Acute otitis media (AOM) is one of the most common childhood infectious diseases and
a significant reason for antibiotic prescriptions in children worldwide. Pain from
middle ear infection and pressure behind the eardrum is the key symptom of AOM. Ear
pain is central to children's and parents' experience of the illness. Because antibiotics
provide only marginal benefits, analgesic treatment including paracetamol (acetaminophen)
and non‐steroidal anti‐inflammatory drugs (NSAIDs) is regarded as the cornerstone
of AOM management in children. Our primary objective was to assess the effectiveness
of paracetamol (acetaminophen) or NSAIDs, alone or combined, compared with placebo
or no treatment in relieving pain in children with AOM. Our secondary objective was
to assess the effectiveness of NSAIDs compared with paracetamol in children with AOM.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 7,
July 2016; MEDLINE (Ovid, from 1946 to August 2016), Embase (from 1947 to August 2016),
CINAHL (from 1981 to August 2016), LILACS (from 1982 to August 2016) and Web of Science
(from 1955 to August 2016) for published trials. We screened reference lists of included
studies and relevant systematic reviews for additional trials. We searched WHO ICTRP,
ClinicalTrials.gov, and the Netherlands Trial Registry (NTR) for completed and ongoing
trials (search date 19 August 2016). We included randomised controlled trials (RCTs)
comparing the effectiveness of paracetamol or NSAIDs, alone or combined, for pain
relief in children with AOM. We also included trials of paracetamol or NSAIDs, alone
or combined, for children with fever or upper respiratory tract infections (URTIs)
if we were able to extract subgroup data on pain relief in children with AOM either
directly or after obtaining additional data from study authors. Two review authors
independently assessed methodological quality of the included trials and extracted
data. We used the GRADE approach to rate the overall quality of evidence for each
outcome of interest. We included three RCTs (327 children) which were assessed at
low to moderate risk of bias. One RCT included 219 children with AOM, and used a three‐arm,
parallel group, double‐blind design to compare paracetamol versus ibuprofen versus
placebo. All children also received antibiotics and those with fever > 39 °C could
have received paracetamol (30 mg to 60 mg) additionally to the studied treatments.
Another RCT involved 156 febrile children (26 of whom had AOM). The study design was
a three‐arm, parallel group, double‐blind design and compared paracetamol versus ibuprofen
versus ibuprofen plus paracetamol. The third RCT included 889 children with respiratory
tract infections (82 of whom had AOM). This study applied a 3 x 2 x 2 factorial, open‐label
design and compared paracetamol versus ibuprofen versus ibuprofen plus paracetamol.
Study participants were randomised to one of the three treatment groups as well as
two dosing groups (regular versus as required) and two steam inhalation groups (steam
versus no steam). Authors of two RCTs provided crude subgroup data on children with
AOM. We used data from the remaining trial to inform comparison of paracetamol versus
placebo (148 children) and ibuprofen versus placebo (146 children) assessments. Data
from all included RCTs informed comparison of ibuprofen versus paracetamol (183 children);
data from the two RCTs informed comparison of ibuprofen plus paracetamol versus paracetamol
alone (71 children). We found evidence, albeit of low quality, that both paracetamol
and ibuprofen as monotherapies were more effective than placebo in relieving pain
at 48 hours (paracetamol versus placebo: proportion of children with pain 10% versus
25%, RR 0.38, 95% CI 0.17 to 0.85; number needed to treat to benefit (NNTB) 7; ibuprofen
versus placebo: proportion of children with pain 7% versus 25%, RR 0.28, 95% CI 0.11
to 0.70; NNTB 6). Very low quality evidence suggested that adverse events did not
significantly differ between children treated with either paracetamol, ibuprofen or
placebo. We found insufficient evidence of a difference between ibuprofen and paracetamol
in relieving ear pain at 24 hours (2 RCTs, 39 children; RR 0.83, 95% CI 0.59 to 1.18;
very low quality evidence), 48 to 72 hours (3 RCTs, 183 children; RR 0.91, 95% CI
0.54 to 1.54; low quality evidence) and four to seven days (2 RCTs, 38 children; RR
0.74, 95% CI 0.17 to 3.23; very low quality evidence). Data on the effectiveness of
ibuprofen plus paracetamol versus paracetamol alone came from two RCTs that provided
crude subgroup data for 71 children with AOM. The small sample provided imprecise
effect estimates and we were consequently unable to draw any firm conclusions (very
low quality evidence). Despite explicit guideline recommendations on its use, current
evidence on the effectiveness of paracetamol or NSAIDs, alone or combined, in relieving
