PRACTICE
BMJ: first published as 10.1136/bmj.n104 on 29 January 2021. Downloaded from http://www.bmj.com/ on 9 February 2021 at SERGAS. Protected by copyright.
1 Institute for Musculoskeletal Health,
University of Sydney and Sydney
Local Health District, Sydney,
Australia
2 Sydney School of Public Health,
Faculty of Medicine and Health,
University of Sydney, Sydney,
Australia
3 Warwick Clinical Trials Unit, University
of Warwick, Coventry, UK
4 University Hospitals Coventry and
Warwickshire, Coventry, UK
5 Department of Clinical Pharmacology
and Toxicology, St Vincent’s Hospital,
Sydney, Australia
6 St Vincent’s Clinical School, University
of New South Wales, Sydney,
Australia
Correspondence to: G C Machado
gustavo.machado@sydney.edu.au
Cite this as: BMJ 2021;372:n104
http://dx.doi.org/10.1136/bmj.n104
Published: 29 January 2021
the bmj | BMJ 2021;372:n104 | doi: 10.1136/bmj.n104
THERAPEUTICS
Non-steroidal anti-inflammatory drugs (NSAIDs) for musculoskeletal
pain
Gustavo C Machado, 1 , 2 Christina Abdel-Shaheed, 1 , 2 Martin Underwood, 3 , 4 Richard O Day5 , 6
What you need to know
• Oral non-steroidal anti-inflammatory drugs (NSAIDs)
can reduce musculoskeletal pain but increase the
risk of gastrointestinal (perforation, ulcers, bleeding),
cardiovascular (myocardial infarction, heart failure,
hypertension), and renal adverse events
• Topical NSAIDs are also effective for osteoarthritis,
with fewer adverse events than oral formulations
• Opioids do not provide greater pain relief than NSAIDs
for musculoskeletal pain and may cause serious
harms such as dependence
A 65 year old patient has been troubled with
intermittent low back pain for years, for which you
prescribed ibuprofen 400 mg up to three times daily
as needed. For the past four months, persistent knee
pain, not associated with stiffness, has limited his
mobility. He is overweight, physically inactive, and has
recently been diagnosed with hypertension.
Paracetamol has had little benefit. He asks if taking
ibuprofen regularly might ease his knee pain.
What are non-steroidal anti-inflammatory
drugs (NSAIDs)?
NSAIDs are commonly used for pain management.
They reduce inflammation and pain by reducing the
activity of cyclo-oxygenase (or COX) enzymes and
inhibiting prostaglandin synthesis.1
Older, non-selective NSAIDs such as ibuprofen,
• radicular pain) need to be treated with NSAIDs, rather
diclofenac and naproxen inhibit both COX-1 and
COX-2 enzymes
• Newer, selective NSAIDs (COX-2 inhibitors, coxibs)
such as celecoxib and etoricoxib selectively inhibit
COX-2, which plays a greater role in prostaglandin
mediated pain and inflammation.
The National Institute for Health and Care Excellence
(NICE) guidelines recommend NSAIDs as first line
analgesics for low back pain and sciatica2 and
osteoarthritis.3 They are also used for musculoskeletal
pain from acute injury. In England there were about
11.5 million prescriptions for oral NSAIDs in 2018.4
In the US around 60% of patients with osteoarthritis
This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with
important new indications or concerns. The series advisers are Robin Ferner, honorary professor of clinical pharmacology, University of
Birmingham and Birmingham City Hospital, and Patricia McGettigan, clinical senior lecturer in clinical pharmacology, Queen Mary's University,
London. To suggest a topic, please email us at practice@bmj.com.
or chronic low back pain are prescribed NSAIDs,
based on analysis of records in a claims database in
2008.5
Search strategy
We searched PubMed (NLM database) and the Cochrane
Library with the terms “non-steroidal anti-inflammatory
drugs” OR “NSAIDs” AND “spinal pain” OR
“osteoarthritis” OR “musculoskeletal pain” for systematic
reviews of randomised trials published from 2000 to June
2020. We prioritised systematic reviews and studies on
the benefits, harms, and cost effectiveness of NSAIDs
for musculoskeletal pain in primary care. We also
searched clinical guidelines, our personal archives of
references, and screened the reference lists of studies
retrieved by the searches.
