Advance Access publication 24 December 2008
Analgesic effects of treatments for non-specific low back pain:a meta-analysis of placebo-controlled randomized trials
L. A. C. Machado1, S. J. Kamper1, R. D. Herbert1, C. G. Maher1 and J. H. McAuley2
Objective. Estimates of treatment effects reported in placebo-controlled randomized trials are less subject to bias than those estimatesprovided by other study designs. The objective of this meta-analysis was to estimate the analgesic effects of treatments for non-specific lowback pain reported in placebo-controlled randomized trials.
Methods. Medline, Embase, Cinahl, PsychInfo and Cochrane Central Register of Controlled Trials databases were searched for eligible trialsfrom earliest records to November 2006. Continuous pain outcomes were converted to a common 0–100 scale and pooled using a randomeffects model.
Results. A total of 76 trials reporting on 34 treatments were included. Fifty percent of the investigated treatments had statistically significanteffects, but for most the effects were small or moderate: 47% had point estimates of effects of <10 points on the 100-point scale, 38% hadpoint estimates from 10 to 20 points and 15% had point estimates of >20 points. Treatments reported to have large effects (>20 points) hadbeen investigated only in a single trial.
Conclusions. This meta-analysis revealed that the analgesic effects of many treatments for non-specific low back pain are small and thatthey do not differ in populations with acute or chronic symptoms.
KEY WORDS: Meta-analysis, Randomized-controlled trial, Treatment efficacy, Low back pain, Placebo effect.
systematic review and meta-analysis of placebo-controlled rando-mized trials investigating the effects of treatments for NSLBP.
Low back pain is a highly prevalent health problem that is
associated with enormous costs worldwide [1–3]. In developedcountries, episodes of back pain are a leading cause of work
absence, accounting for over 25% of all conditions involving days
away from work [4, 5]. About 90% of the patients with low backpain will receive the diagnosis ‘non-specific low back pain’
The electronic databases Medline, Embase, Cinahl, PsychInfo and
(NSLBP), a term that signifies that no specific pathology or
the Cochrane Central Register of Controlled Trials were searched
disease process has been identified by the clinician. Although pain
from the earliest record to November 2006 for placebo-controlled
improves rapidly in the first month with a typical episode of
randomized trials of treatments for NSLBP. Our search strategy
NSLBP, low levels of pain may continue for many months .
followed the recommendations of the Cochrane Back Review
The number of studies investigating the effects of treatments for
Group . The results were combined with the terms ‘placebo’,
patients with NSLBP has increased dramatically in the past
‘sham’, ‘attention-control’ or ‘minimal intervention’. We also
decade. Some of these studies compare outcomes in a treated
searched cited references of relevant trial reports and reviews for
group with outcomes of a group that is given placebo treatment or
sham treatment. The use of a placebo is generally considered to be
Eligible studies were randomized controlled trials comparing
a good design feature because it controls for placebo effects and,
treatments for NSLBP against placebo. To be included, they must
more generally, for changes in patient behaviour caused by
have reported a continuous measure of pain. Studies in which
knowledge of allocation . The provision of a placebo may also
participants presented with radicular syndrome, cauda equina
enable better control of other sources of bias in clinical trials, such
syndrome, infection, neoplasm, fracture, inflammatory disease,
as measurement bias, treatment non-compliance and loss to
pregnancy or spinal surgery in the past 12 months were excluded,
as were primary prevention studies. Trials in which the placebo
The ability of placebos to control for bias in clinical research is
intervention was a contemporary treatment (e.g. an educational
closely linked to the facilitation of blinding . In a recent meta-
epidemiological study, the lack of blinding was associated with a25% over-estimation of treatment effects when these effects were
measured in terms of subjective outcomes, such as pain [odds ratio
Two independent reviewers extracted data using a standard form.