pain in children with AOM is limited. Low quality evidence indicates that both paracetamol
and ibuprofen as monotherapies are more effective than placebo in relieving short‐term
ear pain in children with AOM. There is insufficient evidence of a difference between
ibuprofen and paracetamol in relieving short‐term ear pain in children with AOM, whereas
data on the effectiveness of ibuprofen plus paracetamol versus paracetamol alone were
insufficient to draw any firm conclusions. Further research is needed to provide insights
into the role of ibuprofen as adjunct to paracetamol, and other analgesics such as
anaesthetic eardrops, for children with AOM. Review question We wanted to find out
if pain relievers are effective for relieving pain in children with acute middle ear
infection (acute otitis media (AOM)) and which medications, alone or together, provide
the most effective pain relief. Background Acute middle ear infection or AOM is one
of the most common childhood infections. Ear pain due to middle ear infection and
pressure building up behind the eardrum is the key symptom of AOM and central to children's
and parents' experience of the illness. Because antibiotics provide only marginal
benefits, pain relievers such as paracetamol (acetaminophen) and non‐steroidal anti‐inflammatory
drugs (NSAIDs) are considered the cornerstone of AOM management in children. Search
date Our evidence is current to 19 August 2016. Study characteristics We included
data from three trials of low to moderate risk of bias of 327 children with AOM. One
trial (219 children) compared paracetamol versus ibuprofen versus a dummy drug in
children with AOM. In this trial, all children also received antibiotic treatment
and those with fever > 39 °C may have received paracetamol in addition to the studied
treatments. Two other trials compared the effects of paracetamol versus ibuprofen
versus ibuprofen plus paracetamol in children with fever and patients with respiratory
tract infections, respectively. The authors of these two trials provided crude subgroup
data on children with AOM (26 and 82 children, respectively). Study funding sources
In one trial, paracetamol, ibuprofen and a dummy drug were supplied by a pharmaceutical
company (Ethypharm). No further details were provided about the role of this company
in the design, conduct, analysis, or reporting of the trial. The other two trials
were funded by governmental (non‐commercial) grants. In one trial the drugs were purchased
from and provided by two companies (Pfizer and DHP Investigational Medicinal Products)
which had no role in the design, conduct, analysis, or reporting of the trial. Key
results Very limited information was available to assess how useful painkillers are
for relieving children's pain due to AOM. We found that both paracetamol and ibuprofen
when used alone were more effective than a dummy drug in relieving ear pain at 48
hours (25% of children receiving a dummy drug had residual pain at 48 hours versus
10% in the paracetamol group and 7% in the ibuprofen group). The adverse events reported
in the trials did not significantly differ between children treated with either paracetamol,
ibuprofen or dummy drug, but this finding should be interpreted cautiously, given
there were few participants, and infrequent occurrence of adverse events. We found
insufficient evidence of a difference between paracetamol and ibuprofen in relieving
short‐term (at 24 hours, 48 to 72 hours and 4 to 7 days) ear pain in children with
AOM. We could not draw any firm conclusions on the effects of ibuprofen plus paracetamol
versus paracetamol alone in relieving ear pain in children with AOM mainly because
of the very limited number of participants (very small sample size). Quality of evidence
Evidence quality for ear pain relief at 48 hours for the comparisons paracetamol versus
a dummy drug and ibuprofen versus a dummy drug was judged low (study limitations and
questions about the applicability of evidence affected our confidence in the results);
the quality of evidence for adverse events was judged very low (study limitations,
small sample size and infrequent occurrence of adverse events affected our confidence
in the results). Evidence quality for ear pain relief at 48 to 72 hours for the comparison
ibuprofen versus paracetamol was judged low (study limitations and questions about
the applicability of evidence affected our confidence in the results); the quality
of evidence for ear pain relief at 24 hours and four to seven days was judged very
low (study limitations and very small sample size affected our confidence in the results).
Evidence quality for all outcomes in the trials comparing ibuprofen plus paracetamol
versus paracetamol alone was very low (study limitations and very small sample size
affected our confidence in the results).