How well do NSAIDs work for musculoskeletal
pain?
Oral NSAIDs
Spinal pain
NSAIDs are slightly more effective than placebo at
reducing pain intensity and disability in people with
acute and chronic low back pain,6 7 as per Cochrane
systematic reviews. The differences are small and not
likely to be clinically relevant; about 7 points on a
0–100 pain scale. There is no difference in effects of
selective and non-selective NSAIDs.
Overall, five people (95% CI 4–6) with spinal pain
(that is, low back or neck pain with or without
than placebo, for one additional person to achieve
clinically important pain relief (>10 points on a 0–100
scale) over two weeks.8
Osteoarthritis
NSAIDs marginally improve osteoarthritis pain
compared with placebo over 12 weeks, based on a
network meta-analysis (76 randomised controlled
trials, 58 451 participants).9 More notable benefits
(>10 points on a 0–100 scale) are seen with high daily
doses of diclofenac (150 mg), naproxen (1000 mg),
ibuprofen (2400 mg) and etoricoxib (60 mg).9 Table
1 lists effect sizes for oral and topical NSAIDs
compared with placebo.
1
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Table 1 | Effects of non-steroidal anti-inflammatory drugs (NSAIDs) compared with placebo on musculoskeletal pain from systematic reviews of randomised

BMJ: first published as 10.1136/bmj.n104 on 29 January 2021. Downloaded from http://www.bmj.com/ on 9 February 2021 at SERGAS. Protected by copyright.
trials
Mean difference (95% CI) on
Condition NSAID daily dose* Treatment duration No of trials (participants) Quality of evidence
0-100 pain scale
Acute low back pain6 Non-selective NSAIDs Up to 3 weeks 4 (815) −7.3 (−11.0 to −3.6) Moderate
Non-selective NSAIDs Up to 16 weeks 4 (847) −6.0 (−11.0 to −1.0) Low
Chronic low back pain7
Coxibs Up to 16 weeks 2 (507) −9.1 (−13.6 to −4.7) Low
Sciatica8 Non-selective NSAIDs Up to 1 week 7 (1641) −6.2 (−8.2 to −4.2) High
Etoricoxib 60 mg Up to 12 weeks 3 (2115) −14.1 (−17.8 to −10.5) NR
Osteoarthritis (oral Diclofenac 150 mg Up to 12 weeks 2 (1172) −13.9 (−16.8 to −11.2) NR
formulations)9 Ibuprofen 2400 mg† Up to 12 weeks 5 (3396) −10.5 (−13.4 to −7.5) NR
Naproxen 1000 mg Up to 12 weeks 13 (10 079) −9.7 (−11.4 to −8.0) NR
Diclofenac patch 1.3% Up to 2 weeks 2 (245) −19.7 (−27.2 to –12.6) NR
Ibuprofen cream 5% Up to 2 weeks 3 (214) −16.5 (−23.8 to –9.2) NR
Osteoarthritis (topical
Piroxicam cream 1% Up to 1 week 1 (179) −12.2 (−21.6 to −2.7) NR
formulations)10
Diclofenac gel 1–3% Up to 12 weeks 7 (1776) −7.3 (−10.7 to −4.1) NR
Diclofenac solution 1.5–2% Up to 12 weeks 5 (1272) −7.1 (−10.7 to −3.4) NR
Non-selective NSAIDs Up to 6 weeks 4 (850) −16.5 (−20.8 to −12.2) High
Axial spondyloarthritis11
Coxibs Up to 6 weeks 2 (349) −21.7 (−35.9 to −7.4) High
Rotator cuff tendinopathy12 Non-selective NSAIDs Up to 4 weeks 2 (160) −2.7 (−3.4 to −2.0) Moderate
Diclofenac 150 mg Up to 4 weeks 1 (128) −13.9 (−23.2 to −4.6) NR
Lateral elbow pain13
Diclofenac gel 1.3–2% Up to 2 weeks 3 (153) −16.4 (−24.2 to −8.6) NR
Non-selective NSAIDs and
Acute ankle sprain14 Up to 10 days 2 (162) −6.1 (−7.4 to −4.8) NR
Coxibs
Diclofenac gel 1% Up to 2 weeks 2 (314) NNT 1.8 (1.5 to 2.1)‡ High
Acute soft-tissue injury15 Ibuprofen gel 5% 1 week 2 (241) NNT 3.9 (2.7 to 6.7)‡ Moderate
Ketoprofen gel 2.5% 1 week 5 (348) NNT 2.5 (2.0 to 3.4)‡ Moderate
CI=confidence interval. Coxibs=selective COX-2 inhibitors. NR=not reported.

