Oral aspirin in postoperative pain: a quantitative systematic review
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Pain 81 (1999) 289–297
Oral aspirin in postoperative pain: a quantitative systematic review
Jayne E. Edwards, Anna D. Oldman, Lesley A. Smith, Dawn Carroll, Philip J. Wiffen,
Henry J. McQuay, R. Andrew Moore*
Pain Research and Nuffield Department of Anaesthetics, University of Oxford, Oxford Radcliffe NHS Trust,
The Churchill, Headington, Oxford OX3 7LJ, UK
Received 17 July 1998; received in revised form 22 December 1998; accepted 8 January 1999
Abstract
Objectives: A systematic review of the analgesic efficacy and adverse effects of single-dose aspirin compared with placebo in post-
operative pain. Design: Published studies were identified from systematic searching of bibliographic databases and reference lists of
retrieved reports. Summed pain intensity and pain relief data were extracted and converted into dichotomous information to yield the
number of patients with at least 50% pain relief. This was used to calculate the relative benefit and number-needed-to-treat for one patient
to achieve at least 50% pain relief. For adverse effects, relative risk and number-needed-to-harm were calculated. Sensitivity analyses
were planned to test the impact of different pain models, pain measurements, sample sizes, quality of study design, and study duration on
the results. Results: Seventy-two randomized single-dose trials met our inclusion criteria, with 3253 patients given aspirin, and 3297
placebo. Significant benefit of aspirin over placebo was shown for aspirin 600/650 mg, 1000 mg and 1200 mg, with numbers-needed-to-
treat for at least 50% pain relief of 4.4 (4.0–4.9), 4.0 (3.2–5.4) and 2.4 (1.9–3.2) respectively. Single-dose aspirin 600/650 mg produced
significantly more drowsiness and gastric irritation than placebo, with numbers-needed-to-harm of 28 (19–52) and 38 (22–174) respec-
tively. Type of pain model, pain measurement, sample size, quality of study design, and study duration had no significant impact on the
results. Conclusions: There was a clear dose–response for pain relief with aspirin, even though these were single dose studies. Adverse
effects, drowsiness and gastric irritation were also evident in the single dose studies. The pain relief achieved with aspirin was very similar
milligram for milligram to that seen with paracetamol. 1999 International Association for the Study of Pain. Published by Elsevier
Science B.V.
Keywords: Aspirin; Meta-analysis; Systematic review; Postoperative pain; Randomized controlled trial
1. Introduction here is to determine relative efficacy indirectly, using com-
parisons of different analgesics with placebo in similar clin-
It is important for both prescribers and patients to have ical circumstances, with similar patients included, similar
the best possible information about the efficacy and safety pain measurement and similar outcome measures, and
of analgesics. This need is reflected in patient surveys which deriving the number-needed-to-treat (Cook and Sackett,
show that postoperative pain is often poorly managed (Brus- 1995) for at least 50% pain relief (McQuay and Moore,
ter et al., 1994). We also need to benchmark relative effi- 1998). Using previously established methods for the con-
cacy and safety of current analgesics so that we know how version of pain outcome measures into dichotomous infor-
well new analgesics perform. The ideal would be to judge mation (Moore et al., 1996, 1997ab), we have produced a
from direct comparisons of the various analgesics. Unfortu- quantitative systematic review of the analgesic efficacy of
nately there are few such trials of adequate size, and hence aspirin, to allow comparison with other analgesics.
power, to allow credible conclusions. The alternative used Meta-analyses in pain are based on a number of assump-
tions such as the comparability of different acute pain mod-
els, pain measurements, group sizes, the quality of study
* Corresponding author. Tel.: +44-1865-226-132; fax: +44-1865-226- design, and study duration. Aspirin is widely used in clinical
978; e-mail: andrew.moore@pru.ox.ac.uk trials as a positive control, so these aspirin trials are likely to
0304-3959/99/$20.00 1999 International Association for the Study of Pain. Published by Elsevier Science B.V.
