ArticlePDF AvailableLiterature Review

Abstract

Background While it is now clear that paracetamol is ineffective for spinal pain, there is not consensus on the efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) for this condition. We performed a systematic review with meta-analysis to determine the efficacy and safety of NSAIDs for spinal pain. Methods We searched MEDLINE, EMBASE, CINAHL, CENTRAL and LILACS for randomised controlled trials comparing the efficacy and safety of NSAIDs with placebo for spinal pain. Reviewers extracted data, assessed risk of bias and evaluated the quality of evidence using the Grade of Recommendations Assessment, Development and Evaluation approach. A between-group difference of 10 points (on a 0–100 scale) was used for pain and disability as the smallest worthwhile effect, as well as to calculate numbers needed to treat. Random-effects models were used to calculate mean differences or risk ratios with 95% CIs. Results We included 35 randomised placebo-controlled trials. NSAIDs reduced pain and disability, but provided clinically unimportant effects over placebo. Six participants (95% CI 4 to 10) needed to be treated with NSAIDs, rather than placebo, for one additional participant to achieve clinically important pain reduction. When looking at different types of spinal pain, outcomes or time points, in only 3 of the 14 analyses were the pooled treatment effects marginally above our threshold for clinical importance. NSAIDs increased the risk of gastrointestinal reactions by 2.5 times (95% CI 1.2 to 5.2), although the median duration of included trials was 7 days. Conclusions NSAIDs are effective for spinal pain, but the magnitude of the difference in outcomes between the intervention and placebo groups is not clinically important. At present, there are no simple analgesics that provide clinically important effects for spinal pain over placebo. There is an urgent need to develop new drug therapies for this condition.
EXTENDED REPORT
Non-steroidal anti-inammatory drugs for spinal
pain: a systematic review and meta-analysis
Gustavo C Machado,
1
Chris G Maher,
1
Paulo H Ferreira,
2
Richard O Day,
3
Marina B Pinheiro,
2
Manuela L Ferreira
1,4
ABSTRACT
Background While it is now clear that paracetamol is
ineffective for spinal pain, there is not consensus on the
efcacy of non-steroidal anti-inammatory drugs
(NSAIDs) for this condition. We performed a systematic
review with meta-analysis to determine the efcacy and
safety of NSAIDs for spinal pain.
Methods We searched MEDLINE, EMBASE, CINAHL,
CENTRAL and LILACS for randomised controlled trials
comparing the efcacy and safety of NSAIDs with
placebo for spinal pain. Reviewers extracted data,
assessed risk of bias and evaluated the quality of
evidence using the Grade of Recommendations
Assessment, Development and Evaluation approach.
A between-group difference of 10 points (on a 0100
scale) was used for pain and disability as the smallest
worthwhile effect, as well as to calculate numbers
needed to treat. Random-effects models were used to
calculate mean differences or risk ratios with 95% CIs.
Results We included 35 randomised placebo-controlled
trials. NSAIDs reduced pain and disability, but provided
clinically unimportant effects over placebo. Six
participants (95% CI 4 to 10) needed to be treated with
NSAIDs, rather than placebo, for one additional
participant to achieve clinically important pain reduction.
When looking at different types of spinal pain, outcomes
or time points, in only 3 of the 14 analyses were the
pooled treatment effects marginally above our threshold
for clinical importance. NSAIDs increased the risk of
gastrointestinal reactions by 2.5 times (95% CI 1.2 to
5.2), although the median duration of included trials
was 7 days.
Conclusions NSAIDs are effective for spinal pain, but
the magnitude of the difference in outcomes between
the intervention and placebo groups is not clinically
important. At present, there are no simple analgesics
that provide clinically important effects for spinal pain
over placebo. There is an urgent need to develop new
drug therapies for this condition.
INTRODUCTION
Spinal pain (neck or low back pain) is the leading
cause of disability worldwide,
12
and commonly
managed in general practice by prescription of
medicines.
34
Clinical guidelines recommend non-
steroidal anti-inammatory drugs (NSAIDs) as a
second-line analgesic after paracetamol, with third
choice being opioids.
5
However, recent
meta-analyses have shown that paracetamol is inef-
fective,
67
and opioids appear only to offer small
benets for this condition.
8
Thus, although the use
of NSAIDs has fallen in the past decade,
9
their use
could rapidly rise, given the lack of efcacy of para-
cetamol and increased awareness of risks associated
with opioid use.
10 11
There is still not consensus on the efcacy of
NSAIDs for spinal pain. The most recent
meta-analysis excluded participants with acute low
back pain or neck pain,
12
and to date no reviews
have investigated NSAID injections or topical for-
mulations in this population. Furthermore, previous
meta-analyses have reported standardised mean dif-
ferences (MD) as effect sizes, which are non-
intuitive and difcult to interpret;
13
thus better
measures of treatment effects, such as numbers
needed to treat (NNT), are likely to enhance inter-
pretability for the clinician. There is also concern
about the cardiovascular safety of cyclo-oxygenase-2
(COX-2) inhibitors, while serious gastrointestinal
adverse reactions are more closely linked to non-
selective NSAIDs,
14
although all NSAIDs have been
associated with cardiovascular and gastrointestinal
risks.
15
Thus, there is far greater need to understand
the efcacy and safety of this medicine for spinal
pain.
Therefore, the aim of this systematic review was
to investigate the efcacy and safety of NSAIDs
compared with placebo in patients with spinal pain,
with or without radicular pain. We also aimed to
evaluate whether trial characteristics or methods
are associated with estimates of treatment effect.
METHODS
Literature search
We followed the Preferred Reporting Items for
Systematic Reviews and Meta-analyses (PRISMA)
statement,
16
and prospectively registered the review
protocol on the International Prospective Register
of Systematic Reviews (CRD42015023746). We
searched MEDLINE, EMBASE, CINAHL,
CENTRAL and LILACS from their inception to
February 2016. The search strategy was constructed
based on a combination of the following keywords
and their variations: neck pain, back pain,
lumbago, sciatica, anti-inammatory, placebo and
randomised controlled trial. There were no restric-
tions of language or publication period.
Translations were obtained for non-English studies
(two trials). The complete search strategy is shown
in online supplementary table S1. One author
(GCM) performed the rst selection of studies
based on titles and abstracts, and two authors
(GCM and MBP) independently screened full texts.
We also searched for potentially eligible trials in the
reference lists of included studies and relevant
1269
Machado GC, etal. Ann Rheum Dis 2017;76:1269–1278. doi:10.1136/annrheumdis-2016-210597
Clinical and epidemiological research
To cite: MachadoGC,
MaherCG, FerreiraPH,
etal. Ann Rheum Dis
2017;76:1269–1278.
Handling editor Tore K Kvien
Additional material is
published online only. To view
please visit the journal online
(http://dx.doi.org/10.1136/
annrheumdis-2016-210597).
