BMJ 2013;346:f3195 doi: 10.1136/bmj.

f3195 (Published 11 June 2013) Page 1 of 7

Practice

PRACTICE

THERAPEUTICS

Non-steroidal anti-inflammatory drugs (NSAIDs)

12 12
Richard O Day professor of clinical pharmacology , Garry G Graham professorial visiting fellow

Department of Pharmacology, University of New South Wales, Sydney, Australia; 2Department of Clinical Pharmacology and Toxicology, St Vincent’s
1

Hospital, Sydney, Australia

This is one of a series of occasional articles on therapeutics for common • For acute pain and dysmenorrhoea, meta-analyses indicate
or serious conditions, covering new drugs and old drugs with important that both classes of NSAIDs are highly effective analgesics
new indications or concerns. The series advisers are Robin Ferner, compared with placebo (table 1).
honorary professor of clinical pharmacology, University of Birmingham
and Birmingham City Hospital, and Albert Ferro, professor of • For acute gout, clinical trials show that both groups of
cardiovascular clinical pharmacology, King’s College London. To suggest NSAIDs lead to a rapid relief of pain and inflammation,
a topic for this series, please email us at [email protected]. and are thus recommended by rheumatological
associations.8 Colchicine and corticosteroids are
A 70 year old obese woman asks if more can be done for her alternatives. Colchicine causes considerable diarrhoea and
knee and low back pain, due to osteoarthritis. She used to smoke nausea, but a recent randomised controlled trial indicates
and has type 2 diabetes. Her orthopaedic surgeon does not that the new low dose (1.8 mg over one hour) for an acute
consider the clinical presentation and radiographic changes in attack has greatly decreased the adverse effects.9
her knees severe enough for surgery. Her height is 160 cm,
weight 85 kg, blood pressure 130/80 mm Hg, with normal renal • Both groups of NSAIDs play a useful but adjunctive
function, plasma cholesterol concentration 5.5 mmol/L, and anti-inflammatory role in rheumatoid arthritis, although
HDL cholesterol concentration 0.9 mmol/L. Her present drug disease control with antirheumatic drugs such as
treatment is paracetamol (4 g daily) and metformin. methotrexate and biological agents is critical.

What are non-steroidal anti-inflammatory • Both groups of NSAIDs are often used for osteoarthritis
and low back pain; their effectiveness is generally small
drugs (NSAIDs)? (Table 1). Patients often take either type of NSAID when
NSAIDs act by inhibiting cyclo-oxygenase-1 (COX-1) and osteoarthritis flares. It is generally considered that this
COX-2 enzymes, which are involved in prostaglandin synthesis, approach reduces the risk of adverse effects. However,
resulting in their analgesic, anti-inflammatory, and antipyretic patients taking celecoxib, at least, report a better response
effects (figure⇓). Although the boundary is blurred, there are without an increase in adverse effects when this is taken
two broad groups of NSAIDs—the older, traditional, continuously, rather than just with flares.10 A systematic
non-selective NSAIDs that inhibit both COX-1 and COX-2 and review indicates that walking and strengthening of the
the newer, selective COX-2 inhibitors that predominantly inhibit quadriceps decreases pain and disability of osteoarthritis
COX-2 (figure⇓). The non-selective NSAID aspirin is used of the knee.11 Weight loss in those who are overweight is
primarily for its antiplatelet effect, thus reducing the risk of also important for improvement in symptoms in
myocardial re-infarction and stroke. osteoarthritis of weight-bearing joints.4

How well do NSAIDs work? Topical NSAIDs

Table 1⇓ shows the indications and effectiveness of the various Creams, solutions, gels, sprays, and patches of non-selective
NSAIDs. There is little difference in their mean efficacy, NSAIDs are widely used for their local effects, low systemic
although a review of individual patient data indicates that absorption, and considerable safety. For acute soft-tissue injuries
patients vary in their responses to different NSAIDs.7 (sprains, minor injuries, etc), systematic reviews have shown
Effectiveness may vary with different conditions. that topical products are more effective than placebo products
(table 1⇓). For effects on osteoarthritis, the most comprehensive
data have been obtained with diclofenac. Although the results
of clinical trials are variable, systematic reviews indicate that

Correspondence to: R O Day [email protected]