PII: S03 04-3959(99)000 22-6290 J.E. Edwards et al. / Pain 81 (1999) 289–297
be the largest data-set in acute pain. This gives the oppor- conditions, aspirin in combination with other drugs, trials
tunity to test these various assumptions. The increased which reported data from a cross-over design as a single
power of meta-analysis, increased relative to the individual data set, trials where the number of patients per treatment
component primary trials, also allowed us to test for factors group was less than ten (L’Abbe et al., 1987), and trials
that might bias interpretation of trial results (Khan et al., which included pain relief data collected after additional
1996), as well as the belief that non-steroidal anti-inflam- analgesic was given. Trials using enteric-coated, sustained
matory drugs have a flat dose–response curve for analgesia release or suspension formulations were excluded; tablet
(Brune and Lanz, 1984). formulation was assumed when formulation was not stated
Safety is an important factor in choosing between drugs, (Table 1).
and aspirin in multiple-dosing has a worse gastric safety Each report which could possibly be described as a ran-
record than some other non-steroidal anti-inflammatory domized controlled trial was read independently by at least
drugs (Henry et al., 1996). The single-dose studies in post- three authors (JE, AO, LS) and scored using a commonly-
operative pain which are widely used for assessing analge- used three item, 1–5 score, quality scale (Jadad et al.,
sic efficacy rarely generate sufficient safety data, and some 1996b). Consensus was then achieved. The maximum
adverse effects may only be detected in chronic use. The score of an included study was five and the minimum
large set of single-dose aspirin studies allowed us to explore score was two.
the idea that adverse effects, such as gastric irritation, may
be evident in single-dose use, but only when the results from 2.1. Statistical analyses
many trials are combined.
From each report we took: the numbers of patients trea-
ted, the mean TOTPAR, SPID, VASTOTPAR or VAS-
2. Methods SPID, study duration and the dose given. Information on
adverse effects was also extracted. For each report, the
Single dose, randomized controlled trials of aspirin in mean TOTPAR, SPID, VASTOTPAR or VASSPID values
postoperative pain (post dental extraction, postsurgical or
postpartum pain) were sought. Different search strategies Table 1
were used to identify eligible reports from MEDLINE Study characteristics
(1966–March 1998), EMBASE (1980–Jan 1998), the
Number of comparisons Number of patients
Cochrane Library (Issue 1, 1998), and the Oxford Pain
Relief Database (1950–1994) (Jadad et al., 1996a). A free Dose
text search was undertaken using the terms ‘aspirin’, ‘acetyl 300/325 2 156
500 3 250
salicylic acid’, ‘clinical trial’, ‘trial’, ‘study’, ‘random*’,
600/650 68 5069
‘double blind’, ‘analgesi*’, ‘pain*’, ‘post-operat*’, 900 2 80
‘surg*’, ‘dental’, ‘molar’, ‘extraction’, ‘operat*’, ‘postsur- 1000 8 716
gical’. Variants of the individual terms were also used, for 1200 5 279
example ‘post-surgical’ and ‘postsurgical’. No restrictions
Number of comparisons %
to language were made. Additional reports were identified
from the reference lists of retrieved reports. Neither phar- Pain model
maceutical companies nor authors of papers were contacted Dental 60 68
Episiotomy 11 13
for unpublished reports. Abstracts and review articles were
Post surgical 12 14
not sought. The inclusion criteria used were: randomized Mixed 5 5
allocation to treatment groups which included aspirin and Formulation
placebo, full journal publication, postoperative oral admin- Tablet/capsule 58 66
istration, adult patients, baseline pain of moderate to severe Buffered 7 8
Soluble 4 4
intensity (which for visual analogue scales (VAS) equates to
Did not state 19 22
.30 mm (Collins et al., 1997)), double blind design and an Duration (h)
established measure of postoperative pain. Acceptable pain 4 21 24
measurements were: (i) a five-point pain relief scale with 5 18 20
standard wording (none, slight, moderate, good, complete); 6 49 56
Quality score
or (ii) a four-point pain intensity scale (none, mild, moder-
5 20 23
ate or severe); or (iii) a VAS for pain relief or pain intensity; 4 30 34
or iv) total pain relief (TOTPAR) or summed pain intensity 3 35 40
difference (SPID) or their visual analogue equivalents 2 3 3
(VASTOTPAR or VASSPID) at 4, 5, or 6 h (or sufficient Language
English 86 98
data provided to allow their calculation).