* NSAID daily doses for acute low back pain included diclofenac 75−100 mg, ibuprofen 1200 mg, piroxicam 20−40 mg and tenoxicam 20 mg. NSAID daily doses for chronic low back pain included diflunisal 1000 mg,
etoricoxib 60−90 mg, naproxen 1000 mg, piroxicam patch/cream 14 mg and valdecoxib 40 mg. NSAID daily doses for sciatica included diclofenac 50−150 mg, etodolac 300−600 mg, lornoxicam 16−24 mg, meloxicam
15 mg, piroxicam 40 mg (oral or intramuscular injection) and tenoxicam 20 mg (intramuscular injection). NSAID daily doses for axial spondyloarthritis included celecoxib 100 mg, etoricoxib 90−120 mg, ketoprofen 100 mg,
meloxicam 15−22.5 mg, naproxen 1000 mg, piroxicam 20 mg and ximoprofen 5−30 mg. NSAID daily doses for rotator cuff tendinopathy included diclofenac 150 mg and naproxen 1000 mg. NSAID daily doses for acute
ankle sprain included diclofenac 150 mg and celecoxib 400 mg.
† Doses of ibuprofen 2400 mg/day are not typical in osteoarthritis management, which is usually treated with ≤1200 mg/day.
‡ NNT=number needed to treat, the number of patients who need to be treated with NSAIDs, rather than placebo, for one to respond with 50% pain relief or achieve a clinically important pain reduction (>10 points, on a
0–100 scale).

Other arthritic and musculoskeletal conditions
NSAIDs are effective in reducing pain from axial spondyloarthritis,11
rotator cuff tendinopathy (shoulder pain),12 and acute ankle
sprain,14 as per systematic reviews. There is scant and conflicting
evidence for lateral elbow pain.13 Recent draft NICE guidance advises
against the use of NSAIDs for some types of chronic pain, such as
fibromyalgia and chronic pelvic pain.16
Topical NSAIDs
Osteoarthritis
Topical NSAIDs are superior to placebo in relieving pain from
osteoarthritis, as per a network meta-analysis,10 and a Cochrane
review.17 Diclofenac patches were most effective for pain, and
piroxicam for functional improvement. Only diclofenac patch and
ibuprofen gel/cream provide clinically important pain relief (>1.2
points on a 0–10 scale).10 Pain relief is similar to oral NSAIDs in
knee osteoarthritis with fewer side effects, as per two randomised
controlled trials.18 19 A randomised controlled trial (775 participants)
found no additional benefit of combining topical and oral NSAIDs
over either formulation alone for knee osteoarthritis.20 Topical
NSAIDs do not increase the risk of gastrointestinal adverse events
(odds ratio 1.0, 95% CI 0.7 to 1.3) or cardiovascular events (odds
ratio 1.2, 95% CI 0.6 to 2.4) compared with placebo.21 European
guidelines advise topical NSAIDs as first line treatment for hand
osteoarthritis.22 The Cochrane review found no evidence for their
use in other chronic musculoskeletal pain, such as low back pain.17
Acute injuries
Topical NSAIDs provide good levels of pain relief for musculoskeletal
pain from acute injuries such as a sprained ankle or a muscle pull,
as per high quality evidence from a Cochrane review (61 studies,
8386 participants). Gel formulations of diclofenac, ibuprofen, and
ketoprofen and diclofenac patches are the most effective.15 Topical
NSAIDs may improve lateral elbow pain (or tennis elbow), but the
evidence is of low quality.13
How do NSAIDs compare with other drugs?
Paracetamol23 and opioids24 25 are ineffective for low back pain and
may provide modest short term pain relief in osteoarthritis, as per
systematic reviews.
For acute low back pain, there is no difference between NSAIDs and
paracetamol on pain intensity (mean difference −0.7, 95% CI −2.5
to 1.1), as per a Cochrane review.6 Small trials show comparable

2 the bmj | BMJ 2021;372:n104 | doi: 10.1136/bmj.n104


pain relief between NSAIDs and paracetamol-codeine, tramadol,
or meptazinol—these effects were not clinically important.6 Most
systematic reviews comparing NSAIDs with other drugs focus on
pain intensity. Data on function or quality of life are often limited.