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BMJ 2013;346:f3195 doi: 10.1136/bmj.f3195 (Published 11 June 2013) Page 2 of 7

PRACTICE

the available gel formulations of diclofenac provide greater meta-analysis of 280 randomised controlled trials of NSAIDs
relief of pain than placebo, though the improvement is small versus placebo.14 Conclusions from the two analyses are
(table 1⇓). They are recommended by the UK National Institute generally similar, but a notable difference is the increased risk
for Health and Care Excellence (NICE) for patients with mild of myocardial infarction during ibuprofen therapy at about 2400
or moderate osteoarthritis of the hand and knee, particularly for mg daily14 compared with the statistically non-significant effect
elderly patients.12 at 1200 mg daily in patients at low risk of cardiovascular events
(table 2⇓).15
How safe are NSAIDs? Stroke does not seem to be associated with either class of
NSAID.14 15
Harm from both types of NSAID is a major problem in
osteoarthritis because of their prolonged use in the treatment of Naproxen seems to be the safest NSAID, with a similar rate of
this disease. The risk of adverse effects increases substantially myocardial infarction as with no treatment, from meta-analyses
in patients over 70 years old and with duration of use and size of randomised controlled trials (table 2⇓).14 15 20 The safety of
of dose, and is affected by individual risk factors, particularly naproxen cannot be guaranteed in all patients, but low dose
for cardiovascular or gastrointestinal harm.13 naproxen (≤750 mg per day) is recommended when NSAIDs
need to be used in patients at a low to a moderate risk of
Gastrointestinal adverse effects cardiovascular events and the patients are not taking aspirin.21
Of the non-selective NSAIDs, diclofenac seems to have the
The major adverse effect of the non-selective NSAIDs is serious greatest risk of myocardial infarction, with a rate ratio of 1.7
injury to the upper gastrointestinal tract (perforations, ulcers, versus placebo (95% confidence interval 1.31 to 2.37,
bleeding) (table 2⇓).14 15 COX-2 selective inhibitors are P=0.0032), similar to COX-2 selective drugs (table 2⇓).14-16 Low
associated with less upper gastrointestinal tract toxicity (table dose ibuprofen (≤1200 mg/day) is recommended as an
2),15 although a recent, large meta-analysis of randomised alternative provided that patients are not taking aspirin.16
controlled trials has challenged this conclusion.14 Modelling
indicates that adding a proton pump inhibitor to an NSAID Interactions with aspirin; cardiovascular
reduces the rate of upper gastrointestinal adverse effects, and implications
(because of the small cost of adding a proton pump inhibitor
and the savings from not having to treat gastrointestinal adverse The antiplatelet effect of low dose aspirin is blocked by all
effects) this is cost effective for both non-selective and selective non-selective NSAIDs except diclofenac, provided that
COX-2 inhibitors in the UK at about £1000 per quality adjusted diclofenac is administered two hours after aspirin.22 Selective
life year (QALY) based on UK prices for 2009.15 COX-2 inhibitors do not block the antiplatelet effects of low
dose aspirin. Low dose aspirin is used for patients at high risk
Despite the cost-benefit analysis, the routine use of a proton
of myocardial infarction, and there is obvious concern about
pump inhibitor with any NSAID is still controversial. If either
the use of selective COX-2 inhibitors, which have adverse
type of NSAID is used long term in treating osteoarthritis, NICE
cardiovascular effects. However, low dose aspirin can be used
recommends the concomitant use of a proton pump inhibitor,12
concomitantly with, preferably, low doses of selective COX-2
whereas an advisory group recommends a proton pump inhibitor
inhibitors.17 18
only for patients at high risk of toxicity in the upper
gastrointestinal tract.16
Cardiac failure and renal impairment
Aspirin decreases the gastrointestinal tolerance of selective
COX-2 inhibitors, although a selective COX-2 inhibitor plus As renal prostaglandins and prostacyclin are synthesised by
aspirin may still be better tolerated than a non-selective NSAID both COX-1 and COX-2,23 both classes of NSAIDs increase the
alone.17 risk of further renal impairment and of worsening cardiac failure
(table 2⇓)14 15—the latter being a particular risk for patients with
Dyspepsia is common with both types of NSAID, although a renal impairment. For patients taking angiotensin converting
meta-analysis indicates that the risk is slightly smaller (12%) enzyme inhibitors or angiotensin inhibitors, particularly those
with the selective COX-2 inhibitors.18 Many patients have with impaired renal function, both classes of NSAID can lead
decreasing dyspepsia despite continuing treatment with either to increased plasma potassium concentration and further
type of NSAID.18 It should be noted that the presence of deterioration in kidney function.18
dyspepsia does not predict peptic ulceration, bleeding, or
perforation.
Hypertension
Long term treatment with both classes of NSAIDs may also
All NSAIDs cause a dose dependent increase in blood pressure.
cause bleeding and possible obstruction in the small intestine
The mean increase is around 2-3 mm Hg in systolic blood
beyond the duodenum, even when taken with a proton pump
pressure, but it can be dramatic and may be greater in patients
inhibitor.19 This problem is largely hidden, but in individuals
with hypertension or those taking angiotensin converting enzyme
taking NSAIDs long term, iron deficiency anaemia may indicate
inhibitors, angiotensin II receptor blockers, β blockers, or
damage to the small intestine in the absence of damage to the
diuretics.13 24 The increases may be least in patients taking
upper gastrointestinal tract. There is now good evidence that
calcium channel blockers, but this is not conclusive.24
both classes of NSAID exacerbate ulcerative colitis and Crohn’s
disease19 and may injure the large intestine.
Aspirin induced asthma
Cardiovascular adverse effects A systematic review showed that taking aspirin reduces forced
expiratory volume in one second (FEV1) in about 20% of adults
Arterial thrombosis
and 5% of children with asthma.25 There is almost total cross
There remain some uncertainties about the risk of myocardial reactivity with the non-selective NSAIDs. However, asthma
infarction with both classes of NSAID. Two analyses are of has not been produced by selective COX-2 inhibitors in double
note: a cost effectiveness analysis of data from three large
controlled clinical studies on NSAIDs (table 2⇓)15 and a recent
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BMJ 2013;346:f3195 doi: 10.1136/bmj.f3195 (Published 11 June 2013) Page 3 of 7