Other 2 2
We excluded reports of aspirin for the relief of other painJ.E. Edwards et al. / Pain 81 (1999) 289–297 291
for active and placebo were converted to the percentage of failed to meet our inclusion criteria for baseline pain, 16 had
the maximum possible TOTPAR or SPID, %maxTOTPAR no extractable data, 13 used an inappropriate study design,
or %maxSPID, by division by the calculated maximum eight were not randomized, seven used both postoperative
value (Cooper, 1991). The proportion of patients in each and trauma pain, five were duplicate publications (De
treatment group who achieved at least 50% of the maximum Vroey, 1978; Honig, 1978; Rye and Siegel, 1978; Cooper,
TOTPAR was calculated using verified equations (Moore et 1980; Cooper et al., 1986;), two used excluded formulations
al., 1996; Moore et al., 1997a; Moore et al., 1997b). These of aspirin, and two were not double-blind. The references to
proportions were then converted into the number of patients these excluded trials are available at http://www.jr2.ox.a-
achieving at least 50% of the maximum TOTPAR by multi- c.uk/Bandolier/painres/aspac/aspac.html.
plying by the total number of patients in the treatment Sixty-nine publications, reporting on 72 trials, met our
group. Information on the number of patients with at least inclusion criteria. These trials generated a total of 88 aspirin
50% of the maximum TOTPAR for active and placebo was versus placebo comparisons, providing data on 6550
then used to calculate relative benefit (RB) and number- patients (3253 received aspirin, and 3297 placebo). The
needed-to-treat (NNT). median quality score for the trials was four. Dental surgery
Relative benefit and relative risk (RR) estimates were was the setting for 68% of the comparisons, 66% stated that
calculated with 95% confidence intervals (CI) using a they used tablets or capsules, 56% were 6-h studies and 98%
fixed effects model (Gardner and Altman, 1986). NNT or were published in English. Further study characteristics are
number-needed-to-harm (NNH) with 95% confidence inter- listed in Table 1, and full details of the included trials are
vals were calculated by the method of Cook and Sackett available at http://www.jr2.ox.ac.uk/ Bandolier/painres/
(1995) when the relative benefit or relative risk estimates aspac/aspac.html.
were statistically significant. The confidence interval of the
NNT indicates no benefit of one treatment over the other 3.1. Efficacy analysis
when the upper limit includes infinity. A statistically sig-
nificant difference from control was assumed when the 95% Insufficient data were available for analysis of aspirin
confidence interval of the relative benefit did not include 300/325 mg and 900 mg.
one.
Calculations were performed using Excel v. 5.0 and Stat- 3.1.1. Aspirin 500 mg (256 patients)
View v. 4.5 on a Power Macintosh 8500/150. The proportion of patients with at least 50% pain
Efficacy analysis was carried out for all dose groups with relief varied between 26% and 46% (mean 34%) for as-
sufficient sample size (a minimum of three trials). Sensitiv- pirin 500 mg, and 20–32% (mean 28%) for placebo.
ity analyses were performed using the largest data set The relative benefit of aspirin 500 mg versus placebo
(aspirin 600 mg combined with aspirin 650 mg). Graphical was 1.2 (0.8–1.8), indicating no statistically significant ben-
analysis and analysis of variance were used for the sensitiv- efit of this dose of aspirin over placebo in these trials (Table
ity analyses. 2).
