The Editorial Executive Committee welcomes letters, which should be less than 250 words. Before a decision to publish is made, letters which refer to a published article may be sent to the author for a response. Any letter may be sent to an expert for comment. When letters are published, they are usually accompanied in the same issue by their responses or comments. The Committee screens out discourteous, inaccurate or libellous statements. The letters are sub-edited before publication. Authors are required to declare any conflicts of interest. The Committee's decision on publication is final.

Letter to the Editor

Editor, – Thank you to Dr Murnion for the excellent review of combination analgesics (Aust Prescr 2010;33:113-5). My understanding of the efficacy of codeine is that it is predominantly a prodrug and that the major analgesic effects derive through the actions of two of its major metabolites, codeine-6-glucuronide and morphine.

Under normal circumstances, most of the codeine is metabolised to codeine-6-glucuronide, with perhaps 10% appearing as morphine. The latter is produced through the action of cytochrome P450 2D6. It has been noted that a small proportion of the population have little CYP2D6 and receive less analgesia than expected. A similar effect is noted in those taking drugs such as fluoxetine which inhibit CYP2D6.

The converse is true for those hyper-metabolisers who have multiple copies of CYP2D6 or who take drugs such as dexamethasone which induce the enzyme.

Given the comments by Dr Murnion regarding the usefulness of paracetamol or a non-steroidal anti-inflammatory drug in conjunction with morphine, could she please comment on the possibility of better prescribing codeine (in combination or otherwise) based on the patient's CYP2D6 status.

Peter Bowron
Senior hospital scientist
Toxicology Unit – PaLMS
North Ryde, NSW

Author's comments

Dr Bridin Murnion, the author of the article, comments:

The analgesic efficacy of codeine resides predominantly in the morphine metabolite. Codeine-6-glucuronide is reported to have the low efficacy of the parent compound.1

Low efficacy of codeine in those with low activity of CYP2D6 (poor metabolisers) is recognised. In addition, of concern is the potential for enhanced toxicity in ultra-rapid metabolisers, with reports of a neonatal death.1

Understanding of an individual's cytochrome P450 activity profile, and the impact of drugs on this, is of importance in development of new chemical entities and in optimising drug regimens in many therapeutic areas.2

Cytochrome phenotyping and genotyping for over-the-counter analgesics containing codeine requires further consideration, but may be of limited value given the likely cost of testing, limited efficacy of these preparations and significant public health concerns around opioid dependence and toxicity from co-ingested paracetamol or non-steroidal anti-inflammatory drugs.