From over‐the‐counter to prescription only: early results of the rescheduling of codeine combination analgesics

Upscheduling has not led to substitution with higher strength analgesics, and has reduced the misuse of codeine‐containing preparations

As rates of problematic opioid use and overdose grow in high income countries,1 epidemiologic signals of exposure and harm have increased year by year. It is therefore encouraging to read evidence of a downward trend for one category of this complex crisis described in two papers in this issue of the Journal.2,3

Codeine (methylmorphine) is a weak opiate; the analgesia it provides patients is unreliable because of individual genetic variations in metabolism. Codeine accounted for two‐thirds of the 42.3 million packs of opioid analgesics sold in Australia during 2013, including 15.4 million packs of over‐the‐counter (OTC) codeine combination analgesics.4 OTC codeine sales were worth nearly $116 million in the 12 months to April 2017, contributing 5.9–8.6% to overall pharmacy net profit.5

In contrast to other opioids, codeine has been available without prescription in many countries, including Australia until February 2018. This situation can be traced to 1931 and the finalisation of the international Convention for Limiting the Manufacture and Regulating the Distribution of Narcotic Drugs. Germany, the leading source of codeine, was in a state of political and economic turmoil and in need of foreign exchange for its economic recovery; it refused to sign the Convention unless codeine was subject to less control than other opioids.6

In 2002, the first OTC codeine/ibuprofen combination analgesic was registered in Australia. Whether adding low dose codeine (8–12 mg) to paracetamol or ibuprofen provides additional analgesic benefit is contentious. A Cochrane review of three 1980s trials that evaluated the benefit of adding 20 or 60 mg codeine to ibuprofen found only a small increase in relative benefit (risk ratio, 1.3; 95% confidence interval, 1.01–1.6).7 Further, more recent OTC combinations of ibuprofen and paracetamol provide better analgesia without the risk of codeine addiction.8

Newer OTC codeine/ibuprofen analgesics provide more codeine phosphate (12.8 mg) than the leading OTC codeine/paracetamol product (8 mg). Misuse first became evident in 2005; several reports have since described increasing morbidity and numbers of deaths linked with supratherapeutic doses of ibuprofen secondary to codeine addiction.9,10,11

Nevertheless, OTC products combining low dose codeine (up to 10 mg anhydrous codeine or 13.6 mg codeine phosphate) with non‐opioid analgesics (ibuprofen or paracetamol) were freely available in Australian pharmacies without prescription and could be advertised until 2010. Moreover, packs of 72 tablets could be purchased in New South Wales without consulting a pharmacist, and pharmacists could provide packs of up to 96 tablets. In May 2010, these products were rescheduled as pharmacist only medicines, but this did not restrain their increasing misuse: in 2016, 497 000 Australians aged 14 years or more had used OTC codeine analgesics for non‐medical purposes.12

It was not until February 2018 that codeine was scheduled as a prescription only medicine. The delay was the result of significant opposition to upscheduling, including concerns that it would lead to higher strength codeine products or stronger opioids being prescribed, impede access to pain relief, and increase health care costs.13

The harm associated with these combination products stems largely from the fact that opiates are addictive, potentially leading to dose escalation. At supratherapeutic doses, serious harm can be caused by the otherwise relatively safe analgesics paracetamol and ibuprofen. Several studies have found that most codeine‐addicted patients commenced taking OTC codeine combination analgesics for minor medical conditions,9 but some progress to consuming 30–60 or even more tablets a day.

Adverse effects of codeine/ibuprofen misuse include those associated with nonsteroidal anti‐inflammatory drugs (NSAIDs), such as erosions and ulcers of the upper gastrointestinal tract with anaemia. NSAID enteropathy of the small and large bowel causes gastrointestinal bleeding of obscure origin, iron deficiency anaemia, and protein‐losing enteropathy, leading to hypoalbuminaemia. Small or large bowel diaphragm disease, the result of mucosal ulceration and contraction of rings of scar tissue, causes circumferential web‐like strictures and stenosis. Presenting as endoscopic capsule retention, with non‐specific symptoms making it difficult to diagnose, or as acute or subacute small bowel obstruction, it is pathognomonic of NSAID enteropathy.9,11,14

Less frequent adverse effects linked with supratherapeutic ibuprofen use include renal tubular acidosis, life‐threatening hypokalaemia (with risk of fatal cardiac arrhythmia), and rhabdomyolysis.15 The prevalence of mental health problems in patients experiencing these conditions is high. Concealment or denial of misuse and the non‐specific nature of symptoms often delay diagnosis of the underlying cause.11,16

The two studies reported in this issue of the Journal provide preliminary indications that rescheduling has not led to the adverse outcomes feared by opponents of upscheduling. Schaffer and her colleagues2 examined national pharmaceutical sales data before and after rescheduling, and found that the loss of OTC codeine sales was largely offset by increases in those of over‐the‐counter non‐opioid analgesics (paracetamol, ibuprofen, and their combinations), with only a small increase in sales of prescription codeine and none in those of stronger opioids. This finding is consistent with another recent study that found a large decrease in overall codeine use and no marked increase in that of prescription codeine or stronger opioids.17

Further, the review by Harris and his colleagues3 of codeine‐related presentations to the Princess Alexandra Hospital in Brisbane found that the number of codeine‐related presentations declined by 53% after rescheduling (163 presentations in the 12 months preceding rescheduling, 77 presentations during the 12 months after rescheduling), largely attributable to fewer presentations associated with the rescheduled low dose codeine preparations (less than 30 mg); numbers of presentations involving other opioids had not increased. These findings are consistent with the fact that calls to the NSW Poisons Information Service about codeine‐related intentional poisonings (deliberate self‐poisoning, recreational use, other non‐therapeutic use) declined by 50.8% in the 12 months after upscheduling, with no increase in calls regarding prescription codeine or other prescription opioids.17

Together, these early findings suggest that upscheduling has been successful in avoiding people substituting preparations of higher strength codeine or stronger opioids for OTC codeine‐containing analgesics, and in reducing the misuse of codeine‐containing analgesics. These encouraging trends need to be followed up with investigations of other outcomes.