(OR) 0.75; 95% CI 0.61, 0.93] . Thus, at least from an
A third reviewer extracted data for non-English studies. Trial
explanatory perspective, placebo-controlled trials may provide the
quality was assessed using the PEDro scale , an 11-item quality
least biased estimates of the analgesic effects of treatments.
checklist. The full scale criteria can be viewed at
To our knowledge there have not been any systematic reviews
focusing on the analgesic effects of treatments estimated by
resolved by discussion and consensus. Trials were included in
placebo-controlled trials on NSLBP. Thus, we performed a
the analysis regardless of their quality ratings. Data on continuouspain outcomes are often reported at several time points. We choseto extract data from the first assessment after the end of the
1The George Institute for International Health and 2Faculty of Health Sciences, The
therapy. This timing was decided a priori because it was
University of Sydney, Sydney, Australia.
considered the time-point where the largest analgesic effects
Submitted 30 June 2008; revised version accepted 20 November 2008.
For simplicity, trials comparing multiple treatments of diverse
Correspondence to: C. G. Maher, The George Institute for International Health,
PO Box M201, Missenden Rd, Sydney, NSW 2050, Australia.
nature against the same placebo had each of their comparisons
treated as an individual trial. However, when a single trial
The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
Analgesic effects of treatments for low back pain
compared more than one treatment of the same type (e.g. differentdosages of the same drug) to the same placebo group, only one
comparison per trial was entered into any analysis. In that case,
the preferred studies were those in which the experimental group
consisted of a single treatment as opposed to combinations oftreatments. If there was more than one group receiving single
treatments, one was selected at random.
Where necessary, pain scores were re-scaled to a 0- to 100-point
scale. For each trial, wherever possible, the size of the treatment
effect was estimated by subtracting the mean pain in the treatment
group from the mean pain in the control group. Methods
described in the Cochrane Handbook  were used to calculate
the variance of the estimate. Where there were insufficient data,the S.D. for assessments at baseline or the pooled S.D. of trials
reporting on the same intervention was used . The same
procedure was used in one trial reporting implausible S.D.S .
Where more than one trial estimated the effect of a particular
treatment, a random effects model was used to obtain a pooled
estimate of the effect (weighted mean difference, WMD) of thattreatment. We used MIX (version 1.6) for the analyses .
FIG. 1. Selection of studies for inclusion.
A pre-specified secondary analysis was performed to evaluate
the efficacy of treatments in populations with distinct duration of
symptoms. Acute symptoms were defined as those present for <6
TABLE 1. Contemporary treatments referred to as placebo treatments in trials of
weeks, sub-acute symptoms as those present from 6 weeks to 3
months, and chronic symptoms as those present for over 3 months. Trials not reporting the duration of the symptoms, or having
a mix of patients with acute and chronic symptoms, were not
included in the secondary analysis. To judge the magnitude of
treatment effects (represented by the absolute differences between
experimental and placebo groups at follow-up), we used the
Superficial needling at non-acupuncture points
definitions of the American College of Physicians and the
American Pain Society, as follows: large treatment effect (>20
points), moderate treatment effect (10–20 points) and small
treatment effect (<10 points) .
Superficial needling at non-acupuncture points
Exercises and simulated osteopathic techniques
Superficial needling at non-acupuncture points
Figure 1 describes the process of study selection. A total of 1031
Superficial needling at non-acupuncture points and
papers were identified by the search strategy and screened for
eligibility, of which 946 failed to meet the inclusion criteria. In 21
Low-dose lignocaine injection, non-forceful manipulation,
studies the reason for ineligibility was that the trial employed
Acupuncture needling without electrical stimulation
a placebo that is a contemporary treatment for NSLBP [19–39].
Table 1 lists the treatments used as placebos in these trials. Of the
85 eligible trials, 9 were excluded from the analysis because they
provided insufficient data to estimate treatment effects [40–48].
