Steer Clear of Codeine

Sam Nunn – 29 January 2024

Codeine is often touted as a “weak opioid” that one might prescribe on a low-down rung of the pain ladder. Though I won’t personally slap the pen out of your hand, I am here to tell you that you have much better prescribing choices.

Morphine Roulette 🎰

You see, codeine is but a humble prodrug. Its intrinsic activity at the μ opioid recetor is approximately zilch, so it depends on cytochrome P450 2D6 (CYP2D6) for hepatic bioconversion in good old-fashioned morphine.

And there lies the catch: CYP2D6 is a terribly unreliable enzyme1. There is vast variability in the activity and quantity of CYP2D6 alleles an individual carries (over 100 have been described).

To spare ourselves the headache of describing the many CYP2D6 genotypes, we can group people into four phenotypes

An ultrarapid metaboliser will readily and rapidly convert codeine into potentially-toxic levels of morphine, and a poor metaboliser will have an effective morphone dose near zero.

The risks of ultrarapid codeine metabolism are very real. There are many cases of harm coming to ultrametabolising patients and their young offspring, including a harrowing story of a neonatal death from opioid toxicity after breastfeeding from a mother that took stock-standard doses of codeine.

The distribution of phenotypes varies a good deal between ethnic groups. There is now quite a body of academic publishing concerned with investigating the genetic diversity of CYP2D6 alleles in populations the world over

EthnicityPoor metabolisersUltrafast metabolisers
Western European8-10%1-4%
Southern European7-10%
African0-20%5-30%
East Asian0-1%
Arabian0-20%

Data from Zhou and colleagues tabulated by Joel Iedema.

But don’t get too carried away with profiling your pateints. As Sistonen and colleagues noted, the variation between ethnic groups is generally of equal magnitude to variations within them.

Bad Company 💊

Codeine is most commonly sold in combination with paracetamol. Until recently, any adult in Australia could buy a whole box of twenty codeine/paracetamol tablets over the counter and take the whole thing themselves in one go.

This invovled not only the immediate toxic effect of opioid overdose but also the more insidious risk of liver-ripping paracetamol poisoning. Since the re-scheuduling of codeine in 2018, there has been an “immediate and sustained decrease” in the incidence of paracetamol poisoning from co-ingestion with codeine.

Better Options ✅

The Oxford Analgesic League Table tells us the number needed to treat (NNT) for 50% pain reduction in 4-6 hours for various popular analgesics (and combinations thereof). Though it’s not a perfect way to compare medicines, it certainly gives us the gist of what works.

Here are some selected rows from the (rather large) tables originally published by Moore an colleagues

AgentNNT95% CI
Paracetamol 500mg + ibuprofen 200mg1.61.4 to 1.8
Codeine 60mg + paracetamol 600/650mg3.93.3 to 4.7
Paracetamol 500mg3.52.7 to 4.8
Codeine 60mg128.4 to 18

That’s not a great showing for codeine, especially when used as a single agent. When considering the substantially higher risks of prescribing opioids over NSAIDs, this seems like a slam dunk for paracetamol and ibuprofen.

Closing Thoughts 🧠

Your patient who insists they need oxycodone because “codeine does nothing for me” might be telling the truth after all. If you’re really set on using morphine, just give them morphine! There is nothing “weak” about codeine.

  1. CYP2D6 also metabolises tramadol, which may contributed its reputation for hit-and-miss analgesia.