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Combined acetaminophen and ibuprofen for

pain relief after oral surgery in adults: A
randomized controlled trial

Article in BJA British Journal of Anaesthesia · January 2010

DOI: 10.1093/bja/aep338 · Source: PubMed

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 British Journal of Anaesthesia 104 (1): 80–8 (2010)
doi:10.1093/bja/aep338

Combined acetaminophen and ibuprofen for pain relief after oral

surgery in adults: a randomized controlled trial
A. F. Merry1 2*, R. D. Gibbs3, J. Edwards4, G. S. Ting3, C. Frampton5, E. Davies1 2
and B. J. Anderson1
1
Department of Anaesthesiology, University of Auckland, Private Bag 92019, Auckland, New Zealand.
2
Department of Anaesthesia, Auckland City Hospital, Auckland, New Zealand. 3Oral Health Unit, Greenlane
Clinical Centre, 214 Greenlane West, Epsom, Auckland, New Zealand. 4Oral and Maxillofacial Service, Quay
Park Medical Centre, 68 Beach Road, Auckland Central, Auckland, New Zealand. 5Department of Medicine,
Christchurch School of Medicine and Health Sciences, University of Otago, New Zealand
*Corresponding author. E-mail: [email protected]
Background. Acetaminophen is often used with a non-steriodal anti-inflammatory drug for
acute pain. Hitherto, these drugs have had to be given separately, typically at different time
intervals. Maxigesicw tablets combine acetaminophen and ibuprofen in clinically appropriate
doses to simplify administration and dosage regimen. We compared this combination with each
of the constituent drugs for the relief of pain after extraction of third molar teeth.
Methods. Adults (more than 16 yr) having one or more wisdom teeth removed under general
or local anaesthesia were instructed to take two tablets before operation, then two tablets
every 6 h for up to 48 h of: (i) a combination of acetaminophen 500 mg and ibuprofen 150 mg
per tablet (Maxigesicw); (ii) acetaminophen 500 mg per tablet alone; or (iii) ibuprofen 150 mg
per tablet alone. The primary outcome measure was the area under the curve (AUC) of the
100 mm visual analogue scale pain measurements taken for up to 48 h after surgery, divided by
time, at rest and on activity. Pharmacokinetic data were collected in a subset of patients.
Results. The mean (SEM) time-corrected AUC on rest and activity, respectively, were: combi-
nation group 22.3 (3.2) and 28.4 (3.4); acetaminophen group 33.0 (3.1) and 40.4 (3.3); and ibu-
profen group 34.8 (3.2) and 40.2 (3.4); P,0.01 for each of the four comparisons of combination
vs constituent drug. There was no pharmacokinetic interaction between acetaminophen and
ibuprofen administered together.
Conclusions. Maxigesicw tablets provide superior pain relief after oral surgery to acetamino-
phen or ibuprofen alone.
Br J Anaesth 2010; 104: 80–8
Keywords: anaesthesia, dental; analgesia, postoperative; analgesics non-opioid, acetaminophen;
analgesics non-opioid, ibuprofen; non-steroidal anti-inflammatory drugs
Accepted for publication: October 16, 2009

The relief of pain has been described as a universal human always provide adequate pain relief on its own. Combining
right but is not always easily achieved.1 Opioid analgesics analgesics offers the possibility of increasing effectiveness
are effective, but have troublesome and potentially danger- without increasing dose (and therefore risk).4 5 NSAIDs
ous side-effects, and their potential for abuse may lead to are often combined with acetaminophen, particularly for
regulatory and logistical difficulties. Non-steroidal anti- treating postoperative pain.6 – 10
inflammatory drugs (NSAIDs) have fewer regulatory Prescribing acetaminophen and ibuprofen together is
restrictions, but they too have important adverse effects common in clinical practice.6 8 9 11 – 13 Ibuprofen has the
which are more likely at higher dose or with longer advantage of a well-established safety record ( particularly
courses.2 Acetaminophen is widely used and is very safe at doses below 1.5 g per day in adults),14 and in many
at the recommended dose of 4 g per day,3 but does not countries (including the UK), it is available without