1The George Institute for Global
Health, Sydney Medical School,
University of Sydney, Sydney,
New South Wales, Australia
2Arthritis and Musculoskeletal
Research Group, Faculty of
Health Sciences, University of
Sydney, Sydney, New South
Wales, Australia
3Department of Clinical
Pharmacology, St Vincent’s
Hospital & University of New
South Wales, Sydney, New South
Wales, Australia
4Institute of Bone and Joint
Research, The Kolling Institute,
Sydney Medical School,
University of Sydney, Sydney,
New South Wales, Australia
Correspondence to
Gustavo C Machado, The
George Institute for Global
Health, PO Box M201,
Missenden Road, Camperdown,
Sydney, NSW 2050, Australia;
gmachado@georgeinstitute.
org.au
Received 27 September 2016
Revised 20 December 2016
Accepted 27 December 2016
Published Online First
20January2017
group.bmj.com on June 12, 2017 - Published by http://ard.bmj.com/Downloaded from
systematic reviews. We used consensus to resolve any
disagreement.
Study selection
Only randomised placebo-controlled trials published in peer-
reviewed journals and investigating the effects and safety of
NSAIDs for spinal pain were included in this review. Trials had
to include participants with neck or low back pain, with or
without radicular pain. Trials that included mixed populations
were included if they reported separate data for participants
with spinal pain. We included trials investigating acute or
chronic spinal pain of any intensity and eligible trials had to
compare any class, formulation or route of administration
(topical, oral or injection) of NSAIDs with a matching placebo.
Only trials that reported patient-relevant outcomes, such as pain
intensity, disability status, quality-of-life or adverse events were
included. The dose and frequency of NSAIDs intake were not
restricted, and we investigated the effects of both non-selective
NSAIDs (eg, acetic acids, enolic acids, propionic acids, salicy-
lates) and COX-2 inhibitors. We excluded trials of participants
with serious spinal pathology (cancer, infectious diseases or
cauda equina syndrome). Trials evaluating postoperative anal-
gesia using NSAIDs in participants with spinal pain were
excluded, as were non-randomised controlled trials, review arti-
cles, guidelines and observational studies.
Data extraction and quality assessment
We used a standardised data extraction form to record the
characteristics of included participants, NSAID class and dose,
route of administration, outcomes and duration of follow-up.
Two reviewers (GCM and MBP) independently recorded
the sample size, means and SDs for pain, disability and
quality-of-life measures. We extracted these data following a
hierarchical order: mean difference (MD), change scores and
post-treatment scores. When medians, IQRs, ranges or SEs were
reported, we used previously reported formulae to estimate
means and SDs.
17
According to recommendations in the
Cochrane Handbook,
18
we extracted data from the rst period
of crossover randomised trials, and in multi-arm trials we
extracted data from all groups and divided the number of parti-
cipants in the control group by the number of comparisons.
For the safety outcomes, we extracted the number of partici-
pants reporting any adverse event, any serious adverse event (as
dened by each trial or events including myocardial infarction
and/or stroke), the number of dropouts due to adverse events
and the number of participants reporting gastrointestinal
adverse reactions. We also extracted the number of participants
taking additional analgesics and the number of tablets consumed
per day. We contacted authors of included trials to clarify any
relevant information or to request additional data in case of
incomplete reporting. Consensus or a third reviewer (MLF) was
used to resolve any disagreement.
The Cochrane Collaborations tool was used to assess the risk
of bias of included studies by two independent reviewers (GCM
and MBP).
19
The quality of the evidence from each pooled ana-
lysis was evaluated using the Grade of Recommendations
Assessment, Development and Evaluation (GRADE) approach.
20
The quality of evidence was downgraded by one level according
to the following criteria: limitation of study design (more than a
quarter of studies considered at serious risk of bias), inconsist-
ency of results (substantial heterogeneity, I
2
>50%), imprecision
(pooled sample size <300), indirectness (dissimilar population,
intervention, outcomes and time points) and publication bias
(funnel plot assessment and Eggers test two-tailed p<0.1).
Consensus was used to resolve any disagreement. The quality of
evidence was then judged as high, moderate, low or very low.
Data synthesis and analysis
Trials were pooled for common outcomes and time points. As
our primary analysis we present overall pooled estimates includ-
ing all available trials, and as a secondary analysis we present
separate pooled effects for neck pain, acute/chronic low back
pain and sciatica. We dened a follow-up period <2 weeks as
immediate-term, and a follow-up between 2 weeks and
3 months as short-term. When more than one time point was
available for the same denition, we extracted data at 1 week
for immediate-term, or at 8 weeks for short-term. Although we
attempted to extract data for medium (>3 months but
<12 months) and long-term (12 months) follow-ups, no trials
reported data for these time points.
Pain outcome measures reported in included trials were visual
analogue scales (range, 0100), or numerical rating scales
(range, 010). These two pain measures are highly correlated
and can be used interchangeably when transformed.
21
The dis-
ability scale used in trials was the Roland-Morris Disability
Questionnaire (range, 024). Pain and disability scores were con-
verted to a common 0-point (no pain or disability) to 100-point
(worst possible pain or disability) scale to facilitate the interpret-
ation of our results, and because smallest worthwhile effects for
pain and disability in this population are often reported in a 0
100 scale.
2224
Quality-of-life measures included the 12-item or
the 36-item Short Form (SF) Health Survey (range, 0100); no
score conversion was needed for this outcome.
A between-group difference of 10 points (on a 0100 scale)
for pain, disability and quality-of-life was considered as the smal-
lest worthwhile effect;
22
the mean effect sizes below this thresh-
old were considered clinically unimportant. The smallest
worthwhile effect describes the smallest effect of intervention
(compared with placebo) that patients perceive as important,
and is critical for clinical decision-making.
25
We used
random-effects models to calculate MD or risk ratios (RR) and
95% CIs. We also present the results for the pain intensity ana-
lyses as numbers needed to treat (NNT), using the method pro-
posed by Norman.
26
This expresses the number of patients who
need to be treated with an NSAID rather than placebo, for one
additional person to benet (based on a clinically important
change of 10 points on a 0100 pain scale; and allowing for the
proportion of patients who were improved, the same and dete-
riorated in NSAID and placebo groups). All analyses were con-
ducted using Comprehensive Meta-Analysis V.2 (Biostat,
Englewood, New Jersey, USA).
Secondary exploratory analysis
We conducted subgroup analyses to explore the inuence of dif-
ferent factors on our estimates of treatment effects. We used
meta-regression to generate the difference in effect sizes (with
95% CI) and p values between subgroups for pain at immediate-
term. Subgroups were dened in terms of risk of bias judge-
ments (low, unclear or high), form of drug administration
(topical, oral or injection) and type of NSAID (COX-2 inhibi-
tors or non-selective NSAIDs). We also investigated the differ-
ence of effect sizes of discontinued drugs (eg, rofecoxib and
valdecoxib) and currently marketed NSAIDs, given the aim of
this review in informing current best practice.
