Non-steroidal anti-inflammatory drugs

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Non-steroidal anti-inflammatory drugs: clinical evidence

BMJ 2000;320:1058-1061 ( 15 April )

http://bmj.com/cgi/content/full/320/7241/1058

C Gøtzsche, director. p.c.gotzsche@...

Nordic Cochrane Centre, Rigshospitalet, 9 Blegdamsvej, DK 2100

Copenhagen Ø, Denmark

Background

Definition Non-steroidal anti-inflammatory drugs (NSAIDs) have

anti-inflammatory, analgesic, and antipyretic effects and inhibit

thrombocyte aggregation. The drugs have no documented effect on the

disease process itself.

Incidence/prevalence NSAIDs are widely used. Almost 10% of people in the

Netherlands had used a non-aspirin NSAID in 1987; the overall use was 11

defined daily doses (see box) per 1000 persons a day.1 In Australia in

1994, overall use was 35 defined daily doses per 1000 persons a day,

with 36% of the people receiving NSAIDs for osteoarthritis, 42% for

sprain and strain or low back pain, and 4% for rheumatoid arthritis; 35%

were aged over 60 years.2

Aims To reduce symptoms in rheumatic disorders; to avoid severe

gastrointestinal adverse effects.

Outcomes Primary outcomes: pain intensity, person's preference for one

drug over another, global efficacy, and clinically significant

gastrointestinal complications. Secondary outcomes: number of tender

joints, perforation, gastrointestinal haemorrhage, dyspepsia, and ulcer

detected by routine endoscopy.

Defined daily dose: The assumed average daily dose for the main

indication of a specified drug. The defined daily dose per 1000

population per day is an estimate of the proportion of that population

receiving treatment with that drug.

Methods

We searched Medline and the Cochrane Library in July 1999 for systematic

reviews and randomised controlled trials (RCTs) that included at least

100 people. More than 100 meta-analyses and thousands of RCTs have

compared various NSAIDs. Many trials are unpublished or published in

sources that are not indexed in publicly available databases. The

quality of the trials is variable and bias is common, both in the design

and analysis of the trials, to such an extent that a systematic review

identified false significant findings favouring new drugs over control

drugs in 6% of trials.3

Interventions

Beneficial:

NSAIDs in rheumatoid arthritis

Misoprostol in high risk patients who cannot avoid NSAIDs

Topical NSAIDs in acute and chronic pain conditions

Likely to be beneficial:

Omeprazole and, to a lesser extent, H2 blockers in high risk patients

who cannot avoid NSAIDs

Trade-off between benefits and harms:

NSAIDs in osteoarthritis

Unknown effectiveness:

NSAIDs versus simple analgesics in acute musculoskeletal syndromes

Switch between different NSAIDs

Topical NSAIDs versus systemic NSAIDs or alternative analgesics

Unlikely to be beneficial:

NSAIDs in increased doses

Question: Are there any important differences between available NSAIDs?

Systematic reviews have found no important differences in effect between

different NSAIDs or doses but have found differences in toxicity related

to increased doses and possibly to the nature of the NSAID itself. In

acute musculoskeletal syndromes, no large double blind trials have

compared an NSAID with paracetamol. We found no evidence that NSAIDs

are more effective than simple analgesics.