# The Author [2010]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Combined acetaminophen and ibuprofen for analgesia

prescription. Typically, acetaminophen is given in a dose under GMP); (ii) acetaminophen 500 mg per tablet; or
regimen of 1 g 6 hourly whereas ibuprofen is given in a (iii) ibuprofen 150 mg per tablet.
dose of 400 mg 8 hourly.3 Compliance with the prescribed Patients were first approached by the surgeon and then
dosing regimen is important for achieving the desired by the study nurse. They were given written and verbal
result with any drug and is often poor with asynchronous information about the study, and invited to participate. If
dosing.15 A single formulation with a simplified regimen they consented, patients were then randomized into one of
would probably be appreciated by patients and might the three study groups in a sequential order to receive one
improve compliance. of these formulations, in blinded packs. The randomization
Maxigesicw is a new formulation of acetaminophen 500 sequence was computer generated by the study statistician
mg and ibuprofen 150 mg. Taking two tablets 6 hourly as a 1:1:1 allocation ratio to the three treatments in a
provides the appropriate daily dose of both drugs relatively sequence of permuted blocks with stratification for anaes-
simply. We have investigated the hypothesis that in adult thetic type (local or general) and study centre.
patients undergoing a common surgical procedure (extrac- Stratification by anaesthetic type ensured a balance
tion of third molar teeth), this formulation provides between treatments in terms of the number of teeth
superior analgesia to either of its components alone. extracted, as most patients having more than two teeth
extracted have a general anaesthetic. Only the statistician
had access to the schedule of patient numbers by drug
allocation. Participants and investigators were blinded and
Methods the randomization code was not broken until the final data-
With ethics committee approval, we recruited and fol- base had been checked and locked.
lowed up patients between March 2005 and February
2008. Trial registration: ANZCTR.ORG.AU (identifier:
Intervention
ACTRN12606000291583).
Participants were asked to take two tablets of the study
medication before operation (as close as possible to the
Setting start of surgery) and then 4 times a day (as close as poss-
This study was conducted at a publicly funded teaching ible to 6 hourly) for up to 48 h after surgery. All partici-
hospital and a private day-surgical clinic in metropolitan pants were given bupivacaine local anaesthetic blocks by
New Zealand. the surgeons. For those participants undergoing general
anaesthesia, this was induced with propofol and main-
tained with isoflurane and nitrous oxide in oxygen.
Participants
Monitoring was in accordance with the guidelines of the
We included adults undergoing extraction of at least one Australian and New Zealand College of Anaesthetists.16
lower wisdom tooth with or without one or more upper All extractions were carried out by one of three surgeons,
wisdom teeth by one of three participating surgeons. We each using his normal technique.
excluded patients if they were under 16 yr old; weighed If participants required additional postoperative pain
,50 kg; had taken any NSAID (other than aspirin in a relief while in hospital, a rescue dose of fentanyl 10 mg
dose of 150 mg daily or less) within 24 h of the operation; was given i.v., as required. After discharge to home,
had taken acetaminophen or acetaminophen containing codeine was provided (again, as rescue medication) in 30
medicines within 12 h of the operation; were taking an mg tablets, one to two to be taken as needed up to
angiotensin-converting enzyme inhibitor, warfarin, steroid 4 hourly.
(other than interoperative dexamethasone), or any immu-
nosuppressive drug; were intolerant to any NSAID or acet-
Outcomes
aminophen; were suffering from a severe local infection;
had a history of peptic ulceration, asthma, or severe hae- Participants were asked to rate their pain on 100 mm visual
mopoetic, renal or hepatic disease; were participating in analogue scales (VAS), printed one per double page in a
the investigation of another experimental agent; or if the booklet that they took home. Ratings were requested at
clinician believed for any other reason that participation in baseline (immediately before administration of the first
the study might not be in their best interests. dose of study medication); after operation (once the partici-
pants were sufficiently awake to respond); and 1 – 2 hourly
thereafter, while awake, for 48 h. The study nurse main-
Randomization and blinding tained contact with participants by telephone to facilitate
Tablets of identical appearance, packaging, and dosage compliance with data collection and the return of diaries.
instructions were provided in each of the following formu- The primary outcome measure was the area under the
lations: (i) acetaminophen 500 mgþibuprofen 150 mg per curve (AUC) of these VAS ratings divided by time, at rest
tablet (Maxigesicw; Sigma Laboratories, Nashik, India which and on activity. The AUC was divided by the period of
was MHRA approved for manufacturing pharmaceuticals the completed assessments to adjust for the fact that some