Education by didactic presentation and information sheet
Low-force spinal manipulation and soft-tissue massage
Thus, 76 trials reporting on 34 different treatments were included
Acupuncture needling without electrical stimulation and
SWD: shortwave diathermy; US: ultrasound; TENS: transcutaneous electrical nerve
Table 2 describes the characteristics of the included trials. Fromthe 76 trials included, 81 comparisons against placebo were
pragmatic physiotherapy [62, 64] and the provision of educational
considered. Muscle relaxants were tested in the largest number of
material . Concurrent therapies were allowed in 36 trials,
trials (nine trials), while NSAIDs were tested on the largest
which were mostly rescue medication or the continuation of
number of participants (1349 participants). Trial quality was
previous treatment regimens. Because of the different duration of
highly variable; individual items of the quality checklist are
treatments, we had to use various time-points for data extraction,
described in the Appendix (see supplementary data available at
which ranged from 5 min after the intervention in a trial of
Rheumatology Online). Two trials investigating the effects of
neuroreflexotherapy to 52 weeks after intervention in a trial of
exercise  and spinal manipulative therapy (SMT)  scored
intradiscal steroid injections (ISIs) (Table 2).
3 points on the PEDro scale, a score that has been consideredthe cut-off for low-quality trials in previous reviews [124, 125].
In 10 trials, the treatment under investigation was delivered in
addition to baseline care provided to both the experimental and
Seventeen of the investigated treatments (50%) had statistically
the placebo groups. Baseline treatments included exercise pro-
significant effects compared with placebo (Fig. 2). Point
grammes [82, 103, 104, 107, 121], heat therapy , NSAIDs ,
estimates of the effects were small for 16 treatments (colchicine,
TABLE 2. Characteristics of included trials
aNumber of comparisons against placebo. bTotal number of participants in the experimental and placebo groups for whom data were available at the time-point for data extraction. ATP: adenosine
triphosphate; ISIs: Intradiscal steroid injections; NMDA: N-methyl-D-aspartate; PTIT: percutaneous thermocoagulation intradiscal techniques; RF: radiofrequency; SMT: Spinal manipulative therapy;TENS: transcutaneous electrical nerve stimulation.
N-methyl-D-aspartate antagonists, shortwave, ISIs, percutaneous
NSLBP are small. Large effects were only observed in single
thermocoagulation intradiscal techniques, radiotherapy, traction,
small trials. Additionally, treatment effects do not differ in
physiotherapy, prolotherapy, exercise, anti-depressants, behav-
populations with acute or chronic NSLBP.
ioural, adenosine triphosphate, SMT, NSAIDs and magnets),
Interestingly, treatment recommendations from recent clinical
moderate for 13 treatments (analgesics, radiofrequency denerva-
guidelines do not align with the results of this meta-analysis. For
tion, herbal medicines, facet injections, laser, massage, muscle
example, five of the treatments recommended in the 2007
relaxants, anti-convulsants, back school, nerve blocks, transcuta-
guideline of the American Pain Society (anti-depressants, SMT,
neous electrical nerve stimulation, heat wrap therapy and
exercise, acupuncture, behavioural therapies)  were shown in
acupuncture) and large for five treatments (neuroreflexotherapy,
this review to be not more effective than placebo. Inconsistencies
vitamin B12, infrared, immunoglobulins and electroacupuncture).
like these are not surprising because, unlike our approach,
However, with the possible exception of heat wrap therapy, the CIs
guideline committees also consider the results from trials with a
about moderate estimates were not narrow enough to rule out
no-treatment control and trials comparing two active treatments
small effects. Additionally, all five large estimates were based on
when providing their recommendations. The findings of these
just one small- or moderate-sized study. A post hoc analysis
latter types of trials (known as pragmatic trials) are generally
excluding the two low-quality trials [68, 115] produced even smaller
considered more useful for clinicians because their design
analgesic effects for both exercise (pooled effect À1.7; 95% CI
replicates more closely what happens in everyday clinical practice.
À8.2, 4.8) and SMT (pooled effect À1.4; 95% CI À9.4, 6.6).