PRACTICE

blind challenge tests on asthmatic patients sensitive to aspirin,26 COX-2 inhibitor with proton pump inhibitor. Note that
although a few case reports of this exist. naproxen blocks the antiplatelet effects of aspirin.
Aspirin sensitive asthma—Avoid non-selective NSAIDs.
Pregnancy Selective COX-2 inhibitors can generally be taken, although
A large epidemiological study has found that both classes of the first dose should be taken under medical supervision.26
NSAID may lead to abortion in the first trimester, with an odds Pregnancy—Avoid all NSAIDs as far as possible. Where
ratio of 2.43 (95% confidence interval 2.12 to 2.79) compared NSAID use is essential, limit the dose during early pregnancy
with women not taking NSAIDs.27 Both classes of NSAID may because of the risk of miscarriage and in late pregnancy
also delay labour and lead to premature closure of the ductus because of the risk of delayed delivery and increased blood
arteriosus, while non-selective NSAIDs may increase blood loss loss.
at delivery.28 Pregnant patients should not take NSAIDs with
misoprostol, which is a prostaglandin analogue used to prevent Lactation—Babies may be breast fed if either type of NSAID
NSAID associated ulcers and may also induce miscarriage. is used, as levels of celecoxib and ibuprofen are very low in
breast milk.31 32 This is likely to be the case for all NSAIDs.
Rare adverse effects
These do not seem to be related to dose and include
Monitoring treatment with NSAIDs
hepatotoxicity (particularly with diclofenac and ibuprofen). Gastrointestinal adverse effects—If risk is high, monitor
Aseptic meningitis has been reported mainly in patients with haemoglobin levels for 1-4 weeks after the start of treatment.
inflammatory diseases,29 while serious skin disorders, such as At all times, measure haemoglobin if there are symptoms
Stevens Johnson Syndrome, have been reported very rarely with and signs suggestive of bleeding. If dyspepsia develops
several NSAIDs. without signs of gastrointestinal bleeding, consider trying
another NSAID or add a proton pump inhibitor.15 18 Reinforce
How are NSAIDs taken and monitored? the value of taking an NSAID with food.
Hypertension—Check for increased blood pressure within
Selection of NSAIDs 1-4 weeks if starting long term treatment with any NSAID
Discuss with patients any successes or adverse effects from in elderly patients or patients with hypertension.
previous treatments with NSAIDs. For future treatment, it is
Renal function—Check for increased plasma creatinine
important to discuss the likelihood of success or toxicity, signs
concentration and decreased estimated glomerular filtration
of adverse effects, and other useful therapeutic measures, such
rate after 1-2 weeks of starting treatment and then
as weight loss and muscle strengthening in the treatment of
intermittently, especially in elderly patients and patients with
osteoarthritis (box 1). Some patients may prefer a treatment
cardiac failure.
with a greater chance of efficacy than a safer treatment but with
lesser efficacy. Some may prefer the converse. Inadequate response—Check level of exercise and weight
Oral NSAIDs are second line drugs—For osteoarthritis and loss. Use topical NSAIDs for osteoarthritis or increase dose
back pain, use paracetamol and topical NSAIDs before or change oral NSAID.
consideration of oral NSAIDs, particularly for prolonged
treatment. How do NSAIDs compare with other
Elderly patients—For patients over 75 years old, advise use analgesics?
of topical rather than oral NSAIDs as far as possible.
Paracetamol
Concomitant NSAIDs—Patients should be told to avoid