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RESULTS
Initial search and results
Our search resulted in a total of 5208 individual records. After
the screening of titles and abstracts, two independent reviewers
assessed 302 full-text articles. We included 35 randomised trials
after full-text examination with data for 6065 participants with
spinal pain (gure 1).
2761
Twenty-two trials investigated the
effects of NSAIDs for low back pain, of which 11 included par-
ticipants with acute back pain and 11 (10 published reports)
included participants with chronic low back pain. Eleven trials
investigated participants with sciatica and two included neck
pain only. The median treatment duration in included trials was
7 (IQR, 57) days. NSAIDs were mostly administered orally, but
ve trials used intravenous or intramuscular injection,
35 3739 59
and three used a topical formulation, such as a gel, patch or
cream.
51 53 56
Nine trials had a three-arm parallel design and
two were randomised crossover trials. These trials compared
two different drugs, or two different dosages of the same drug
with a matching placebo. Online supplementary table S2 pro-
vides more detail on the characteristics of included trials and
the medications evaluated.
The risk of bias assessment (see online supplementary gure
S1) shows that overall, studies had no serious risk of bias.
However, about half of the trials had at least one bias domain
judged as high risk. A third of included trials reported an appro-
priate method of randomisation, and only four reported suitable
allocation concealment. Nearly all trials were therapist and
assessor-blinded, but 20% of trials had high dropout rates
(>15%). Seven trials did not report relevant outcomes or failed
to report results previously described in their methods and were
judged at high risk of reporting bias. Eleven trials were judged
at high risk for the otherbias domain as they reported that
pharmaceutical companies that funded the trial were involved in
running the study, analysing the data or writing the manuscript.
The risk of bias assessment for each individual trial is shown in
online supplementary gure S2. The inspection of the funnel
plot including all trials reporting data for immediate pain reduc-
tion and the non-signicant Eggers test ( p=0.86) revealed no
publication bias (see online supplementary gure S3).
Therefore, none of our meta-analyses was downgraded for pub-
lication bias according to the GRADE approach. Data extracted
from individual trials and calculations of effect sizes are shown
in online supplementary tables S3 and S4.
Efcacy of NSAIDs for spinal pain
Pooling of all included trials revealed moderate-quality evidence
that NSAIDs reduced pain in the immediate (MD 9.2, 95% CI
11.1 to 7.3) and short-term (MD 7.7, 95% CI 11.4 to
4.1) compared with placebo (gure 2). The NNT to achieve a
clinically signicant effect of NSAIDs over placebo on pain
reduction in the immediate-term was 5 (95% CI 4 to 6) and 6
(95% CI 4 to 10) in the short-term. The effects of NSAIDs on
disability were slightly smaller than for pain, with effect at
immediate-term follow-up being 8.1 (95% CI 11.6 to 4.6),
and at short-term 6.1 (95% CI 9.5 to 2.8) (gure 3). The
magnitude of the difference in outcomes between the interven-
tion and placebo groups, however, was less than the 10-point
threshold for clinical importance.
There was high-quality evidence of clinically unimportant
effects of NSAIDs compared with placebo for the physical
component of the SF-12 (MD 2.9, 95% CI 3.7 to 2.1),
and no effects over placebo were found for the mental compo-
nent (MD 0.3, 95% CI 1.2 to 0.6). None of the included
studies used the SF-36 to measure quality-of-life. Table 1 pro-
vides more detailed information on the summary of ndings
and the GRADE assessment. None of the included trials
reported medium-term or long-term effects of NSAIDs.
Safety of NSAIDs for spinal pain
For the safety analyses, we included up to 21 trials (5153 parti-
cipants) with median treatment duration of 7 (IQR, 57) days
(gure 4). No difference in any event rate between NSAIDs and
placebo was found (RR 1.1, 95% CI 1.0 to 1.2). Only two trials
including 635 participants reported serious adverse event data
and again there was no difference between groups (RR 1.5,
95% CI 0.4 to 5.2). Similarly, nine trials with 3283 participants
revealed no difference in the number of dropouts due to
adverse events (RR 1.0, 95% CI 0.6 to 1.6). However, we
found a signicantly higher number of participants in the
NSAIDs group reporting gastrointestinal adverse events com-
pared with placebo (RR 2.5, 95% CI 1.2 to 5.2); 28/702 partici-
pants taking NSAIDs had gastrointestinal adverse reactions
compared with 9/465 in the placebo groups. Overall, these
results were based on high-quality evidence according to the
GRADE evaluation.
Use of rescue medication
The use of rescue medication was measured in a variety of ways
in eight trials, such as the number of participants taking add-
itional analgesics and the number of tablets taken per day. Four
trials revealed moderate-quality evidence of no difference in the
number of participants taking an additional analgesic (RR 1.0,
95% CI 0.6 to 1.4). However, pooling of four trials showed
high-quality evidence that participants taking NSAIDs required
less tablets/day of a rescue medication (MD 0.4, 95% CI 0.5
to 0.3), a difference that is arguably not clinically important.
Figure 1 Study selection. CENTRAL, Cochrane Central Register of
Controlled Trials. *Number of citations listed for each database includes
duplicates.
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Secondary exploratory analysis
Results from our meta-regression analyses showed that trials
with low risk of selection bias had larger effects (MD 11.2,
95% CI 13.9 to 8.5) than trials judged at unclear risk (MD
6.7, 95% CI 8.6 to 4.9). The difference between these sub-
groups (MD 4.2, 95% CI 7.7 to 0.8) was statistically sig-
nicant ( p=0.02). COX-2 inhibitors had larger effects (MD
13.4, 95% CI 15.7 to 11.1) compared with non-selective
NSAIDs (MD 7.7, 95% CI 9.8 to 5.6). This difference was
Figure 2 Mean differences for pain in placebo-controlled trials on efcacy of non-steroidal anti-inammatory drugs (NSAIDs) for spinal pain. Pain
is expressed on scale of 0100. Immediate-term=follow-up 2 weeks; short-term=follow-up >2 weeks but 3 months; LBP, low back pain. Studies
ordered chronologically within subgroups.
1272 Machado GC, etal. Ann Rheum Dis 2017;76:1269–1278. doi:10.1136/annrheumdis-2016-210597
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also statistically signicant (MD 5.7, 95% CI 9.4 to 1.9;
p=0.003), but of questionable clinical relevance. There was no
difference between the effect sizes of discontinued drugs com-
pared with currently marketed NSAIDs (MD 0.3, 95% CI 3.7
to 4.3; p=0.88), although no trials investigating celecoxib were
found (table 2). Different delivery routes resulted in similar
effects compared with a matching placebo: topical (MD 13.2,
95% CI 18.5 to 7.9), oral (MD 8.5, 95% CI 10.4 to
6.6) and injection (MD 9.5, 95% CI 14.7 to 4.4).
