Placebo N 5 36
2014
Median (range)
Control 57%
Age placebo: 47 (39-54)
Control N 5 33
Median (range)
Age control: 52.5 (49-58)
Chronic
Light intervention
Prestudy therapy
Placebo 55.6%
Control 69.5%
·
NA
Mixed, mostly Chronic
Sham straincounterstrain
exercise
Laying in a sleeping N 5 1
position for 6 min 6 min
VAS pain
NA
NA
1-3 d
Licciardone et
al.,41 2003
Placebo N 5 23
Age placebo: 52 (12)
Control N 5 17
Age control: 49 (12)
Placebo 57%
Control 65%
Chronic
Sham
manipulation
therapy
Received no
intervention
N57
5 mo
VAS pain
NA
NA
1, 3 and 6
mo
Luz Jr et al.,42
2015
Placebo N 5 20
Placebo 65%
Age placebo: 50.1 (17.5) Control 85%
Control N 5 20
Age control: 48.1 (13.4)
Chronic
Sham taping
No intervention
N51
48 h
NRS
RMDQ
NA
1 wk
Marchand et al.,43
1993
Placebo N 5 12
Placebo 50%
Age placebo: 35.08
Control 50%
(7.38)
Control N 5 16
Age control: 37.25 (8.18)
Chronic
Sham tense
therapy
Waiting list
N 5 20
10 wk
VAS pain
NA
NA
3, 6 mo
Chronic
Sham
acupuncture
Standard therapy
N 5 12
4 wk
VAS pain
NA
NA
3 mo
Placebo 45.90%
Control 53.33%
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Placebo N 5 28
Age: 39.2 (11.1)*
Control N 5 28
Age: 39.2 (11.1)*
Number 12
N59
3 wk
Lewis et al.,40
2010
Molsberger et al.,45 Placebo N 5 61
2002
Age placebo: 50 (6)
Control N 5 60
Age control: 49 (7)
Volume 162
Comparison
control group
·
Duration of complaints Placebo
acute (<6 wk),
intervention
subacute (6-12 wk), or group
chronic (>12 wk)
December 2021
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Table 1 (continued)
First author, journal, Population total
Percentage
year of publication sample participants
female
(N) mean age in y (SD) participants
Placebo 75%
Control 81%
No. of treatments.
Total duration of
treatment.
Pain outcome Physical functioning Quality of life
measures
outcome measures outcome
measures
Follow-up
available
Chronic
Sham
acupuncture
No orientation, no
intervention.
N55
5 wk
Brief Pain
Inventory
NA
NA
2 wk
Chronic
Sham injection
No treatment
N 5 12
8 wk
VAS pain
FFbH-R
SF-36, MCS, and
PCS
2, 6 mo
N52
8d
NRS
FFbH-R
NA
8d
·
Placebo N 5 36
Age placebo: 51.03
(14.9)
Control N 5 37
Age control: 46.19
(15.73)
Comparison
control group
R.H.W. Strijkers et al. 162 (2021) 2792–2804
Moura et al.,46
2019
Duration of complaints Placebo
intervention
acute (<6 wk),
subacute (6-12 wk), or group
chronic (>12 wk)
2798
Placebo 56.3%
Pach et al.,50 2011 Placebo N 5 43
Age placebo: 54.8 (11.3) Control 56.9%
Control N 5 50
Age control: 56.7 (10.7)
Schmitz et al.,54
2019
Placebo N 5 21
Placebo 76.19%
Age placebo: 55.48
Control 57.14%
(10.72)
Control N 5 14
Age control: 48.07(8.49)
Chronic
Sham transdermal No treatment
infusion
Vas et al.,58 2012
Placebo N 5 69
Placebo 49.3%
Age placebo: 43.6 (12.2) Control 64.3%
Control N 5 70
Age control: 41.2 (12)
Acute
Sham
acupuncture
Treatment as usual N 5 5
2 wk
VAS pain
RMDQ
NA
3 wk
Wepner et al.,62
2008
Placebo N 5 18
Age: 47.06 (9.33)*
Control N 5 18
Age: 47.06 (9.33)*
Chronic
Sham singing
bowls therapy
Treatment as usual N 5 6
4 wk
VAS pain
RMDQ
SF-36, MCS, and
PCS
5 wk
NA
* Not separately available.
FFbH-r, Hannover Functional Ability Questionnaire; MCS, mental component summary; NRS, numerical rating scale; NA, not available; ODI, Oswestry Disability Index; PCS, physical component summary; RMDQ, Roland–Morris Disability Questionnaire; VAS, visual analog scale; SF-36, Short-Form 36.