additional oral NSAIDs, such as over the counter For chronic conditions, such as osteoarthritis and back pain,
preparations, as increased total dose of NSAIDs is associated paracetamol is generally recommended as first line treatment
with higher risk of adverse reactions. Topical products and even though meta-analyses indicate that both groups of NSAID
paracetamol can be used concomitantly. are, on average, superior in reducing pain. For example, the
effect size for pain relief with paracetamol is estimated at 0.14
High risk of gastrointestinal adverse effects—Risk factors
(95% confidence interval 0.05 to 0.22) compared with 0.29
include age >65 years; previous ulcer, gastrointestinal
(0.22 to 0.35) for NSAIDs (table 1⇓). NICE recommends that
bleeding, or perforation; other drugs known to increase upper
combinations of paracetamol and opioids can be considered for
gastrointestinal adverse events (anticoagulants, aspirin,
treatment of osteoarthritis if the response to paracetamol is
serotonin reuptake inhibitors); corticosteroids; and serious
inadequate.12 Paracetamol is not suitable for the treatment of
comorbidities (hepatic, renal, or cardiac impairment,
acute gout or rheumatoid arthritis.
excessive alcohol intake, heavy smoking).16 A proton pump
inhibitor can be used with non-selective NSAIDs or selective The reason for the preference of paracetamol is its superior
COX-2 inhibitors. Misoprostol reduces the gastrointestinal tolerability compared with both classes of NSAID. Paracetamol
adverse reactions of non-selective NSAIDs but is poorly has little gastrointestinal toxicity, minimal effect on blood
tolerated because of diarrhoea and should not be used by pressure and renal function, no reported increase in the rate of
women who may become pregnant.30 myocardial infarction, and no effect on the antiplatelet effect
of aspirin.25 In patients with aspirin sensitive asthma, a
Low risk of gastrointestinal adverse effects (and low to systematic review indicates that paracetamol produces a mild
moderate risk of thrombosis)—Naproxen or ibuprofen reaction in about 7%.25
(<1200 mg total ibuprofen) can be used with a proton pump
inhibitor.
Opioids
High risk of thrombosis (in patients taking aspirin)—If
These drugs should not be used as first line treatment of
physical measures, paracetamol, and topical NSAIDs are
osteoarthritis because of their adverse effects such as
insufficient, continue aspirin and add low doses of a selective
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BMJ 2013;346:f3195 doi: 10.1136/bmj.f3195 (Published 11 June 2013) Page 4 of 7

PRACTICE

constipation, drowsiness, and cognitive blunting. Use of opioids 6 Roelofs PD, Deyo RA, Koes BW, Scholten RJ, van Tulder MW. Non-steroidal
anti-inflammatory drugs for low back pain. Cochrane Database Syst Rev
in elderly patients is also associated with a high incidence of 2008;(1):CD000396.
falls and fractures. For example, the incidence of fractures was 7 Brooks P, Day R. Nonsteroidal antiinflammatory drugs—differences and similarities. N
Engl J Med 1991;324:1716-25.
about 27 per 100 patient years in a large observational study on 8 Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, et al. EULAR
the use of codeine and other opioids by elderly patients (mean evidence based recommendations for gout. Part II: Management. Report of a task force
of the EULAR Standing Committee For International Clinical Studies Including Therapeutics
age 78 years) with non-malignant diseases.33 (ESCISIT). Ann Rheum Dis 2006;65:1312-24.
9 Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. High versus low