81
 Merry et al.

patients recorded pain for shorter periods than others. This included in the safety evaluations. As the first dose of
calculation in effect produces a measure of average pain study medication was taken before operation while under
intensity over the study period. the supervision of the surgeon, all randomized patients
Secondary efficacy outcome measures were: a categorical took at least a single dose of study medication. A last
global pain rating by the participants, taken at the end of the observation carried forward approach was used for those
study period; rescue analgesia consumption over the study subjects who left the study prematurely for non-AUC
period; a categorical global rating of nausea by the partici- based variables.
pants, taken at the end of study period; the number of epi- We compared the primary endpoint between the combi-
sodes of vomiting over the study period; and a rating of nation group and each of the acetaminophen and ibuprofen
sleep disturbance on a 100 mm VAS assessed after each arms, at rest and on activity, using a general linear model
night during the study period. In addition, participants were (GLM) which included terms for treatment, the centre, and
asked to rate their experiences of participating in the study. anaesthetic stratum. Additionally, to confirm the consist-
ency of the treatment effects across strata, the stratum
Sample size estimation treatment interaction terms were tested and included in
the final model. The analysis was also checked with
We obtained blood samples from the 38 participants number of teeth extracted as an additional factor.
undergoing general anaesthesia in order to have evaluable Continuous secondary efficacy endpoints were tested for
pharmacokinetic data for at least 30 patients. The first significance using the same models as used for the
sample was obtained 30 min after the first dose of study primary endpoint.
medication, the second sample at the end of anaesthesia, A one-tailed P0.05 was pre-specified to indicate stat-
and additional one or two samples after operation in hospi- istical significance. We required a statistically significant
tal. The plasma concentration of acetaminophen and ibu- result favouring the combination from each of the two
profen were measured by the sponsor and used to form planned comparisons with the constituents to define super-
individual time – concentration profiles. The analytical iority for either rest or on activity measures. We used one-
method used an HPLC-DAD (Diode Array Detector) assay tailed tests as there seemed no theoretical or empirical
for the simultaneous determination of acetaminophen and basis for expecting that combining these analgesics could
ibuprofen in plasma. Precision and accuracy for acetami- result in a reduction in efficacy, and because the require-
nophen and ibuprofen assay were validated over the con- ment for each of two comparisons to be significant at
centration range 0.5– 50 mg ml21 for both drugs. The P0.05 is stringent. Secondary categorical efficacy end-
intra- and inter-batch precision of the assays at low, points were compared between the groups using x2 tests
medium, and high concentrations of acetaminophen and and Mann – Whitney U-tests as appropriate.
ibuprofen varied from theoretical values by ,15%. The We used non-linear mixed effect models (NONMEM
lower limit of quantification for each drug was 0.5 mg VI, Globomax LLC, Hanover, MD, USA) to estimate
ml21. The sponsor monitored all data collected during the population pharmacokinetics, with a Compaq Digital
study and queries and corrections were made when any Fortran Version 6.6A compiler on an Intel Celeron 333
inaccuracies or inconsistencies were identified. MHz CPU (Intel Corp., Santa Clara, CA, USA) under MS
Windows XP (Microsoft Corp., Seattle, WA, USA). This
Sample size estimation model allows assessment of inter-individual variability,
We estimated that 120 participants (40 per group) in the covariance between pharmacokinetic parameters and
intention-to-treat (ITT) population would provide 80% residual error. We judged the quality of fit of the pharma-
power to detect differences between the groups of 9 (SD cokinetic model to data using the NONMEM objective
14) mm in our primary endpoint for resting assessments function examination of plots of observed vs predicted
and 13 (SD 21) for measures during activity,10 17 with a concentrations and visual predictive checks.
one-sided type I error rate of 5%. These differences equate
to 25%. Differences of this magnitude were considered
clinically important and comparable with differences Results
typical of previous published studies.10
After initial screening, 189 patients were approached; 135
agreed to participate. One to four teeth were extracted
Statistical methods with local anaesthetic alone in 69 patients and with local
The data were analysed using SPSS version 15.0 (SPSS anaesthetic in combination with general anaesthesia in 66.
Inc., Chicago, IL, USA). Efficacy analyses were conducted Thirteen patients did not return their patient diaries, so
on an ITT basis with the additional provision that 122 patients were included in the evaluable ITT popu-
there were at least three VAS measurements over at lation for the analysis of the primary endpoints (Fig. 1).
least 12 h available to calculate the primary endpoint. All The treatment groups were adequately matched in baseline
participants who were randomized into the study were patient and clinical characteristics (Table 1). Of those in