Benefits

Rheumatoid arthritis: A systematic review of 37 crossover trials

compared indomethacin with 10 newer NSAIDs; it included 1416 patients

treated for a median of two weeks with each drug. Only 5% more people

(95% confidence interval 0% to 10%) preferred the newer NSAID to

indomethacin.4 Four of the trials included a placebo period and one

trial compared four drugs. Another systematic review of 88 trials

comparing two NSAIDs, and 27 trials comparing an NSAID with placebo, in

a total of 6440 patients, found no differences in the number of tender

joints in 17 different NSAIDs.5 Studies claiming that individuals may

benefit from different NSAIDs are not convincing; people's preferences

for particular drugs have not been replicated and could therefore be due

to chance or to the considerable natural fluctuations in disease

activity. 6 7

Osteoarthritis: Two reviews found no clear differences between various

NSAIDs used to treat osteoarthritis of the hip (39 trials)8 or the knee

(16 trials).9 A systematic review comparing tenoxicam with three other

NSAIDs for osteoarthritis10 found superiority of tenoxicam over

piroxicam both for global efficacy (10 trials, 834 people; odds ratio

1.46, 1.08 to 2.03) and for global tolerability (seven trials, 974

people; 1.46, 1.01 to 2.15). This result is at variance with a large RCT

of 1328 people with osteoarthritis or rheumatoid arthritis, which found

no significant differences in global efficacy or tolerability between

the two drugs; improvement was noted for 55% of patients receiving

tenoxicam compared with 53% of patients on piroxicam (difference 2%, 5%

to 9%)11 12

Acute musculoskeletal syndromes: The RCTs were generally of poor

quality,13 and we found few systematic reviews. One review of 17 NSAID

trials for shoulder pain was inconclusive. 14 15 Another systematic

review of 84 studies included 32 025 people with soft tissue injuries of

the ankle; it was unable to pool data to perform a statistical analysis

of the different forms of treatment.13 We found no good evidence that

NSAIDs are more effective than paracetamol in acute musculoskeletal

syndromes.

Dose-response relation: A systematic review of 19 trials in which

participants were randomised to more than one dose of nine different

NSAIDs found a dose-response relation that saturated at high doses,16 as

for most other drugs. This and another systematic review found that the

recommended dosages were close to providing a ceiling effect. 16 17 The

review of the 115 trials mentioned above found no differences between

various doses of drugs5; 10 of 21 studies of ibuprofen had used a daily

dosage of 1200 mg or less.

Harms

Versus placebo: A systematic review of 100 trials (12 853 people) found

an increased risk of gross haemorrhage (ARI (absolute risk increase) for

NSAID v placebo 0.7%, 0.1% to 1.5%) and for proved ulcer (ARI for NSAID

v placebo 0.05%, 0.01% to 0.11%); the effect was not significant but

mean treatment duration was only two months.18 For 40 aspirin trials (22

234 people, mean treatment duration one year) the review found an

increased risk of gross haemorrhage (ARI 0.6%, 0.2% to 1.0%) and for

proved ulcer (ARI 0.6%, 0% to 1.2%).18 The number needed to harm was in

the range 100-1000. A systematic review of 38 placebo controlled trials

found that NSAIDs raised mean blood pressure by 5.0 mm Hg (1.2 mm Hg to

8.7 mm Hg).19 Versus other NSAIDs: A meta-analysis of 11 case-control

studies and one cohort study found that ibuprofen was significantly less

toxic than other NSAIDs; the 11 comparator drugs were associated with a

1.6-9.2 fold increase in risk of serious upper gastrointestinal

complications.20 An overall assessment of newer cox-2 inhibitors is not

yet possible as trials assessing the frequency of clinically important

ulceration have been published only as abstracts, and there are concerns

that these drugs may retard ulcer healing.21 Dose response relation:

Three systematic reviews found no ceiling effect for adverse effects;

the incidence of adverse effects increased in an approximately linear

fashion with dose. 17 20 22

Comment

Important differences in adverse effects seem to exist between different

NSAIDs. In contrast, their beneficial effects seem to be similar. The

only meta-analysis that found one drug to be more effective than another

was funded by the manufacturer; the studies it included were small and

the result was not replicated in a large RCT. If the effect of one NSAID

is not satisfactory, a switch to another NSAID cannot be expected to

solve the problem. Likewise, doubling the dose of an NSAID leads to only

a small increase in effect, which may not be clinically relevant. In

acute musculoskeletal problems it is doubtful whether NSAIDs have any

clinically relevant anti-inflammatory effect; it is therefore

unfortunate that not one, large double blind RCT has compared an NSAID

with paracetamol. Paracetamol has been studied in osteoarthritis, where

it had much the same effect as ibuprofen or naproxen.12

Question: What are the effects of cotreatments to reduce the risk of

gastrointestinal adverse effects of NSAIDs?