Alternative drugs for acute gout dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first
multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison

Corticosteroids such as prednisolone or the old drug, colchicine, 10

colchicine study. Arthritis Rheum 2010;62:1060-8.
Strand V, Simon LS, Dougados M, Sands GH, Bhadra P, Breazna A, et al. Treatment
may be used when all NSAIDs are contraindicated.8 with osteoarthritis with continuous versus intermittent celecoxib. J Rheumatol
2011;38:2625-34.
11 Roddy E, Zhang W, Doherty M. Aerobic walking or strengthening exercise for osteoarthritis
Case outcome 12
of the knee? A systematic review. Ann Rheum Dis 2005;64:544-8.
National Institute for Health and Clinical Excellence. Osteoarthritis: the care and

The patient is referred to a guided exercise and rehabilitation management of osteoarthritis in adults. (Clinical guideline 59.) 2008. www.nice.org.uk/
CG059.
programme, given its value in increasing muscle strength and 13 Laine L, White WB, Rostom A, Hochberg M. COX-2 selective inhibitors in the treatment
improving symptoms. Although she has no history of of osteoarthritis. Semin Arthritis Rheum 2008;38:165-87.
14 Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper
cardiovascular disease, her risk of myocardial infarction or gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual
stroke is still high at 30% in 10 years.34 She is prescribed topical participant data from randomised trials. Lancet 2013; doi:10.1016/S0140-6736(13)60900-
9. [Epub ahead of print.]
NSAID in addition to her full dose, regular paracetamol, as this 15 Latimer N, Lord J, Grant RL, O’Mahony R, Dickson J, Conaghan PG, et al. Cost
should help reduce pain without adding to her cardiovascular effectiveness of COX 2 selective inhibitors and traditional NSAIDs alone or in combination

