The decision of the TGA to up-schedule low-dose codeine was a long, evidence-based and consultative process.1 The consultation started in April 2015, and included an extra deferral of the decision in November 2015 and an extra consultation period to assess further concerns. A detailed financial analysis was also carried out. But what is the evidence? There are many aspects.
Little incremental benefit of codeine
Medicines affected by the change are those combining low-dose codeine (≤ 15 mg) with paracetamol or a non-steroidal anti-inflammatory (NSAID) such as ibuprofen, and/or an antihistamine or decongestant.2,13 Studies in acute pain suggest only a modest additional analgesic effectiveness when a high dose of codeine (60 mg) is added to paracetamol, but a higher rate of adverse effects after repeated doses.21-24
For low-dose codeine medicines affected by the decision, the evidence is mixed regarding the incremental benefit of codeine in such combinations, with the majority of studies showing no added benefit.13
Risks of the variable metabolism of codeine
Codeine delivers its analgesic effects when it is converted to morphine inside the body. Genetic differences lead to different rates of metabolism of codeine to morphine, and thus different responses to codeine. It is difficult, however, to predict the metabolism rate by studying the genotype alone.25 Between 75% and 92% of people metabolise codeine to morphine at a normal rate. At the low end of the spectrum, around 5% to 10% of people are poor metabolisers and receive little analgesic effect from codeine. Around 1% to 2% of people are ultra-rapid metabolisers who can convert codeine into large amounts of morphine.25,26 The ultra-rapid metabolisers should avoid codeine use due to the potential for toxicity.25
The ultra-rapid metaboliser phenotype has resulted in paediatric deaths26,27 and a neonatal death from morphine toxicity through breast milk,28 prompting safety warnings across the world.25,29-31
High human and financial costs
The addictive nature of codeine can result in people developing tolerance and escalating their dose. Such escalations can result in dangerous doses of the paracetamol or NSAIDs contained in codeine combination medicines.8 There is much documented evidence of the harm caused by OTC codeine in the Australian setting. Between 2000 and 2009 codeine related deaths increased from 3.5 to 8.7 deaths per million population, with a significant fraction of these patients recorded as also using OTC codeine.32
New research33 has assessed one aspect of the costs of OTC codeine misuse – those related to hospital admissions. The study used records from a 593-bed Australian public hospital taken over a 5-year period from June 2010 to June 2015. A total of 99 OTC codeine misuse admissions, involving 30 patients, were found. The estimated cost to the local healthcare system from OTC codeine misuse in this one hospital was $1,008,082, with a mean cost per hospital admission of $10,183.
People admitted to hospital had taken OTC codeine to help with a range of conditions, most commonly musculoskeletal pain (26.7%) and headache/migraine (13.3%). Some were consuming over six times (18 g) the daily recommended dose of ibuprofen, with others taking similarly excessive doses of paracetamol. Many had taken the medication over a prolonged period (up to 10 years for one patient).
Codeine misuse increasing despite earlier up-scheduling decision
The codeine misuse issue has been growing. A retrospective review27 of calls about codeine misuse made to the New South Wales Poison Information Centre (Australia’s largest poison centre) found the frequency of cases increased significantly from 2004 to 2015. The study examined 400 cases of codeine combination analgesic misuse in that period and found an average percentage increase of 19.5% for paracetamol/codeine and 17.9% for ibuprofen/codeine.
In 2010 the TGA up-scheduled codeine to ‘pharmacist only’ to address the risks, but there was no significant change in the upward trend of codeine misuse seen after this rescheduling.27