A Randomised, Controlled Trial of
Acetaminophen, Ibuprofen, and
Codeine for Acute Pain relief in
Children with Musculoskeletal Trauma
Clark et al, Paediatrics 2007
Tom Larsen, ST4, Addenbrookes
Objectives
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Clearly stated objective – to determine
which of the three analgesics, given as a
single dose, provides the most efficacious
analgesia for children presenting to the
ED with musculoskeletal injury.
◦ Common clinical problem
◦ Lack of pre-existing ED based evidence
(equivocal evidence from post operative
studies referenced)
Design/Methods
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Single centre – Children’s Hospital of Eastern Ontario
with ED attendance of 55000 per annum
Powered adequately (although power calculation
subsequently found to have been done incorrectly)
Randomised – computer generated sequence
Blinded – patients, parents and researcher blinded
Inclusion criteria: 6 to 17 years old, presenting with
musculoskeletal injury which occurred within 48 hrs
Exclusion criteria: Contraindication to a study drug,
requiring resuscitation, open fracture, IV line in situ,
recent use of a study drug, significant cognitive
impairment
Recruitment
Recruitment 8 hrs/day by research
assistant
 780 eligable children during this time
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◦ 336 enrolled
◦ 324 refused consent
◦ 48 not approached as research assistant with
another patient
◦ 38 missed
◦ 34 other reasons
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? Recruitment bias
Interventions
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3 arms
◦ 15mg/kg acetaminophen (max 650mg)
◦ 10mg/kg ibuprofen (max 600mg)
◦ 1mg/kg codeine (max 60mg)
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? Bias introduced by dosing – dose of
ibuprofen seems closer to maximum safe
dose.
Data collection
Children reported pain on visual analogue scale at
baseline and at 30 min intervals for 120 mins
 Asked at 60, 90 and 120 minutes if requiring
further analgesia
 Questioned for adverse events with open
questioning in ED and with open questioning and
checklist at 2 day telephone follow up
 Patients discharged before observation period
complete given materials to complete remaining
scores and mail in results
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◦ ? Source of bias
Follow up - ? Attrition bias
Outcome measures
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Primary outcome: Change in patient’s selfreported pain from baseline at 60 minutes
Secondary outcomes
◦ Change in pain score from baseline at 30, 90,
120mins
◦ Requirement for additional analgesia
◦ Number achieving adequate analgesia at 60 and
120 minutes (defined as VAS score <30mm)
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Unclear if outcome measures defined
prospectively
Results
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From 60 minutes and onwards the ibuprofen group
had significantly greater improvement in pain score
(no significant difference between codeine and
acetaminophen at any time point)
At 60 minutes more patients in ibuprofen group
achieved adequate analgesia
No significant difference in number of patients
requiring additional analgesia across the groups
No significant adverse events
No significant difference in rate of minor side
effects
Results - subgroups
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Subgroup analysis showed ibuprofen
produced greater improvement in
patients with fractures
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No significant difference between the
three medications in patients with soft
tissue injuries
Analysis
Appropriate statistical analysis of baseline
and outcome data
 Data analysed on a per protocol basis
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◦ Included if received dose, had baseline data
and had primary outcome data
◦ ?attrition bias
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Subsequent intention to treat analysis not
presented although stated to be similar to
the per protocol analysis presented
Discussion
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Despite ibuprofen providing greater
reduction in pain score only 52% were
defined as having adequate analgesia with
ibuprofen alone and there was no significant
difference in the requirement for further
analgesia between the groups
Concerns regarding effects of NSAIDS on
fracture healing
Possible that more adequate dosage of
paracetamol may have improved outcomes
in this group, particularly in older children
Conclusion
Well designed study providing good
evidence for the superiority of ibuprofen
as a single agent for analgesia after
musculoskeletal injury in children
 Difficulties with recruitment, follow up,
dosing and per protocol analysis may
introduce some bias.
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