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Eur Spine J

DOI 10.1007/s00586-015-3891-4

REVIEW ARTICLE

Are non-steroidal anti-inflammatory drugs effective


for the management of neck pain and associated disorders,
whiplash-associated disorders, or non-specific low back pain?
A systematic review of systematic reviews by the Ontario Protocol
for Traffic Injury Management (OPTIMa) Collaboration
Jessica J. Wong1,2,3 • Pierre Côté1,4 • Arthur Ameis5 • Sharanya Varatharajan1,6 •

Thepikaa Varatharajan1,7 • Heather M. Shearer1,6 • Robert J. Brison8,9 •


Deborah Sutton1,6 • Kristi Randhawa1,6 • Hainan Yu1,6 • Danielle Southerst1,10 •
Rachel Goldgrub4 • Silvano Mior4,6 • Maja Stupar1 • Linda J. Carroll11 •
Anne Taylor-Vaisey1

Received: 5 November 2014 / Revised: 18 March 2015 / Accepted: 19 March 2015


 Springer-Verlag Berlin Heidelberg 2015

Abstract included systematic reviews with a low risk of bias in our


Purpose To evaluate the effectiveness of non-steroidal best evidence synthesis.
anti-inflammatory drugs (NSAIDs) for the management of Results We screened 706 citations and 14 systematic re-
neck pain and associated disorders (NAD), whiplash-as- views were eligible for critical appraisal. Eight systematic
sociated disorders, and non-specific low back pain (LBP) reviews had a low risk of bias. For recent-onset NAD,
with or without radiculopathy. evidence suggests that intramuscular NSAIDs lead to
Methods We systematically searched six databases from similar outcomes as combined manipulation and soft tissue
2000 to 2014. Random pairs of independent reviewers therapy. For NAD (duration not specified), oral NSAIDs
critically appraised eligible systematic reviews using the may be more effective than placebo. For recent-onset LBP,
Scottish Intercollegiate Guidelines Network criteria. We evidence suggests that: (1) oral NSAIDs lead to similar
outcomes to placebo or a muscle relaxant; and (2) oral
NSAIDs with bed rest lead to similar outcomes as placebo
Systematic Review Registration Number: CRD42014009782.

& Jessica J. Wong 6


Graduate Education and Research Programs, Canadian
jessica.wong@uoit.ca Memorial Chiropractic College (CMCC), 6100 Leslie Street,
1 Toronto, ON M2H 3J1, Canada
UOIT-CMCC Centre for the Study of Disability Prevention
7
and Rehabilitation, University of Ontario Institute of Graduate Studies in Masters of Public Health, University of
Technology (UOIT) and Canadian Memorial Chiropractic Saskatchewan, 104 Clinic Place, Saskatoon, SK S7N 5E5,
College (CMCC), 6100 Leslie Street, Toronto, ON M2H 3J1, Canada
Canada 8
Kingston General Hospital, 76 Stuart Street, Kingston,
2 ON K7L 2V7, Canada
Undergraduate Education, Canadian Memorial Chiropractic
College, 6100 Leslie Street, Toronto, ON M2H 3J1, Canada 9
Department of Emergency Medicine, School of Medicine,
3 Queen’s University, Kingston, ON, Canada
Division of Graduate Studies, Canadian Memorial
Chiropractic College, 6100 Leslie Street, Toronto, 10
Rebecca MacDonald Centre for Arthritis and Autoimmune
ON M2H 3J1, Canada Disease, Mount Sinai Hospital, Joseph and Wolf Lebovic
4 Health Complex, 60 Murray Street, 2nd Floor (Main),
Faculty of Health Sciences, University of Ontario Institute of
Technology (UOIT), 2000 Simcoe Street North, Oshawa, Toronto, ON M5T 3L9, Canada
ON L1H 7L7, Canada 11
Injury Prevention Centre, University of Alberta, 4075 RTF,
5 8308 114 Street, Edmonton T6G 2E1, AB, Canada
Certification Program in Insurance Medicine and Medico-
legal Expertise, Faculty of Medicine, University of Montreal,
N-414, Roger-Gaudry Building, 2900, Boulevard Edouard-
Montpetit, Montreal, QC H3T 1J4, Canada

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Eur Spine J

with bed rest. For persistent LBP, evidence suggests that: low back pain [25, 26]. For lumbar radiculopathy, two
(1) oral NSAIDs are more effective than placebo; and (2) systematic reviews reported that NSAIDs are not more
oral NSAIDs may be more effective than acetaminophen. effective than placebo [27, 28].
For recent-onset LBP with radiculopathy, there is incon- Different methodologies used to conduct the previous
sistent evidence on the effectiveness of oral NSAIDs versus reviews likely contributed to the differences in their con-
placebo. Finally, different oral NSAIDs lead to similar clusions. The methodologies differed in the application of
outcomes for neck and LBP with or without radiculopathy. critical appraisal and evidence synthesis methods. Across
Conclusions For NAD, oral NSAIDs may be more ef- reviews, different instruments were used to critically ap-
fective than placebo. Oral NSAIDs are more effective than praise the literature and synthesize the evidence [21–28].
placebo for persistent LBP, but not for recent-onset LBP. Inclusion of studies with a high risk of bias may threaten
Different oral NSAIDs lead to similar outcomes for neck the internal validity of a systematic review. Randomized
pain and LBP. controlled trials (RCTs) with poor internal validity were
used in the evidence synthesis of six reviews [21, 25, 26,
Keywords Whiplash-associated disorders  Neck pain 29–31]. Considering the varying methodologies used in
and associated disorders  Nonspecific low back pain  previous systematic reviews, an in-depth review of their
Nonsteroidal anti-inflammatory drugs  Systematic review  quality is warranted prior to accepting their results.
Medication We conducted a systematic review of systematic re-
views to examine the effectiveness of NSAIDs for the
management of neck pain and associated disorders (NAD),
Introduction whiplash-associated disorders (WAD), or non-specific low
back pain with or without radiculopathy.
Neck and back pain are experienced by more than 80 % of
the population during their lifetime, and are common rea-
sons for seeking healthcare [1–6]. These conditions are Methods
costly, and work absenteeism and lost productivity are
frequent complications [7–9]. Most neck and back pain are Registration
common sources of disability, whether attributed to work,
traffic collision, or daily activities [1, 3, 10–13]. To date, We registered our protocol with the International
few interventions demonstrate efficacy on a scientifically Prospective Register of Systematic Reviews (PROSPERO)
valid basis and most interventions are only associated with on May 14, 2014 (CRD42014009782).
short-term benefits [14, 15].
Non-steroidal anti-inflammatory drugs (NSAIDs) are Eligibility criteria
commonly used for neck and low back pain. NSAIDs
suppress inflammatory processes that produce swelling and Population
pain [16]. In the United States, NSAIDs are the most
common intervention prescribed for non-malignant chronic Our review targeted systematic reviews of adults or chil-
pain, including musculoskeletal disorders, with use re- dren with NAD or WAD (grades I–III), or non-specific low
ported in approximately 95 % of visits to physicians [17]. back pain (with or without radiculopathy) and excluded
In the United Kingdom, general practitioners prescribed pain from major pathology (fractures, dislocations, spinal
NSAIDs to approximately 30 % of patients with chronic cord injury, infection, neoplasms, systemic disease). We
low back pain [18]. In Spain, 41 % of patients with low defined NAD and WAD according to previous classifica-
back pain reported taking NSAIDs for more than 1 month tions [32, 33] (Table 1). We defined non-specific low back
in the past year [19]. pain as low back pain with or without radiculopathy in the
Despite its common use, the effectiveness of NSAIDs absence of specific pathological entities [24].
for the management of neck and low back pain is not firmly
established [20–22]. Several systematic reviews examining Intervention
NSAIDs for neck and low back pain have reported limited
or unclear evidence [20–22]. In contrast, two systematic We restricted our review to systematic reviews that tested
reviews concluded (based on low quality evidence and the effectiveness of NSAIDs. NSAIDs are defined as
small effect sizes) that NSAIDs are effective for short-term medications that block the action of cyclo-oxygenase
symptomatic relief in patients with low back pain [23, 24]. (Cox)-1 and/or Cox-2 (necessary for prostaglandin pro-
Furthermore, two reviews found evidence supporting the duction), thus reducing inflammation and pain [16]. Cox-1
use of NSAIDs in individuals with acute [25] or chronic enzymes are also cyto-protective; blocking their action is

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Table 1 Classification of grades for neck pain and associated dis- systematic review of studies (with or without meta-analy-
orders [32] and whiplash-associated disorders [33] sis); and (4) adults or children with NAD, WAD, or non-
Grade Definition specific low back pain with or without radiculopathy
(mixed populations must have stratified results for NAD,
Neck pain and associated disorders
WAD, or non-specific low back pain).
I No signs or symptoms suggestive of major structural We excluded: (1) guidelines, letters, editorials, com-
pathology and no or minor interference with activities of
daily living mentaries, unpublished manuscripts, dissertations, govern-
II No signs or symptoms of major structural pathology, ment reports, books, conference proceedings, meeting
but major interference with activities of daily living abstracts, lectures and addresses, consensus development
III No signs or symptoms of major structural pathology, but statements; (2) non-systematic reviews, RCTs, cohort
presence of neurologic signs such as decreased deep tendon studies, case–control studies, cross-sectional studies, case
reflexes, weakness or sensory deficits reports/series, qualitative studies, biomechanical studies,
IVa Signs or symptoms of major structural pathology laboratory studies, studies not reporting on methodology;
Whiplash-associated disorders (3) cadaveric or animal studies; (4) reviews on patients
I Subjects with neck pain and associated symptoms in the with severe injuries (spinal cord injuries, amputations,
absence of objective physical signs
open wounds, grade III sprains/strains, fractures, disloca-
II Subjects with neck pain and associated symptoms in the
tions); (5) previous versions of updated systematic reviews;
presence of objective physical signs and without evidence
of neurological involvement (6) systematic reviews of systematic reviews; and (7)
III Subjects with neck pain and associated symptoms with systematic reviews that do not stratify the analysis by study
evidence of neurological involvement including decreased design (e.g., combine systematic reviews and primary
or absent reflexes, decreased or limited sensation, or studies in their synthesis).
muscular weakness
IVa Subjects with neck pain and associated symptoms with Information sources
evidence of fracture or dislocation
a
Grade IV was excluded from this review We developed our search strategy with a health sciences
librarian, which was reviewed by a second librarian using
associated with gastrointestinal ulcers and bleeds. Most the Peer Review of Electronic Search Strategies (PRESS)
NSAIDs act non-selectively on Cox-1 and Cox-2 en- Checklist [34]. We systematically searched MEDLINE,
zymes, whereas selective Cox-2 inhibitors are preferen- EMBASE, CINAHL, PsycINFO, DARE, and Cochrane
tially directed at Cox-2 sites. Possible routes of Database of Systematic Reviews from January 1, 2000 to
administration include: topical (local effect or systemic April 8, 2014. Search terms consisted of subject headings
absorption), intra-nasal, intra-aural, eye drop, subcuta- specific to each database and free text words relevant to
neous, oral (ingestion), oral (sublingual), rectal, vaginal, systematic review, NSAIDs, NAD, WAD, non-specific low
and intramuscular. back pain, and lumbar radiculopathy (‘‘Appendix I’’). We
used EndNote X6 to create a bibliographic database to
Comparison groups manage the search results [35].