Most studies consider a between-group difference of 10 points (on
a 0–100 scale) as clinically important.
A Cochrane review on chronic low back pain found no difference
between NSAIDs and paracetamol and pregabalin in pain intensity,
based on data from small trials.7 A single trial reported greater
global improvement with celecoxib compared with tramadol (risk
ratio 1.3, 95% CI 1.2 to 1.4).7 There is insufficient evidence on the
comparative effectiveness of NSAIDs versus other drugs for sciatica
or neck pain.
For knee or hip osteoarthritis, NSAIDs are slightly more effective
than paracetamol (standardised mean difference −0.3, 95% CI −0.4
to −0.2) as per a systematic review (15 randomised controlled
trials).26 This small effect is equivalent to 7.3 points on a 0–100
Table 2 | Risk ratios (95% confidence intervals) for adverse events of oral NSAIDs compared with placebo from randomised trials30
NSAID daily dose GI adverse events
Coxibs* 1.81 (1.17 to 2.81)
Diclofenac 150 mg 1.89 (1.16 to 3.09)
Ibuprofen 2400 mg† 3.97 (2.22 to 7.10)
Naproxen 1000 mg 4.22 (2.71 to 6.56)
GI=gastrointestinal. NSAIDs=non-steroidal anti-inflammatory drugs.
* Selective COX-2 inhibitors: celecoxib, rofecoxib, etoricoxib, and lumiracoxib.
† Doses of 2400 mg ibuprofen daily are not typical in the management of osteoarthritis, which is usually treated with ≤1200 mg daily. The adverse event estimates are based on a meta-analysis30 of individual participant
data from randomised trials on non-selective or selective NSAIDs versus placebo in patients with rheumatoid arthritis and osteoarthritis and treatments lasting for up to 26 weeks.
Gastrointestinal events
Taking any NSAID increases the risk of upper gastrointestinal
adverse events (perforations, ulcers, bleeding) by two to four times
compared with non-use, as per a systematic review (639 randomised
trials).30 Coxibs and diclofenac yield the lowest increase in risk.
Dyspepsia (indigestion) affects 8-12% of people taking high dose
non-selective NSAIDs.31 The risk is 12% lower with coxibs and 66%
lower with a combination of a non-selective NSAID plus a proton
pump inhibitor.32
The increase in gastrointestinal risk can be up to sevenfold greater
with use of high versus low/medium daily doses of NSAIDs.30 33 For
example, diclofenac <75 mg/day does not increase risk of
gastrointestinal bleeds, but daily doses of 75-149 mg or ≥150 mg
increase the risk by three and 12 times respectively compared with
non-use.33 The risk seems to be higher in the first week, reduces
thereafter with continuing use, and drops one week after stopping
use.33 Taking two or more NSAIDs concurrently substantially
increases gastrointestinal risk.33
In older adults, combining NSAIDs with aspirin or anticoagulants
increases the risk of gastrointestinal bleeding by 13 times compared
with non-use of either drug.34
Cardiovascular events
Coxibs and diclofenac increase the risk of myocardial infarction by
about 70% compared with placebo,30 while ibuprofen 2400 mg daily
doubles the risk.30 Naproxen seems to be safer, but observational
data show it increases the odds of myocardial infarction by 53%.35
A trial with 24 081 participants found that celecoxib was equivalent
the bmj | BMJ 2021;372:n104 | doi: 10.1136/bmj.n104
PRACTICE
scale. A trial with 892 participants found that combining ibuprofen
with paracetamol reduces knee pain in the short term more than
BMJ: first published as 10.1136/bmj.n104 on 29 January 2021. Downloaded from http://www.bmj.com/ on 9 February 2021 at SERGAS. Protected by copyright.
paracetamol but not ibuprofen alone.27 A systematic review (17
studies) found comparable reduction in pain from knee osteoarthritis
with NSAIDs (−18 points), weak opioids such as tramadol (−18
points), and strong opioids such as hydromorphone and oxycodone
(−19 points).28 Withdrawal rates due to toxicity were lower with
NSAIDs. There was no difference between duloxetine, an
antidepressant, and oral NSAIDs in osteoarthritis in a systematic
review.29
What are the harms?