One large RCT found that misoprostol slightly reduced the incidence of

clinically important gastrointestinal complications of oral NSAIDs. A

large RCT found that omeprazole 20 mg and 40 mg daily and misoprostol

800 µg daily had similar effects in reducing endoscopically diagnosed

adverse effects. However, misoprostol caused more adverse effects

(mostly diarrhoea and abdominal pain). RCTs found that H2 blockers were

inferior to omeprazole and misoprostol. The absolute risk of serious

upper gastrointestinal complications is approximately doubled for

patients aged over 75 and for those with a history of peptic ulcer,

bleeding, or cardiovascular disease.

Benefits

We found one systematic review and four large subsequent RCTs.

Misoprostol versus placebo: The systematic review of 24 trials included

5005 people who all received NSAIDs.23 In trials lasting more than four

weeks, misoprostol compared with placebo reduced the development of

gastric ulcer detected by routine endoscopy (ARR (absolute risk

reduction) 8%, 1% to 18%). H2 blockers had no effect on gastric ulcer

(ARR 1%, 2% to 3%) but reduced the risk of duodenal ulcer (ARR 2%, 0% to

5%). Misoprostol also reduced duodenal ulcer risk with long term use

(ARR 3%, 0% to 6%) but not with short term use (ARR 2%, 2% to 6%). In a

six month RCT published after the systematic review, 8843 people with

rheumatoid arthritis (mean age 68 years, all treated with NSAIDs) were

randomised to misoprostol 800 µg daily or placebo.24 Serious upper

gastrointestinal complications (such as perforation, gastric outlet

obstruction, or bleeding detected by clinical symptoms or investigation)

were reduced by misoprostol compared with placebo (absolute risk 0.6% in

misoprostol group, 1.0% in placebo group; ARR 0.4%, 0% to 0.7%; NNT

(number needed to treat) 263). The risk of serious upper

gastrointestinal complications was approximately doubled for people aged

over 75 and for those with a history of peptic ulcer, bleeding, or

cardiovascular disease. People with all four risk factors had an

absolute risk of a major complication in six months of 9%, corresponding

to a number needed to treat with misoprostol rather than placebo of 28

people.

Misoprostol versus omeprazole: In an RCT of

935 patients treated with NSAIDs who had ulcers or more than 10 erosions

at endoscopy, treatment success was defined as fewer than five erosions

at each site, no ulcers, and not more than mild dyspepsia.25 At eight

weeks, treatment was successful in 76% of those given omeprazole 20 mg

daily, 75% given omeprazole 40 mg daily, and 71% of those given

misoprostol 800 µg daily. Participants (732) in whom treatment was

successful were re-randomised to maintenance treatment for six months.

More people remained in remission with 20 mg of omeprazole (61%) than

with 400 µg of misoprostol (48%), and with either drug than with placebo

(27%) (ARR for omeprazole v placebo 34%, 25% to 43%; NNT 3; ARR for

misoprostol v placebo 21%, 12% to 30%; NNT 5).

H2 blockers: In a similarly designed trial in 541 participants,

treatment was successful in 80%, 79%, and 63% of participants given 20

mg or 40 mg of omeprazole or 300 mg of ranitidine daily, respectively.26

The estimated proportions in remission after six months were 72% with

omeprazole 20 mg and 59% with ranitidine 300 mg (ARR for omeprazole v

ranitidine 13%, 4% to 22%; NNT 8). In an eight week study, 538 people

with NSAID related upper gastrointestinal pain without endoscopic

evidence of ulcers were randomised to either misoprostol 800 µg or

ranitidine 300 mg daily.27 One third were excluded from analysis because

of problems with adherence and missing endoscopic examinations. Gastric

ulcers at least 3 mm in diameter were found in 1% of people with

misoprostol and in 6% of people with ranitidine (ARR for misoprostol v

ranitidine 5%, 2% to 9%; NNT 20). Duodenal ulcer rate was 1% with both

drugs.