3.1.2. Aspirin 600/650 mg (5069 patients)
3. Results Fig. 1 (top panel) shows the proportion of patients with at
least 50% pain relief on aspirin 600/650 mg (11–90%, mean
One hundred and seventy-five publications were identi- 40%) compared with placebo (0–50%, mean 17%), relative
fied. Of these, six could not be obtained from the British benefit 2.0 (1.8–2.2). For a single dose of aspirin 600/650
Library (Gallardo et al., 1982, 1984; Cordero, 1985; mg compared with placebo, the number-needed-to-treat for
Mandujano; Or and Bozkurt, 1985; Carstens et al., 1987). at least 50% pain relief was 4.4 (4.0–4.9) over 4–6 h (Table
Of the remaining studies 31 were not placebo controlled, 16 2).
Table 2
Summary of relative benefit and number-needed-to-treat for trials of aspirin compared with placebo
Aspirin dose (mg) Number of Patients with at Patients with at Relative NNT (95% CI)
comparisons least 50% pain least 50% pain benefit (98% CI)
relief with aspirin relief with placebo
500 3 45/135 32/115 1.2 (0.8–1.8) nc
600/650 68 960/2499 404/2562 2.0 (1.8–2.2) 4.4 (4.0–4.9)
1000 5 153/357 64/359 2.2 (1.4–3.4) 4.0 (3.2–5.4)
1200 5 85/140 27/139 3.3 (1.8–6.3) 2.4 (1.9–3.2)
nc, Not calculated because relative risk not statistically significant.292 J.E. Edwards et al. / Pain 81 (1999) 289–297
together with the dose–response for paracetamol (Moore et
al., 1997c).
3.2. Sensitivity analyses
Trials of aspirin 600/650 mg versus placebo were used for
the sensitivity analyses. Numbers-needed-to-treat for
analgesic efficacy, at least 50% pain relief single-dose post-
operative pain for 4–6 h, compared with placebo, were
calculated by group size, quality score, pain model, type
of pain measurement, and study duration.
3.2.1. Group size
The median aspirin group size for all comparisons was 38
patients. For group sizes below the median the number-
needed-to-treat for at least 50% pain relief was 4.1 (3.5–
5.0) compared with 4.6 (4.1–5.3) for group sizes greater
than or equal to 38. There was no significant difference
between the numbers-needed-to-treat of the larger and smal-
ler group sizes (P = 0.8).
3.2.2. Quality score
Trials with quality scores of three and above were com-
Fig. 1. L’Abbe plots of the results from the aspirin trials included in the
review. Percentage of patients achieving at least 50% pain relief on aspirin
3.1.3. Aspirin 1000 mg (716 patients)
Fig. 1 (middle panel) shows the proportion of patients
with at least 50% pain relief on aspirin 1000 mg (24–
65%, mean 44%) compared with placebo (0–32%, mean
20%), relative benefit 2.2 (1.4–3.4). For a single dose of
aspirin 1000 mg, compared with placebo, the number-
needed-to-treat for a least 50% pain relief was 4.0 (3.2–
5.4) over 4–6 h (Table 2).
3.1.4. Aspirin 1200 mg (279 patients)
Fig. 1 (bottom panel) shows the proportion of patients
with at least 50% pain relief on aspirin 1200 mg (50–
75%, mean 62%) compared with placebo (7–36%, mean
19%), relative benefit 3.3 (1.8–6.3). For a single dose of
aspirin 1200 mg compared with placebo, the number-
needed-to-treat for a least 50% pain relief was 2.4 (1.9– Fig. 2. Dose–response curves for aspirin and paracetamol (paracetamol
3.2) over 4–6 h (Table 2). data from (Moore et al., 1997c)). Numbers indicate the number of studies
The efficacy dose–response for aspirin is shown in Fig. 2 for each dose.J.E. Edwards et al. / Pain 81 (1999) 289–297 293
pared with those with a quality score of two. Little differ-
ence was evident between the NNTs for studies with differ-
ent quality scores (Fig. 3).