Safety is a concern for all NSAIDs, especially in older people, those
with multi-system disorders, and persons at higher risk of
cardiovascular and renal adverse events. The risk of adverse events
with NSAIDs seems to be dose dependent. There is insufficient
evidence on long term risks. Table 2 provides relative risks of
common NSAIDs compared with placebo.
Myocardial infarction Stroke Heart failure
1.76 (1.31 to 2.37) 1.09 (0.78 to 1.52) 2.28 (1.62 to 3.20)
1.70 (1.19 to 2.41) 1.18 (0.79 to 1.78) 1.85 (1.17 to 2.94)
2.22 (1.10 to 4.48) 0.97 (0.42 to 2.24) 2.49 (1.19 to 5.20)
0.84 (0.52 to 1.35) 0.97 (0.59 to 1.60) 1.87 (1.10 to 3.16)
to ibuprofen and diclofenac for cardiovascular risk, but the trial
had significant methodological concerns such as high drop-out rate
and low average dose of celecoxib taken.36 Observational studies
find NSAIDs increase the risk of haemorrhagic stroke by a third,
mostly related to diclofenac or meloxicam use.37
NSAIDs double the risk of heart failure compared with placebo in
randomised trials,30 and observational data confirm this.38 NSAIDs
can worsen heart failure, the risk being greater in people with renal
impairment, particularly if they are taking diuretics.39 The risk of
hospitalisation for heart failure while taking NSAIDs is higher in
patients with established cardiovascular disease than in those
without; odds ratio 10.5 (95% CI 2.5 to 44.9) versus 1.6 (95% CI 0.7
to 3.7).40
No safe NSAID treatment window exists in people with
cardiovascular disease. Risk starts to increase within a week of
starting NSAID treatment35 and increases further with longer use.
Stopping NSAID use drops the risk level similar to that of non-users
after three months.41 Diclofenac was associated with the highest
risk of death and recurrent myocardial infarction immediately after
the start of treatment (hazard ratio 3.3, 95% CI 2.6 to 3.9, at day 1-7
of treatment) and throughout the treatment course in a Danish
nationwide cohort study.42 The increased cardiovascular risk seems
to be dose dependent for celecoxib, ibuprofen, and naproxen,
whereas both low and high doses of diclofenac increase risk by
similar amounts.43
Renovascular events and hypertension
NSAIDs can impair renal function because COX enzymes are also
involved in the synthesis of renal prostaglandins and prostacyclin.
3
 PRACTICE
Risk ratios range from 1.3 to 2.2 among individual NSAIDs compared
with non-use.44 Coxibs have a similar risk of renal failure. The risk
seems to be dose dependent, regardless of the type of NSAID
used—relative risk of renal failure in NSAID users (compared with
non-users) is 2.5 with low or medium daily doses and 3.4 with high
daily doses.45 High daily doses of NSAIDs also increase the risk of
renal events in active young and middle aged adults.46
Most NSAIDs increase blood pressure, which could be a mechanism
for increased cardiovascular risk. NSAID use can increase mean
blood pressure by 5.0 mm Hg (95% CI 1.2 to 8.7).47 Ibuprofen,
compared with celecoxib or naproxen, is associated with increased
systolic blood pressure and a higher incidence of new onset
hypertension.48
Pregnancy
In the first trimester NSAIDs can increase the risk of miscarriage.49
In the third trimester, NSAIDs pose fetal risks, such as preterm
birth50 and premature closure of the ductus arteriosus.51 NSAID use
in the second trimester is reasonably safe, but there have been
reports of ductus arteriosus constriction and oligohydramnios
(deficient volume of amniotic fluid).52 Fetal monitoring from 20
weeks of pregnancy onwards is recommended in women with long
term NSAID use.
Respiratory events
The prevalence of NSAID-exacerbated respiratory disease is about
9% in adults with chronic asthma.53 Coxibs are less likely to be a
problem for asthmatic patients, although there have been case
reports.54 NSAID use is associated with a complicated course of
respiratory tract infections, as per a recent review of case-control
studies.55
Despite recent concerns, there is currently no evidence that the
acute use of NSAIDs causes an increased risk of developing covid-19
or of developing more severe covid-19 mortality.56 However, there
is only limited data for those taking NSAIDs long term.