We included systematic reviews comparing NSAIDs to Study selection


another intervention, placebo/sham intervention, wait list,
or no intervention. Random pairs of trained, independent reviewers selected
eligible reviews using a two-phase screening process (ti-
Outcomes tles/abstracts and full text). Reviewers met to resolve dis-
agreements and reach consensus on the eligibility of
Systematic reviews had to include: self-rated recovery, reviews. We involved a third reviewer if consensus could
functional recovery (e.g., disability, return to activities, not be reached.
work, or school), clinical outcomes (e.g., pain, health-re-
lated quality of life, depression), administrative data (e.g., Assessment of risk of bias
time on benefits), or adverse events.
Random pairs of independent reviewers critically appraised
Study characteristics the internal validity of eligible systematic reviews using the
Scottish Intercollegiate Guidelines Network (SIGN) crite-
Eligible reviews met the following criteria: (1) English ria [36] (Table 2). The SIGN checklist was developed
language; (2) published in a peer-reviewed journal; (3) based on the AMSTAR measurement tool for assessing the

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methodological quality of systematic reviews [37]. Re- analysis, we extracted effect sizes from individual studies
viewers reached consensus on the overall assessment of the (where reported). We also extracted results on adverse
methodological quality through discussion. We involved an events from the reviews.
independent third reviewer if consensus could not be Some reviews with a low risk of bias may reach dif-
reached. We contacted authors when additional informa- ferent conclusions even though they included some of the
tion was required to complete the critical appraisal. same primary studies. In this case, we examined the rea-
During critical appraisal, we assessed for the presence sons for these differences (e.g., differences in search date,
of selection bias and information bias, and any impact inclusion or exclusion criteria, threshold for determining
these may have on the internal validity of the review. We which primary studies are included in evidence synthesis,
did not use a rating scale cut-off or quantitative score to interpretation of results using statistical significance versus
judge the quality of the review. Instead, we focused on clinical importance) and described them in our results.
the presence or absence of important methodological is- Furthermore, we: (1) used the results of the review with
sues. Systematic reviews were considered to have a high higher methodology if possible; or (2) made a consensus
risk of bias if reviewers considered the internal validity decision on which results would be adopted in cases where
markedly compromised due to biases and methodological methodological quality of both reviews was similar. We
flaws. Systematic reviews with adequate internal validity placed emphasis on systematic reviews that demonstrated
and a low risk of bias were included in our evidence methodological rigor and had the more recent literature
synthesis. search date.

Data extraction and synthesis of results Statistical analysis

The lead author extracted data from systematic reviews We computed agreements between reviewers for the
with a low risk of bias and built evidence tables (Tables 3, screening of articles and reported the kappa statistic (k) and
4). A second reviewer independently checked the extracted 95 % confidence interval (CI) [39]. We also calculated the
data. We performed a qualitative synthesis of findings from percentage agreement for the independent critical appraisal
reviews with low risk of bias to develop evidence state- of articles for scientifically admissible/inadmissible results.
ments according to principles of best evidence synthesis Where available, we used minimal clinically important
[38]. For each systematic review with low risk of bias, we differences (MCIDs) to judge the clinical importance of
extracted data from studies with low and high risk of bias differences in outcomes between groups: 10/100 mm for
(as determined by the authors of the systematic reviews); the Visual Analog Scale [40]; 2/10 for the Numeric Rating
however, we included only studies with a low risk of bias Scale [41]; 5/50 for the Neck Disability Index [42]; 5/24
in our evidence synthesis. For systematic reviews with a for the Roland–Morris Disability Questionnaire [43];
meta-analysis, we extracted only clinically and statistically 10/100 for the Oswestry Disability Index [43]; 7.7 points
homogeneous pooled effect sizes (e.g., weighted mean for the Physical Component Summary and 10 points for
difference). For systematic reviews without a meta- Bodily Pain on the Short-Form-36 [44].

Table 2 Scottish Item Criteria


Intercollegiate Guidelines
Network (SIGN) criteria for the 1.1 The study addressed a clearly defined research question
critical appraisal of systematic
1.2 At least two people should select studies and extract data
reviews [36]
1.3 A comprehensive literature search is carried out
1.4 The authors clearly state if or how they limited their review by publication type
1.5 The included and excluded studies are listed
1.6 The characteristics of the included studies are provided
1.7 The scientific quality of the included studies is assessed and documented
1.8 The scientific quality of the included studies was assessed appropriately
1.9 Appropriate methods are used to combine the individual study findings
1.10 The likelihood of publication bias is assessed
1.11 Conflicts of interest are declared
2.1 What is the overall assessment of the methodological quality of this review?
2.2 Are the results of this study directly applicable to the patient group targeted by this guideline?

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Reporting
Table 3 Risk of bias for accepted systematic reviews on the effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) for neck pain and low back pain based on Scottish Intercollegiate

Conflicts

declared
interest
of We reported our systematic review based on the Preferred

N
N
Y
Y
Y
N
Y
Y
Reporting Items for Systematic Reviews and Meta-A-
Publication

nalyses (PRISMA) statement [45].


assessed
bias

CS
CS
N
N

N
N
N
N
Results
methods for
Appropriate

combining
findings

Study selection
Y
N
Y
Y
Y
Y
Y
Y
Our search yielded 801 articles. We removed 95 duplicates
appropriately

and screened 706 citations for eligibility (Fig. 1). Fourteen


Scientific

assessed

articles were eligible for critical appraisal [15, 21–31, 46,


quality

47] and eight demonstrated a low risk of bias and were


Y
Y
Y
Y
Y
Y
Y
Y

included in our evidence synthesis [15, 22–24, 27, 28, 46,


documented

47]. The inter-rater agreement for the screening of articles


Scientific

was k = 0.86 (95 % CI 0.77–0.94). The percentage


quality

agreement for the admissibility of systematic reviews


Y
Y
Y
Y
Y
Y
Y
Y

during independent critical appraisal was 78.5 % (11/14).


We reached consensus through discussion where reviewers
Characteristics

disagreed.
of included
studies

Study characteristics
Y
Y
Y
Y
Y
Y
Y
Y

We found one systematic review with a low risk of bias for


excluded
included

studies
List of

the management of NAD and WAD [15]. Seven reviews


and

with a low risk of bias addressed non-specific low back


N
N
Y
N
Y
N
N
Y

pain with or without radiculopathy (Tables 5, 6) [22–24,


publication

27, 28, 46, 47].


review by
Limiting

type

Risk of bias within systematic reviews


Y
Y
Y
Y
Y
Y
Y
Y
Literature

All systematic reviews with a low risk of bias [15, 22–24,


search

27, 28, 46, 47]: (1) had a clear research question; (2)
CS
Y
Y
N
Y
Y

Y
Y

indicated whether they limited their review by publication


type; (3) described the characteristics of the included
extraction
selection
and data

studies; and (4) appropriately assessed the scientific quality


Study

of studies (i.e., the critical appraisal method assessed for


CS
CS
CS
N
Y

Y
Y
Y

sources of potential selection bias and information bias).


Y yes, N no, CS can not say, NA not applicable
Research
question

Most reviews: (1) conducted a comprehensive literature


search (6/8); (2) documented the scientific quality of the
Guidelines Network (SIGN) criteria [36]

Y
Y
Y
Y
Y
Y
Y
Y

studies (7/8); and (3) used appropriate methods for com-


bining findings (7/8) (Table 3).
Six systematic reviews with a high risk of bias [21, 25,
26, 29–31] had important methodological limitations and
Abdel Shaheed et al. [23]

were excluded from our synthesis: (1) unclear whether two


Luijsterburg et al. [27]

reviewers conducted the study selection and data extraction


Kuijpers et al. [22]
Hurwitz et al. [15]

Roelofs et al. [24]


Hahne et al. [46]

Keller et al. [47]

(3/6); (2) poorly reported literature search or literature


Pinto et al. [28]

search that was not comprehensive (4/6); (3) did not indi-
References

cate the excluded studies (5/6); (4) did not adequately re-
port the characteristics of the included studies (3/6); (5) did
not appropriately assess the scientific quality of studies (5/

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Table 4 Risk of bias for inadmissible systematic reviews on the effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) for neck pain and low back pain based on Scottish
6); (6) did not use appropriate methods for combining

of interest
Conflicts

declared
findings (4/6); and (7) did not declare whether there were
conflicts of interest (3/6) (Table 4).

N
Y
Y
Y
N
N
Publication
Summary of evidence

assessed
bias
Whiplash-associated disorders

CS
CS

CS
N

N
N
One systematic review with a low risk of bias searched the

methods for
Appropriate
literature on NSAIDs for the management of WAD, but did

combining
findings
not find any relevant studies [15].

N
Y
Y
N
N
N
Neck pain and associated disorders

appropriately
Evidence from one systematic review suggests that oral

Scientific

assessed
NSAIDs may be more effective than placebo, but different

quality
NSAIDs lead to similar outcomes for recent-onset NAD

Y
N
N
N
N
N
[15]. The same review reported that intramuscular NSAIDs

documented
versus manipulation and soft tissue therapy lead to similar

Scientific
outcomes for NAD [15]. Hurwitz et al. [15] included two

quality
studies with a low risk of bias on the effectiveness of

Y
N
N
Y
Y
Y
NSAIDs for NAD (Tables 5, 6). One trial comparing oral

Characteristics
Indomethacin, Piroxicam, and placebo found: (1) statisti-

of included
cally significant differences in pain reduction favoring In-
domethacin or Piroxicam over placebo (clinical significance

studies
not reported in systematic review); and (2) no statistically

N
Y
Y
Y
N
N
significant differences in pain reduction between the two
included and

NSAIDs [48]. Another trial compared intramuscular ke-


excluded

torolac to manipulation with soft tissue therapy and found


studies
List of

statistically significant between-group differences in pain


N
N
N
Y
N
N
reduction favoring NSAIDs. However, the between-group
differences were not clinically significant [49].
publication
review by
Limiting

Non-specific low back pain without radiculopathy


type

Y
Y
Y
Y
Y
Y

Recent-onset
Literature
search

Three systematic reviews with a low risk of bias [23, 24,


Intercollegiate Guidelines Network (SIGN) criteria [36]

CS
CS
N

Y
N
Y

47] included 32 studies on NSAIDs for recent-onset low


back pain without radiculopathy. Twenty-three studies had
selection and

Y yes, N no, CS can not say, NA not applicable


extraction

important methodological limitations (Tables 5, 6). Nine


studies (with 19 treatment arms) had a low risk of bias [50–
Study

data

CS

CS
CS

58]: (1) two studies compared NSAID to placebo [50, 51];


Y

Y
Y

(2) one study compared NSAID with bed rest to bed rest
Research
question

alone [55]; (3) one study compared NSAID to a muscle


relaxant (in a factorial design with a placebo comparison)
Y
Y
Y
Y
Y
Y

[50]; (4) six studies compared two different NSAIDs [52–


Schnitzer et al. [25]
Vroomen et al. [29]

54, 56–58].
Klinge et al. [31]
Chung et al. [26]

Moore et al. [30]


Peloso et al. [21]

Evidence from two studies with a low risk of bias sug-


gests that oral NSAIDs (Indomethacin or Diflunisal) pro-
References

vide similar outcomes (pain reduction or global


improvement) to placebo for recent-onset low back pain
[50, 51]. Evidence from one study with a low risk of bias

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Fig. 1 Flow diagram of the


selection of systematic reviews
on the effectiveness of non-
steroidal anti-inflammatory
drugs (NSAIDs) for neck
pain and associated disorders,
whiplash-associated disorders,
and low back pain

suggests that an oral NSAID (tenoxicam) combined with low back pain without radiculopathy. Six studies had im-
bed rest leads to similar outcomes (pain or range of motion) portant methodological limitations (Tables 5, 6). Eight
as placebo with bed rest [55]. Evidence from one study studies (with 17 treatment arms) had a low risk of bias [47,
with a low risk of bias suggests that similar improvements 59–65]: (1) four studies compared NSAID to placebo [59,
are obtained between: NSAID, muscle relaxant, and 60, 62, 66]; (2) one study compared NSAID to ac-
NSAID combined with muscle relaxant [55]. etaminophen [63]; (3) one study compared NSAID to a
The preponderance of evidence from six studies with a reference treatment (Doloteffin) [61]; (4) three studies
low risk of bias suggests that different oral NSAIDs lead to compared two different NSAIDs [59, 64, 65].
similar outcomes for recent-onset low back pain [52–54, 56– Evidence from four studies with a low risk of bias
58]. Four studies found similar outcomes (pain, disability, or suggests that oral NSAIDs are more effective than placebo
satisfaction) for: (1) Diflunisal versus Indomethacin [52] and for persistent low back pain [59, 60, 62, 66]. There were
Piroxicam versus Indomethacin (no statistically significant statistically significant differences in pain reduction fa-
differences) [56]; (2) Valdecoxib versus Diclofenac (no voring: (1) Naproxen over placebo [59]; (2) Etoricoxib
clinically or statistically significant differences) [57]; (3) over placebo (also clinically significant for Etoricoxib at
Aceclofenac versus Diclofenac (no clinically significant 60 mg/day but not 90 mg/day) [60, 66]; (3) Valdecoxib
differences; statistical significance not reported) [54]. over placebo (also clinically significant) [62]. Further,
However, two studies found statistically significant differ- evidence from one study with a low risk of bias suggests
ences favoring: (1) Lornoxicam over Diclofenac for pain that NSAID (Diflunisal) leads to statistically significant
reduction [58]; (2) Nimesulide over Ibuprofen (for improv- outcomes in satisfaction over acetaminophen (clinical
ing disability; no statistically significant differences for pain significance not reported) [63]. One study compared an
reduction); clinical significance was not reported [53]. NSAID to a reference treatment (Doloteffin) for reducing
pain [61]; however, neither clinical nor statistical sig-
Persistent nificance was reported in the systematic review.
Evidence from three studies suggests that different oral
Three systematic reviews with a low risk of bias [22, 24, NSAIDs lead to similar outcomes [59, 64, 65]. There were
47] included 14 studies investigating NSAIDs for persistent no statistically significant differences in outcomes (pain,