82
 Combined acetaminophen and ibuprofen for analgesia

the combination group, 60.0% had three or four teeth (local vs general) and number of teeth extracted did not
extracted compared with 43.6% for ibuprofen and 53.5% change the outcome of either analysis.
for acetaminophen. Although all four secondary endpoints favour the com-
bination treatment (Table 3), only the global pain rating
Efficacy reached statistical significance. More participants experi-
The time-adjusted AUCs were substantially and signifi- enced ‘nil’ or ‘mild’ pain with the combination (68.4%)
cantly lower at rest and on activity in the combination than with either other group; this difference was significant
group than in either of the other two treatment groups for acetaminophen (37.5%; P¼0.008), but not for ibupro-
(Table 2, Figs 2 and 3), with all four P,0.01. The consist- fen (54.3%; P¼0.263). The use of any rescue medication
ency of the treatment effects across strata was confirmed also favoured the combination treatment (Table 4), but this
from the GLM with P-values for the treatment stratum did not reach statistical significance.
interaction of 0.955 and 0.984 for time-adjusted AUCs at
rest and on activity, respectively. The type of anaesthetic
Pharmacokinetics
Screened There were no significant differences between the combi-
(n =189) nation group and either constituent group in any of the
estimated pharmacokinetic parameters (Table 5). The
visual predictive plots of individual concentration showed
that 90% of the observations were within the 90% pre-
Randomized
(n =135) diction intervals.
Twelve participants were given both acetaminophen and
ibuprofen. For calculation of the pharmacokinetic vari-
ables, a scaling factor was applied to clearance and
Acetaminophen Ibuprofen Combination volume of distribution in turn for those participants receiv-
treatment treatment group treatment group ing the combination of acetaminophen and ibuprofen. This
group (n =44) (n =44)
scaling factor had no impact on either acetaminophen or
(n =47)
ibuprofen pharmacokinetic parameters, indicating that
there was no pharmacokinetic interaction between acetami-
Patient diaries Patient diaries Patient diaries
nophen and ibuprofen when administered together
not returned not returned not returned (P.0.05).
(n =4) (n =5) (n =4) Clearance (CL/F) and volume of distribution (V/F) par-
ameters observed in the study are consistent with those
reported previously (acetaminophen: CL/F¼12.6 – 21.0
Included in the Included in the Included in the litre h21 70 kg21, V/F¼48.3 –71.0 litre 70 kg21; ibupro-
analysis analysis analysis
(n =43) (n =39) (n =40)
fen: CL/F¼2.9– 5.9 litre h21 70 kg21, V/F¼6.4– 23.5 litre
70 kg21).18 – 20
Fig 1 Flow of participants through trial. Not randomized (n¼54): (i)
declined to participate (n¼15), (ii) did not meet inclusion criteria
Adverse effects
(n¼14), (iii) other reasons (n¼25); other reasons: the surgery was
cancelled or rescheduled; patient could not be contacted; patient was The frequency of adverse effects was consistent with the
given the wrong date of the surgery. known effects of the constituent drugs, and there were no

Table 1 Patient characteristic and baseline information (SD)

Acetaminophen (n547) Ibuprofen (n544) Combination (n544)