risk. If her pain remains substantial, the topical NSAID could 16

with a proton pump inhibitor for people with osteoarthritis. BMJ 2009;339:b2538.
Adebajo A. Non-steroidal anti-inflammatory drugs for the treatment of pain and
be replaced with oral naproxen (starting at low doses) because immobility-associated osteoarthritis: consensus guidance for primary care. BMC Fam
it has the lowest cardiovascular risk. A proton pump inhibitor 17
Pract 2012;13:23.
Strand V. Are COX-2 inhibitors preferable to non-selective non-steroidal anti-inflammatory
should also be taken to protect the upper gastrointestinal tract drugs in patients with risk of cardiovascular events taking low-dose aspirin? Lancet
(table 2⇓). The patient’s renal function is normal, and naproxen 2007;370:2138-51.
18 Hunt RH, Lanas A, Stichtenoth DO, Scarpignato C. Myths and facts in the use of
is thus not contraindicated. Occasional intra-articular injection anti-inflammatory drugs. Ann Med 2009;41:423-37.
of the knee with corticosteroids is also an option. 19 Fortun P, Hawkey C. Nonsteroidal antiinflammatory drugs and the small intestine. Curr
Opin Gastroenterol 2005;21:169-75.
20 Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, et al.
Contributors: Both authors contributed equally to the conceptualisation Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis.
BMJ 2011;342:c7086.
and writing of this article. ROD has expertise in medicine, clinical 21 McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs:
pharmacology, and toxicology. GGG has expertise in basic and clinical systematic review of population-based controlled observational studies. PloS Med
2011;8:1-18.
pharmacology. ROD is guarantor.
22 Solomon DH, Goodson NJ. The cardiovascular system in rheumatic disease: the newest
Competing interests: We have read and understood the BMJ Group “extraarticular” manifestation? J Rheumatol 2005;32:1415-7.
23 Hao C, Breyer M. Physiological regulation of prostaglandins in the kidney. Annu Rev
policy on declaration of interests and declare the following interests: Physiol 2008;70:357-77.
ROD has been involved with consultancies with several drug companies 24 Wilson S, Poulter N. The effect of non-steroidal anti-inflammatory drugs and other
commonly used non-narcotic analgesics on blood pressure level in adults. J Hypertens
on patents and advice on paracetamol, ibuprofen, selective COX-2
2006;24:1457-69.
inhibitors, and other drugs used for osteoarthritis; all payments for 25 Graham GG, Davies MJ, Day RO, Mohamudally A, Scott KF. The modern pharmacology
consultancies were made to a trust fund at St Vincent’s Hospital. of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent
pharmacological findings. Inflammopharmacology 2013; DOI 10.1007.
Payment to ROD was made for expert testimony regarding a veterinary 26 Stevenson D. Aspirin and NSAID sensitivity. Immunol Allergy Clin N Am 2004;24:495-505.
anti-arthritic product unrelated to NSAIDs. We acknowledge the 27 Nakhai-Pour HR, Broy P, Sheehy O, Bérard A. Use of nonaspirin nonsteroidal
anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion. CMAJ
assistance of the National Health and Medical Research Council 2011;183:1713-20.
programme grant (568612) for general toxicological research relating 28 Risser A, Donovan D, Heintzman J, Page T. NSAID prescribing precautions. Am Fam
Physician 2009;80:1371-8.
to patient safety.
29 Hoppmann R, Peden J, Ober S. Central nervous system side effects of nonsteroidal
Provenance and peer review: Commissioned; externally peer reviewed. anti-inflammatory drugs. Aseptic meningitis, psychosis, and cognitive dysfunction. Arch
Intern Med 1991;151:1309-13.
Patient consent not required (patient anonymised, dead, or hypothetical). 30 Rostom A, Dube C, Wells G, Tugwell P, Welch V, Jolicoeur E, et al. Prevention of
NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev 2002;(4):CD002296.
31 Gardiner SJ, Doogue MP, Zhang M, Begg EJ. Quantification of infant exposure to celecoxib
1 Moore RA, Derry S, McQuay HJ, Wiffen PJ. Single dose oral analgesics for acute
through breast milk. Br J Clin Pharmacol 2006;61:101-4.
postoperative pain in adults. Cochrane Database Syst Rev 2011;(9):CD008659.
32 Townsend RJ, Benedetti TJ, Erickson SH, Cengiz C, Gillespie WR, Gschwend J, et al.
2 Massey T, Derry S, Moore RA, McQuay HJ. Topical NSAIDs for acute pain in adults.
Excretion of ibuprofen into breast milk. Am J Obstet Gynecol 1984;149:184-6.
Cochrane Database Syst Rev 2010;(6):CD007402.
33 Solomon DH, Rassen JA, Glynn RJ, Garneau K, Levin R, Lee J, et al. The comparative
3 Marjoribanks J, Proctor M, Farquhar C, Derks RS. Nonsteroidal anti-inflammatory drugs
safety of opioids for nonmalignant pain in older adults. Arch Intern Med 2010;170:1979-86.
for dysmenorrhoea. Cochrane Database Syst Rev 2010;(1):CD001751.
34 ClinRisk. Welcome to the QRISK2-2013 risk calculator. http://qrisk.org.
4 Zhang W, Nuki G, Moskowitz RW, Abramson S, Altman RD, Arden NK, et al. OARSI
recommendations for the management of hip and knee osteoarthritis: part III: Changes
in evidence following systematic cumulative update of research published through January Cite this as: BMJ 2013;346:f3195
2009. Osteoarthritis Cartilage 2010;18:476-99.
5 Derry S, Moore RA, Rabbie R.Topical NSAIDs for chronic musculoskeletal pain in adults. © BMJ Publishing Group Ltd 2013
Cochrane Database Syst Rev 2012;(9):CD007400.