123
Table 5 Evidence table—characteristics of accepted systematic reviews on the effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) for neck pain and associated disorders,
whiplash-associated disorders, and low back pain
References, Search date, databases, Population Intervention Comparison Outcomes Authors’ conclusion about

123
study design language, limiters NSAIDs from systematic
review

Neck pain and associated disorders


Hurwitz 1980–2006; MEDLINE; Participants with neck pain All non-invasive interventions, Placebo or All outcomes Lack of scientifically
et al. [15], English, French, Swedish; with or without its associated including NSAIDs sham, usual acceptable evidence
systematic RCTs, cohort studies disorders (e.g., arm pain care, no care, precludes summary
review radiating from neck, upper another statements on NSAIDs in the
thoracic pain, headache, TMJ intervention treatment of WAD. The risk
pain) of serious side effects from
NSAIDs is negligible;
however, minor side effects
may be much more frequent
Non-specific low back pain with or without radiculopathy
Abdel Inception to 2013; MEDLINE, Individuals with acute Over the counter medicine (e.g. Placebo, no Pain (primary outcome), There was very low-quality
Shaheed Embase, Cochrane database (\12 weeks) non-specific low paracetamol, NSAID), treatment, disability, global perceived evidence that NSAIDs
et al. [23], of systematic reviews, back pain complementary/herbal usual care recovery, sickness leave, or (Ibuprofen and Diclofenac
systematic AMED, CENTRAL, remedies, or topical adverse events outcomes ‘‘when required’’ dosing)
review PsycINFO; English; RCTs applications that could be provide an immediate
self-administered by a person analgesic effect [mean
with low back pain and were differences -10.9 (95 % CI
readily accessible from a -17.6 to -4.2) and -11.3
community pharmacy/drug (95 % CI = -17.8 to -4.9),
store without prescription respectively]
Hahne et al. 1971–2008; MEDLINE, Adults ([18 y.o.) with referred Conservative intervention All other Back specific functional status, Moderate evidence favors the
[46], CINAHL, EMBASE, PEDro, leg symptoms (with or (defined as intervention that comparisons pain intensity, global addition of mechanical
systematic Current Contents, Cochrane, without LBP), where C75 % did not involve penetration measures of improvement, traction to medication and
review AMED, ISI Web of Science, participants had confirmed through deep skin layers), adverse events electrotherapy
Australasian Medical Index; LDH via CT or MRI including NSAIDs
English; RCTs
Keller et al. Up to 2005; MEDLINE, Individuals in the general Non-surgical treatments (i.e., No treatment Self-reported pain intensity, For acute LBP, the effect size
[47], PubMed, EMBASE, population with non-specific NSAIDs, exercise, (placebo, self-reported physical of NSAIDs was only modest
systematic CINAHL, Amed; RCTs low back pain manipulation, behavioral sham, no functioning (effect size: 0.51). For
review treatment, acupuncture) treatment, chronic LBP, NSAIDs had
waiting list) only a modest effect (RR
0.61)
Kuijpers Up to 2008; MEDLINE, Adults (C18 y.o.) with chronic NSAIDs (including COX-2), All other At least one of the following: NSAIDs lead to somewhat
et al. [22], EMBASE, CINAHL, ([12 weeks) nonspecific LBP muscle relaxants, comparisons pain intensity (primary higher relief in pain on the
systematic CENTRAL, PEDro; English, (including discopathy or antidepressants, opioids outcome), back-specific short term (\3 months) as
review Dutch, German; RCTs with nonspecific degenerative functional status (primary compared to placebo in
C1 day follow-up pathology e.g., osteoarthritis) outcome), perceived patients with chronic
recovery, return to work nonspecific LBP, but show
more adverse effects than
placebo
Eur Spine J
Table 5 continued
References, Search date, databases, Population Intervention Comparison Outcomes Authors’ conclusion about
study design language, limiters NSAIDs from systematic
Eur Spine J

review

Luijsterburg Up to 2004; MEDLINE, Individuals with acute, All types of conservative Placebo, Primary outcomes: symptoms At long-term there is no
et al. [27], EMBASE, CENTRAL, subacute, or chronic interventions including inactive (e.g. pain), overall evidence in favor of
systematic CINAHL, PsycINFO, PEDro; lumbosacral radicular NSAIDs treatment, no improvement, function, corticosteroids injections
review English, Dutch, French, syndrome treated in a primary treatment, return to work compared to placebo, no
German; RCTs health care or occupational other types Secondary outcomes: treatment or NSAID or
setting of physiological or physical anesthetic injection, apart
conservative examinations, quality of life, from conflicting evidence for
treatment, psycho-social outcomes, short-term pain relief
surgery medical consumption,
adverse events
Pinto et al. Up to 2010; MEDLINE, Individuals with sciatica or Analgesic and adjuvant pain Placebo, no At least one of the following: Most of the pooled estimates
[28], EMBASE, CINAHL, lumbar radiculopathy drugs, including NSAIDs treatment, or overall pain intensity, leg or did not favor NSAIDs over
systematic PsycINFO, Cochrane Central (included radiculopathy, other back pain intensity, disability placebo
review Register of Clinical Trials, nerve root compromise, nerve intervention status, work status, adverse
International Pharmaceuticals root compression, events
Abstracts, LILACS; English, lumbosacral radicular
German, Dutch, Portuguese, syndrome, nerve root pain,
Spanish; RCTs nerve root entrapment, and
pain radiating below the
knee)
Roelofs et al. Up to 2007; MEDLINE, Adults (C18 y.o.) with non- NSAIDs and COX-2 inhibitors Placebo, other Primary outcomes: pain NSAIDs are effective for short-
[24], EMBASE, Cochrane Central specific low back pain with or drugs, other intensity, global measure, term symptomatic relief in
systematic Register of Controlled Trials; without sciatica type of back pain-specific functional patients with acute and
review English, Dutch, German, NSAID, non- status, return to work, side chronic low-back pain
randomized and double-blind drug effects; secondary outcomes: without sciatica. However,
controlled trials treatment physiological outcomes, effect sizes are small. There
generic functional status, does not seem to be a specific
health care consumption type of NSAID which is
clearly more effective than
others. The selective COX-2
inhibitors showed fewer side
effects compared to
traditional NSAIDs in the
RCTs included in this review
(however, recent studies have
shown increased
cardiovascular risks in
specific patient populations)

LBP low back pain, LDH lumbar disc herniation, NSAID non-steroidal anti-inflammatory drug, RCT randomized controlled trial, TMJ temporomandibular joint, WAD whiplash-associated
disorders, y.o. years old

123
Table 6 Evidence table—effectiveness data from primary studies included in accepted systematic reviews on non-steroidal anti-inflammatory drugs (NSAIDs) for the management of neck
pain and associated disorders, whiplash-associated disorders, and low back pain
Population; Type/ combination of Comparison Effect size(s) for outcomes Quality of the study/ Interpretation of

123
reference of primary NSAID (where available) evidencea studies with low risk
study of biasb (?/-/=)

Neck pain and associated disorders


Adults with acute NSAID—intramuscular Osteopathic manipulative Mean difference in 10-point NRS favoring Low risk of bias [15] CS (=)
neck pain ketorolac tromethamine treatment (HVLA thrust, osteopathic manipulative therapy (1.1, 95 % SS (?)
(\3 weeks) [49] (30 mg) muscle energy, soft tissue CI 0.2–1.9)
techniques) Greater pain reduction in OMT group (2.8, 95 %
CI 2.1–3.4) than in ketorolac group (1.7, 95 %
CI 1.1–2.3), mean difference = 1.1, 95 % CI
0.2–1.9; greater proportion of OMT than
ketorolac group reported ‘‘a lot of’’ or
‘‘complete’’ relief 1-h post-treatment (37 vs.
21 %); clinical significance questionable
Adverse effects reported by eight patients in
ketorolac group vs. 1 in OMT group
Individuals with NSAID—indomethicin NSAID—Piroxicam 20 mg Both drugs improved outcomes compared to Low risk of bias [15] CS (NR)
cervicobrachial 25 mg 3 times daily once daily (1 week placebo placebo. No significant difference in efficacy NSAID vs. NSAID:
syndrome wash out ? physical Fewer side effects in the Piroxicam group. SS (=)
(duration not therapy)
specified) [48] NSAID vs. placebo:
SS (?)
Non-specific low back pain without radiculopathy—recent onset
Acute LBP [53] NSAID (i): Nimesulide NSAID (ii): Ibuprofen Oswestry LBP disability questionnaire pre-mean Low risk of bias [24] CS (NR)
100 mg b.i.d. ? placebo 600 mg t.i.d., 10 days (SD), post-mean day 10 (SD): (i, N = 52) 35.8 Nimesulide vs.
once a day, 10 days (15,0), 10.0 (10.8); (ii, N = 50) 35.1 (19.1), ibuprofen:
16.5 (19.0), (i) vs. (ii) significantly lower
(P \ 0.05) SS (?) for disability

Pain, 100 mm VAS, pre-mean (SD), post-mean SS (=) for pain


day 10 (SD): (i, N = 52) 57.9 (20.6), 12.8
(15.4); (ii, N = 50) 55.2 (21.4), 18.5 (19.9),
(i) vs. (ii) not significant
Schobers test, cm, pre-mean (SD), post-mean
day 10 (SD): (i, N = 52) 5.2 (1.8), 6.9 (1.6);
(ii, N = 50) 5.
4 (2.3), 6.3 (1.6); no significance test reported
Side effects: (i) 7 patients (2 withdrew); (ii) 11
patients (1 withdrew)
Acute LBP [54] NSAID (i): Aceclofenac NSAID (ii): Diclofenac Pain mean changed score (SD), 100 mm VAS, Low risk of bias [24] CS (=)
100 mg b.i.d., 10 days 75 mg b.i.d., 10 days after 10 days: (i, N = 114) -62 (25); (ii, SS (NR)
N = 113) -57 (23); QBPDS change form
baseline (SD) after 4 days (i, N = 100) 25.5
(14.8); (ii, N = 105) 20.6 (12.1)
Side effects: (i) 17 patients; (ii) 18 patients
Eur Spine J
Table 6 continued
Population; reference Type/ combination of NSAID Comparison Effect size(s) for outcomes Quality of the study/ Interpretation of
of primary study (where available) evidencea studies with low risk
Eur Spine J

of biasb (?/-/=)