Age [mean (range)] (yr) 23.5 (16.0 –40.4) 23.7 (16.8 –38.9) 25.0 (18.3 –40.4)
Weight [mean (SD)] (kg) 71.3 (15.6) 80.8 (20.1) 71.1 (13.5)
Ethnicity [n (%)]
Asian 4 (8.5) 1 (2.3) 2 (4.5)
Black 1 (2.1) 0 (0.0) 1 (2.3)
Caucasian 33 (70.2) 31 (70.5) 34 (77.3)
Maori 4 (8.5) 4 (9.1) 4 (9.1)
Pacific Islander 4 (8.5) 5 (11.4) 2 (4.5)
Other 1 (2.1) 3 (6.8) 1 (2.3)
Male [n (%)] 13 (27.7) 21 (47.7) 13 (29.5)
Shift workers [n (%)] 10 (21.3) 5 (11.4) 3 (6.8)
Preoperative pain scores at rest [mean (SD)] (mm) 1.9 (5.1) 2.1 (5.2) 2.6 (6.8)
Preoperative pain scores on activity [mean (SD)] (mm) 4.1 (13.3) 2.7 (8.3) 2.9 (6.6)
Sleep disturbance for night before surgery as VAS [mean (SD)] (mm) 64.7 (22.9) 69.1 (26.0) 71.5 (24.1)

83
 Merry et al.

Table 2 Mean (SEM, 95% CI) of time-adjusted AUC of visual analogue pain Table 3 Secondary efficacy endpoints by treatment group. The only
scores at rest and on activity by treatment group. The differences between significant difference was between the global pain ratings for combination and
combination and each constituent were significant at rest (vs acetaminophen acetaminophen (P¼0.008, Mann – Whitney U-test)
P¼0.007 and vs ibuprofen P¼0.003) and on activity (vs acetaminophen
P¼0.006 and vs ibuprofen P¼0.007) Acetaminophen Ibuprofen Combination

Acetaminophen Ibuprofen (n539) Combination Global pain rating [n (%)]

(n543) (n540) Nil 3 (7.5) 4 (11.4) 4 (10.5)
Mild 12 (30.0) 15 (42.9) 22 (57.9)
At rest 33.0 (3.1, 27.9 –38.1) 34.8 (3.2, 29.4– 40.2) 22.3 (3.2, 17.0– 27.7) Moderate 22 (55.0) 14 (40.0) 12 (31.6)
On 40.4 (3.3, 35.0 –45.8) 40.2 (3.4, 34.6– 45.9) 28.4 (3.4, 22.8– 34.1) Severe 3 (7.5) 2 (5.7) 0 (0.0)
activity Global nausea rating [n (%)]
Nil 26 (65.0) 25 (71.4) 30 (79.0)
Mild 10 (25.0) 8 (22.9) 7 (18.4)
Moderate 3 (7.5) 2 (5.7) 1 (2.6)
100 Severe 1 (2.5) 0 (0.0) 0 (0.0)
Vomiting episodes (n) 5 (in 3 subjects) 0 0
90 Sleep disturbance night 221.9 (29.2) 217.4 (22.9) 216.6 (24.7)
Acetaminophen alone
80 1 vs baseline VAS
Ibuprofen alone [mean (SD)] (mm)
70 Sleep disturbance night 213.7 (32.9) 29.6 (25.8) 28.5 (20.1)
Combination
AUC/h (mm)

60 2 vs baseline VAS
[mean (SD)] (mm)
50
40
30 Table 4 Rescue analgesia by group, n (%); none of these differences were
significant
20
10 Rescue analgesic Acetaminophen Ibuprofen Combination

0 Fentanyl in hospital 5 (11.6%) 9 (23.7%) 6 (15.4%)

Rest Activity
Codeine in the first 24 h 21 (47.70%) 16 (43.20%) 13 (32.50%)
Codeine in the second 24 h 22 (53.70%) 14 (42.40%) 16 (42.10%)
Fig 2 Mean (þ95% CI) mm of time-adjusted AUC (AUC/time) for VAS Any rescue medication over 48 h 25 (62.5%) 18 (58.10%) 21 (56.8%)
at rest and on activity by treatment group.

