Sex differences in type and occurrence of adverse reactions to opioid analgesics: a retrospective cohort study

BMJ Open. 2021 Jun 30;11(6):e044157. doi: 10.1136/bmjopen-2020-044157.


Objectives: Sex as a biological variable affects response to opioids. However, few reports describe the prevalence of specific adverse reactions to commonly prescribed opioids in men and women separately. A large cohort was used to investigate sex differences in type and occurrence of adverse reactions associated with use of codeine, tramadol, oxycodone and hydrocodone.

Design: Retrospective cohort study.

Setting: Participants in the Right Drug, Right Dose, Right Time (RIGHT) Study.

Participants: The medical records of 8457 participants in the RIGHT Study who received an opioid prescription between 1 January 2004 and 31 December 2017 were reviewed 61% women, 94% white, median age (Q1-Q3)=58 (47-66).

Primary and secondary outcome measures: Adverse reactions including gastrointestinal, skin, psychiatric and nervous system issues were collected from the allergy section of each patient's medical record. Sex differences in the risk of adverse reactions due to prescribed opioids were modelled using logistic regression adjusted for age, body mass index, race and ethnicity.

Results: From 8457 participants (of which 449 (5.3%) reported adverse reactions), more women (6.5%) than men (3.4%) reported adverse reactions to at least one opioid (OR (95% CI)=2.3 (1.8 to 2.8), p<0.001). Women were more likely to report adverse reactions to tramadol (OR (95% CI)=2.8 (1.8 to 4.4), p<0.001) and oxycodone (OR (95% CI)=2.2 (1.7 to 2.9), p<0.001). Women were more likely to report gastrointestinal (OR (95% CI)=3.1 (2.3 to 4.3), p<0.001), skin (OR (95% CI)=2.1 (1.4 to 3.3), p=0.001) and nervous system issues (OR (95% CI)=2.3 (1.3 to 4.2), p=0.004).

Conclusions: These findings support the importance of sex as a biological variable to be factored into pain management studies.

Keywords: ANAESTHETICS; Adverse events; EPIDEMIOLOGY.

Publication types

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

MeSH terms

  • Analgesics, Opioid* / adverse effects
  • Cohort Studies
  • Female
  • Humans
  • Male
  • Oxycodone / adverse effects
  • Retrospective Studies
  • Sex Characteristics*


  • Analgesics, Opioid
  • Oxycodone