How are NSAIDs given and monitored?
Managing chronic musculoskeletal pain is complex. Given the
potential harms of drugs, it is important to discuss the benefits and
risks with your patient, and their expectations for symptomatic
relief. Box 1 lists useful pointers to discuss with your patient. It is
important to consider non-pharmacological therapies as well.
Box 1: Tips for patients about use of NSAIDs
• NSAIDs provide small to moderate pain relief for back pain,
osteoarthritis, and musculoskeletal pain from overuse or injury
• Topical preparations are just as good as, and safer than, oral NSAIDs
for knee or hand osteoarthritis
• NSAIDs should be used for the shortest possible time and at the lowest
effective dose (if any beneficial effect), and stopped if no benefit is
experienced
• There is no added benefit from taking two different oral NSAIDs at
once, nor combining oral with topical NSAIDs, and this can be harmful
• If you have asthma, renal disease, or a history of stomach ulcers or
are taking blood pressure lowering medication or blood clotting
inhibitors such as aspirin, taking NSAIDs can increase your risk of
serious adverse events. Check with your doctor first before taking any
NSAID
• Bleeding from the stomach is uncommon, but taking NSAIDs can
increase the risk by up to four times. Speak to your doctor or
pharmacist about how this could be avoided
4 the bmj | BMJ 2021;372:n104 | doi: 10.1136/bmj.n104
• Oral NSAIDs may double the risk of developing heart disease, may
BMJ: first published as 10.1136/bmj.n104 on 29 January 2021. Downloaded from http://www.bmj.com/ on 9 February 2021 at SERGAS. Protected by copyright.
increase blood pressure, and may triple the risk of kidney disease if
you have impaired kidney function
• Look out for signs and symptoms of NSAID related adverse events,
such as blood in stools (black, tarry stools) or any unusual changes,
including difficulty breathing, nausea, fatigue, reduced urine output,
fainting, ankle or leg swelling, and chest or abdominal pain. Report
these to your doctor immediately
Assess your patient’s risk profile before prescribing NSAIDs—such
as age, history of gastrointestinal or cardiovascular events,
hypertension, asthma, renal insufficiency, or bleeding disorders.
Lower doses, and intermittent or as needed use may be safer than
regular use, particularly for gastrointestinal safety. NSAIDs often
have a ceiling dose, above which additional benefit is unlikely but
risk of harm is more likely—for example, the analgesic ceiling dose
of ibuprofen is 400 mg/dose,57 with a maximum dose of 2400
mg/day. Box 2 lists tips for safer prescribing.
Box 2: Tips for safer prescribing of NSAIDs
• Use with caution—that is, for the shortest time and lowest effective
dose possible
• Review existing medications, such as concurrent use of anticoagulants
or antiplatelet medicines, before prescribing NSAIDs
• For knee or hand osteoarthritis, topical preparations are preferred to
oral NSAIDs as they are associated with similar benefits and less risk
of harms
• Ibuprofen (≤1200 mg daily) and naproxen have the lowest
cardiovascular risk but do increase risk of gastrointestinal adverse
events58
• Avoid high dose ibuprofen (2400 mg daily), diclofenac, and coxibs
in people with cardiovascular conditions58
• Moderate doses of celecoxib may be non-inferior to naproxen and
ibuprofen in terms of cardiovascular safety
• Avoid NSAIDs in people with chronic kidney disease. Regularly monitor
renal function in people at risk of renal failure, including obtaining a
baseline serum creatinine level when starting NSAID therapy
• NICE guidelines advise co-prescription of a proton pump inhibitor
with non-selective NSAIDs in people with musculoskeletal pain aged
over 45 years3 and in those with a history of dyspepsia or past ulcer
or taking antithrombotic medicines58
• For people who have had an NSAID-related upper gastrointestinal
bleed, but who must take NSAIDs, co-prescription of a proton pump
inhibitor, misoprostol, or double-dose histamine blockers has been
shown to prevent future events59
• Avoid NSAIDs in pregnancy, particularly in the first and third trimester
Drug interactions are important. NSAIDs can block the antiplatelet
effect of low dose aspirin used for prevention of cardiovascular
disease, so combined use is discouraged; aspirin should not be
stopped however. Coxibs such as celecoxib do not seem to do this
as aspirin affects platelets via COX-1,60 but they can nevertheless
increase cardiovascular risk.61 62 The antihypertensive effect of
diuretics may be negated with NSAID use because of blockage of
prostaglandins responsible for natriuresis.
