Regulatory and other responses to the pharmaceutical opioid problem

To the Editor: We read with interest the article regarding Australia's approach to managing the challenges of pharmaceutical opioid utilisation.1 The various regulatory, service delivery and educational activities described would appear to provide a comprehensive response to this problem. However, we were surprised to note the absence of any reference to the potential of pharmacogenomics in identifying patients at increased risk of opioid toxicity.

Various factors dictate how much opioid reaches the brain, how long it stays there, and how sensitive a patient may be to central nervous system (CNS) depression. Many risk factors for opioid toxicity are familiar to doctors. These include high daily opioid dose, extremes of age (neonates and older patients), comorbid conditions (eg, liver, kidney and respiratory disease), concomitant CNS depressants (sedatives and alcohol), and strong inhibitors or inducers of metabolism. In contrast, pharmacogenomics is unfamiliar to many Australian doctors. A recent position statement from major medical colleges describes a coordinated effort by doctors to develop the role of pharmacogenomics in Australian clinical practice.2

Codeine is converted to the active metabolite morphine by the cytochrome P450 enzyme encoded by the gene CYP2D6. Due to variants in CYP2D6, some patients are poor metabolisers (5–10%), have low CNS exposure to morphine, and are unlikely to benefit from or be harmed by codeine. Conversely, other patients are ultrarapid metabolisers of codeine (up to 10%), resulting in high and prolonged CNS exposure to morphine and an increased risk of CNS depression.3

There is an ongoing debate about the place of pharmacogenomics in managing the prescribing of opioids. There is strong support for testing children and nursing mothers taking codeine due to fatal cases of respiratory failure in ultrarapid metabolisers.4 International clinical guidelines recommend that codeine be avoided in poor metabolisers and ultrarapid metabolisers because of lack of efficacy and risk of CNS depression, respectively.3 Considerable research is underway to determine whether pre‐emptive pharmacogenomic testing can help with the pharmaceutical opioid problem.5

To reduce harm from opioids, we recommend testing for CYP2D6 variants as part of a benefit–risk assessment when prescribing codeine, especially for patients with other risk factors for opioid toxicity.