Published: 8 June 2018

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Spotlight on Codeine

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Prescriber Update 39(2): 18-19
June 2018

Codeine is a weak opioid analgesic indicated for the relief of mild to moderately severe pain. Codeine also has antitussive properties and is used in some cough and cold medicines to control non-productive cough. Codeine is metabolised in the liver to the active compounds morphine and morphine-6-glucuronide.

Codeine metabolism

Metabolism of codeine to morphine predominantly involves the cytochrome P450 enzyme CYP2D6. Genetic polymorphism in the CYP2D6 gene results in significant variation in the ability of individuals to metabolise codeine to morphine. Individuals may be classified as a poor, intermediate, extensive or ultra-rapid metabolisers¹.

The extensive metaboliser phenotype represents normal (wild-type) enzyme activity, and most people fall into this category. The frequency of poor metaboliser and ultra-rapid metaboliser phenotypes varies between populations. The relative frequencies of these phenotypes in the New Zealand population are not known.

Poor metabolisers are unable to convert codeine to morphine and receive little if any, analgesic benefit. Extensive metabolisers convert 5–15% of codeine to morphine via the CYP2D6 enzyme. In these patients, a 30 mg dose of codeine phosphate would yield approximately 1.5 mg to 4.5 mg of morphine. Ultra-rapid metabolisers convert codeine to morphine very efficiently, which can lead to morphine toxicity, such as respiratory depression and death.

Both codeine and morphine are excreted into breast milk. This is of particular concern for breastfeeding mothers who are ultra-rapid metabolisers. Exposure of the infant to breast milk containing morphine may lead to opioid toxicity in the infant, with the potential for respiratory depression and death. Furthermore, opioid toxicity in the mother (such as somnolence) may compromise her ability to identify signs of opioid toxicity in her infant.

Deaths associated with the use of codeine

The United States Food and Drug Administration (FDA) undertook a review of adverse events submitted to the FDA Adverse Event Reporting System from 1969 to 2015. The review identified 64 cases of serious breathing problems, including 24 deaths, associated with codeine-containing medicines in children aged under 18 years² . Many of these cases concerned children with obstructive sleep apnoea who received codeine after surgery to remove tonsils or adenoids³ . Since these children already had underlying breathing problems, they may have been particularly sensitive to morphine-induced respiratory depression.

In New Zealand, 53 deaths were recorded in the National Coronial Information System for the period 1 January 2008 to 31 December 2014 in which codeine was assessed as the primary contributor (JS Fountain, personal communication, April 2018). The median age of death was 48 years (range 18–86 years). In 26.4% of cases, death was considered to be unintentional. Overall, codeine phosphate ranked fourth as the primary contributor to deaths due to pharmaceuticals.

Pain management in children

Codeine is no longer recommended by the World Health Organization or the Australian and New Zealand College of Anaesthetists for analgesia in children^4,5.

CYP2D6 status is not routinely determined therefore it is not possible to predict whether codeine will provide an analgesic effect or a toxic effect.

Changes to age restrictions and contraindications for codeine-containing medicines

The Medicines Adverse Reaction Committee (MARC) recently reviewed the benefits and risks of using codeine in children.

The MARC recommended:

• the use of all codeine-containing medicines should be contraindicated in:
  • children aged under 12 years for all indications
  • adolescents aged under 18 years for pain following surgery to remove tonsils and adenoids
  • adolescents aged under 18 years in whom respiratory function might be compromised
  • adolescents aged under 18 years for cough
• the warning to avoid using codeine in breastfeeding mothers should be strengthened to a contraindication.

The MARC noted that codeine-containing cough and cold medicines are already contraindicated in children aged under 12 years⁶ .

Read more on the recommendations in the minutes of the 173rd meeting www.medsafe.govt.nz/profs/MARC/Minutes.asp. Medsafe is working with the New Zealand sponsors of codeine-containing medicines to update the data sheets in line with the MARC’s recommendations.

Although the MARC only reviewed the use of codeine in children, health care professionals are advised to inform all patients about the signs and symptoms of morphine toxicity when prescribing codeine.

Please report any adverse reactions to codeine to CARM (http://nzphvc.otago.ac.nz/report/).

References

1. Crews KR, Gaedigk A, Dunnenberger HM, et al. 2014. Clinical Pharmacogenetics Implementation Consortium Guidelines for Cytochrome P450 2D6 Genotype and Codeine Therapy: 2014 Update. Clinical Pharmacology and Therapeutics 95(4): 376–82.
2. US Food and Drug Administration. 2017. FDA Drug Safety Communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. URL: www.fda.gov/Drugs/DrugSafety/ucm549679.htm (accessed 7 May 2018).
3. US Food and Drug Administration. 2013. FDA Drug Safety Communication: Safety review update of codeine use in children; new Boxed Warning and Contraindication on use after tonsillectomy and/or adenoidectomy. URL: www.fda.gov/downloads/Drugs/DrugSafety/UCM339116.pdf (accessed 7 May 2018).
4. World Health Organization. 2012. WHO Guidelines on the Pharmacological Treatment of Persisting Pain in Children with Medical Illnesses. Switzerland: World Health Organization.
5. Schug SA, Palmer GM, Scott DA, et al (eds). 2015. Acute Pain Management: Scientific Evidence. Melbourne: Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine.
6. Medsafe. 2016. Reminder: Using cough and cold medicines in children is inappropriate. Prescriber Update 37(2): 18. URL: www.medsafe.govt.nz/profs/PUArticles/PDF/Prescriber%20Update%20June%202016.pdf (accessed 7 May 2018).