3.2.3. Pain model
Trials in dental pain were compared with all the other
pain models (episiotomy, post-surgical and trauma plus
post-surgical models) (Fig. 3). There was no statistically
significant difference between the number-needed-to-treat
of 4.7 in dental pain (95%CI, 4.2–5.4) and the number-
needed-to-treat of 3.9 for the other pain models (3.3–4.7)
(Fig. 3).
3.2.4. Pain measurement and study duration
There was no significant difference between the numbers-
needed-to-treat for the different pain measurements or for
the different study durations (Fig. 4).
3.3. Adverse effects
3.3.1. Total adverse effects
Sixty of the 72 trials reported adverse effect information
for the various doses of aspirin and placebo. Six trials
reported no adverse effects with either aspirin or placebo.
A total of 313/2619 (12%) of the patients on aspirin (all
Fig. 3. Sensitivity analyses: number-needed-to-treat (NNT) by quality
doses) and 261/2660 (10%) of the patients on placebo
score (top panel) and by pain model (bottom panel).
reported at least one adverse effect (Table 3), relative risk
1.3 (0.9–1.5). The most frequently reported effects were
dizziness, drowsiness, gastric irritation, nausea and vomit- treat it. The Egyptians were also aware of the pain-relieving
ing. All effects were of mild or moderate severity and no effects of potions made from myrtle or willow leaves.
patients withdrew as a result. Edward Stone, a vicar from Chipping Norton in Oxford-
shire, is generally recognized as the man who gave the
3.3.2. Analysis by dose of aspirin first scientific description of the effects of willow bark. In
Among the various doses tested in the trials, there was 1763 he wrote a letter to the Earl of Macclesfield, then
sufficient information for the analysis of individual adverse President of the Royal Society in London, in which he
effects only for aspirin 600/650 mg compared with placebo. described treating patients suffering from ague (fever)
A total of 257/1976 (13%) of the patients on aspirin 600/650 with 20 grains (approximately a gram) of powdered willow
mg and 229/2088 (11%) of the patients on placebo reported bark in a dram of water every 4 h.
an adverse effect, relative risk 1.2 (1.03–1.4). The number- The results of the present systematic review confirm
needed-to-harm was 44 (23–345) for aspirin 600/650 mg aspirin’s efficacy as a single dose postoperative analgesic.
compared with placebo. The analgesic dose–response tells us that bigger doses give
Significantly higher incidences of drowsiness and more analgesia, and comparing aspirin with paracetamol the
gastric irritation were reported with aspirin 600/650 mg analgesia produced by the two drugs is very similar. One
than with placebo, numbers-needed-to-harm 28 (19– gram of aspirin gives the same analgesia as one gram of
52) and 38 (22–174) respectively (Table 3). No significant paracetamol (Fig. 2). This mg for mg equivalence is the
difference between aspirin 600/650 mg and placebo was same conclusion reached by Houde and Wallenstein after
shown for nausea, vomiting, dizziness or headache (Table their randomized comparison of 600 mg of aspirin and 600
3). mg paracetamol, cited in (Houde et al., 1965).
Houde and Wallenstein also quite correctly emphasized
that with NSAIDs (unlike opioids) it was often very difficult
4. Discussion to show an analgesic dose–response for outcomes such as
peak relief. When differences were apparent in single trials,
Aspirin has been known to be an effective analgesic for they were seen using total pain relief. This meta-analysis
many years. Rheumatism has affected man since the great shows that there is indeed an underlying dose–response, and
river cultures of the Middle East. Clay tablets from the we used total pain relief (area-under-the-curve for pain
Sumerian period described the use of willow leaves to relief against time). As Fig. 2 shows, the slope of the294 J.E. Edwards et al. / Pain 81 (1999) 289–297
Table 3
Adverse effects: aspirin 600/650 mg compared with placebo
Dose Number Patients with adverse Patients with adverse Relative risk NNH (95% CI)
of trials effects with aspirin effects with placebo (95% CI)
All doses Total adverse effects 60 313/2619 261/2660 1.3 (0.0–1.5) NC
Aspirin 600/650 mg Total adverse effects 53 257/1976 229/2088 1.2 (1.03–1.4) 44 (23–345)
Dizziness 30 41/1429 27/1557 1.6 (0.9–2.6) nc
Drowsiness 33 103/1542 56/1672 1.9 (1.4–2.5) 28 (19–52)
Gastric irritation 11 20/546 6/562 2.5 (1.2–5.1) 38 (22–174)
Headache 29 34/1237 56/1363 0.7 (0.4–1.02) nc
Nausea 34 54/1563 68/1683 0.8 (0.6–1.2) nc
Vomiting 21 12/835 18/927 0.7 (0.4–1.6) nc
nc, Not calculated because relative risk not statistically significant.