Harms

In one of the large studies more participants receiving misoprostol

(27%) than placebo (20%) withdrew from the study because of adverse

events, primarily diarrhoea and abdominal pain.24 There were 17 and 21

deaths respectively. One death was a direct result of gastrointestinal

toxicity. In another study, adverse events were noted in 48%, 46%, and

59% of participants receiving omeprazole 20 mg and 40 mg, and

misoprostol, respectively; treatment discontinuations (all causes)

occurred in 10%, 11%, and 17%.25 Few adverse events were reported in the

third study; treatment discontinuations (all causes) occurred in 10%,

10%, and 14%.26 In the fourth study, adverse events (mostly

gastrointestinal) occurred in 77% of participants taking misoprostol and

66% taking ranitidine, with withdrawal rates of 13% and 7%, respectively

(ARR for ranitidine v misoprostol 6%, 1% to 11%; NNT 17).27

Comment

The clinical relevance of these findings is doubtful. The only trial

that used clinically relevant outcomes found little difference between

active drug and placebo, except for high risk patients. The rate of

ulcers was more than 10 times higher in the studies where the

investigators looked for them with regular endoscopy, than in earlier

trials of NSAIDs.18 These ulcers were sometimes defined as endoscopic

lesions with a size of only 3 mm, or as any lesion of an unequivocal

depth, or no definition was provided at all.23

Question: What are the effects of topical NSAIDs?

One systematic review has found that topical NSAIDs are effective

compared with placebo in acute pain conditions (NNT 5 to obtain good

pain relief) and chronic pain conditions (NNT 3). Topical and oral

formulations of the same drug have not been compared in high quality

trials. Topical NSAIDs have not been compared directly with paracetamol.

It is therefore uncertain whether topical treatment has advantages over

these alternatives.

Key messages

Systematic reviews of RCTs have found no important differences in effect

between different NSAIDs or doses but have found differences in toxicity

related to increased doses and possibly to the nature of the NSAID

itself

In acute musculoskeletal syndromes, we found no large double blind trial

that compared an NSAID with paracetamol

One large RCT has found that misoprostol slightly reduces the incidence

of clinically important gastrointestinal complications of oral NSAIDs

One large RCT has found that omeprazole 20 mg and 40 mg daily and

misoprostol 800 µg daily produce similar reductions of endoscopically

diagnosed ulceration. Misoprostol causes more adverse effects (mostly

diarrhoea and abdominal pain)

A systematic review of RCTs has found that topical NSAIDs are effective

compared with placebo in acute pain conditions (NNT 5 to obtain good

pain relief) and chronic pain conditions (NNT 3)

Topical NSAIDs have not been compared in high quality trials against

oral forms of the same drug or against paracetamol. Whether or not

topical administration is advantageous remains uncertain

Benefits Versus placebo: We found one systematic review of 86 trials in

10 160 people,28 most comparing a topical NSAID with placebo. The review

was partly sponsored by two manufacturers. Many trials of acute pain

conditions (soft tissue trauma, strains, and sprains) were small; in 37

trials, the average number of actively treated patients was 32, and the

effect declined significantly with sample size. In seven trials with

more than 80 patients per group, the relative benefit was 1.6 (1.3 to

1.9) and number needed to treat for a good outcome was 5 (4 to 6). In 12

trials in chronic pain conditions (osteoarthritis, tendinitis) the

relative benefit was 2.0 (1.5 to 2.7) and the number needed to treat was

3 (3 to 4). In an additional trial, which was not included in this

review, copper-salicylate gel or placebo was applied to the forearm of

116 people with osteoarthritis of the hip or knee.29 There was no

difference between groups (22% v 21% patients reported good effect).

Versus oral NSAIDs: Five trials in the systematic review compared

topical with oral NSAIDs but they all had inadequate design and power.28

Versus paracetamol: We found no RCTs.

Harms

In the systematic review, local adverse effects occurred in 3% of

participants in both groups and systemic adverse events in 1%.28 In the

trial of copper-salicylate gel, more participants taking the drug

reported adverse reactions than with placebo (83% v 52%), most commonly

skin reactions, and more withdrew from the trial because of these

reactions (17% v 2%).29

Comment

Sample size bias hampers the interpretation of the available trials.

Further, no high quality trials have compared topical with systemic

administration of the same NSAID, and no trials have compared a topical

NSAID with paracetamol. It is therefore not possible to judge the

relative benefit of this route of administration.

Footnotes

This review is one of 87 chapters from the second issue of Clinical

Evidence www.evidence.org Clinical Evidence is published by BMJ

Publishing Group and American College of Physicians-American Society of

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