PAIN®
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Table 1 (continued)
First author, journal, Population total
Percentage
year of publication sample participants
female
(N) mean age in y (SD) participants
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Figure 2. Cochrane risk of bias analysis summary of included studies.
very low-quality evidence (2 RCTs, N 5 89) that placebo spinal
manipulation does not improve back pain compared with no
intervention at short-term follow-up (SMD 20.28, 95% CI 21.15
to 0.59, P 5 0.53). There was low-quality evidence (2 RCTs, N 5
80) that placebo taping therapy does not improve physical
functioning compared with no intervention at short-term followup (SMD 0.15, 95% CI 20.29 to 0.59, P 5 0.51). We found highquality evidence (2 RCTs, N 5 205) that open-label placebo pill
treatment improves short-term pain intensity compared with no
intervention (SMD 20.33 95% CI 20.61 to 20.05, P 5 0.02)
and also improves physical functioning (SMD 20.34 95% CI
20.62 to 20.07, P 5 0.01). None of these between-group
differences was clinically relevant. We found no difference in
short-term pain intensity outcomes with exclusion of open-label
placebo trials (SMD 20.437, 95% CI 20.5559 to 20.216, P 5
0.20007) (appendix C, supplemental digital content available at
http://links.lww.com/PAIN/B345).
acute LBP was too small for conducting meta-analyses and to draw
conclusions for this subgroup of patients. In patients with chronic
LBP, 19 studies were identified. Meta-analyses showed that placebo
interventions are more effective than no intervention for pain intensity
at short-term follow-up (SMD 20.37; moderate-quality evidence), but
this effect, which corresponds to about 8 point on a 0 to 100 scale,
may not be considered as clinically relevant. No significant effect was
found on pain intensity at medium-term follow-up (SMD 20.26; lowquality evidence). A statistically significant positive effect on physical
functioning at short-term follow-up (SMD 20.19; moderate-quality
evidence) was found for placebo interventions as compared with no
intervention control, but also this effect may not be clinically relevant.
Placebo interventions were more effective than no intervention on
short-term HRQoL physical health (MD 2.71 on a 0-100 scale; highquality evidence) but not more effective for short-term HRQoL mental
health (MD 20.49 on a 0-100 scale; high-quality evidence). No longterm follow-up data were available on any outcome.
4. Discussion
4.1. Results in perspective of the available literature
This systematic review shows the magnitude of the placebo effect in
patients with LBP. The number of studies (n 5 2) focusing on (sub)
Multiple nonpharmacological interventions for chronic LBP have
previously been studied and recommended, among these individual
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2800
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R.H.W. Strijkers et al. 162 (2021) 2792–2804
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Figure 3. Forest plots for pain intensity at short-term and medium-term follow-up. Risk of bias assessment: The red circle corresponds with a high risk of bias. The
yellow circle corresponds with an unclear risk of bias. The green circle corresponds with a low risk of bias.
education, exercise therapy, and multidisciplinary rehabilitation.49
Hayden et al. recently published an individual patient data metaanalysis on exercise therapy for chronic LBP showing a 10.7-point
improvement in pain intensity scores at short-term follow-up in
comparison with no intervention or usual care, which met our
predefined 20% between-group difference for clinical relevance.
Regarding physical functioning, a short-term clinically relevant
improvement was also reported for exercise therapy.25 Only shortterm effects on pain were found in our analysis. This can in part be
explained by the inability to blind the no intervention group. Literature
demonstrates there is an effect of expectations on treatment
outcome in patients with LBP, and this effect is not expected to last
in the medium-term to long-term follow-up.23
Another recent systematic review showed that spinal manipulative therapy (SMT) did not improve pain intensity at short-term
follow-up (1 month) compared with sham SMT in patients with
chronic LBP, but disability improved only slightly at one month
compared with sham SMT.53
Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently the
most recommended medications for patients with chronic LBP.49
Interestingly, in a Cochrane review on NSAIDs, authors found an 8point improvement on a pain scale of 0 to 100 compared with
placebo.15 Therefore, the magnitude of improvement on pain and
functioning of NSAIDs vs placebo intervention is similar to the
magnitude of effect for placebo interventions vs no interventions
found in this review, both being not clinically relevant effects.
