Codeine in mothers and children: where are we now?

The death of a child is always a tragedy, so when it was reported that a toddler had died at home in North America following ingestion of codeine prescribed for postoperative analgesia [1], clinicians were understandably alarmed. This child was subsequently found to be what is described as an ultra-rapid metaboliser of codeine. A study in children demonstrated hypercarbia and a depressed ventilatory response to carbon dioxide at plasma morphine concentrations above 20 ng.l 1 [2], and his post-mortem plasma concentration of morphine was 32 ng.l . It was presumed that excessively high morphine levels, together with airway obstruction, caused fatal respiratory depression. There followed a further report of two deaths and a ‘near miss’ related to the use of postoperative codeine in children [3]. In the ensuing months, the Food and Drug Administration (FDA) in the USA [4], the European Medicines Agency (EMA) [5] and the Medicines and Healthcare products Regulatory Agency (MHRA) [6] all issued warning notices related to the use of codeine in children. The MHRA recommended that “codeine should only be used to relieve acute moderate pain in children older than 12 years and only if it cannot be relieved by other painkillers such as paracetamol or ibuprofen”. In addition, the MHRA stated that “codeine is contraindicated in all children (i.e. younger than 18 years) who undergo tonsillectomy or adenoidectomy (or both) for obstructive sleep apnoea”, and that it “is not recommended for children whose breathing might be compromised, including those with neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures” [6]. The MHRA provided no advice regarding children without obstructive sleep apnoea having intermediate-sized surgery such as tonsillectomy/adenoidectomy. In November 2013, a joint statement by the Royal College of Anaesthetists (RCoA), the Association of Paediatric Anaesthetists (APA) and the Royal College of Paediatrics and Child Health (RCPCH) was released [7]. Their conclusions were non-committal; “Within the UK different solutions are being employed. These include continuing to use codeine with increased caution or adopting alternative opioid medication regimens: oral morphine, dihydrocodeine, oxycodone or tramadol are potential alternatives.” So what is the problem with codeine; after all, it has been in use for many years and prescribed, without apparent problems, for millions of patients worldwide? One issue is that codeine’s precise mechanism of action is unclear. Seventy to eighty percent of codeine is metabolised by glucuronyltransferase enzymes in the liver to codeine-6-glucuronide, the analgesic activity of which is unknown in humans, and 10% to norcodeine, a metabolite with no analgesic properties. A small proportion (5–10%) is metabolised by the cytochrome P450 2D6 enzyme system to morphine. Because codeine has only 0.5% of the affinity for mu-opioid receptors compared with morphine, it is widely believed that the major analgesic effect of codeine is as a result of its conversion to morphine [8, 9]. Codeine therefore behaves like a pro-drug, requiring metabolism to become clinically active. The bigger problem, however, is that there are a substantial number of different alleles coding for activity of the cytochrome 2D6 enzyme system and, indeed, gene duplication in a number of important ethnic groups. This results in a wide spectrum of enzyme activity (phenotype) across the range of different genotypes (genetic polymorphism). At one extreme, two abnormal genes lead to individuals with no 2D6 enzyme activity and no ability to convert codeine to morphine, socalled poor metabolisers. At the other extreme, duplication of active alleles results in individuals with