Table 5 Mean (SD) pharmacokinetic parameters (individual Bayesian

A 100 estimates used for descriptive statistics) for a one-compartment, first-order
90 absorption, first-order elimination model; none of the differences for
Acetaminophen alone combination formulations was significant. CL/F, clearance; V/F, volume of
80
VAS score (mm)

Ibuprofen alone distribution; Tabs, absorption half-time; Cmax, maximum concentration; Tmax,
70
Combination time to achieve Cmax
60
50 Acetaminophen Acetaminophen Ibuprofen Ibuprofen in
40 alone (n515) in combination alone combination
30 (n512) (n511) (n512)
20
CL/F (litre 14.1 (2.6) 14.2 (1.8) 3.9 (1.7) 3.8 (1.3)
10
h21)
0 V/F (litre) 55.7 (19.4) 48.2 (18.3) 10.6 (2.1) 9.8 (1.5)
0 4 8 12 16 20 24 28 32 36 40 44 48
Tabs (h) 0.42 (0.76) 0.16 (0.10) 0.58 (0.78) 0.85 (0.85)
Hours post-surgery Tmax (h) 1.09 (1.12) 0.64 (0.31) 1.16 (0.90) 1.44 (0.93)
B 100 Cmax (mg 15.8 (6.5) 19.2 (6.4) 20.8 (8.3) 19.1 (7.8)
90 litre21)
80
VAS score (mm)

70
60
50
comparisons between the groups. Two participants experi-
40 enced postoperative bleeding (attributed to surgical
30 causes), which resolved without readmission to hospital.
20 No gastrointestinal bleeding was reported during the study.
10 Most adverse events were evaluated as mild (57.4%) or
0
moderate (35.2%) and on review were considered not
0 4 8 12 16 20 24 28 32 36 40 44 48
Hours post-surgery related (17.5%) or unlikely to be related (66.7%) to study
medication.
Fig 3 Mean (SE) mm VAS out of 100 at rest (A) and on activity (B).

definitive indications that the adverse event profile is General

changed when the two drugs are combined (Table 6); The majority of participants rated the experience of taking
however, the numbers were too small to make meaningful part in the study as very positive (31%) or positive (47%)

84
 Combined acetaminophen and ibuprofen for analgesia

Table 6 Adverse events and their relationship with study medication as evaluated by the investigators. Postoperative pain was noted as a complication in 2, 0,
and 1 patient in the acetaminophen, ibuprofen, and combination groups, respectively. Some individuals experienced more than one adverse event

Relationship System organ class Acetaminophen Ibuprofen Combination Total

Not related Gastrointestinal disorders (numbness of tongue) 1 0 0 1

General disorders and administration site conditions (swollen arm, infusion site 0 0 2 2
phlebitis)
Infections and infestations (dry socket, alveolitis of jaw) 1 0 1 2
Injury, poisoning, and procedural complications (bruising of arm, postoperative 0 0 2 2
pain)
Musculoskeletal and connective tissue disorders ( jaw stiffness) 0 0 1 1
Skin and s.c. tissue disorders (swelling face) 1 1 0 2
Subtotal 3 1 6 10
Unlikely related Blood and lymphatic system disorders (swollen glands) 1 0 0 1
Ear and labyrinth disorders (pain in ear, tinnitus) 2 0 0 2
Gastrointestinal disorders (vomiting, nausea, stomach cramps, dry lips) 6 1 2 9
Injury, poisoning, and procedural complications (postoperative bleeding) 0 0 1 1
Musculoskeletal and connective tissue disorders ( jaw stiffness, aches and pains in 2 0 1 3
legs, jaw pain)
Nervous system disorders (headache, felt faint, sleepy, balance difficulty, light 6 4 4 14
headiness, dizziness, drowsiness, lethargic)
Psychiatric disorders (disorientation) 0 1 0 1
Respiratory, thoracic, and mediastinal disorders (sore throat, pharyngeal ulceration, 1 1 2 4
hypoventilation, coughing)
Investigations (body temperature increased) 0 0 1 1
Skin and s.c. tissue disorders (rash, redness of external ear, swelling face) 0 1 1 2
Subtotal 18 8 12 38
Possibly related Gastrointestinal disorders (stomach cramps, abdominal pain, constipation, stomach 3 0 2 5
ache, vomiting)
General disorders and administration site conditions (fever) 1 0 0 1
Injury, poisoning, and procedural complications (postoperative bleeding) 0 0 1 1
Nervous system disorders (sleepy, headache) 1 0 1 2
Subtotal 5 0 4 9
Total 26 9 22 57