DISCUSSION
Our review of 35 randomised placebo-controlled trials demon-
strates that NSAIDs are effective in reducing pain and disability in
patients with spinal pain, although treatment effects above those
of placebo are small and arguably not clinically important. For
every six patients treated with NSAIDs, rather than placebo, only
one additional patient would benet considering a between-group
difference of 10 points for clinical importance in the short-term.
Furthermore, when looking at different spinal pain, outcomes or
time points in only 3 of the 14 analyses were the pooled effects
only marginally above our 10-point threshold for clinical rele-
vance. NSAIDs were associated with higher number of patients
reporting gastrointestinal adverse effects in the short-term
follow-up (ie, <14 days). No data on safety at medium-term or
long-term follow-ups were provided by included trials.
The strengths of our review include that it was prospectively
registered and followed the PRISMA recommendations, includ-
ing the use of GRADE to appraise the quality of the evidence.
We were able to identify a signicantly larger number of trials
than past reviews,
12 6270
which have often limited their inclu-
sion criteria to a specic language, population or type of
NSAID. Including more studies (35 randomised placebo-
controlled trials) enabled us to conduct a more thorough evalu-
ation of the effects of NSAIDs for various forms of spinal pain,
and to include a range of forms of drug administration. We have
also provided valuable information on pooled treatment effects
for specic populations, including neck pain, acute/chronic low
back pain and sciatica. Furthermore, we have provided clinically
interpretable estimates on a 0100 scale, and compared our
effect sizes with a predetermined smallest worthwhile effect of
10 points, which reects the smallest effect of the intervention
on outcomes compared with placebo that patients would con-
sider meaningful or important.
22
Given physicians often nd
the interpretation of effect sizes reported in meta-analysis chal-
lenging,
71
we have also presented our results on pain reduction
as the NNT for a clinically signicant effect of NSAIDs over
placebo. Moreover, potential factors that could have inuenced
our treatment effects, such as risk of bias judegments, class of
NSAIDs and route of administration, were investigated through
meta-regression analyses. Although COX-2 inhibitors showed
larger effects than non-selective NSAIDs on pain reduction, the
size of the difference is of arguable clinical relevance. COX-2
inhibitors trials included in our review were fairly recent (all
were conducted after 2003) and substantially larger (mean
sample size of 280). They were also more likely to report safety
outcomes than older trials.
Figure 3 Mean differences for disability in placebo-controlled trials on efcacy of non-steroidal anti-inammatory drugs (NSAIDs) for spinal pain.
Disability is expressed on scale of 0100. Immediate-term=follow-up 2 weeks; short-term=follow-up >2 weeks but 3 months; LBP, low back
pain. Studies ordered chronologically within subgroups.
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Our review has some limitations. First, we did not nd any
trials investigating the efcacy and safety of celecoxib versus
placebo, a commonly used COX-2 selective drug. Second,
some of the trials included in our meta-analysis used drugs that
are discontinued or are no longer commercialised in major
markets (eg, rofecoxib and valdecoxib), but our
meta-regression revealed that this was not a factor that inu-
enced our estimates; discontinued drugs (MD 8.9, 95% CI
10.8 to 7.0) had similar effects as currently marketed
NSAIDs (MD 9.3, 95% CI 12.1 to 6.5). Third, there is no
evidence on the long-term effects and safety of NSAIDs, as the
median follow-up time was 1 week in included trials, with
some treatment schedules lasting <1 day. Fourth, our overall
pooled estimates resulted in substantial between-trial hetero-
geneity (I
2
ranged from 59% to 87%), which, however, was
found considerably reduced in the stratied meta-analyses
according to the type of spinal pain (ie, neck pain, acute/
chronic low back pain, or sciatica). Finally, another limitation
of our study is that there were very few trials on neck pain,
and none on whiplash.
Table 1 Summary of findings and quality of evidence assessment
Summary of findings Quality of evidence assessment (GRADE)
Overall Trials Participants I
2
, % MD (95% CI) Study limitation Inconsistency Imprecision Quality
Immediate-term
Pain 23 5217 59 9.2 (11.1 to 7.3) None 1 None Moderate
Disability 12 2667 87 8.1 (11.6 to 4.6) None 1 None Moderate
Short-term
Pain 9 2611 81 7.7 (11.4 to 4.1) None 1 None Moderate
Disability 8 2086 85 6.1 (9.5 to 2.8) None 1 None Moderate
Quality-of-life (PC) 4 1330 0 2.9 (3.7 to 2.1) None None None High
Quality-of-life (MC) 4 1330 15 0.3 (1.2 to 0.6) None None None High
Neck pain
Immediate-term
Pain 2 225 36 16.3 (20.6 to 12.0) None None 1 Moderate
Disability 2 225 98 12.2 (34.3 to 10.0) None 11Low
Acute low back pain
Immediate-term
Pain 5 814 26 6.4 (10.3 to 2.5) None None None High
Disability 3 476 43 7.1 (12.4 to 1.9) None None None High
Short-term
Pain 1 120 0 1.0 (5.9 to 3.9) None None 1 Moderate
Disability 1 120 0 0.4 (5.4 to 4.5) None None 1 Moderate
Chronic low back pain
Immediate-term
Pain 9 2537 52 11.1 (13.8 to 8.4) None 1 None Moderate
Disability 6 1752 30 8.4 (10.6 to 6.3) None None None High
Short-term
Pain 7 2277 60 9.8 (12.7 to 7.0) None 1 None Moderate
Disability 6 1752 87 7.9 (11.8 to 4.0) None 1 None Moderate
Sciatica
Immediate-term
Pain 7 1641 0 6.2 (8.2 to 4.2) None None None High
Disability 1 214 0 1.2 (3.8 to 6.1) None None 1 Moderate
Short-term
Pain 1 214 0 3.3 (1.5 to 8.1) None None 1 Moderate
Disability 1 214 0 2.4 (2.6 to 7.3) None None 1 Moderate
Safety outcomes
All time points
Adverse events (any)* 21 5153 16 1.1 (1.0 to 1.2) None None None High
Adverse events (serious)2 635 56 1.5 (0.4 to 5.2) None 1 None Moderate
Adverse events (dropout)9 3283 38 1.0 (0.6 to 1.6) None None None High
Adverse events (gastro)§ 3 1167 0 2.5 (1.2 to 5.2) None None None High
Negative values favours NSAIDs.
*Number of patients reporting any adverse effect.
Number of patients reporting any serious adverse effect (as defined by each study).
Number of patients withdrawn from study due to adverse effects.
§Number of patients reporting gastrointestinal adverse effects.
MC, mental component; MD, mean differences; NSAIDs, non-steroidal anti-inflammatory drugs; PC, physical component.
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We provide sound evidence that NSAIDs are effective, but do
not offer clinically important benets for spinal pain above
those attributable to placebo, given overall pooled estimated dif-
ferences were <10 points. This is crucially important because
we now know paracetamol is ineffective,
67
and opioids only
offer small benets for spinal pain.
