title: Codeine-related adverse drug reactions in children following tonsillectomy: a prospective study.
abstract: OBJECTIVE
  To prospectively determine factors associated with codeine's adverse drug reactions (ADRs) at home in a large homogenous population of children undergoing outpatient tonsillectomy.
  
  
  METHODS
  Prospective, genotype blinded, observational study with a single group and repeated ADR measures documented by parents at home.
  
  
  METHODS
  A total of 249 children 6 to 15 years of age scheduled for tonsillectomy were enrolled. The primary outcome was number of daily codeine-related ADRs. We examined the number and type of ADR by race and by days and further modeled factors potentially associated with ADR risk in a subcohort of white children. Sedation following a dose of codeine was a secondary outcome measure. Parents recorded their children's daily ADRs and sedation scores during postoperative days (POD) 0 to 3 at home.
  
  
  RESULTS
  Diaries were returned for 134 children, who were given codeine. A total of 106 (79%) reported at least one ADR. The most common ADRs were nausea, lightheadedness/dizziness for white children and nausea, and vomiting for African American children. In a subcohort of white children ≤ 45 kg, increased ADR risk was associated with the presence of one or more full function CYP2D6 alleles (P < 0.001), POD (P < 0.001), and sex (P = 0.027). Increased pain intensity (P = 0.009) and PODs 0 and 1 (P = 0.001) contributed to a higher sedation risk. Neither obstructive apnea nor predicted CYP2D6 phenotype were associated with sedation risk.
  
  
  CONCLUSIONS
  Our results provide evidence that multiple factors are associated with codeine-related ADRs and support the FDA recommendation to avoid codeine's routine use following tonsillectomy in children.
authors.affiliation: Division of Human Genetics, University of Cincinnati, Cincinnati, Ohio; Division of Pharmacy, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Prows
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.forename: Myra M
authors.initials: MM
authors.lastname: Huth
authors.forename: Kejian
authors.initials: K
authors.lastname: Zhang
authors.forename: Shannon N
authors.initials: SN
authors.lastname: Saldaña
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Daraiseh
authors.forename: Hope R
authors.initials: HR
authors.lastname: Esslinger
authors.forename: Edita
authors.initials: E
authors.lastname: Freeman
authors.forename: John H
authors.initials: JH
authors.lastname: Greinwald
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Senthilkumar
authors.initials: S
authors.lastname: Sadhasivam
mesh_terms: D000293:Adolescent; D000701:Analgesics, Opioid / Q000009:adverse effects*; D002648:Child; D003061:Codeine / Q000009:adverse effects*; D019389:Cytochrome P-450 CYP2D6; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D010149:Postoperative Pain / Q000517:prevention & control*; D010641:Phenotype; D011446:Prospective Studies; D012307:Risk Factors; D014068:Tonsillectomy
chemical_list: D000701:Analgesics, Opioid; D019389:Cytochrome P-450 CYP2D6; D003061:Codeine
keywords: Pharmacogenetics; adverse drug reactions; adverse events; pharmacogenomics