Acute LBP [57] NSAIDs (i): Valdecoxib NSAIDs (ii): Diclofenac Mean difference (95 % CI) pain intensity scale Low risk of bias [24] CS (=)
40 mg per day, second dose 75 mg b.i.d., 7 days (100 mm VAS) at 7 days; (i, N = 167 vs. ii, SS (=)
on day 1, 7 days N = 166) 0.26 (-3.76 to 4.28)
Mean difference (95 % CI) OLBPDQ (0–24 pt
scale) over 4 weeks; (iv vs. ii) 0.02 % (-3.21
to 3.16)
Acute LBP [58] NSAIDs (i): Lornoxicam on NSAIDs (ii): Diclofenac on Sum of pain intensity differences from baseline Low risk of bias [24] CS (NR)
day 1: 16 mg once a day day 1: 150 mg once a day on days 1-6 (SE); (i, N = 109) 4.2 (0.17); (ii, Lornoxicam vs.
and 8 mg once a day; days and 50 mg once a day; days N = 110) 3.8 (0.17); (i) significantly lower Diclofenac: SS (?)
2 to 7: 8 mg b.i.d. 2–7: 50 mg b.i.d. than (ii) P \ 0.05
Side effects: (i) 27; (ii) 28
Acute LBP [50] NSAID (i): Diflunisal (iii): Muscle relaxant No. of patients reporting marked improvement Low risk of bias [24] CS (NR)
capsules 500 mg (cyclobenzaprine/flexeril) after 2, 4, and 7 days: (i) 10, 14, 24 (ii) 10, 14, SS (?) favoring
b.i.d. capsules 5 mg b.i.d. 31 (iii) 8, 18, 30 (iv) 10, 14, 20; group (ii) NSAID plus muscle
(iv): Placebo capsules b.i.d. significantly better after 4 days (based on total relaxant after
NSAID plus muscle relaxant distribution); no other significant differences
(ii): Diflunisal capsules 4 days; SS (=) for
500 mg 1 5 mg No significant side effects reported all other outcomes
cyclobenzaprine b.i.d.
Acute LBP [55] NSAID (i): Tenoxicam Bed rest (ii): 7 days strict, Mean % improvement ± SD between baseline Low risk of bias CS (NR)
20 mg, 1 tablet daily, 7 days intermittent and 14 days in ROM (I) 123 ± 24, (ii) [24, 47] SS (?) favoring
14 days plus bed rest, 114 ± 23; significant 86 % (i) versus 70 % NSAID
7 days strict, 7 days (ii) no need for further treatment
intermittent Side effects: 2 patients in (i)
Acute LBP [56] NSAID (i): Piroxicam NSAID (ii): Indomethacin Mean improvement on VAS (range, 0–31) after Low risk of bias [24] CS (NR)
20 mg ? placebo capsules, 25-mg capsules, t.i.d., 6 weeks (i) 8, (ii) 9; similar improvement rates SS (=)
one per day ? twice 6 weeks (data in graphs)
placebo, 6 weeks Side effects similar (i) 13, (ii) 15
Acute LBP [51] NSAID (i): Indomethacin (ii): Placebo capsules No. of patients with complete relief of pain after Low risk of bias [24] CS (NR)
25 mg capsules, t.i.d., 7 and 14 days (i) 7, 14 (ii) 9, 16; no significant SS (=)
course of 50 capsules differences
Side effects comparable (i) 8 (ii) 5
Acute LBP [52] NSAID (i): Diflunisal NSAID (ii): Indomethacin Percentage of patients assessing therapy as good Low risk of bias [24] CS (NR)
500-mg capsules, twice 50-mg capsules, t.i.d., or excellent after 3 and 7 days (i) 45 %, 64 % SS (=)
daily, 7 days 7 days (ii) 45 %, 64 %; no significant differences
More side effects in (ii) 31 % than in (i) 18 %

123
Table 6 continued
Population; reference Type/ combination of NSAID Comparison Effect size(s) for outcomes Quality of the study/ Interpretation of
of primary study (where available) evidencea studies with low risk

123
of biasb (?/-/=)

Acute LBP NSAIDs (Diflunisal capsules 1. NSAID plus muscle Number of patients reporting marked High risk of bias [24] CS (N/A)
500 mg b.i.d.) relaxant (Diflunisal improvement after 2, 4, and 7 days was SS (?) at 4 days
capsules 500 mg ? 5 mg significantly better in NSAID plus muscle favoring NSAIDs
cyclobenzaprine b.i.d.) relaxant group after 4 days; no other plus muscle relaxant
2. Muscle relaxant significant differences
SS (=) for all other
(cyclobenzaprine/flexeril No serious side effects reported outcomes
capsules 5 mg b.i.d.)
3. Placebo capsules (b.i.d.)
Acute LBP NSAID (i): dexketorofen- NSAID (ii): Pain difference mean changed score, 100 mm High risk of bias [24]
trometamol 25 mg t.i.d., tramadolhydrochloride VAS, after 7 days: (i, N = 81) vs. (ii, N = 79)
7 days 50 mg t.i.d., 7 days -6 (4) (P \ 0.05)
Finger to floor distance mean changed score
(±SEM klopt… zieboven), cm, after 7 days:
(i) -22 (17); (ii) -18 (13); (i) vs. (ii)
significantly lower (P \ 0.05)
Acute LBP NSAID (i): Diflunisal NSAID (ii): Naproxen Percentage of patients reporting no pain (on an High risk of bias [24] N/A
capsules, 1000 mg initially, capsules, 500 mg initially, ordinal 4-point scale) after 2 weeks (i) 81 %
500 mg every 8–12 h, 250 mg every 6–8 h, (ii) 41 %. No significance tests reported
2 weeks 2 weeks
No adverse experiences reported by the patients
Acute LBP NSAID (i): Aceclofenac NSAID (ii): Diclofenac Mean improvement in pain intensity (VAS) after High risk of bias [24] N/A
150 mg, intramuscular 75 mg intramuscular b.i.d. 8 days: (i) 65 (ii) 62; global improvement
b.i.d. for 2 days ? 100 mg for 2 days ? 50 mg tablets good/very good in (i) 87 % and (ii) 79 % of
tablets b.i.d. for 5 days ? 1 t.i.d. for 5 days patients
placebo tablet for 5 days Side effects: (i) 1 (ii) 8 patients
Acute LBP NSAID (i): Piroxicam 20 mg (ii): Placebo capsules (i) More pain relief than (ii) measured with VAS High risk of bias [24] N/A
capsules, b.i.d. first 2 days, after 3 days. After 7 days no significant
one per day differences
next 5 days, 7 days Side effects similar (i) 13 % (ii) 17 %
Acute LBP NSAID (i): Diflunisal (ii): Physiotherapy: local Mean change in pain intensity on 4-point scale High risk of bias [24] N/A
500-mg capsules, 1000 mg heat, ultrasound, and after 4 and 12 days: (i) -0.9, -1.7 (ii) -0.9, -
immediately, 500 mg twice exercises (5 weekly 1.6 (iii) -1.1, -1.7; no significant differences
daily, 10 days sessions of 45 min in pain and mobility
(iii): Spinal manipulation
and/
or McKenzie therapy (5
sessions of 45 min weekly)
Acute LBP NSAID (i): Diclofenac NSAID (ii): Etofenamat Mean pain score (11-point NRS) at baseline and High risk of bias [24] N/A
intramuscular 3 mL 3 mL (1500 mg), 1–3 after 3–5 days: (i) 5.3, 2.7, (ii) 5.3, 2.4;
(75 mg), 1–3 injections, injections, 1–3 days physical examination (Schober): (i) 30, 52, (ii)
1–3 days 31, 59; no. of patients recovered after
3–5 days: (i) 27/47, (ii) 34/49; not significant
Eur Spine J

Side effects: (i) 2, (ii) 0


Table 6 continued
Population; reference Type/ combination of NSAID Comparison Effect size(s) for outcomes Quality of the study/ Interpretation of
of primary study (where available) evidencea studies with low risk
Eur Spine J

of biasb (?/-/=)

Acute LBP NSAID (i): Mefenamic acid (ii): Chlormezanone 100 mg No. of patients reporting no pain after 1 and High risk of bias [24] N/A
500 mg t.i.d. ? placebo and paracetamol 450 mg 2 7 days (i) 7, 21 (ii) 12, 23 (iii) 10, 20
b.i.d. capsules ? placebo t.i.d. No. of patients with adverse events (i) 9 (ii) 10
(iii): Ethoheptazine 75 mg (iii) 16
and meprobamate 150 mg
and aspirin 250 mg 2
capsules ? placebo t.i.d.
Acute LBP NSAID (i): Tenoxicam (ii): Placebo Mean pain intensity on VAS on day 1, 8, and 15 High risk of bias [24] N/A
20 mg intramuscular injection ? placebo (i) 7.4, 1.9, 0.6 (ii) 7.1, 2.8, 0.8;
injection on day 1 ? 20-mg capsules (?7 days bed rest) (i) significantly better on day 8
capsules 1 per day for days Side effects: one patient in group (i)
2–14 (?7 days bed rest)
Acute LBP NSAID (i): Flurbiprofen (ii): Acetaminophen, 4 g, No. of patients improved (physician’s High risk of bias [24] N/A
200 mg, 3 weeks 3 weeks assessment of pain) after 1, 2, 3, and 6 weeks:
(i) 13/23, 17/18, 7/8, 16/17, (ii) 8/22, 13/18,
8/9, 18/18; no significant difference
Side effects not specified
Acute LBP NSAID (i): Etodolac 200 mg NSAID (ii): Diclofenac Percentage of patients showing improvement High risk of bias [24] N/A
t.i.d., 5 days 50 mg t.i.d., 5 days after 5 days on pain intensity, global measure,
Laseque in (i) 50, 65, 66 %, and (ii) 55, 60,
74 %
Side effects not specified
Acute LBP NSAIDs (i): Naproxen (ii): Naproxen 500 mg Physical examination (Schober), days to High risk of bias [24] N/A
500 mg initially plus initially plus 250 mg q.i.d., resolution of pain, days to sit without pain,
250 mg q.i.d., 14 days plus cyclobenzaprine functional capacity after 14 days: (i) 5, 12.5,
10 mg t.i.d., 14 days 7, 15; (ii) 5, 8.5, 5, 9
Side effects: (i) 4 patients, (ii) 12 patients
Acute LBP NSAID (i): Piroxicam 10-mg (ii): Placebo capsules Patient (%) improved after 1 week only in High risk of bias [24] N/A
capsules, first 2 days, next subgroups with initial moderate/severe pain
12 days, 14 days (i) 82/49 % (ii) 53/38 %; no differences for
subgroup with mild initial pain; results after
2 weeks not reported (no data presented on side
effects for subgroup with back pain)
Acute LBP NSAID (i): Ketoprofen (ii): Combination Mean pain intensity at baseline and after 4 and High risk of bias [24] N/A
(Orudis) 200 mg (phenylbutazon-sodium, 9 days: (i) 68, 56, 42 and (ii) 68, 52, 39;
intramuscular b.i.d. for carbamoylphenoxyacetose, Laseque: (i) 48, 65, 74 and (ii) 51, 51, 60;
3 days plus dexamethasone, lidocaine- fingertip-to-floor distance: (i) 28, 25, 17 and
50 mg, 4 capsules plus hydrochloride, (ii) 36, 30, 26; no significant differences
100 mg drink for 5 days cyanocobalamin) 1 No adverse effects
intramuscular placebo
injection, 3 days plus 3
tablets for 5 days plus 1
placebo drink for 5 days

123
Table 6 continued
Population; reference Type/ combination of NSAID Comparison Effect size(s) for outcomes Quality of the study/ Interpretation of
of primary study (where available) evidencea studies with low risk

123
of biasb (?/-/=)