dose–response is very similar for aspirin and paracetamol. Another view of the same problem is that about one elderly
The area-under-the-curve for pain relief against time may person will be admitted to hospital with ulcer bleeding per
conceal differences between formulations of a particular 3000 NSAID prescriptions (Hawkey et al., 1997). We do not
drug, and indeed difference between drugs. Fast-onset know the predictive value of single dose gastric irritation for
fast-offset medications may theoretically underperform the chronic problem, but we do know that we can detect
compared with slower-onset longer-offset alternatives. single dose gastric irritation by pooling data from multiple
That question could not be addressed adequately from this small trials. The significant drowsiness seen with aspirin
data. Whether it is clinically relevant is also unclear. Within 600/650 mg, NNH 28 (19–52), has been seen with a similar
the aspirin trials we saw little indication of substantial dif- analysis for ibuprofen (Edwards et al., 1999), with higher
ferences in time-effect curves between formulation, or incidence after dental surgery than after other procedures.
between drug. Extreme differences in time-effect curves Imagine a meta-analysis of an analgesic, in which we
would clearly require us to investigate with a finer tool pooled data from different postoperative pain states, such
than the area-under-the-curve, for pain relief against time. as dental or orthopaedic surgery, or pooled data from trials
For the present we believe that the NNT derived from that which used different pain measurements. Any conclusions
area is a robust and clinically useful comparator.
The importance of this aspirin dose–response, and that
found with similar analytic methods for ibuprofen but not
diclofenac (Collins et al., 1998), is that it suggests that
potentially safer NSAIDs, such as COX-2 drugs, might
allow us to exploit the analgesic potential of higher
NSAID doses. We do not know whether higher doses of
NSAIDs alone could replicate the analgesia which high
doses of opioid alone can achieve. Injecting 20 mg of mor-
phine has a NNT of less than two, better than the NNT of 10
mg of morphine (2.9; 2.6–3.6) (McQuay et al., 1999; Nor-
holt et al., 1996). If higher doses of COX-2 NSAIDs can
emulate this feat, this opens up the prospect of NSAID
replacing opioid for certain indications.
A second intriguing feature of this review is the informa-
tion about adverse effects. Single-dose trials of analgesics
are usually too small to pick up rare, but severe adverse
effects like the hepatic problems with bromfenac (FDA
Talk Paper, 1998). They are also usually too small to give
us credible incidence data for more common adverse
effects. A third problem is that we are sceptical of the pre-
dictive value of single dose trials for the adverse effects that
become apparent with chronic use. Within this meta-analy-
sis, however, is an indication that pooled data from many
single-dose trials may be a better predictor than the compo-
nent trials alone. Gastric irritation showed up as a significant
adverse effect so that about one patient in 40 will have Fig. 4. Sensitivity analyses: number-needed-to-treat (NNT) by pain out-
gastric irritation from a single dose of aspirin (Table 3). come (top panel) and by duration of study observations (bottom panel).J.E. Edwards et al. / Pain 81 (1999) 289–297 295
might be said to be faulty because apples were pooled with [6] Clark, M.S., Lindenmuth, J.E., Silverstone, L.M. and Fryer, G.E.Jr.,
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