Codeine-related adverse drug reactions in children following tonsillectomy: a prospective study

Laryngoscope. 2014 May;124(5):1242-50. doi: 10.1002/lary.24455. Epub 2013 Nov 13.


Objectives/hypothesis: To prospectively determine factors associated with codeine's adverse drug reactions (ADRs) at home in a large homogenous population of children undergoing outpatient tonsillectomy.

Study design: 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.

Trial registration: NCT01140724.

Keywords: Pharmacogenetics; adverse drug reactions; adverse events; pharmacogenomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Analgesics, Opioid / adverse effects*
  • Child
  • Codeine / adverse effects*
  • Cytochrome P-450 CYP2D6
  • Drug-Related Side Effects and Adverse Reactions*
  • Female
  • Humans
  • Male
  • Pain, Postoperative / prevention & control*
  • Phenotype
  • Prospective Studies
  • Risk Factors
  • Tonsillectomy*


  • Analgesics, Opioid
  • Cytochrome P-450 CYP2D6
  • Codeine

Associated data