Acute LBP NSAID (i): Diflunisal (ii): Acetaminophen 300 mg Pain assessments by patient and investigator on High risk of bias [24] N/A
(capsules), initial dose with codeine 50 mg, two 3-point ordinal scale show similar
1000, 500 mg every 12 h, capsules initially, one improvement curves (data in graphs). No. of
15 days capsule every 4 h, 15 days patients rating drugs as excellent or very good
(i) 9 (ii) 9; no significant differences
Side effects: more side effects in (ii) 10 than in
(i) 3
Acute LBP NSAID (i): Diclofenac (ii): Diclofenac sodium plus After 1 week 49 % of (i) and 56.5 % of (ii) no High risk of bias [24] N/A
sodium, 25 mg 2 capsules vitamin B1, B6, B12, 2 or weak pain and 25 % in (i) and 29 % in (ii)
t.i.d., 7–14 days capsules t.i.d., 7–14 days improved; mean overall pain score at baseline
and after 1 and 2 weeks: (i) 78.7, 37.7, 23.7,
(ii) 83.7, 34.4, 23.6; tolerability good or very
good in 90 % (i) and 88 % (ii); side effects:
(i) 7 patients (ii) 12 patients
Acute LBP NSAIDs (i): Meloxicam NSAIDs (ii): Diclofenac Percentage of patients recovered after 8 days on High risk of bias [24] N/A
intravenous 1.5 mL intramuscular pain intensity, overall improvement,
(15 mg) 1 injection day 1 3 mL (75 mg) 1 injection day functional status, and tolerance: (i) 91, 89, 67,
plus 15 mg tablets once a 1 plus 96 %; (ii) 88, 91, 54, 98 %; side effects: (i) 6
day, 7 days patients (1 severe), (ii) 8 patients (1 severe)
100 mg tablets once a day,
7 days
Acute LBP NSAID (i): Etodolac 200 mg NSAID (ii): Piroxicam-beta- Mean degree of pain at baseline and after High risk of bias [24] N/A
b.i.d., 7 days cyclodextrin one 20-mg 7 days: (i) 3.1, 0.8, (ii) 3.13, 0.3; no significant
tablet, 7 days difference
Side effects (i) 3 patients, (ii) 2 patients
Acute LBP NSAID (i): aspirin 300 mg, 3 (v): Dextropropoxyphene Mean daily pain index during intervention High risk of bias [24] N/A
capsules, q.i.d., 1 week 32.5-mg and paracetamol period (on 4-point ordinal scale) (i) 1.4, (ii)
NSAID (ii): Indomethacin 325-mg capsules, 2 1.5, (iii) 1.4, (iv) 1.4, (v) 1.7, (vi) 1.7; (iii)
50 mg, t.i.d.,1 week capsules q.i.d., 1 week significantly different from (v) and (vi);
(vi): Paracetamol 500-mg (i) significantly different from (v)
NSAID (iii): Mefenamic acid
250 mg, 2 capsules t.i.d., capsules, 2 capsules q.i.d., Side effects: more side effects in (i) 20 (ii) 19
1 week 1 week and (v) 19 than in (iii) 12 (vi) 13 and (iv) 4
NSAID (iv): Phenylbutazone
100 mg, t.i.d., 1 week
Acute LBP NSAID (i): Indomethacin NSAID (ii): Total pain score (4-point scale) at baseline and High risk of bias [24] N/A
25 mg, q.i.d., 7 days Oxyphenbutazone 100 mg, after 3 and 7 days: (i) 52, 48, 39, (ii) 60, 47,
q.i.d., 7 days 44; total functional status score (movements;
4-point scale): 113, 105, 77, (ii) 142, 117, 99;
paracetamol use: after 3 and 7 days: (i) 7.4,
3.8, (ii) 7.7, 4.1; only pain after 3 days
significantly different
Side effects: (i) 5/40, (ii) 3/43
Eur Spine J
Table 6 continued
Population; reference Type/ combination of NSAID Comparison Effect size(s) for outcomes Quality of the study/ Interpretation of
of primary study (where available) evidencea studies with low risk
Eur Spine J

of biasb (?/-/=)

Acute LBP NSAIDs (i): Azapropazone NSAIDs (ii): Ketoprofen No data presented. Side effects: (i) 3 patients (1 High risk of bias [24] N/A
300 mg q.i.d., 1 week 50 mg q.i.d., 1 week severe), (ii) 14 patients (10 severe)
Acute LBP NSAID (i): Ibuprofen (ii): Paracetamol 1000 mg Percentage of patients cured after 10 weeks: High risk of bias N/A
800 mg t.i.d., 7 days t.i.d., 7 days (i) 67 %, (ii) 54 %, (iii) 82 %; no significant [23, 24]
(iii): No drug treatment difference
Side effects not specified
Acute LBP NSAID (i): Ibuprofen NSAID (ii): Felbinac (foam Patients (%) reporting none or mild severity High risk of bias [24] N/A
capsules 400 mg three 3 %) 3 times after 1 and 2 weeks (i) 84, 92 (ii) 76, 88; no
times per day ? placebo daily ? placebo capsules 3 significant differences between the groups
foam 3 times daily, 14 days times daily, 14 days No. of side effects (i) 22 (ii) 26
Non-specific low back pain without radiculopathy—persistent
Chronic LBP 1. NSAID—Naproxen Placebo capsules (iii) Decrease in pain by visual analog scale. Group Low risk of bias [22] CS (NR)
([3 months) [59] sodium 275 mg capsules, 2 (i) reduction of pain (ii) no change (iii) NSAID vs NSAID:
times 2 capsules per day, increase of pain SS (=)
14 days Data in graphs. Group (i) significantly better Naproxen vs. placebo:
2. NSAID—Diflunisal than (iii) and somewhat better than (ii) SS (?)
250 mg capsules, 2 times 2 Side effects similar in the three groups (i) 18 (ii)
capsules per day, 14 days 18 (iii) 16.
(in cross-over design)
Chronic LBP 1. NSAID—Etoricoxib Placebo, daily, 12 weeks Mean difference (95 % CI) pain intensity scale Low risk of bias [22] Pain: CS (?), SS (?)
([3 months) [60] 60 mg/day, 12 weeks (100 mm VAS) at 12 weeks; (iv vs. iii) - LBP bothersomeness:
2. NSAID—Etoricoxib 10.45 (-16.77 to -4.14); CS (NR), SS (?)
90 mg/day, 12 weeks (ii vs iii) -7.5 (-13.71 to -1.28) RMDQ: CS (=), SS
Mean difference (95 %CI) LBP bothersomeness (?)
scale over 12 weeks (4-pt Likert, 0 = not at
all, 4 = extremely); (iv vs. iii) -0.38 (-0.62
to -0.14); (ii vs iii) -0.33 (-0.57 to -0.09)
Mean difference (95 % CI) RMDQ (0–24 pt
scale) over 12 weeks; (iv vs. iii) -2.42 (-3.87
to -0.98); (ii vs. iii) -2.06 (-3.46 to -0.65)
Side effects: (i) 60 patients (14 withdrew); (ii)
56 patients (17 withdrew); (iii) 51 patients (10
withdrew)
Chronic LBP NSAID—Valdecoxib Placebo tablets, once daily, Mean changed score on pain intensity scale Low risk of bias
([3 months) [62] 40 mg/day, 4 weeks 4 weeks (100 mm VAS) at 1 week and 4 weeks; [22, 47]
(i) 29.2 and 41.9; (ii) 17.7 and 31.1; (iv vs. ii)
all P \ 0.001
Side effects: (i) 52 patients (1 withdrew); (ii) 35
patients (3 withdrew)

123
Table 6 continued
Population; reference Type/ combination of NSAID Comparison Effect size(s) for outcomes Quality of the study/ Interpretation of
of primary study (where available) evidencea studies with low risk

123
of biasb (?/-/=)

Chronic LBP [61] NSAIDs (i): Rofecoxib Reference treatment (ii): Number of patients pain free after 3 and Low risk of bias [24] CS (NR)
12.5 mg/day, 6 weeks Doloteffin 2400 mg/day, 6 weeks: (i) 4, 7; (ii) 5, 10 SS (NR)
6 weeks Side effects: (i) 14 patients (1 withdrew); (ii) 14
patients (6 withdrew)
Chronic LBP [65] NSAIDs (i): Etoricoxib NSAIDs (ii): Diclofenac 3 * Mean difference (95 % CI) pain intensity scale Low risk of bias [24] NSAID vs NSAID:
60 mg per day, 4 weeks 50 mg per day, 4 weeks (100 mm VAS) at 4 weeks; (i, N = 222 vs ii, pain: SS (=), CS (=)
N = 218) 2.51 (-1.50 to 6.51) RMDQ: SS (=), CS
Mean difference (95 % CI) RMDQ (0–24 pt (=)
scale) over 4 weeks; (iv vs. ii) -0.23 (-1.14 LBP bothersomeness:
to 0.67) SS (=)
Mean difference (95 %CI) LBP bothersomeness
scale over 4 weeks (4-pt Likert, 0 = not at all,
4 = extremely); (iv vs. ii) -0.02 (-0.17 to
0.13)
Side effects: (i) 79 patients (15 withdrew); (ii)
87 patients (13 withdrew)
Chronic LBP [64] NSAID (i): Ketoprofen NSAID (ii): Diclofenac Percentage of patients improved after 1, 2 weeks Low risk of bias [24] CS (NR)
25-mg capsules, sodium 25-mg capsules, (i) 71 %, 86 % (ii) 62 %, 79 %; no significant SS (=)
150 mg per day, duration not 75 mg per day, duration not differences
given given Side effects similar in both groups (i) 18 % (ii)
21 %
Chronic LBP [63] NSAID (i): Diflunisal (ii): Paracetamol 1000 mg, No. of patients with none or mild low back pain Low risk of bias [24] CS (NR)
500 mg capsules, b.i.d., q.i.d., 4 weeks after 2 and 4 weeks (i) 11, 13 (ii) 9, 7; SS (?)
4 weeks significantly more patients in (i) (10 of 16)
considered the therapy as good or excellent
than in (ii) (4 of 12)
Side effects similar (i) 2 (ii) 1
Chronic LBP [66] NSAID (Etoricoxib) Placebo Pain (VAS 0–100 mm): Relative risk 0.57 Low risk of bias [47] CS (NR)
(95 % CI 0.44, 0.74) SS (?)
Chronic LBP 1. NSAID (Rofecoxib Placebo, daily for 4 weeks Mean difference (Group 1—placebo): symptom High risk of bias N/A
([3 months) 25 mg/day, 4 weeks) bothersomeness: -0.5 (95 % CI -0.6 to -0.3) [22, 47]
2. NSAID (Rofecoxib RMDQ: -2.2 (95 % CI -3.2 to -1.3)
50 mg/day, 4 weeks) Group 2—placebo: symptom bothersomeness:-
0.5 (95 % CI -0.7 to -0.3)
RMDQ: -2.3 (95 % CI -3.3 to -1.3)
Adverse events: Group 1—112/233 (10
withdrew); Group 2—106/229 (10 withdrew);
Group 3—93/228 (3 withdrew)
Eur Spine J
Table 6 continued
Population; reference Type/ combination of NSAID Comparison Effect size(s) for outcomes Quality of the study/ Interpretation of
of primary study (where available) evidencea studies with low risk
Eur Spine J

of biasb (?/-/=)