8
Thus, given our results and
evidence from these recent high-quality meta-analyses, it seems
that there are no analgesics with clinically important effects over
placebo for spinal pain. This is a problem, as current guidelines
for spinal pain endorse these three medicines.
5
For instance, the
National Institute for Health and Care Excellence (NICE) guid-
ance on low back pain and sciatica now recommends NSAIDs as
rst analgesic option and suggests the use of opioids with para-
cetamol to treat spinal pain. In our review, even when the
effects of NSAIDs were analysed for different spinal pain strata
(ie, neck pain, acute/chronic low back pain or sciatica), only 3
of the 14 analyses revealed effects that were marginally above
our threshold for clinical relevance. The effects observed in
Figure 4 Risk ratio for safety outcome measures in placebo-controlled trials on efcacy of non-steroidal anti-inammatory drugs (NSAIDs)
compared with placebo. Any adverse event=no. of patients reporting any adverse event; serious adverse events=no. of patients reporting any serious
adverse event (as dened by each study); GI adverse events=no. of patients reporting gastrointestinal adverse events; withdrawals=no. of patients
withdrawn from study because of adverse events. Studies are ordered chronologically within subgroups.
1275
Machado GC, etal. Ann Rheum Dis 2017;76:1269–1278. doi:10.1136/annrheumdis-2016-210597
Clinical and epidemiological research
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trials including participants with neck pain were unexpected,
particularly because these trials investigated topical NSAIDs
only. Our safety analysis revealed that NSAIDs increased the risk
of gastrointestinal adverse effects by 2.5 times compared with
placebo, although safety data were limited to trials that used
non-selective NSAIDs. However, it is established that all
NSAIDs, including COX-2 inhibitors, have been linked to
gastrointestinal harms.
15 72
Our safety results should be inter-
preted with caution given the short duration of exposure to
NSAIDs in included trials.
In summary, compared with placebo, NSAIDs do not provide
a clinically important effect on spinal pain, and six patients
must be treated with NSAIDs for one patient to achieve a clinic-
ally important benet in the short-term. When this result is
taken together with those from recent reviews on paracetamol
and opioids, it is now clear that the three most widely used, and
guideline-recommended medicines for spinal pain do not
provide clinically important effects over placebo. There is an
urgent need to develop new analgesics for spinal pain.
Twitter Follow Gustavo Machado @gustavocmachado
Contributors All authors made substantial contributions to the study conception
and design or analysis and interpretation of data and were involved in drafting the
manuscript and approved the nal version.
Funding GCM and MBP are supported by an Australian Postgraduate Award from
the Department of Education and Training of Australia. CGM is supported by a
Principal Research Fellowship from the National Health and Medical Research
Council. MLF holds a Sydney Medical Foundation Fellowship, Sydney Medical School.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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Table 2 Secondary exploratory analyses for pain at immediate-term
Variable
Summary of findings Meta-regression
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2
, % MD (95% CI) MD (95% CI) p Value
Sequence generation
Low 12 2594 65 11.2 (13.9 to 8.5)
Unclear 11 2623 13 6.7 (8.6 to 4.9) 4.2 (7.7 to 0.8) 0.02
Allocation concealment
Low 4 680 25 5.9 (9.3 to 2.4)
Unclear 19 4537 60 9.8 (11.9 to 7.8) 3.6 (8.4 to 1.2) 0.14
Blinding
Low 22 5037 62 9.3 (11.2 to 7.4)
Unclear 1 180 0 7.1 (14.8 to 0.6) 2.1 (7.5 to 11.8) 0.70
Incomplete data
Low 12 2384 72 9.0 (12.2 to 5.8)
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High 5 1192 32 11.8 (15.1 to 8.5) 2.5 (7.5 to 2.4) 0.31
Selective reporting
Low 18 4592 64 9.4 (11.4 to 7.3)
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High 1 80 0 6.0 (15.0 to 3.0) 3.4 (8.6 to 15.6) 0.59
Other (funding)
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Discontinued drug
Yes 8 1774 0 8.9 (10.8 to 7.0)
No 15 3443 71 9.3 (12.1 to 6.5) 0.3 (3.7 to 4.3) 0.88
COX-2, cyclo-oxygenase-2; MD, mean difference; NSAIDs, non-steroidal anti-inflammatory drugs.
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meta-analysis
spinal pain: a systematic review and
Non-steroidal anti-inflammatory drugs for
Marina B Pinheiro and Manuela L Ferreira
Gustavo C Machado, Chris G Maher, Paulo H Ferreira, Richard O Day,
doi: 10.1136/annrheumdis-2016-210597
2, 2017 2017 76: 1269-1278 originally published online FebruaryAnn Rheum Dis
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... The most common medications include non-steroidal antiinflammatory drugs (NSAIDs) or acetaminophen. However, for some types of pain (e.g., acute low back pain), skeletal muscle relaxants/antispasticity drugs, antidepressants, corticosteroid injections (for back pain with radiculopathy), and opioids (for otherwise intractable pain) may be appropriate (Chou and Huffman, 2007;Pinto et al., 2012;Witenko et al., 2014;Machado et al., 2017). The non-pharmacological treatment strategy is to reduce the pain and related edema, while also promoting nerve repair to promote the restoration of normal function and activity (Jacobs et al., 2011;Savage et al., 2015). ...
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Background: The early identification of factors that increase risk of poor recovery from acute low back pain (LBP) is critical to prevent the transition to chronicity. Although most studies of risk factors for poor outcome in LBP tend to investigate the condition once it is already persistent, there is evidence to suggest that this differs from risk factors measured during the early-acute stage. This study aimed to identify early risk factors for poor outcome in the short- and long-term in individuals with acute LBP, and to compare this with factors identified at 3 months in the same cohort. Methods: One hundred and thirty-three individuals were recruited within 2 weeks of an acute LBP episode and completed questionnaires related to their sociodemographic, psychological, clinical and history/treatment status at baseline and 3 months later, and their pain-level fortnightly for 12 months. Results: Of the 133 participants recruited, follow-up data was provided by 120 at 3 months, 97 at 6 months, 85 at 9 months and 94 at 12 months. Linear regression identified various factors at baseline (acute phase) and 3 months later that predicted short- and long-term outcome (pain level, change in pain). Key findings were that: (1) depressive symptoms at baseline most consistently predicted worse outcome; (2) psychological factors in general at 3 months were more predictive of outcome than when measured at baseline; (3) early health care utilisation predicted better outcome, whereas use of pain medication later (3 months) predicted worse outcome; and (4) sex and BMI predicted outcome inconsistently over 12-months. Conclusions: The results highlight the multidimensional nature of risk factors for poor outcome in LBP and the need to consider time variation in these factors.
