Codeine, ultra-rapid metabolisers, children and breastfeeding

Most people think of codeine as a mild painkiller. In reality it works partly through its conversion into morphine, and that conversion is carried out by the CYP2D6 enzyme in the liver. The gene for CYP2D6 varies a great deal between individuals, so the same tablet can yield very different amounts of morphine in different bodies.

At one end are people whose enzyme barely works and who may get little pain relief. At the other are ultra-rapid metabolisers, who convert codeine to morphine faster or in greater quantity than expected. The FDA's table of pharmacogenetic associations describes the concern for ultra-rapid metabolisers as life-threatening respiratory depression.

The MHRA reviewed codeine in children after fatal and life-threatening cases linked to ultra-rapid metabolism. In its review the agency said the concern arose from three fatal cases and one case of life-threatening respiratory depression, and that frequency of ultra-rapid metabolism differs by ethnicity and geography.

The resulting advice restricts codeine for pain to children over 12 years with acute moderate pain when other painkillers have not worked, and only for a short course. The MHRA also advised avoiding it in anyone whose breathing is already compromised. For cough and cold, the agency found limited evidence that codeine helps children and made it contraindicated under 12.

• Under 12 years: contraindicated.

• Aged 12 to 18: reserved for acute moderate pain when other medicines have failed, for the shortest time.

• After tonsillectomy or adenoidectomy for sleep apnoea, under 18: contraindicated.

• Any age with known CYP2D6 ultra-rapid metabolism: contraindicated.

Codeine and its products can pass into breast milk. The MHRA stresses that most breastfeeding mothers who use codeine-containing painkillers do not cause problems for their babies, and that harmful effects are very rare. The concern is a mother who is an ultra-rapid metaboliser and does not know it, because her milk may then carry more morphine.

The MHRA update notes that most people are unaware of their CYP2D6 status and puts the proportion of ultra-rapid metabolisers in the UK population at roughly one to two per cent. Because testing is not routine, the advice relies on teaching mothers to recognise warning signs rather than on genotype results.

The signs of morphine toxicity listed by the MHRA are reduced consciousness, lack of appetite, drowsiness, constipation, slowed or shallow breathing, pin-point pupils, nausea and vomiting. In breastfed babies the agency highlights nausea, vomiting, poor feeding and unusual sleepiness, and says severe cases can affect circulation and breathing.

If a mother or baby shows these signs, the advice is to stop all codeine-containing medicines and to have alternative pain relief prescribed. Severe breathing problems or unresponsiveness are an emergency: call 999. For milder concerns after taking codeine, NHS 111 is the starting point. The NHS also warns that anyone who feels sleepy after codeine should not drive or use machinery.

Codeine appears in many over-the-counter and prescription products, often alongside paracetamol. Check the ingredients on any compound painkiller, and mention codeine when you tell a prescriber or pharmacist about your medicines.

If you have previously had an unusual reaction to codeine, such as marked drowsiness after a normal dose, tell your GP. A future prescriber can use that history to choose a different painkiller, and a pharmacogenetic test is sometimes discussed where the history is suggestive, although it is not routine.

A CYP2D6 result classifies a person as a poor, intermediate, normal or ultra-rapid metaboliser. That classification is useful for codeine because the extremes carry the main risk, but the MHRA material relies on symptoms and age-based rules for the great majority of people, who have never had such a test.

Other factors, including liver and kidney function, other medicines that block CYP2D6 and the presence of breathing problems, also shape how a person responds. A genotype is one piece of information to be read alongside them.