Subacute or chronic NSAIDs (i): Nimesulide Reference treatment (ii): Sum of patients with none, mild moderate/sum High risk of bias [24] N/A
LBP 100 mg, b.i.d., 4 weeks Diclofenac sodium 50 mg of patients with severe, very severe pain at:
b.i.d., 4 weeks rest, motion, night, standing. Data in graphs.
No differences found between treatments
Side effects (i) 26, (ii) 41; (i) vs (ii) P = 0.05
Chronic LBP NSAID (i): Diflunisal (ii): Meptazinol 200 mg Mean change in degree of pain on 100-mm VAS High risk of bias [24] N/A
250-mg capsule, q.i.d., capsule, q.i.d., 3 weeks at 3 weeks (i) 45 (ii) 40; similar improvement
3 weeks regarding capacity for daily tasks (data in
graphs); no significant differences
Side effects similar (i) 19, (ii) 23 patients
Chronic LBP NSAID (i): Ibuprofen SR NSAID (ii): Diclofenac SR Mean ± SD improvement in pain intensity, High risk of bias [24] N/A
800 mg b.i.d. plus placebo, 100 mg once per day plus global measure, physical examination
14 days placebo, 14 days (Schober), level of activity: (i) 2.0, 2.2 ± 1.5,
0.6 ± 0.6, 2.2 (ii) 2.3, 3.0 ± 1.7, 0.4 ± 0.6,
1.9; no significant differences; side effects in
(i) 4 patients, (ii) 16 patients; significant
Non-specific low back pain without radiculopathy—duration not specified or variable
LBP (variable NSAIDs (i): Alclofenac 1 g NSAIDs (ii): Indomethacin Mean ± SEM change score in pain intensity (5- Low risk of bias [24] CS (NR)
duration) [67] t.i.d., 7 days (N = 15 acute; 50 mg t.i.d., 7 days point NRS) and functional status (4-point SS (=)
N = 16 chronic) (N = 15 acute; N = 15 NRS) after 7 days for acute low back pain:
chronic) (i) 1.46 ± 0.28, 1.80 ± 0.03; (ii) 1.45 ± 0.27,
1.53 ± 0.23; not significant; mean ± SEM
change score in pain intensity and functional
status after 7 days for chronic low back pain
(i) 1.66 ± 0.62, 1.31 ± 0.63; (ii) 1.01 ± 0.71,
1.00 ± 0.58; not significant
Side effects: (i) 5 patients, (ii) 3 patients
LBP (duration not NSAID (i): Indomethacin (ii): Dextropropoxyphene Data extraction not possible; side effects: (i) 7 High risk of bias [24] N/A
specified) 25 mg t.i.d., 4 days HCL, 150 mg t.i.d., 4 days patients, (ii) 13 patients
LBP (duration not NSAID (i): Diclofenac full (ii): Chiropractic Mean improvement on combined pain, High risk of bias [24] N/A
specified) dosage, 10–14 days (acute manipulation disability, and spinal mobility score (5–32)
patients), 15–20 days (iii): Physiotherapy after 3 weeks, 2, and 6 months; in subgroup
(chronic patients) with acute pain (i) 3.0, 10.7, 14.0, (ii) 7.5, 9.7,
(iv): Bedrest 12.3, (iii) 5.0, 8.4, 10.2, (iv) 5.4, 7.5, 7.3,
(v): Back school (v) not included, (vi) 1.8, 7.3, 11.0; group (ii)
(vi): Placebo (anti-edema gel) significantly better than others after 3 weeks,
no other differences; in subgroup with chronic
pain (i) 2.6, 2.2, 4.0, (ii) 2.2, 2.6, 4.3, (iii) 3.9,
4.2, 6.0, (iv) not included, (v) 0.5, 4.6, 8.9, (vi)
0.7, 1.2, 2.0; group (i) not significantly better;
no data on side effects reported

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Table 6 continued
Population; reference Type/ combination of NSAID Comparison Effect size(s) for outcomes Quality of the study/ Interpretation of
of primary study (where available) evidencea studies with low risk

123
of biasb (?/-/=)

LBP (duration not NSAID (i): Ibuprofen, NSAID (ii): Diclofenac, No. of patients reporting to be improved after 1, High risk of bias [24] N/A
specified) 1200 mg per day, 14 days 75 mg per day, 14 days 3, 4 weeks (i) 5, 10, 6 (ii) 5, 12, 11; no
significant differences
Side effects similar: one in each group
LBP (duration not NSAID (i): Indomethacin NSAID (ii): Mean ± SD score on 30-point total rating scale High risk of bias [24] N/A
specified) plaster b.i.d., 4 weeks plus Diclofenacemulgel, 2 cm at baseline and after 1, 2 and 3 weeks:
1 mg oral vitamin B b.i.d. q.i.d., 4 weeks plus 1 mg (i) 18.13 ± 4.32, 21.43 ± 4.10, 24.27 ± 5.30,
oral vitamin B b.i.d. 25.87 ± 4.50, (ii) 18.65 ± 4.53,
20.46 ± 6.68, 24.30 ± 5.39, 26.33 ± 4.12;
not significant; % of patients with good
improvement, safety, and usefulness after
3 weeks: (i) 87, 97, 87 %, (ii) 82, 100, 82 %;
not significant
Side effects: (i) 3 patients, (ii) none
LBP (duration not NSAID (i): Loxoprofen NSAID (ii): Naproxen Mean ± SD therapeutic results according to High risk of bias [24] N/A
specified) 60 mg t.i.d., 6 weeks 250 mg t.i.d., 6 weeks criteria of the Japanese orthopedic Academic
Society at baseline and after 1 and 6 weeks:
(i) 16.86 ± 4.90, 22.27 ± 5.08, 27.44 ± 2.87
and (ii) 15.42 ± 5.03, 20.97 ± 6.05,
26.23 ± 3.11; not significant
Side effects (i) 6 patients, (ii) 6 patients
LBP (duration not NSAID (i): aspirin 625-mg (iii): Acetaminophen (dosage Mean no. of days before return to full activity High risk of bias [24] N/A
specified) capsules, q.i.d., 2 weeks not given), b.i.d., 2 weeks (i) 5.7 (ii) 6.5 (iii) 5.7; no significant
NSAID (ii): Phenylbutazone differences
100-mg capsules, q.i.d. No data on side effects given
(first 5 days), no further
information
LBP (duration not NSAID (i): Piroxicam 20 mg NSAID (ii): Indomethacin No. of patients who are (very much) improved High risk of bias [24] N/A
specified) capsules, once per day, 25 mg capsules, t.i.d., after 1 and 2 weeks assessed by a physician
14 days 14 days (i) 49 % (70 %) (ii) 46 % (58 %); patients’
assessment after 2 weeks (very) good (i) 69 %
(ii) 62 %; no significant differences
Side effects similar (i) 11 % (ii) 13 %
Non-specific low back pain with radiculopathy
Acute sciatic pain NSAIDs (i): Dipyrone (iii): Placebo, 5 mL isotonic Mean (SD) pain intensity (VAS) at baseline and Low risk of bias CS (NR)
[68] intramuscular, 5 mL (5 saline, 1–2 injections, after 6 h: (i) 80.2 (15.4), 33.4 (25.5); (ii) 79.2 [24, 47] Dipyrone versus
2.5 g) 1–2 injections, 1–2 days (14.5), 41.7 (25.9); (iii) 78.2 (14.8), 54.8 Diclofenac: SS (?)
1–2 days (25.3); (i) significantly better than (ii) and (iii);
no. of patients recovered after 2 days (5-point Dipyrone versus
NSAIDs (ii): placebo: SS (?)
Diclofenac intramuscular, NRS); (i) 27 (32 %); (ii) 10 (12 %); (iii) 7
(9 %)
3 mL (75 mg), 1–2
injections, 1–2 days Side effects: (i) 4, (ii) 1, (iii) 2 patients
Eur Spine J
Table 6 continued
Population; reference Type/ combination of NSAID Comparison Effect size(s) for outcomes Quality of the study/ Interpretation of
of primary study (where available) evidencea studies with low risk
Eur Spine J

of biasb (?/-/=)

Acute lumbosacral NSAID (Piroxicam) Placebo medication Sick leave: RR 1.0 (95 % CI 0.8, 1.3) Low risk of bias [27] CS (N/A)
radicular SS (=)
syndrome [73]
Acute sciatica [71] 1. NSAID (7.5 mg oral NSAID—Diclofenac 150 mg Mean difference in Diclofenac 150 mg— Low risk of bias [23, CS (NR)
meloxicam, 19 daily for meloxicam 7.5 mg: reduction in pain: 0.0 28, 47] SS (=)
4 days) (95 % CI -15.2, -15.2)
SS (=)
2. NSAID (15 mg oral Diclofenac 150 mg—meloxicam 15 mg:
meloxicam, 19 daily for reduction in pain -1.0 (95 % CI -4.5, 6.5)
4 days) Adverse events: 13 % of Group 1, 17 % of
Group 2, 15 % of Diclofenac Group—
abdominal pain, diarrhea, dizziness,
dyspepsia, flatulence, headache, nausea
Acute sciatica [70] 1. Lornoxicam 8 mg Placebo Lornoxicam Group—placebo: reduction in pain: Low risk of bias [28] CS (NR)
2. Diclofenac 50–150 mg 8.3 (95 % CI -1.4, 17.9) SS (=)
Diclofenac Group—placebo: SS (?)
Reduction in pain: 10.3 (95 % CI 0.7, 19.9) SS (=)
Diclofenac Group—Lornoxicam: reduction in
pain: 2.0 (95 % CI -7.7, 11.7)
Adverse events: 11 % in Lornoxicam Group,
12 % Diclofenac Group, 7 % placebo Group-
dyspepsia, diarrhea, nausea, abdominal pain,
flatulence, bronchitis, coughing, sputum,
hyperuricaemia, bilirubinaemia, myalgia, leg
cramps
Acute lumbar disc NSAID (i): Diclofenac 25-mg NSAID (ii): Proquazone Average improvement on ordinal 5-point scale Low risk of bias [24] CS (NR)
herniation [69] capsules, q.i.d. first 4 days (Biarison) 300-mg (0 = no response, 4 = very good response) SS (=)
and t.i.d. next 8 days, capsules, q.i.d. first 4 days during and after the intervention period of
12 days and t.i.d. next 8 days, 12 days according to physician and patient
12 days (i) 2.6 and 2.8 (ii) 2.8 and 3; no significant
differences in recovery rate
Side effects: mild side effects in three patients in
each group
Acute and subacute NSAID (i): Phenylbutazone (ii): Placebo capsules No. of patients reporting definite positive effect Low risk of bias [24] CS (NR)
sciatica [72] 200-mg capsules, 2 after intervention period (i) 14 (ii) 8; no SS (=)
capsules t.i.d. for 3 days, 1 significant differences
capsule t.i.d. next 2 days, No side effects reported by the patients
5 days
Acute sciatica [73] NSAID (i): Piroxicam 20-mg (ii): Placebo capsules Reduction of pain in back and leg measured by Low risk of bias [24] CS (NR)
capsules, 40 mg per day VAS after 4 weeks the same in the two groups SS (=)
first 2 days, 20 mg per day (data in graphs); no significant differences
next 12 days, 14 days More side effects in (i) 22 than in (ii) 13

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Table 6 continued
Population; reference Type/ combination of NSAID Comparison Effect size(s) for outcomes Quality of the study/ Interpretation of
of primary study (where available) evidencea studies with low risk

123
of biasb (?/-/=)

Individuals with Diclofenac sodium orally Caudal epidural injection Diclofenac is less effective than caudal epidural High risk of bias [46] N/A
lumbar disc injection for reducing pain intensity at short-
herniation with and intermediate-term follow-ups, and for
radiculopathy reducing function at short-term follow-up
There is no difference in function measured at
intermediate-term follow-up between
Diclofenac and caudal epidural injection.
2 weeks:
VAS: -2.2 (95 % CI -2.8, -1.6)
Oswestry: -1.5 (95 % CI -2.0, -1.0)
1 month:
VAS: -1.0 (95 % CI -1.5, -0.5)
Oswestry: -0.6 (95 % CI -1.2, -0.2)
3 months:
VAS: -0.6 (95 % CI -1.1, -0.1)
Oswestry: -0.4 (95 % CI -1.9, 0.1)
Individuals with Diclofenac sodium orally Sarpogrelatehydroxychloride There is no difference between Diclofenac and High risk of bias [46] N/A
lumbar disc sarpogrelatehydroxychloride for short-term
herniation with outcomes of back pain intensity or leg pain
radiculopathy intensity
2 weeks:
VAS-1: 0.0 (95 % CI -0.6, 0.7)
VAS-2: 0.5 (95 % CI -0.1, 1.1)
Lumbosacral NSAID via intramuscular NSAID via intramuscular Pain (VAS 0-100): day 1: 0.1 (95 % CI -0.6, High risk of bias [27] N/A
radicular injection (Tiaprofenic injection (Ketoprofen 0.7)
syndrome (acute, 200 mg) 100 mg) day 2: 0.3 (-0.3, 0.9)
subacute, and
chronic) day 3: 0.6 (95 % CI 0.0, 1.3)
day 4: 0.6 (95 % CI 0.0, 1.3)
Side effects: stomach pain (5 times reported),
skin reaction (3 times reported)
Acute sciatica 1. NSAID (7.5 mg oral Oral placebo (19 daily for Mean difference in Meloxicam 7.5 mg— High risk of bias [28] N/A
meloxicam, 19 daily for 4 days) placebo: reduction in pain (0–100): 6.0 (95 %
4 days) CI 0.4, 11.5)
2. NSAID (15 mg oral Meloxicam 15 mg—placebo: reduction in pain
Meloxicam, 19 daily for (0–100): 5.0 (95 % CI -0.5, 10.5)
4 days) Adverse events: 8 % of Group 1, 7 % of Group
2, 4 % of placebo Group—abdominal pain,
diarrhea, dizziness, dyspepsia, hepatic
enzymes increased, nausea
Eur Spine J
Table 6 continued
Population; reference Type/ combination of NSAID Comparison Effect size(s) for outcomes Quality of the study/ Interpretation of
of primary study (where available) evidencea studies with low risk
Eur Spine J

of biasb (?/-/=)