However, this is not a direct comparison because the comparator
groups are different. It would be more meaningful to compare the
placebo effect found in this review with the effect of NSAIDs as
compared to no intervention; this indirect comparison would be
possible using network meta-analysis but it was outside the scope
of this review. This systematic review further contributes to the
literature discussion on the magnitude of placebo effects. In 2010,
the latest version of the Cochrane review of Hrobjartsson et al.
concluded, on basis of 156 trials, that there is no powerful placebo
effect, only a potential small effect on subjective outcomes (eg,
pain). Contrary to the review of Hrobjartsson, a recent narrative
review on the placebo and nocebo effects of Colloca et al.
concluded that placebo effects are “powerful and pervasive,”
based on the results of laboratory studies.10 Such powerful effects
were not found in our meta-analyses that focused on placebo
effects on subjective outcomes in RCTs in the field of nonspecific
LBP. We argue that laboratory studies, although representing a
good platform to modulate placebo effects, may not have a
sufficiently controlled setting to determine the magnitude of these
effects, which was the focus of this systematic review. In fact,
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Figure 4. Forest plot for physical functioning at short-term follow-up. Risk of bias assessment: The red circle corresponds with a high risk of bias. The yellow circle
corresponds with an unclear risk of bias. The green circle corresponds with a low risk of bias.
laboratory research is not usually used to assess the effectiveness
of health interventions.1 In this review, a larger effect size was found
for open-label placebo RCTs as compared to 3-arm RCTs not
including an open-label placebo treatment. A possible explanation
for the discrepancy in effect size might be that the researchers in
the open-label studies are focused on purposively delivering an
enhanced placebo intervention, increasing its effectiveness. Given
all these observations, we conclude there is a short-term placebo
effect on pain intensity in patients with chronic LBP. Although
previous research suggested that the magnitude of effect may
depend on how exactly the placebo is delivered,59,60 our subgroup
analysis separating open-label placebo from placebo controls did
not confirm this assertion, at least for patients with chronic LBP.
However, it should also be acknowledged that the small number of
included studies (n 5 2) prevents definite conclusions at the
moment. Most recently, another small open-label placebo trial in
patients with chronic LBP was published, showing again a small
effect in favor of the placebo intervention as compared to no
intervention.34 Another large and adequately powered clinical trial
is probably needed to draw firm conclusions on the clinical
relevance of the effect of open-label placebos in patients with
chronic LBP.
Figure 5. Forest plots of health-related quality of life at short-term follow-up. Risk of bias assessment: The red circle corresponds with a high risk of bias. The yellow
circle corresponds with an unclear risk of bias. The green circle corresponds with a low risk of bias.
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R.H.W. Strijkers et al. 162 (2021) 2792–2804
A previous systematic review in patients with osteoarthritis
concluded that contextual effects of interventions are very large
and that the more invasive is an intervention, the larger is the
placebo effect.65 This conclusion was not confirmed by the
subgroup analyses undertaken in this review (supplement E,
supplemental digital content available at http://links.lww.com/
PAIN/B345). In fact, an arguably more intensive intervention such
as placebo injections did not show a significant reduction in pain
intensity compared with no intervention and did not show a larger
effect than placebo taping and placebo spinal manipulation (SMD
0.03, SMD 0.09, and SMD 20.28, respectively; see supplement
C, supplemental digital content available at http://links.lww.com/
PAIN/B345). Only placebo acupuncture and open-label placebo
pills exhibited a significant result in reduction of pain intensity
compared with no intervention (SMD 20.37, 95% CI 20.64 to
20.10; N 5 2; P 5 0.007, and SMD 20.33, 95% CI 20.61 to
20.05, P 5 0.02, respectively), but this effect may not be clinically
relevant. Hence, in contrast with Zou et al. we could not identify a
specific intervention that elicits more profound effects on shortterm pain intensity. This difference could be due to the fact that
Zou et al.65 did not rule out the effect of no intervention
interventions in their review and the difference in patient
population (ie, LBP vs osteoarthritis). Therefore, for patients with
chronic LBP, the effect of placebo intervention may not be
dependent on the type of intervention but more on other factors
such as interaction with researchers or physicians. It is also
important to note, however, that the number of studies was very
small in these subgroup analyses, and certainly the power to
detect significant differential findings was limited.
4.2. Strengths and limitations
The use of no intervention control groups corrected for factors
such as regression to the mean and natural course of disease
thus allows for a valid estimate of symptom improvement that
may be attributed to the administration of placebo interventions.