However, in some pragmatic trials the interpretation of findings
We sought to determine if the effects of treatment, compared
may be more difficult than in placebo-controlled trials. For
with placebo, varied with the duration of symptoms (acute, sub-
example, a null result in a trial comparing two active treatments of
acute or chronic). There were no studies reporting exclusively on
unknown efficacy, often observed in the NSLBP literature, may
sub-acute NSLBP, so trials having a mix of patients with acute
mean that the treatments are equally effective or equally
and sub-acute symptoms (<3 months) or with sub-acute and
ineffective since they may not be superior to a placebo.
chronic symptoms (>6 weeks) were treated in our secondary
During the conduct of the present meta-analysis, another study
analysis as acute or chronic NSLBP, respectively (Table 2).
with a similar aim was published by Keller et al. . Despite the
Figure 3 shows the analgesic efficacy, compared with placebo, of
similar aims of the two meta-analyses, their methods and
four treatments investigated in both acute and chronic popula-
execution were fundamentally different. First, the search in the
tions. There was no evidence of substantial differences in effects
Keller review was less comprehensive than ours: the review did not
include trials reporting on 27 treatments included in our review,including some commonly prescribed treatments for NSLBP, suchas analgesics and anti-depressants. Second, the Keller review
included trials with a no-treatment control, rather than restricting
A meta-analysis of 76 placebo-controlled randomized trials
the analysis to trials with a placebo control. Trials with a
revealed that the analgesic effects of many treatments for
no-treatment control have a higher risk of bias and so may
Analgesic effects of treatments for low back pain
FIG. 2. Analgesic efficacy of treatments for NSLBP of any duration. Squares represent pooled estimates of random effects (multiple trials) or means (single trials). Error barsare 95% CIs. Negative values favour treatment. In parentheses: number of trials; total number of participants. The dotted lines define the magnitude of effects: large(>20 U); moderate (10–20 U); small (<20 U). ATP: adenosine triphosphate; ISIs: Intradiscal steroid injections; NMDA: N-methyl-D-aspartate. PTIT: percutaneousthermocoagulation intradiscal techniques; RF: radiofrequency; SMT: Spinal manipulative therapy; TENS: transcutaneous electrical nerve stimulation;
provide overly optimistic estimates of treatment effects. Given
The opposite problem can also arise in placebo-controlled trials:
these differences, we believe the present meta-analysis provides a
some placebos may lack credibility, which could cause an over-
more robust evaluation of the analgesic effects of treatments for
estimation of treatment effects. Unfortunately, trial reports
usually contain insufficient information to judge whether this is
Despite the greater control of bias provided by the use of a
a problem , so we could not exclude trials using placebos that
placebo control in clinical trials, the use of placebos in trials
are not credible. As a consequence it is possible that our estimates
evaluating non-pharmaceutical treatments for NSLBP has been
of the effects of treatments were exaggerated. It would seem
contentious. Much of the debate does not relate to ethical
unlikely, therefore, that our finding of small effects of treatments
issues, but to problems encountered during the design of proper
for NSLBP is due to the inadequate design of placebo in placebo-
placebos for these trials. The distinction between placebo effects
and specific treatment effects may be ill-defined in trials of non-
Some authors have argued that the small effects of treatments
pharmaceutical treatments. This problem arises, in part, because
for acute NSLBP are a consequence of the favourable natural
there is often not a clear understanding of the mechanisms
history of acute NSLBP. The theory is that, at the conclusion of
underlying some non-pharmaceutical treatments . Thus, the
treatment in trials, control groups have improved substantially
selection of a placebo for these trials generally requires consider-
and so there is not ‘room’ for large treatment effects. To evaluate
able thought to ensure that the placebo intervention does not share
this argument we examined the baseline and follow-up scores from
some of the specific therapeutic components of the experimental
the acute trials included in the present meta-analysis. Three trials
intervention. This issue is more of a concern when placebos are
[64, 73, 85] did not report sufficient baseline data and were not
designed to resemble the experimental intervention .
considered. In 18 trials [49, 72, 78, 84, 86–91, 95–97, 114, 115, 117,
In some placebo-controlled trials, the placebo treatment is
120, 121] mean pain levels at baseline were 62.1 (S.D. 16.5) points
actually used in clinical practice as a treatment. Examples are
in the treatment group and 61.5 (S.D. 15.9) points in the placebo
educational booklets [23, 28], massage  and exercises [25, 27,
group. At follow-up mean pain levels were 29.5 (S.D. 13.2) points
36]. In this meta-analysis, we excluded trials using a placebo
in the treatment group and 39.6 (S.D. 17.1) points in the placebo
consisting of a contemporary treatment. We took this approach to
group. This indicates that there is scope for treatment effects (i.e.
