title: Paracetamol (acetaminophen) or non-steroidal anti-inflammatory drugs, alone or combined, for pain relief in acute otitis media in children.
abstract: 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.
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, Utrecht, Netherlands, 3508 GA.
authors.forename: Alies
authors.initials: A
authors.lastname: Sjoukes
authors.affiliation: Julius Center for Health Sciences and Primary Care & Department of Otorhinolaryngology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, Netherlands, 3508 GA.
authors.forename: Roderick P
authors.initials: RP
authors.lastname: Venekamp
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, Utrecht, Netherlands, 3508 GA.
authors.forename: Alma C
authors.initials: AC
authors.lastname: van de Pol
authors.affiliation: Centre for Academic Primary Care, NIHR School for Primary Care Research, School of Social and Community Medicine, Unversity of Bristol, Canynge Hall, 39 Whatley Road, Bristol, UK, BS8 2PS.
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Hay
authors.affiliation: Primary Care and Population Sciences, Faculty of Medicine, Aldermoor Health Centre, University of Southampton, Aldermoor Close, Southampton, UK, S016 5ST.
authors.forename: Paul
authors.initials: P
authors.lastname: Little
authors.affiliation: evidENT, Ear Institute, Faculty of Brain Sciences, University College London, 330 Grays Inn Road, London, UK, WC1X 8DA.
authors.forename: Anne Gm
authors.initials: AG
authors.lastname: Schilder
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, Utrecht, Netherlands, 3508 GA.
authors.forename: Roger Amj
authors.initials: RA
authors.lastname: Damoiseaux
mesh_terms: D000082:Acetaminophen / Q000627:therapeutic use*; D000208:Acute Disease; D018712:Analgesics, Non-Narcotic / Q000627:therapeutic use*; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D005334:Fever / Q000188:drug therapy; D006801:Humans; D007052:Ibuprofen / Q000627:therapeutic use; D010033:Otitis Media / Q000150:complications*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D016032:Randomized Controlled Trials as Topic
chemical_list: D018712:Analgesics, Non-Narcotic; D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000082:Acetaminophen; D007052:Ibuprofen