Nevertheless, even including a waiting list or no intervention
group in a trial gives rise to potential bias.18 For instance, patients
in the no intervention group may seek more alternative
interventions than patients in the placebo group. Our RoB
analyses did not control for the potential impact of co-medication
or other co-intervention, and this may have slightly underestimated the magnitude of placebo effects. Conversely,
considering that it is not possible to blind personnel and patients
in a trial with a no intervention group, there may have also been
some overestimation of the effectiveness of placebo interventions, although there is conflicting evidence on the difference in
intervention effects between study with or without blinding.47,48
Furthermore, the heterogeneity of placebo interventions summarized in our meta-analyses might be considered a limitation.
However, in all analyses the t2 estimate of between study
heterogeneity indicated only low variation between effect sizes
from individual studies, which allows for meta-analytic summary
across the pool of studies despite the obvious diversity in placebo
interventions approaches. Another limitation of our study is that
by choosing to conduct meta-analyses on aggregate data only
we were not able to investigate differential placebo effects with
respect to certain patient characteristics. It is known from
laboratory research that some individuals experience larger
effects of placebo intervention than others depending on
personality traits,20 and this aspect could be further explored
within individual patient data meta-analyses of the trials included
in this review.
4.3. Future research
Future research should focus on the factors that moderate and
cause the effect in the placebo groups of RCTs. Most of the RCTs
included in this systematic review reported pain intensity, but
fewer studies reported on physical functioning or disability
outcomes, and an even smaller number of studies reported
HRQoL as an intervention outcome. We stress the need for
uniformity in reporting outcomes, as previously suggested.8 All
studies on LBP should at least report on these 3 outcomes. Other
outcome measures such as pain interference and pain selfefficacy can also be of use. Furthermore, we observed considerable variation regarding the follow-up period. We advise to use
the standard follow-up moments as suggested by the Cochrane
Back and Neck review group.19 Only few data were available for
medium-term follow-up, and only one study reported on longterm follow-up. However, from a clinical perspective it would be
most relevant to see whether the effects caused by placebo
interventions sustain over time in patients with LBP. More
research is needed in (sub)acute LBP. With the overview on the
current evidence based on the effects of placebo interventions
from our meta-analysis and other literature, we suggest that
future intervention trials in LBP should consider using a 3-arm
design, which includes an intervention group, a placebo group
(which closely resembles the intervention group), and a waiting list
or no intervention group. We recognize recruitment of patients
might prove difficult with such a design.56 A potential solution to
this problem could consist of an adaptive clinical trial design,51 in
which the no intervention group could be dropped if there is an
apparent great difference in effectiveness. Alternatively, a trial
with multiple baseline assessments might be considered if the
use of a no intervention group is unfeasible or considered
unethical.
5. Conclusion
Placebo interventions in any form seem to be mildly effective in
reducing pain intensity in patients with chronic nonspecific LBP at
short-term follow-up compared with no intervention. The reduction in pain intensity of 8 points on a 0 to 100 pain scale was
statistically significant but may be of limited clinical relevance.
Results are independent of the actual type of placebo intervention. A small difference was seen in physical functioning
outcome between placebo and no intervention, but this
difference may also not be clinically relevant. Placebo intervention
improved the physical summary component score of the ShortForm 36 compared with no intervention.
Conflict of interest statement
The authors have no conflicts of interest to declare.
Acknowledgements
The authors would like to thank Wichor M. Bramer for his help in
developing the database search syntaxes for this systematic
review.
M. Schreijenberg, A. Chiarotto, and B.W. Koes made substantial
intellectual contributions to the development of the original study
protocol of this systematic review. R.H.W. Strijkers and
M. Schreijenberg performed the data selection, data extraction,
and risk of bias assessment. R.H.W. Strijkers conducted the
analyses under supervision of H. Gerger and A. Chiarotto.
R.H.W. Strijkers, A. Chiarotto, and H. Gerger interpreted the
Copyright © 2021 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
December 2021
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results. R.H.W. Strijkers and M. Schreijenberg drafted the
manuscript, which was revised by A. Chiarotto, B.W. Koes, and
H. Gerger. All authors have read and approved the final manuscript.
www.painjournalonline.com
[18]
[19]
Appendix A. Supplemental digital content
Supplemental digital content associated with this article can be
found online at http://links.lww.com/PAIN/B345.
Article history:
Received 23 August 2020
Received in revised form 4 March 2021
Accepted 5 March 2021
Available online 24 March 2021
[20]
[21]
[22]
[23]
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