... Omkring en tredjedel av konsultasjonene hos fastleger er relatert til muskel-og skjele plager (6). Ofte får pasientene forskrevet ikke-steroide antiinflammatoriske midler (NSAID), selv om det mangler vitenskapelig evidens for effekten ved nakkesmerter (7)(8)(9). I en randomisert, placebokontrollert multisenterstudie undersøkte man effekten av NSAID-preparater for aku e nakkesmerter og fant at 400 mg ibuprofen pluss 100 mg koffein eller 400 mg ibuprofen alene ikke var signifikant overlegen placebo (9). ...
... In patients with acute whiplash, there is moderate evidence that intravenousmethylprednisolone is more effective than placebo at lowering pain intensity after one week [17]. For patients with neck pain, there is moderate quality evidence that NSAIDs are beneficial in lowering pain intensity when compared to placebo in the short term [35]. For chronic neck pain, there is also modest evidence that injectable lidocaine and neck stretching are more helpful than neck stretches alone at 3 months [17]. ...
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Neck pain is a prevalent ailment that affects many people around the world. Neck pain is linked to a high level of disability and is usually regarded as a serious public health issue. Pain between the superior nuchal line and the spinous process of the first thoracic vertebra is referred to as neck pain. The pain in the neck might refer to the head, trunk, and upper limbs in some cases. This article seeks to offer a summary of the existing evidence on the prevalence, costs, diagnosis, prognosis, risk factors, prevention, and management of neck pain patients.
... Aceclofenac is a nonsteroidal anti-in lammatory drug (Machado et al., 2017) (NSAID) analog of diclofenac. It is used for the relief of pain and in lammation (Mantovani et al., 2008) in rheumatoid arthritis (Smolen et al., 2016), osteoarthritis (Glyn-Jones et al., 2015) and ankylosing spondylitis (Smith, 2015). ...
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A For the simultaneous evaluation of Aceclofenac and Misoprostol using RP-HPLC, an accurate, rapid, economical, and straightforward, reliable assay technique was developed and demonstrated. The proposed method achieved effective chromatographic separation by using an inertsil ODS column (150mmx4.6mm, 3.5), acetonitrile, and 0.1 percent orthophosphoric acid (OPA) (50:50 v/v) as a mobile phase with a low rate of 1 ml/min and a wavelength of 227 nm. The retention time (Rt) of Aceclofenac was 3.189 minutes and Misoprostol was 6.966 minutes. Chromatography was performed isocrat-ically at room temperature with a run time of around 10 minutes. The suit-ability parameters of the system were investigated by multiplying the quality six times, and the results were well within acceptable limits. The linearity analysis was conducted at 10 percent to 150 percent stages, with a regression coef icient of 0.999. Aceclofenac and Misoprostol had LOD and LOQ values of 0.063 ug/ml, 0.063 g/ml, and 0.208 ug/ml and 0.208 g/ml, respectively. The drug was recovered at a rate of 98-102 percent, which means that the recovery is within reasonable limits. The validation results were satisfactory, and the approach was found to be suitable for bulk and formulation analysis. As a result, it was obvious that the proposed approach was ideal for routine pharmaceutical preparation review and quality control. Validation results were very close to the appropriate maximum. RSD values of less than 2.0 percent indicate that this approach is accurate and precise. The above method was used to perform a retail formulation assay, which showed that 100.24 percent of the formulation was present. Degradation stress conditions in acidic, alkaline, peroxide, and thermal media were investigated. Under ideal conditions , the established method provided ef icient, precise, and accurate results. According to ICH guidelines, the approach was justi ied.
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Objective: To evaluate the efficacy and safety of opioids for analgesic therapy for people with osteoarthritis. Study design: Systematic review and meta-analysis of randomised, placebo-controlled trials of opioid therapies for treating the pain of osteoarthritis. The primary outcome was medium term pain relief (six weeks to less than 12 months). Quality of evidence was assessed with GRADE criteria. Data sources: MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and Central Register of Controlled Trials, CINAHL, PsycINFO, AMED, and the WHO International Clinical Trials Registry; trials published to 31 October 2020. Data synthesis: We extracted pain, disability, health-related quality of life, and adverse events data for 36 eligible trials (overall dose range: 10-210 oral morphine milligram equivalents [MME] per day). Continuous pain and disability outcomes were converted to common 0-100-point scales; changes of less than ten points were deemed to be very small effects. Differences in dichotomous outcomes were expressed as risk ratios. Data were pooled for meta-analysis in random effects models. The evidence from 19 trials (8965 participants; dose range, 10-126 MME/day) for very small medium term pain relief (mean difference [MD], -4.59 points; 95% CI, -7.17 to -2.02 points) was low quality, as was that from 16 trials (6882 participants; dose range, 10-126 MME/day) for a very small effect on disability (MD, -4.15 points; 95% CI, -6.94 to -1.35 points). Opioid dose was not statistically significantly associated with either degree of pain relief or incidence of adverse events in a meta-regression analysis. Evidence that opioid therapy increased the risk of adverse events (risk ratio, 1.43; 95% CI, 1.29-1.59) was of very low quality. Conclusions: Opioid medications may provide very small pain and disability benefits for people with osteoarthritis, but may also increase the risk of adverse events. Prospero registration: CRD42019142813 (prospective).
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Pain is the most impactful symptom of hidradenitis suppurativa (HS) and is highly correlated with patients' quality of life. This narrative review incorporates literature about HS pain, management of other chronic painful conditions, and expert opinion. HS causes complex pain with nociceptive, neuropathic, and nociplastic components. This article draws from knowledge about other painful conditions to propose a holistic approach to helping patients with HS manage their pain including characterizing the pain type, tips for effective physician‐patient communication, and suggestions for pharmacologic and non‐pharmacologic therapies. Pain is one of the most impactful and debilitating symptoms of HS. Improved understanding of the mechanisms that drive pain in HS as well as disease‐specific data supporting effective strategies for managing HS pain are greatly needed.
