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Codeine

Classification: B

Drug products: Altermol, Ardinex®, Burana Comp, Citodon®, Citodon® forte, Citodon® minor, Codalvonil, Kodein Alternova, Kodein RPH Pharma, Kodeinfosfat APL, Panocod®, Paracetamol/Kodein Evolan, Treo® comp

ATC code: A07DA, N02AJ06, N02AJ08, N02AJ09, R05DA04

Substances: codeine, codeine hydrobromide, codeine hydrochloride, codeine phosphate, codeine phosphate anhydrous, codeine phosphate hemihydrate, codeine phosphate, sesquihydrate

Summary

Controlled studies on differences between men and women regarding efficacy, safety, and pharmacokinetics of codeine are lacking. Codeine is a pro-drug and must be metabolized to morphine to exert effect.

Additional information

The prevalence of several clinical pain conditions is higher in women than in men. Differences in pharmacokinetics, sex hormones, stress response, or socio-cultural aspects may be of importance [1-3]. Therefore, sex and gender differences of pain medications are difficult to interpret [4].Studies on abuse potential of opioids have not been included in this document.

Pharmacokinetics and dosing

Codeine is metabolized to its active metabolite morphine by the CYP2D6 isoenzyme. No sex differences in CYP2D6 activity has been reported [5, 6]. Clinical studies have shown effect with similar doses in men and women and no sex differentiation in dosing has been suggested [7].

Effects

The effect of opioids for pain-relief may differ between men and women. According to a systematic review, women may require lower doses of opioids, both in treatment of acute and chronic pain. However, no specific data on codeine in acute pain were presented [8]. No other studies with a clinically relevant sex analysis of codeine efficacy have been found.

Adverse effects

Codeine is contraindicated in children <12 years of age due to increased risk for morphine overdose [7].In a double-blind trial evaluating the analgesic effect and adverse events of 1000 mg paracetamol/60 mg codeine after tooth extraction (44 men, 50 women) women were found to report more adverse events when not adjusting for body weight. A lower mean body weight in women might explain this (76 kg in men and 62 kg in women) [9].Sex differences in adverse effects of opioid were investigated in a large retrospective cohort study (3319 men, 5138 women). Women had a higher tendency (OR 1.4 after adjusting for BMI and age) to report adverse reactions to codeine, however the sex difference was not significant. For opioids in general, women had a higher risk of gastrointestinal issues (OR 3.1), skin and subcutaneous tissue complications (e.g. rash, itching; OR 2.1), and nervous system issues (e.g. migraines, dizziness; OR 2.3) [10].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Updated: 2023-01-20

Date of litterature search: 2022-12-13

References

  1. Greenspan JD, Craft RM, LeResche L, Arendt-Nielsen L, Berkley KJ, Fillingim RB et al. Studying sex and gender differences in pain and analgesia: a consensus report. Pain. 2007;132 Suppl 1:S26-45. PubMed
  2. Bartley EJ, Fillingim RB. Sex differences in pain: a brief review of clinical and experimental findings. Br J Anaesth. 2013;111(1):52-8. PubMed
  3. Sorge RE, Totsch SK. Sex Differences in Pain. J Neurosci Res. 2017;95(6):1271-1281. PubMed
  4. Dance A. Why the sexes don't feel pain the same way. Nature. 2019;567(7749):448-450. PubMed
  5. Franconi F, Brunelleschi S, Steardo L, Cuomo V. Gender differences in drug responses. Pharmacol Res. 2007;55:81-95. PubMed
  6. Nicolson TJ, Mellor HR, Roberts RR. Gender differences in drug toxicity. Trends Pharmacol Sci. 2010;31:108-14. PubMed
  7. Kodein Alternova (codeine). Summary of Product Characteristics. Swedish Medical Products Agency [updated 2019-01-22, cited 2022-12-13]
  8. Pisanu C, Franconi F, Gessa GL, Mameli S, Pisanu GM, Campesi I et al. Sex differences in the response to opioids for pain relief: A systematic review and meta-analysis. Pharmacol Res. 2019;148:104447. PubMed
  9. Sagne S, Henrikson PA, Kahnberg KE, Thilander H, Bertilson SO. Analgesic efficacy and side-effect profile of paracetamol/codeine and paracetamol/dextropropoxyphene after surgical removal of a lower wisdom tooth. J Int Med Res. 1987;15:83-8. PubMed
  10. Lopes GS, Bielinski S, Moyer AM, Jacobson DJ, Wang L, Jiang R et al. Sex differences in type and occurrence of adverse reactions to opioid analgesics: a retrospective cohort study. BMJ Open. 2021;11(6):e044157. PubMed
  11. Statistikdatabas för läkemedel. Stockholm: Socialstyrelsen. 2021 [cited 2022-03-15.] länk

Authors: Linnéa Karlsson Lind

Reviewed by: Carl-Olav Stiller, Diana Rydberg

Approved by: Karin Schenck-Gustafsson