Richard Day and Garry Graham: Codeine — is it too risky?

CODEINE has been available over the counter or by prescription for a long time.

Essentially it is a pro-drug for morphine. To be an effective analgesic, it needs to be metabolised in the liver by cytochrome P450 2D6 to morphine, this pathway accounting for about 10% of the metabolism of codeine.

The gene coding for CYP 2D6 has a number of variants and some of the 2D6 proteins coded for by these variants are inactive.

Thus, in some people (about 8% of Caucasian people and 2% of Asian people) the drug is ineffective.

Also, an individual can have more than one copy of the 2D6 gene, leading to an enhanced, but variable, ability to produce morphine from codeine.

Because of opioid toxicity, withdrawal of codeine has been recommended by Canadian public health physicians, paediatricians and journal editors in the Canadian Medical Association Journal — but this is contentious.

The evidence in support of this was largely derived from studying opioid toxicity in new-born babies and their newly post-partum and breast-feeding mothers prescribed codeine.

There was a correlation between codeine daily dose and toxicity and enhanced toxicity in those mothers with multiple copies of 2D6.

Additionally, the death of a breast-fed baby was linked to the multiple copies of 2D6 identified in her mother.

There does seem to be a good case for very cautious or non-use of codeine post-partum in lactating mothers.

Codeine is subject to abuse and, recently, accounts of excessive chronic intake of OTC ibuprofen–codeine combination tablets have been associated with serious gastrointestinal bleeding and cardiovascular complications as well as opioid addiction.

Codeine is associated with all the known adverse effects seen with morphine. Constipation is a particular problem in the elderly, and problems with falls and cognitive impairment in the elderly are well known.

Concomitant CNS suppressants, including alcohol, increase the risk of drowsiness and therefore of accidents.

The effectiveness of the drug as an analgesic is not impressive.

It is difficult to find strong evidence that the small amounts (8–13 mg) of codeine found in OTC combination tablets deliver substantially more analgesia than paracetamol or ibuprofen alone for everyday pains, especially when taken as single or small doses.

However, the large number of products available and their popularity indicates effectiveness at some level.

Prescription-only formulations such as Panadeine Forte, that contain codeine 30 mg and paracetamol 500 mg in each tablet, taken regularly in doses up to the maximum safe daily dose for paracetamol of 4 g daily, do provide more analgesia but at the cost of the opioid side effects noted.

The recommendation to withdraw OTC codeine-containing oral medications and prescription formulations begs the question, what would replace these drugs that are extensively purchased and prescribed?

The obvious answer is morphine, and this has been suggested.

The argument is that although morphine is also subject to variation in effectiveness and risk of adverse effects related to genetic variability in pharmacokinetics and effect pathways, it is less of a problem than with codeine and would be more easily identified and managed.

However, new formulations containing morphine would need to be developed and registered which would cause a substantial cost. And tablets containing the combination would likely be subject to more abuse than combinations with codeine.

Wider awareness of the benefits and risks with codeine formulations would be a reasonable reaction to the emerging concerns.

Restrictions on the use of OTC and prescription codeine combinations for children are appropriate, but the advice in Australian pharmaceutical product information is quite variable across codeine-containing products, and requires attention.

For example, prescription codeine is labelled “Not for use in children”, but Panadeine Forte can be used in children in lower doses!

Lactating mothers need to be aware of the possibility of significant levels of morphine in their breast milk if regular codeine is taken.

As always, the instructions on the pack for OTC medications and in the product information and consumer medicine information for prescription medicines need to be heeded.

Prescribers not only need to educate their patients but also to question them about their use of non-prescribed analgesics.

Professor Richard O Day is Professor of Clinical Pharmacology at St Vincent's Hospital, Sydney, and the University of NSW.

Professor Garry G Graham is a Professorial Visiting Fellow, School of Medical Sciences, at the University of NSW.

Posted 25 October 2010