How cost effective are they?
NSAIDs that are available by over the counter (such as ibuprofen
and naproxen) or on prescription (such as celecoxib) are relatively
cheap. In England the average cost of NSAIDs per prescription item
in 2018 was £5.38.4 Cost effectiveness of long term oral NSAID

therapy has been evaluated for osteoarthritis in modelling studies.
A modelling study found that co-prescribing a proton pump inhibitor
with any NSAID is cost effective in osteoarthritis, even in those at
low risk of gastrointestinal events.63 In a simulation model,
naproxen or ibuprofen with a proton pump inhibitor are more
cost-effective in managing osteoarthritis pain than opioids or
celecoxib.64 In a decision-tree modelling, perceived optimal
osteoarthritic pain relief from paracetamol, ibuprofen, or celecoxib
seems to depend on the willingness-to-pay threshold (that is, the
maximum amount a patient might be prepared to pay for the health
benefit),65 but another modelling found celecoxib more cost-effective
than paracetamol and non-selective NSAIDs.66
Education into practice
• In which situations would you consider prescribing oral NSAIDs for
musculoskeletal pain relief?
• What are the implications of prescribing NSAIDs for musculoskeletal
pain in patients taking aspirin?
• How would you discuss the risks and benefits with your patient when
prescribing NSAIDs for chronic musculoskeletal pain?
How patients were involved in the creation of this article
Two patients from a community pharmacy in Sydney reviewed this paper
and had an informal interview with one of the authors. The patients
suggested it was important to clarify whether taking two different oral
NSAIDs at once or combining oral with topical NSAIDs result in additional
benefits. They also suggested recommendations for identifying adverse
events associated with NSAIDs, such as stomach bleeds, and examples
of health conditions and medications where it may be best to check with
a doctor or a pharmacist before taking NSAIDs. Based on their feedback,
we searched for evidence and revised the manuscript and the content
for the section “Tips for patients” accordingly. We thank the patients for
their comments.
Contributors: GCM wrote the first draft of the manuscript. All authors complemented, revised, and
finalised subsequent versions and approved the final version of the manuscript. GCM is guarantor.
Funding: None.
Competing interests: We have read and understood the BMJ Group policy on declaration of interests
and declare the following interests: GCM holds an Australian National Health and Medical Research
Council (NHMRC) Early Career Fellowship (APP1141272). Flexeze provided heat wraps at no cost for
the SHaPED trial that GCM is an investigator on. CAS is an academic fellow at the University of Sydney.
Flexeze provided heat wraps at no cost for the HEAT pilot trial that CAS is lead investigator on. MU is
chief investigator or co-investigator on multiple previous and current research grants from the UK NIHR,
Arthritis Research UK, and is a co-investigator on grants funded by the Australian NHMRC. He is an
NIHR senior investigator. He has received travel expenses for speaking at conferences from the
professional organisations hosting the conferences. He is a director and shareholder of Clinvivo, which
provides electronic data collection for health services research. He is part of an academic partnership
with Serco related to return to work initiatives. He is a co-investigator on two NIHR funded studies that
receive additional support from Stryker. He has accepted honoraria for teaching/lecturing from a
consortium for advanced research training in Africa. Until March 2020 he was an editor of the NIHR
journal series, and a member of the NIHR Journal Editors Group, for which he received a fee. ROD has
been involved with consultancies for Reckitt Benkiser on advice on ibuprofen; all payments were made
to an audited trust fund at St Vincent’s Hospital. Payment to ROD was made for expert testimony
regarding a veterinary anti-arthritic product unrelated to NSAIDs.
Transparency: The lead author (GCM) affirms that the manuscript is an honest, accurate, and transparent
account of the study being reported; no important aspects of the study have been omitted.
Provenance and peer review: Commissioned, based on an idea from the author; externally peer
reviewed.
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2 National Institute for Health and Care Excellence. Low back pain and sciatica in over 16s:
assessment and management (NICE guideline NG59). 2020. https://www.nice.org.uk/guid-
ance/ng59.
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