and 19% rated the experience as neutral. Four participants combination is superior to ibuprofen alone.12 In a smaller
(3%) found the experience negative, and none rated it as study in an orthopaedic pain model (which was positive
very negative. The ratings were not significantly different for the combination in comparison with acetaminophen),
between the study groups. Dahl and colleagues8 showed no such benefit whereas
Viitanen and colleagues13 (in a paediatric tonsillectomy
study) showed an advantage for the combination only in
the period after discharge from hospital. The similarity in
Discussion efficacy between ibuprofen and acetaminophen on their
We found that patients using the combination of acetami- own seen in our study contrasts with the findings of
nophen and ibuprofen experienced less pain during the superior pain relief from ibuprofen after dental surgery by
first 48 h after oral surgery than those using the same Cooper and colleagues,22 but theirs was a single-dose
daily dosage of either agent alone and we think the differ- study.
ence was clinically relevant. There was no evidence of any
pharmacokinetic interaction between acetaminophen and
ibuprofen. Patients receiving ibuprofen alone reported the Limitations and strengths of the study
lowest frequency of adverse events, but the numbers are Our results are limited to adults, and to the doses and
too small for meaningful comparisons between the groups, model of pain studied. We think our conclusions are likely
and we saw no cause for concern in any group. to apply to other age groups and other types of pain, but
Our data are consistent with previous evidence showing this will require confirmation. We have not explored the
that a combination of ibuprofen and acetaminophen pro- optimal dosage of the combination drug, but the dosage
vides better analgesia than acetaminophen alone.8 9 13 21 used is consistent with current clinical practice. The
Note, however, that two of these studies were in children,9 13 inclusion of patients who underwent both general and
so data in adults are relatively limited. On the other hand, local anaesthesia implies that our findings are likely to
there are many studies supporting the more general point apply in either case. It is not possible to draw firm con-
that the addition of various NSAIDs improves the pain clusions on the safety of any drug from a study of only 40
relief obtainable from acetaminophen alone. More impor- participants per group, but acetaminophen and ibuprofen
tantly, our data add convincingly to the sparse evidence are well established, widely used, and considered very safe
supporting the more controversial proposition that this in appropriate doses.3 23 There is no theoretical reason,