Patients with acute Piroxicam orally, 20 mg, Placebo, twice daily for Piroxicam—placebo: High risk of bias [28] N/A
sciatica twice daily for 2 days, 2 days, followed by once Leg pain/immediate: 0.0 (95 % CI -6.9, 6.9)
(\14 days) followed by once daily for daily for next 12 days.
next 12 days. Additional Additional analgesics Leg pain/short term: 3.0 (95 % CI -3.9, 9.9)
analgesics allowed. allowed Back pain/immediate: 3.0 (95 % CI -3.9, 9.9)
Back pain/short term: 5.0 (95 % CI -1.9, 11.9)
Disability/immediate: 2.4 (95 % CI -4.5, 9.3)
Disability/short term: 2.9 (95 % CI -4.0, 9.8)
Lumbar disc NSAID (i): Indomethacin (ii): Placebo capsules Group (i) significantly more effective than (ii) High risk of bias [24] N/A
herniation 25 mg capsules, 3 capsules (N = 25 with nerve root only for patients with nerve root pain (data in
per day for 2 days, 4 pain, and N = 30 without graphs)
capsules per day next nerve root pain) Number of side effects (i) 38 (ii) 23
5 days (N = 25 with nerve
root pain, and N = 30
without nerve root pain)
Lumbar disc NSAID (i): Phenylbutazone (ii): Placebo capsules Group (i) improvement in motor weakness and High risk of bias [24] N/A
herniation 100-mg capsules, 6 per day painful straight-leg raising; no results are
for 2 days, t.i.d. next 8 days reported for group (ii);
Side effects reported in group (i) 3
Lumbar disc NSAID (i): Tenoxicam NSAID (ii): Tenoxicam Mean ± SD pain intensity (VAS) before High risk of bias [24] N/A
herniation or 20 mg intramuscular 20-mg tablet plus treatment and after 24 h: (i) 55 ± 15,
degeneration injection plus 1 placebo intramuscular placebo 34 ± 29, (ii) 50 ± 13, 37 ± 13
tablet, 4 days injection Side effects: (i) 5 patients, (ii) 5 patients

1 indicates that the effect size favors the intervention (i.e., NSAIDs); 2 indicates that the effect size favors the comparison; = indicates that there is no difference between groups (with respect
to statistical significance or clinical significance based on the interpretation of results by the OPTIMa Collaboration)
CI confidence interval, CS clinically significant, HVLA high velocity low amplitude, LBP low back pain, No. number, NRS numeric rating scale, NSAID non-steroidal anti-inflammatory drug,
OMT osteopathic manipulative therapy, RCT randomized controlled trial, RR relative risk, SD standard deviation, SS statistical significant, VAS Visual Analog Scale
a
The quality of the studies are based on the appraisal/ratings listed in the accepted systematic reviews
b
The results from low-quality studies or studies with high risk of bias are not included in our evidence synthesis

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disability, recovery, or symptom bothersomeness) between: Persistent


(1) Ketoprofen versus Diclofenac [64]; (2) Naproxen ver-
sus Diflunisal [59]; (3) Etoricoxib versus Diclofenac (also None of the included studies with a low risk of bias ad-
not clinically significant for improving pain or disability) dressed persistent low back pain with radiculopathy.
[65].
Adverse events
Variable duration
Five of the eight reviews with a low risk of bias addressed
One systematic review with a low risk of bias included adverse events related to NSAIDs [15, 22–24, 28]. These
eight studies investigating NSAIDs for low back pain of reviews suggest that adverse events such as dyspepsia or
variable duration [24]. Seven studies had important gastrointestinal bleeding with NSAIDs are more frequent
methodological limitations (Tables 5, 6). One study had a than with placebo (Table 7).
low risk of bias [67]: evidence from one study with a low
risk of bias suggests that different oral NSAIDs lead to
similar outcomes for low back pain of variable duration Discussion
[67]. There were no statistically significant differences in
improving pain or function between Alclofenac versus Summary of evidence
Indomethacin in individuals with low back pain of variable
duration. We found eight systematic reviews with a low risk of bias
on NSAIDs for the management of NAD and low back
Non-specific low back pain with radiculopathy pain. For recent-onset NAD, evidence suggests that intra-
muscular NSAIDs lead to similar outcomes as combined
Recent-onset manipulation and soft tissue therapy. For NAD (duration
not specified), evidence suggests that oral NSAIDs may be
Six systematic reviews with a low risk of bias included more effective than placebo. For recent-onset low back
15 studies evaluating NSAIDs for low back pain with pain, evidence suggests that: (1) oral NSAIDs lead to
radiculopathy [23, 24, 27, 28, 46, 47]. Eight studies had similar outcomes as placebo or a muscle relaxant; and (2)
important methodological limitations (Tables 5, 6). oral NSAIDs with bed rest lead to similar outcomes as
Seven studies had a low risk of bias [68–73] and all placebo with bed rest. There is also consistent evidence
addressed recent-onset low back pain with radiculopathy. that bed rest is not an effective treatment for back pain and
Of these, five studies compared an NSAID to placebo may delay recovery [75]. For persistent low back pain,
[68, 70–74] and four studies compared two different evidence suggests that: (1) oral NSAIDs are more effective
NSAIDs [68–71]. than placebo; and (2) oral NSAIDs may be more effective
Five studies with a low risk of bias suggest that there is than acetaminophen. For recent-onset low back pain with
inconsistent evidence on the effectiveness of oral NSAIDs radiculopathy, there is inconsistent evidence on the effec-
versus placebo for recent-onset low back pain with tiveness of oral NSAIDs versus placebo. Different oral
radiculopathy. Three studies with a low risk of bias found NSAIDs lead to similar outcomes for neck and low back
that an NSAID (Piroxicam, Phenylbutazone, or Diclofe- pain with or without radiculopathy. Side effects such as
nac) leads to similar outcomes (pain, recovery, or sick dyspepsia and gastrointestinal bleeding were more frequent
leave) as placebo tablets [72–74], whereas two studies with NSAIDs versus placebo.
found that an NSAID (Diclofenac) was more effective
than placebo in reducing pain [68, 70] (clinical sig- Comparison with previous systematic reviews
nificance not reported).
The preponderance of evidence from four trials with a For neck pain, Peloso et al. [21] reported that there was
low risk of bias suggests that Meloxicam, Diclofenac, limited and unclear evidence on the effectiveness of
Lornoxicam, and Proquazone administered orally may be NSAIDs. However, we found that NSAIDs may be more
equally effective in improving pain or recovery for recent- effective than placebo and lead to similar outcomes as
onset low back pain with radiculopathy [68–71]. However, combined manipulation and soft tissue therapy. This is
one study found statistically significant differences in pain likely due to differences with the critical appraisal method
reduction between Dipyrone and Diclofenac (with intra- used in their review (the Jadad scale), which does not place
muscular administration), favoring Dipyrone [68] (clinical much emphasis on the assessment of selection bias, infor-
significance not reported). mation bias, and confounding for each study.

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Table 7 Adverse events from non-steroidal anti-inflammatory drugs randomized to placebo). This study serves as a preliminary
(NSAIDs) as reported by systematic reviews with a low risk of bias indication that NSAIDs may be more effective than placebo
Condition Adverse events for the management of NAD. There is an urgent need for
high-quality studies investigating the use of oral NSAIDs for
Neck pain The systematic review on neck pain reported that
the management of recent onset and persistent NAD.
dyspepsia was common ([10 %), gastrointestinal
bleeding was occasional (1–10 %), and heart attacks The high-quality systematic reviews used different tools
were rare (0.001–1 %) [15, 32] to assess the quality of studies included in their reviews.
Low back Kuijpers et al. [22] reported that there are statistically Specifically, three reviews used the PEDro scale [23, 28,
pain significantly more adverse events in the NSAIDs 46], three reviews used the Cochrane Back Review Group
group compared to placebo based on low quality criteria [22, 24, 47], one review used the Delphi list [27],
evidence [relative risk (RR) 1.24, 95 % CI
1.07–1.43] and one review used criteria focused on sources of poten-
Pinto et al. [28] reported that the median rate of tial selection bias, information bias, and confounding
adverse events was 17 % (interquartile range (name of criteria not reported) [15]. It is important that
10–30 %) for NSAIDs and 11 % (3–23 %) for critical appraisal methods assess for potential selection
placebo bias, information bias, and confounding. Reviewers should
Roelofs et al. [24] reported that there were statistically also consider whether these biases would likely lead to
more patients with side effects with NSAIDs
compared to placebo. They also reported that misleading conclusions.
selective Cox-2 inhibitors showed fewer side effects There was a lack of information on adverse events
than non-selective oral NSAIDs [24] provided by the high-quality systematic reviews. There
Abdel Shaheed et al. [23] reported that side effects are limitations to using systematic reviews of clinical
were more common with placebo than NSAID; trials for information on adverse events, including: (1)
however, this was based on one study. They also
reported that using higher NSAID doses are
adverse events are often not the primary endpoints in
associated with an increased risk of side effects than clinical trials, which can lead to incomplete reporting;
low dose or taken when necessary [23] (2) inconsistent definitions of adverse events; (3) with-
drawal or loss to follow-up in the trial due to adverse
events; and (4) inadequate consideration of follow-up
For low back pain, two systematic reviews have reported and potential time required to develop adverse events
limited or unclear evidence [20, 22], whereas two sys- with drugs [76]. Therefore, adverse events related to
tematic reviews reported that NSAIDs are effective for drugs should be informed by improved methodology of
short-term symptomatic relief [23, 24]. Two systematic clinical trials and observational cohort studies examining
reviews found evidence supporting the use of NSAIDs in adverse events.
individuals with acute [25] or chronic low back pain [25,
26]. Our results differ from these conclusions; this is likely
due to our best evidence synthesis methods, where only Strengths and limitations
reviews with a low risk of bias are included in the syn-
thesis. Including studies with a high risk of bias in the Our review has several strengths. The literature search was
evidence synthesis may produce unreliable results that comprehensive and peer-reviewed to minimize errors. We
threaten the validity of the conclusions. outlined detailed inclusion and exclusion criteria to identify
Two systematic reviews reported that NSAIDs are not relevant systematic reviews. Pairs of trained, independent
more effective than placebo for lumbar radiculopathy [27, reviewers critically appraised the literature using the SIGN
28]. Our findings agree with these reviews, as we found criteria [36] to standardize the critical appraisal process.
inconsistent evidence on the effectiveness of NSAIDs over Our conclusions were based on the best evidence synthesis
placebo for recent-onset low back pain with radiculopathy. method to minimize the risk of bias associated with using
Despite its common use, there are few high-quality low-quality reviews [38].
studies informing the use of NSAIDs for the management of Our review has limitations. We only searched the Eng-
NAD. We identified one study investigating the use of in- lish literature; however, systematic reviews of clinical tri-
tramuscular NSAIDs for recent-onset NAD [49], and one als investigating the impact of language restriction found
study investigating the use of oral NSAIDs for NAD (du- that it does not lead to bias as most large trials are pub-
ration not specified) [48]. The latter study [48] was pub- lished in English [77–81]. The critical appraisal of reviews
lished in 1983 and has important limitations: (1) the may vary between reviewers. This potential bias was
outcome measure has not been tested for its validity and minimized by using standardized appraisal forms, con-
reliability; and (2) the study used pre-post analysis of ducting training sessions, and using a consensus process to
NSAID use compared to placebo (no groups were determine admissibility of systematic reviews.

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Conclusions 15. ‘‘cervicalgia*’’.ab,ti.