minimize the possibility of under-estimation of treatment effects.
mean between-group differences) as large as 40 points to be
FIG. 3. Analgesic efficacy, compared with placebo, of treatments for acute and chronic non-specific low back pain. Squares represent pooled estimates of random effects(multiple trials) or means (single trials). Error bars are 95% CIs. Negative values favour treatment. In parentheses: number of trials; total number of participants. SMT:Spinal manipulative therapy. TENS: transcutaneous electrical nerve stimulation.
demonstrated in trials of NSLBP. Thus, the theory that there is no
of all treatments for NSLBP that have been tested against placebo.
‘room’ for trials to show large effects of treatments for acute
We used a comprehensive search strategy to identify potentially
NSLBP does not seem consistent with the data. Given the mean
eligible trials, in contrast to other reviews that used previously
baseline pain observed in the present meta-analysis, on average, a
published systematic reviews as the primary source of data [126,
10-point difference in pain between treatment and placebo groups
136, 137]. Additionally, we excluded placebo-controlled trials in
is equivalent to a 16% difference between groups in improvement
which the choice of placebo was inappropriate. One potential
limitation of the present meta-analysis is the investigation of just
Another argument used to explain the small treatment effects
one outcome. The outcome of pain was chosen because pain relief
found in the NSLBP literature is that most trial samples are
is ranked by patients as one of the most important components for
conducted on samples from clinically heterogeneous populations.
the satisfactory management of low back pain and it is often the
It is possible that specific treatments have large treatment effects
original motivation for seeking care from a health practitioner
on specific subgroups of patients with NSLBP [128, 129].
, and because most interventions appear to produce consis-
However, the evidence of a differential response of identifiable
tently greater reductions in pain than in other outcomes.
subgroups in the NSLBP literature is contradictory, as some
The available evidence from placebo-controlled trials shows
authors report a differential response of subgroups [130–132]
only small to moderate treatment effects, over and above placebo,
for many interventions that are currently used in the management
The small effects found in this meta-analysis might also be
of NSLBP. There seems to be a considerable scope for treatments
attributed to the choice of outcome measure; i.e. reduction in pain.
for NSLBP to show large treatment effects but how this can be
It could be argued that pain is not the most appropriate outcome
to make a judgement on the efficacy of treatments that aredesigned to improve other outcomes, such as function or quality
of life. However, we feel it is unlikely that an examination of otheroutcomes would produce meaningfully different conclusions to
The average effects of treatments for NSLBP are not much greater
those in the current meta-analysis because, in previous reviews,
pain has consistently shown larger responses to treatment than
There is a considerable scope for large treatment effects to be
other outcomes for NSLBP [126, 135]. For example, in a previous
meta-analysis on the effects of exercise therapy , the pooledeffect of exercise for chronic NSLBP was, at short-term follow-up,
Disclosure statement: The authors have declared no conflicts of
7.3 points on a 100-point scale (95% CI 3.7, 10.9) for pain
outcomes, and only 2.5 points on a 100-point scale (95% CI 1.0,3.9) for functional outcomes. A similar pattern was observed forintermediate- and long-term follow-ups .
Our meta-analysis has a number of strengths. First, this is the
first meta-analysis to provide the estimates of true treatment effects
Supplementary data are available at Rheumatology Online.
Analgesic effects of treatments for low back pain
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En primer lugar quiero agradecer al Círculo de Economía de Andorra su amable invitación para participar en este acto. El foro de debate, el tema que se suscita y, por descontado, la categoría del otro ponente invitado, han sido acicates para intentar hilvanar una serie de consideraciones relativas a los paraísos fiscales que voy a Deseo hacer constar mi no-adscripción a ninguna de las p
Z4: Handelingen met risicovolle stoffen en preparaten Versie juni 2013 INLEIDING Bij handelingen met risicovol e stoffen dienen naast de maatregelen die bij de bereiding gebruikelijk zijn om het product te beschermen, extra maatregelen te worden genomen om de risico’s voor de bereider te beperken. Het doel van dit hoofdstuk is om aan te geven hoe zowel aan specifieke arbo-wetgev