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Összefoglaló. Nemzetközi kutatások szerint a deréktáji fájdalom 2019-ben 568 millió embert érintett világszerte. Magyarországon a lakosság 20%-a él krónikus derékfájdalommal, ami nemcsak egészségügyi, de szociális és ökonómiai krízist is jelent. A probléma aktualitását jól mutatja az is, hogy a Nemzetközi Fájdalomkutatási Társaság a 2021. évet a derékfájdalomról szóló globális évnek kiáltotta ki. A derékfájdalmak megfelelő kezelése és a krónikussá válás megelőzése tehát kiemelten fontos. Ebben nyújthatnak segítséget az evidenciákon alapuló irányelvek. Magyarországon azonban jelenleg nincs hatályos, egységes irányelv, mely a derékfájdalmakkal, azon belül is a krónikus derékfájdalom kezelésével foglalkozna. A jelen közleményben a krónikus derékfájdalom evidenciákon alapuló diagnosztikai és kezelési lehetőségeinek áttekintését tűztük ki célul. Az irodalomkutatást követően, a jelenleg is hatályos, AGREE II. rendszer szerinti magas minőségű besorolást elérő, krónikus deréktáji fájdalomra vonatkozó, angol nyelvű nemzetközi irányelvek ajánlásainak összehasonlítását végeztük el. Tanulmányunkban hét irányelvet dolgoztunk fel (négy európai, kettő amerikai, egy kanadai), melyek mindegyikében a következő közös ajánlások kerültek megfogalmazásra: a súlyos patológiák kizárása az alarm tünetek alapján, a pszichoszociális tényezők figyelembevétele, a szükségtelen képalkotó vizsgálat visszaszorítása, az elsősorban aktív, nem gyógyszeres terápiák preferálása és a nemszteroid gyulladáscsökkentők körültekintő felírása. Az európai irányelvekben új elemként szerepelt a krónikussá válás korai rizikóbecslése. Orv Hetil. 2021; 162(49): 1951-1961. Summary. In 2019, low back pain caused the highest burden globally, among musculoskeletal disorders, affecting 568 million people. According to Hungarian sociodemographic data, 20% of the Hungarian adults live with chronic low back pain that is a global health priority. Therefore, the International Association for the Study of Pain announced 2021 as the global year about back pain. Evidence-based guidelines about the appropriate treatment of acute low back pain and prevention of chronic low back pain are therefore of paramount importance. However, there are currently no valid, uniform treatment guidelines in Hungary about acute and chronic lower back pain. In this paper, we aimed at summarizing up-to-date, evidence-based diagnostic and treatment recommendations for chronic low back pain. Using a literature review, we identified seven international treatment guidelines (four from Europe, two from the United States and one from Canada) in English for the management of chronic low back pain that were previously assessed by the AGREE II quality assessment tool. We found consistent recommendations in the guidelines such as exclusion of alarm symptoms, assessment of psycho-social factors, reduction of unnecessary imaging, initialization of primarily active, non-pharmacological therapies, and careful and cautious prescription of non-steroidal anti-inflammatory medications. A new recommendation in the European guidelines is the early risk assessment of low back pain becoming chronic. Orv Hetil. 2021; 162(49): 1951-1961.
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This guideline provides recommendations for primary care clinicians who are prescribing opioids for chronic pain outside of active cancer treatment, palliative care, and end-of-life care. The guideline addresses 1) when to initiate or continue opioids for chronic pain; 2) opioid selection, dosage, duration, follow-up, and discontinuation; and 3) assessing risk and addressing harms of opioid use. CDC developed the guideline using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, and recommendations are made on the basis of a systematic review of the scientific evidence while considering benefits and harms, values and preferences, and resource allocation. CDC obtained input from experts, stakeholders, the public, peer reviewers, and a federally chartered advisory committee. It is important that patients receive appropriate pain treatment with careful consideration of the benefits and risks of treatment options. This guideline is intended to improve communication between clinicians and patients about the risks and benefits of opioid therapy for chronic pain, improve the safety and effectiveness of pain treatment, and reduce the risks associated with long-term opioid therapy, including opioid use disorder, overdose, and death. CDC has provided a checklist for prescribing opioids for chronic pain (http://stacks.cdc.gov/view/cdc/38025) as well as a website (http://www.cdc.gov/drugoverdose/prescribingresources.html) with additional tools to guide clinicians in implementing the recommendations.
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Importance Opioid analgesics are commonly used for low back pain, however, to our knowledge there has been no systematic evaluation of the effect of opioid dose and use of enrichment study design on estimates of treatment effect. Objective To evaluate efficacy and tolerability of opioids in the management of back pain; and investigate the effect of opioid dose and use of an enrichment study design on treatment effect. Data Sources Medline, EMBASE, CENTRAL, CINAHL, and PsycINFO (inception to September 2015) with citation tracking from eligible randomized clinical trials (RCTs). Study Selection Placebo-controlled RCTs in any language. Data Extraction and Synthesis Two authors independently extracted data and assessed risk of bias. Data were pooled using a random effects model with strength of evidence assessed using the grading of recommendations assessment, development, and evaluation (GRADE). Main Outcomes and Measures The primary outcome measure was pain. Pain and disability outcomes were converted to a common 0 to 100 scale, with effects greater than 20 points considered clinically important. Results Of 20 included RCTs of opioid analgesics (with a total of 7925 participants), 13 trials (3419 participants) evaluated short-term effects on chronic low back pain, and no placebo-controlled trials enrolled patients with acute low back pain. In half of these 13 trials, at least 50% of participants withdrew owing to adverse events or lack of efficacy. There was moderate-quality evidence that opioid analgesics reduce pain in the short term; mean difference (MD), −10.1 (95% CI, −12.8 to −7.4). Meta-regression revealed a 12.0 point greater pain relief for every 1 log unit increase in morphine equivalent dose (P = .046). Clinically important pain relief was not observed within the dose range evaluated (40.0-240.0-mg morphine equivalents per day). There was no significant effect of enrichment study design. Conclusions and Relevance For people with chronic low back pain who tolerate the medicine, opioid analgesics provide modest short-term pain relief but the effect is not likely to be clinically important within guideline recommended doses. Evidence on long-term efficacy is lacking. The efficacy of opioid analgesics in acute low back pain is unknown.