85
 Merry et al.

and no empirical suggestion from our data, to suggest that groups. It is notable that most patients did require rescue
the combination would be any less safe than the constitu- medication, suggesting that pain after oral surgery can some-
ent drugs on their own. Our safety data are observational times be severe enough that even the combination of ibupro-
rather than based on prospective laboratory investigations, fen and acetaminophen requires supplementation (and it
but we followed up participants for adverse events for 3 might be asked whether it would be a good idea for codeine,
weeks, and it seems unlikely that clinically important for example, to be added to the combined formulation).
harm would have been missed. Nevertheless, we think it important that the vast majority of
Pain after oral surgery can persist for several days,10 but the participants in all groups reported pain scores that were
we considered 48 h to be a clinically relevant period, and reasonably low, and that all received analgesic regimens
a longer period of study is likely to have resulted in poorer accepted in contemporary practice. The predominantly posi-
compliance with data collection. tive evaluation by participants of their experience in taking
It could be asked whether a more typical (albeit part in the study provides empirical reassurance on this point
complex) regimen for ibuprofen alone might have pro- (and also other aspects of the conduct of the study).
vided better analgesia than seen with the 4 hourly The treatment of pain is central to medical practice in
approach used here, but this seems unlikely, particularly hospitals and in primary care. If these results are con-
given that our clinical efficacy data were supported by esti- firmed in other settings, the already widely used combi-
mates of population pharmacokinetics. We had planned to nation of acetaminophen and ibuprofen may become the
correlate drug plasma concentration with pain scores, but standard of care for the initial management of moderate
the drug plasma concentration results were too sparse and acute pain, at least for those patients who do not have
there were too many confounding variables (such as ethni- contra-indications to NSAIDs. Even using the drugs indi-
city, comparators, and rescue analgesia) for this to be vidually, the dosage regimen studied here is simpler than
undertaken. We did demonstrate a lack of interaction that currently recommended, and may well improve com-
between the constituent drugs when used in combination pliance with and therefore success with this combination.
and provided evidence that equivalent and predicted blood Providing both drugs in one tablet simplifies this regimen
concentrations were achieved (the observations of time– even further, and our data confirm that the specific formu-
concentration profile decreased within 90% of prediction lation studied here is effective, and that there is no inter-
limits for both acetaminophen and ibuprofen). Furthermore, action between its constituent drugs.
pharmacokinetic parameter estimates observed in the current
study are very similar to those previously reported.18 – 20
The evaluations used in the efficacy analysis have
established construct validity and are appropriate for Conclusions
parametric analysis.24 25 Doctors treating pain after oral surgery, in hospital and at
In designing analgesic studies, it is an advantage to home, and probably pain in many other situations, should
minimize the exposure of participants to inadequate consider using acetaminophen and ibuprofen together four
analgesia while controlling for various sources of bias. times a day, provided there are no contraindications to
Some designs incorporate a placebo group, but the efficacy either drug, and taking into account the known risks of
of both ibuprofen26 and acetaminophen27 in comparison NSAIDs. The combination formulation studied here sim-
with placebo are well established by previous research, plifies this regimen.
and we would argue that the use of a placebo in this situ-
ation is unnecessary and perhaps even unethical.28 There
would be little value in another ‘me too’ analgesic unless
it had clear advantages over established agents. Therefore, Funding
the question of interest lies in the comparisons between This work was supported by AFT Pharmaceuticals Ltd,
the new agent (Maxigesicw) and the reference standard of assisted by New Zealand Trade and Enterprise
care, and in this case, we have actually shown superiority to Development Grants.
both of two possible reference standards—acetaminophen
alone and ibuprofen alone. One classic approach to analgesic
studies involves treating established acute pain. This has the Appendix
alleged advantage that pain relief can be assessed (e.g. by
using AUC to estimate total pain relief, or TOTPAR,29 30 or
by calculating a pain reduction index per tablet).31 Our Declaration of interest
design, in contrast, follows the widely accepted clinical prac- The Department of Anaesthesiology of the University of
tice of anticipating and treating pain before it occurs, which, Auckland has received payment from AFT
in our unit at least, has long been considered best practice. Pharmaceuticals for conducting this study, but none of the
Furthermore, rescue medication was readily available and investigators has received payment in their personal
those requiring it were evenly distributed between the capacity.

86
 Combined acetaminophen and ibuprofen for analgesia

Contributors New Zealand, for the plasma sample assays; Sally Merry
A.F.M., B.J.A., C.F., and Hartley Atkinson* designed the for proofreading and editing on the manuscript; the anaes-
study with input from R.D.G. and J.E. Hartley Atkinson* thetists: Judy Bent, Jack Hill, Joanna Rose, Joanne Paver,
obtained funding. R.D.G., G.S.T., and J.E. performed the Andrew Warmington, and Lisa Chapman at Greenlane
surgery, and contributed to patient recruitment and to the Clinical Centre; Kerry Gunn, Chris Chambers, and
care of patients during their participation in the study. Jonathan Cross at Quay Park Clinic, for facilitating the
E.D. was the study coordinator, and was responsible for administration of the study protocol and contributing
patient recruitment and follow-up, data collection, quality substantially to the clinical care of the patients; and the
control, and many other logistic aspects of the study. The participants for their participation.
statistical analysis of clinical data was undertaken by C.F.
and of the pharmacokinetic data by B.J.A. A.F.M. took
primary responsibility for the manuscript, with assistance
from Jennifer Zhang**. All authors edited and commented
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