16. ‘‘cervicodynia*’’.ab,ti.
For NAD (duration not specified), oral NSAIDs may be 17. ‘‘radiculopath*’’.ab,ti.
more effective than placebo. Oral NSAIDs are more ef- 18. ‘‘brachial plexus neuropath*’’.ab,ti.
fective than placebo for persistent but not recent-onset low 19. torticollis.ab,ti.
back pain. For recent-onset low back pain with radicu- 20. or/1-19
lopathy, there is inconsistent evidence on the effectiveness 21. exp Back/
of NSAIDs versus placebo. Different oral NSAIDs lead to 22. exp Back Injuries/
similar outcomes for neck and low back pain with or 23. exp Back Pain/
without radiculopathy. The high-quality systematic re- 24. Coccyx/in [Injuries]
views lacked detailed information on the nature and fre- 25. Intervertebral Disc Degeneration/
quency of adverse events related to NSAIDs. 26. Intervertebral Disc Displacement/
27. Lumbar Vertebrae/in [Injuries]
Acknowledgments The authors acknowledge the invaluable 28. exp Lumbosacral Plexus/
contributions to this review from: Angela Verven, J. David Cas- 29. Lumbosacral Region/in [Injuries]
sidy, Douglas Gross, Gail Lindsay, John Stapleton, Leslie Verville,
Margareta Nordin, Michel Lacerte, Mike Paulden, Murray Krahn, 30. Osteoarthritis, Spine/
Patrick Loisel, and Roger Salhany. The authors also thank Trish 31. Piriformis Muscle Syndrome/
Johns-Wilson at the University of Ontario Institute of Technology 32. Polyradiculopathy/
for her review of the search strategy. This study was funded by the 33. Sacrococcygeal Region/
Ontario Ministry of Finance and the Financial Services Commis-
sion of Ontario (RFP No.: OSS_00267175). The funding agency 34. Sacroiliac Joint/
was not involved in the collection of data, data analysis, inter- 35. Sacrum/
pretation of data, or drafting of the manuscript. The research was 36. Sciatica/
undertaken, in part, thanks to funding from the Canada Research 37. Spinal Diseases/
Chairs program to Dr. Pierre Côté, Canada Research Chair in
Disability Prevention and Rehabilitation at the University of On- 38. Spinal Stenosis/
tario Institute of Technology. 39. (avulsed lumbar adj3 (disc* or disk*)).ab,ti.
40. (back adj3 (ache* or injur* or pain*)).ab,ti.
Conflict of interest Dr. Pierre Côté has received a grant from the 41. (backache* adj3 (injur* or pain*)).ab,ti.
Ontario Government, Ministry of Finance; a grant from Aviva
Canada; and funding from the Canada Research Chairs program. 42. (back pain or back-pain).ab,ti.
Dr. Robert Brison and Dr. Silvano Mior have received an honorarium 43. coccydynia.ab,ti.
as a guideline expert panel member. For the remaining authors, no 44. coccyx.ab,ti.
conflicts of interest were declared. 45. dorsalgia.ab,ti.
46. (lumbar disc* adj3 (extruded or degenerat* or herni-
at* or prolapse* or sequestered or slipped)).ab,ti.
Appendix I: MEDLINE (Ovid Technologies 47. (lumbar disk* adj3 (extruded or degenerat* or
Inc.) search strategy for whiplash-associated herniat* or prolapse* or sequestered or slipped)).ab,ti.
disorders, neck pain and associated disorders, non- 48. ‘‘low* back pain’’.ab,ti.
specific low back pain, and non-steroidal anti- 49. ‘‘low*-back-pain*’’.ab,ti.
inflammatory drugs (NSAIDs) 50. (lumbar adj3 (pain or facet or nerve root* or
osteoarthritis or radicul* or spinal stenosis or
1. Whiplash Injuries/ spondylo* or zygapophys*)).ab,ti.
2. Neck Injuries/ 51. ‘‘lumbarsacr*’’.ab,ti.
3. Neck Pain/ 52. lumboischialgia.ab,ti.
4. Neck Muscles/in [Injuries] 53. ‘‘lumbosacr*’’.ab,ti.
5. exp Cervical Vertebrae/in [Injuries] 54. ‘‘Piriformis syndrome*’’.ab,ti.
6. Radiculopathy/ 55. radiculalgia.ab,ti.
7. exp Brachial Plexus Neuropathies/ 56. (sacral adj2 pain*).ab,ti.
8. Torticollis/ 57. (sacrococcygeal adj2 pain*).ab,ti.
9. whiplash.ab,ti. 58. (sacroiliac or sacro-iliac).ab,ti.
10. ‘‘neck injur*’’.ab,ti. 59. ‘‘sciatic*’’.ab,ti.
11. ‘‘neck pain*’’.ab,ti. 60. (SI adj joint).ab,ti.
12. ‘‘cervical pain*’’.ab,ti. 61. (spinal adj stenos?s).ab,ti.
13. ‘‘neck ache*’’.ab,ti. 62. spondylosis.ab,ti.
14. ‘‘neckache*’’.ab,ti. 63. ‘‘tailbone adj3 pain*’’.ab,ti.

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64. ‘‘vertebrogenic adj3 pain*’’.ab,ti. 117. Algesalona.ti,ab.


65. or/21-64 118. Amigesic.ti,ab.
66. 20 or 65 119. Anacin.ti,ab.
67. exp Anti-Inflammatory Agents, Non-Steroidal/ 120. Anaflex 750.ti,ab.
68. alclofenac.ab,hw,ti,nm. 121. Anaprox.ti,ab.
69. Aspirin.ab,hw,ti,nm. 122. Ansaid.ti,ab.
70. Cyclooxygenase 2.ab,hw,ti,nm. 123. Arthitab.ti,ab.
71. benoxaprofen.ab,hw,ti,nm. 124. Arthropam.ti,ab.
72. Benzydamine.ab,hw,ti,nm. 125. Arthrotec.ti,ab.
73. Bufexamac.ab,hw,ti,nm. 126. Ascriptin.ti,ab.
74. celecoxib.ab,hw,ti,nm. 127. Bayer.ti,ab.
75. dexibuprofen.ab,hw,ti,nm. 128. Bayro.ti,ab.
76. dexketoprofen trometamol.ab,hw,ti,nm. 129. Bextra.ti,ab.
77. Diclofenac.ab,hw,ti,nm. 130. Bufferin.ti,ab.
78. Dipyrone.ab,hw,ti,nm. 131. Cambia.ti,ab.
79. Diflunisal.ab,hw,ti,nm. 132. Cataflam.ti,ab.
80. droxicam.ab,hw,ti,nm. 133. celebrex.ti,ab.
81. Etodolac.ab,hw,ti,nm. 134. Clinoril.ti,ab.
82. etofenamate.ab,hw,ti,nm. 135. Cuprofen.ti,ab.
83. etoricoxib.ab,hw,ti,nm. 136. Daypro.ti,ab.
84. Fenoprofen.ab,hw,ti,nm. 137. Diflamil.ti,ab.
85. firocoxib.ab,hw,ti,nm. 138. Dignodolin.ti,ab.
86. Flufenamic Acid.ab,hw,ti,nm. 139. Disalcid.ti,ab.
87. Flurbiprofen.ab,hw,ti,nm. 140. Doan’s Pills.ti,ab.
88. Ibuprofen.ab,hw,ti,nm. 141. Dolinac.ti,ab.
89. Indomethacin.ab,hw,ti,nm. 142. Dolobid.ti,ab.
90. isoxicam.ab,hw,ti,nm. 143. Duexis.ti,ab.
91. Ketoprofen.ab,hw,ti,nm. 144. Ecotrin.ti,ab.
92. Ketorola.ab,hw,ti,nm. 145. Feldene.ti,ab.
93. loxoprofen.ab,hw,ti,nm. 146. Fenbid.ti,ab.
94. lumiracoxib.ab,hw,ti,nm. 147. Fenomel.ti,ab.
95. lysine clonixinate.ab,hw,ti,nm. 148. Fentiazac.ti,ab.
96. Magnesium Salicylate.ab,hw,ti,nm. 149. Flector.ti,ab.
97. Meclofenamic Acid.ab,hw,ti,nm. 150. Flexidol.ti,ab.
98. Mefenamic Acid.ab,hw,ti,nm. 151. Flexium.ti,ab.
99. meloxicam.ab,hw,ti,nm. 152. Flogoprofen.ti,ab.
100. morniflumate.ab,hw,ti,nm. 153. Flurwood.ti,ab.
101. Naproxen.ab,hw,ti,nm. 154. Froben.ti,ab.
102. Niflumic Acid.ab,hw,ti,nm. 155. Hifenac.ti,ab.
103. Oxyphenbutazone.ab,hw,ti,nm. 156. Ibuprofen.ti,ab.
104. piketoprofen.ab,hw,ti,nm. 157. Indocin.ti,ab.
105. Piroxicam.ab,hw,ti,nm. 158. Indomethegan.ti,ab.
106. salicylsalicylic acid.ab,hw,ti,nm. 159. Ketofen.ti,ab.
107. Sulindac.ab,hw,ti,nm. 160. Lodine.ti,ab.
108. tenoxicam.ab,hw,ti,nm. 161. Magan.ti,ab.
109. Tolmetin.ab,hw,ti,nm. 162. Marthritic.ti,ab.
110. valdecoxib.ab,hw,ti,nm. 163. Meclomen.ti,ab.
111. or/67-110 164. Mobic.ti,ab.
112. Actron.ti,ab. 165. Mobidin.ti,ab.
113. Acular.ti,ab. 166. Mobogesic.ti,ab.
114. Advil.ti,ab. 167. Mono-Gesic.ti,ab.
115. Afrolate.ti,ab. 168. Motrin.ti,ab.
116. Aleve.ti,ab. 169. Nalfon.ti,ab.

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170. Naprelan.ti,ab. 223. NSAID*.ti,ab.


171. Naprosyn.ti,ab. 224. NSAIM*.ti,ab.
172. Niflatol.ti,ab. 225. salicylate*.ti,ab.
173. Niflugel.ti,ab. 226. or/209-225
174. Nifluril.ti,ab. 227. 208 or 226
175. Nixyn.ti,ab. 228. 66 and 227
176. Nuprin.ti,ab. 229. Meta-Analysis as Topic/
177. Oftalar.ti,ab. 230. Meta-Analysis.pt.
178. Orudis.ti,ab. 231. (meta adj analy*).ti,ab.
179. Oruvail.ti,ab. 232. metaanaly*.ti,ab.
180. Paraderm.ti,ab. 233. (systematic adj3 (review* or overview*)).ti,ab.
181. Parfenac.ti,ab. 234. (methodologic* adj3 (review* or overview*)).ti,ab.
182. Pennsaid.ti,ab. 235. (integrative adj3 (review* or overview*)).ti,ab.
183. Ponstel.ti,ab. 236. (collaborative adj3 (review* or overview*)).ti,ab.
184. Pranox.ti,ab. 237. exp Review Literature as Topic/
185. Relafen.ti,ab. 238. medline.ab.
186. Salflex.ti,ab. 239. pubmed.ab.
187. Salsitab.ti,ab. 240. cochrane.ab.
188. Sastridex.ti,ab. 241. embase.ab.
189. Solaraze.ti,ab. 242. (psychlit or psyclit).ab.
190. Solpaflex.ti,ab. 243. (psychinfo or psycinfo).ab.
191. Sprix.ti,ab. 244. (cinahl or cinhal).ab.
192. Suxibuzone.ti,ab. 245. science citation index.ab.
193. Tiloket.ti,ab. 246. (reference adj list*).ab.
194. Tolectin.ti,ab. 247. bibliograph*.ab.
195. Toradol.ti,ab. 248. (hand-search* or handsearch).ab.
196. Transact Lat.ti,ab. 249. manual search*.ab.
197. Traumalix.ti,ab. 250. or/229-249
198. Traumon.ti,ab. 251. Review/
199. Traxam.ti,ab. 252. (selection adj3 criteria).ab.
200. Trilisate.ti,ab. 253. (data adj3 (extraction or synthes*)).ab.
201. Triparsean.ti,ab. 254. 251 and (252 or 253)
202. Triscosal.ti,ab. 255. 250 or 254
203. Vimovo.ti,ab. 256. 228 and 255
204. Vioxx.ti,ab. 257. limit 256 to (english language and humans and
205. voltaren*.ti,ab. yr = ‘‘2000 -Current’’)
206. Voltarol.ti,ab.
207. or/112-206
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