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PRACTICE

Tips for patients taking NSAIDs

• You may have used these drugs before, but it is important that you review their benefits and risks with your doctor
• Other measures such as weight loss and muscle strengthening are part of the treatment for osteoarthritis and are effective
• Make sure your doctor knows about other medications you are taking, especially blood thinners, aspirin, and any drugs that you are
taking for arthritis
• Avoid other aspirin-like drugs such as ibuprofen, or combinations of ibuprofen with codeine or paracetamol. If in doubt, contact your
doctor
• Make sure your doctor knows if you have had heart problems, stroke, kidney problems, or are being treated for high blood pressure
• Do not take more than is prescribed and use NSAIDs only as long as they are helpful
• Stop the medication and talk to your doctor if you have stomach discomfort or heartburn
• Keep an eye on your stools and report promptly to your doctor if they change colour to black as this may be due to bleeding from the
gut

Tables

Table 1| Indications and effectiveness for non-selective and selective NSAIDs. Comparisons are made against placebo and results are
derived from systematic reviews

Clinical condition and treatment time NSAID Quantitative effect (95% CI)
Postoperative pain (including dental extraction); over Ibuprofen 400 mg NNT 2.5 (2.4 to 2.6)1
4-6 hours, single oral dose
Diclofenac 50 mg NNT 2.7 (2.4 to 3)1
Naproxen 500 or 550 mg NNT 2.7 (2.3 to 3.3)1
Celecoxib 400 mg NNT 2.5 (2.2 to 2.9)1
Etoricoxib NNT 1.9 (1.7 to 2.1)1
Sprains, soft tissue injury; over 7 days Several, topical NNT 4.5 (3.9 to 5.3)2
Dysmenorrhea Several, oral Odds ratio 4.5 (3.85 to 5.27)3
Osteoarthritis pain (knee); over 2-4 weeks Several, oral, non-selective and selective Effect size 0.29 (0.22 to 0.35)4
Osteoarthritis (knee); up to 12 weeks Diclofenac, topical gel NNT 11 (7.7 to 17)5
Low back pain; one week. Several, oral Benefit risk 1.19 (1.07 to 1.33)6

NNT = number needed to treat. That is, the number of patients who need to be treated with the active drug for one to respond with 50% pain relief who would not
have done so with placebo. The smaller the NNT the better the treatment effect.
Effect size = difference between treated and control groups divided by the standard deviation of the groups. An effect size of 0.2 is considered small, 0.5 is moderate,
and >0.8 is large.
Benefit risk = ratio of proportions of patients with >50% pain relief from active drug compared with proportion with >50% pain relief from placebo.

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PRACTICE

Table 2| Adverse event rates for patients aged 55 at low baseline risk of gastrointestinal and cardiovascular adverse events
14

Mean (95% CI) adverse event rates per 10 000 patient years at risk
Total daily dose of
NSAID Symptomatic ulcer Gastrointestinal bleed Myocardial infarction Stroke Heart failure
None 14 7 26 11 5
Diclofenac 100 mg 56 (41 to 74) 28 (19 to 39) 35 (26 to 44) 26 (18 to 34) 9 (5 to 13)
Naproxen 750 mg 112 (66 to 169) 30 (15 to 49) 26 (18 to 34) 32 (12 to 62) 34 (0 to 176)
Ibuprofen 1200 mg 80 (27 to 161) 30 (6 to 73) 61 (6 to 174) 24 (4 to 60) 34 (0 to 176)
Etoricoxib 30 mg 30 (21 to 40) 23 (14 to 33) 35 (25 to 46) 24 (16 to 34) 14 (7 to 22)
Celecoxib 200 mg 38 (11 to 80) 20 (4 to 50) 59 (8 to 162) 10 (2 to 25) 16 (0 to 87)

The adverse event rates were estimated from a model based on data from three major controlled trials on non-selective NSAIDs and COX-2 selective inhibitors
on patients with rheumatoid arthritis and osteoarthritis.

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Figure

Arachidonic acid is metabolised by the cyclo-oxygenase isoenzymes COX-1 and COX-2 to intermediate prostaglandins
(PGG2, then PGH2), which are then converted to other prostaglandins that are mediators of pain, inflammation, and fever,
and are gastroprotective. Thromboxane A2 causes platelet aggregation, and prostacyclin produces vasodilation. By blocking
COX enzymes, NSAIDs inhibit the synthesis and thus the effects of prostaglandins, prostacyclin, and thromboxane A2. The
clinical effects of NSAIDs depend largely on their selectivity for these enzymes. Aspirin works by irreversibly inhibiting
COX-1 mediated synthesis of thromboxane A2, and is used to inhibit platelet aggregation

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