Article
Background: Chronic back pain is an important health problem. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat people with low back pain, especially people with acute back pain. Short term NSAID use is also recommended for pain relief in people with chronic back pain. Two types of NSAIDs are available and used to treat back pain: non-selective NSAIDs and selective COX-2 NSAIDs. In 2008, a Cochrane review identified a small but significant effect from NSAIDs compared to placebo in people with chronic back pain. This is an update of the Cochrane review published in 2008 and focuses on people with chronic low back pain. Objectives: To determine if NSAIDs are more efficacious than various comparison treatments for non-specific chronic low back pain and if so, which type of NSAID is most efficacious. Search methods: We searched CENTRAL, MEDLINE, EMBASE, PubMed and two clinical trials registry databases up to 24 June 2015 for randomized controlled trials (RCTs) published in English, German or Dutch. We also screened references cited in relevant reviews. Selection criteria: We included RCTs (double-blind and single-blind) of NSAIDs used to treat people with chronic low back pain. Data collection and analysis: Two review authors independently screened trials for inclusion in this Cochrane review according to the inclusion criteria. One review author extracted the data, and a second review author checked the data. Two review authors independently evaluated the risk of bias of all included trials. If data were clinically homogeneous, we performed a meta-analysis and assessed the quality of evidence using the GRADE approach. Main results: We included 13 trials in this Cochrane review. Ten studies were at 'low' risk of bias. Six studies compared NSAIDs with placebo, and included 1354 participants in total. There is low quality evidence that NSAIDs are more effective than placebo, with a mean difference in pain intensity score from baseline of -3.30 (95% CI -5.33 to -1.27) on a 0 to 100 visual analogue scale (VAS) with a median follow-up of 56 days (interquartile range (IQR) 13 to 91 days). Four studies measured disability using the Roland Morris Disability Questionnaire. There is low quality evidence that NSAIDs are more effective than placebo on disability, with a mean difference from baseline of -0.85 (95% CI -1.30 to -0.40) on a scale from 0 to 24 with a median follow-up of 84 days (IQR 42 to 105 days). All six placebo controlled studies also reported adverse events, and suggested that adverse events are not statistically significant more frequent in participants using NSAIDs compared to placebo (RR 1.04, 95% CI 0.92 to 1.17). Due to the relatively small sample size and relatively short follow-up in most included trials, it is likely that the proportion of patients experiencing an adverse event is underestimated. Two studies compared different types of non-selective NSAIDs, namely ibuprofen versus diclofenac and piroxicam versus indomethacin. The trials did not find any differences between these NSAID types, but both trials had small sample sizes. One trial reported no differences in pain intensity between treatment groups that used selective or non-selective NSAIDs. One other trial compared diflunisal with paracetamol and showed no difference in improvement from baseline on pain intensity score. One trial showed a better global improvement in favour of celecoxib versus tramadol. One included trial compared NSAIDs with 'home-based exercise'. Disability improved more in participants who did exercises versus participants receiving NSAIDs, but pain scores were similar. Authors' conclusions: Six of the 13 included RCTs showed that NSAIDs are more effective than placebo regarding pain intensity. NSAIDs are slightly more effective than placebo regarding disability. However, the magnitude of the effects is small, and the level of evidence was low. When we only included RCTs at low risk of bias, differences in effect between NSAIDs and placebo were reduced. We identified no difference in efficacy between different NSAID types, including selective versus non-selective NSAIDs. Due to inclusion of RCTs only, the relatively small sample sizes and relatively short follow-up in most included trials, we cannot make firm statements about the occurrence of adverse events or whether NSAIDs are safe for long-term use.
Article
Importance Primary care clinicians find managing chronic pain challenging. Evidence of long-term efficacy of opioids for chronic pain is limited. Opioid use is associated with serious risks, including opioid use disorder and overdose.Objective To provide recommendations about opioid prescribing for primary care clinicians treating adult patients with chronic pain outside of active cancer treatment, palliative care, and end-of-life care.Process The Centers for Disease Control and Prevention (CDC) updated a 2014 systematic review on effectiveness and risks of opioids and conducted a supplemental review on benefits and harms, values and preferences, and costs. CDC used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework to assess evidence type and determine the recommendation category.Evidence Synthesis Evidence consisted of observational studies or randomized clinical trials with notable limitations, characterized as low quality using GRADE methodology. Meta-analysis was not attempted due to the limited number of studies, variability in study designs and clinical heterogeneity, and methodological shortcomings of studies. No study evaluated long-term (≥1 year) benefit of opioids for chronic pain. Opioids were associated with increased risks, including opioid use disorder, overdose, and death, with dose-dependent effects.Recommendations There are 12 recommendations. Of primary importance, nonopioid therapy is preferred for treatment of chronic pain. Opioids should be used only when benefits for pain and function are expected to outweigh risks. Before starting opioids, clinicians should establish treatment goals with patients and consider how opioids will be discontinued if benefits do not outweigh risks. When opioids are used, clinicians should prescribe the lowest effective dosage, carefully reassess benefits and risks when considering increasing dosage to 50 morphine milligram equivalents or more per day, and avoid concurrent opioids and benzodiazepines whenever possible. Clinicians should evaluate benefits and harms of continued opioid therapy with patients every 3 months or more frequently and review prescription drug monitoring program data, when available, for high-risk combinations or dosages. For patients with opioid use disorder, clinicians should offer or arrange evidence-based treatment, such as medication-assisted treatment with buprenorphine or methadone.Conclusions and Relevance The guideline is intended to improve communication about benefits and risks of opioids for chronic pain, improve safety and effectiveness of pain treatment, and reduce risks associated with long-term opioid therapy.
Article
Study Design. Two replicate, 4-week, randomized, double-blind, placebo-controlled, trials of rofecoxib 25 and 50 mg versus placebo for chronic low back pain. Objectives. To determine the efficacy and safety of two doses of rofecoxib compared to placebo in the treatment of chronic low back pain. Summary of Background Data. Although nonsteroidal anti-inflammatory drugs are commonly prescribed for chronic low back pain, their efficacy is unproven and toxicity can be serious. These studies evaluated the efficacy and tolerability of rofecoxib, a selective COX-2 inhibitor, in the treatment of chronic low back pain. Methods. Patients with chronic low back pain were randomized 1:1:1 to rofecoxib 25 mg, 50 mg, or placebo once daily. Primary endpoint: Low Back Pain Intensity. Secondary endpoints: Pain Bothersomeness, Global Assessments of Response to Therapy, Global Assessment of Disease Status, Roland-Morris Disability Questionnaire, SF-12 Health Survey, Use of Rescue Acetaminophen, and Discontinuations Due to Lack of Efficacy. Results. Combining both studies, 690 patients were randomized to placebo (N = 228), rofecoxib 25 mg (N = 233), or rofecoxib 50 mg (N = 229). Mean (+/- SD) age was 53.4 (+/- 12.9) years, pain duration 12.1 (+/- 11.8) years, 62.3% female. Both rofecoxib groups improved significantly. Mean differences from placebo in pain intensity were -13.50 mm, -13.81 mm (25, 50 mg doses) respectively (P < 0.001). Both regimens were superior to placebo in eight of nine secondary endpoints. Fifty mg provided no advantage over 25 mg. Both rofecoxib regimens were well tolerated, although 25 mg had a slightly better safety profile. Conclusions. Rofecoxib significantly reduced chronic low back pain in adults and was well tolerated.
Article
The onset and intensity of analgesic activity of two NSAIDs has been compared to those of a placebo after a single administration, in 194 in-patients showing an acute sciatica. Both NSAIDs were: etodolac, 300 mg per os, and tenoxicam, 20 mg intramuscular (i.m.). The study design was double-blinded, parallel groups (3 arms), double-placebo technique (each patient receiving one tablet and one i.m. shot). The assessment of efficacy, frequent during the four first hours, then until 12 hours after administration of the drug, has shown a significant time-related effect on pain-intensity and pain relief. However, the placebo group has not been significantly different from both active drugs groups during the first hour; both active groups had a similar activity during the 12 hours of the trial, with an improvement of pain as soon as the tenth minute. Pharmacokinetics (PK) have been undertaken on 25 patients under active drugs and have shown a mean t(max) at 45 minutes after administration for both groups; this time is similar to the one where active groups are distinct from placebo one, although no strong correlation has been established between PK and clinical items. Etodolac per os (with placebo i.m.) is as active as tenoxicam i.m. (with placebo per os) on an acute pain, as soon as the first administration.