What is the problem?

On this page: What is the problem | What is codeine? | What are the health concerns with codeine use? | International regulation of codeine | Australian risk management framework

Following announcements on the TGA website of proposed changes in codeine scheduling, and safety information describing the health concerns relating to OTC codeine use, misuse and abuse, over 230 public submissions have been received (see 'Overview of consultation activities' p. 95 for further details). The opinions expressed in the public submissions were polarised, and when similar opinions that support regulatory action were grouped they generally expressed the following thoughts and feelings:

Conversely, public submissions from those consumers that oppose any regulatory change such as up-scheduling (approximately 77%) express views that are similar to that below:

This indicates that an emphasis on consumer education will be critical following any changes in codeine scheduling to better inform the public about the potential harms of chronic codeine use, especially when used in combination products.

What is codeine?

Codeine is an opioid drug closely related to morphine and, like morphine, is also derived from opium poppies. Codeine is contained in the World Health Organization (WHO) Model list of essential medicines as an important medicine to be provided in a basic healthcare system. There are many forms of codeine, including various salts (phosphate, phosphate hemihydrate, hydrochloride, sulfate, camsilate and hydrobromide forms) and there are also derivatives such as acetyldihydrocodeine, codeine-N-oxide, dihydrocodeine, and norcodeine. These derivatives are outside the scope of the current RIS; however, they may need to have their scheduling reconsidered once a scheduling decision is made for codeine. Of the salts, codeine phosphate hemihydrate is the dominant form in the Australian marketplace today.

Codeine is an old and commonly used analgesic for mild and moderate pain and is used in many medicines across both the prescription and over-the-counter (OTC) markets. In the prescription medicine context, high dose codeine products (30* mg to 120 mg/dose), either alone or in combination with paracetamol, provide a good level of strong pain relief for some people with cancer pain, post-operative pain and other acute pain conditions.^[1,2]

In comparison, low-dose codeine products (10-12* mg/unit dose, referred to as low-dose codeine medicine hereafter) in OTC products, are used to manage milder pain conditions such as migraine, headache, dental pain,^[3] or for the management of cold and flu symptoms (including cough).

* The concentration of codeine on the medicine pack may be different due to the salt component.

Codeine is a prodrug

Codeine itself is a weak analgesic in its original form, and must be metabolised to its active metabolite, morphine, by the liver enzyme cytochrome P450 2D6 (CYP2D6) to have a therapeutic effect. Codeine should therefore be regarded as a prodrug that requires bioactivation before an effect is observed. Codeine's effectiveness depends on the individual's ability to metabolise codeine to morphine.

There are a number of genetic variants of CYP2D6, resulting in large variability in individual responses to codeine. At one extreme are poor metabolisers, who lack functional CYP2D6 (5-10% of the population) and experience very little therapeutic effect from codeine. At the other extreme, ultrarapid metabolisers (up to 10% of the Caucasian population and 30% of the African population)^[4] have increased conversion of codeine to morphine, leading to a higher risk of toxicity.

Since codeine was first made available and scheduled, the ability to measure CYP2D6 polymorphism (i.e. the existence of variable forms of the gene within the population) has become possible, but it is not a routinely conducted clinical test due to its complexity and expense.

While morphine is a strong opioid analgesic, the analgesic efficacy of codeine itself is very low, as demonstrated by the lack of analgesic effect in poor metabolisers. Since very few individuals who purchase OTC codeine medicines are aware of their own CYP2D6 status, the dosing instructions are inappropriate for many consumers, with specified doses being too low to achieve an analgesic effect for some and too high for others.

Published reviews on the efficacy of codeine when given in small to moderate doses (30 mg or less), either alone or in combination with another analgesic such as paracetamol or a non-steroidal anti-inflammatory (NSAID), have had varied results. For example, a review of nine randomised controlled trials of analgesia post-laparotomy showed no greater efficacy of paracetamol plus 30 mg codeine compared with a variety of NSAIDs given alone.^[5]

How is codeine used?

Codeine may be used as an analgesic for the relief of mild to moderate pain, and for the symptomatic relief of non-productive cough. As a prescription medicine containing greater than 30 mg of codeine, these medicines provide a good level of pain relief in some people experiencing strong pain, such as cancer pain.

Combination medicines containing codeine are widely available OTC in pharmacies and are self-selected by consumers to manage mild pain conditions, such as headaches or backache. Consumers appear to choose low-dose codeine combination analgesics for strong pain relief, as they are marketed to be effective for strong pain, while simple pain relievers such as paracetamol and ibuprofen are thought to provide more general pain relief. However, there is limited data on the incremental effectiveness of combination medicines that contain low-dose codeine when compared to other analgesics.

With respect to cough and cold medicines containing codeine, often consumers choose such products to relieve a cough (cough suppressant). However, there is limited information from good quality clinical trials to indicate that codeine-containing cough suppressants are effective for treating coughs in children.^[6] Indeed the health risks associated with codeine cough suppressants used in children are significant and therefore should not be used in children younger than 6 years.

Analgesia

In oral pain relief OTC preparations, codeine phosphate (usually 8 mg per dosing unit) is often combined with a non-opioid analgesic such as aspirin, ibuprofen or paracetamol. The approved indication for Schedule 3 codeine products is for the 'temporary relief of strong pain and discomfort associated with a number of different medical conditions'. However there is significant use of Schedule 3 codeine products for long term relief of chronic pain and a number of public submissions by consumers have noted that this is how they use it.

Opioid analgesics are generally not considered suitable for a first-line therapy to treat chronic non-cancer pain, nor are they appropriate for long-term use.^[7] Instead, clinical therapeutic guidelines for analgesia^[8] and proponents of up-scheduling state that the management of chronic non-cancer pain would be better achieved via medical practitioner evaluation and advice with regards to appropriate pharmacological and non-pharmacological treatments.

Cough and cold preparations

Codeine or its salts (especially the phosphate salt)^[9] are given orally in the form of linctuses (low-dose, 5 mg/mL) for the relief of cough. Cough and cold preparations containing codeine are often compounded with phenylephrine, and may include additional non-opioid analgesics or other therapeutic substances.

What are the health concerns with codeine use?

Information from within Australia and from other comparable international regulators indicates that codeine-containing medicines are being abused and/or inappropriately used. Over the last decade this has resulted in a rise in morbidity and deaths^[10] associated with liver damage, gastrointestinal perforations and respiratory depression.

Health Safety Reports

The TGA has undertaken or commissioned three separate reviews which have included the efficacy and/or safety of codeine over the past 7 years. The outcomes and recommendations of these reviews are provided in the following paragraphs.

Safety and efficacy of registered over-the-counter (OTC) cough and cold medicines for children aged 2-12 years (TGA, 2012)

Between the years of 2009-2012, the TGA carried out a comprehensive review of the medical literature relating to the safety and efficacy of OTC medicines containing various substances for the symptomatic treatment of cough and cold in children aged less than 12 years. Codeine was considered as part of this review due to its purported antitussive activity. This review was published on the TGA website in 2012.

As a result of this review, the TGA concluded that there was a lack of evidence to support the efficacy of OTC cough and cold medicines in children under 12 years of age, although there was no immediate safety risk associated with their use in adults. Further, the potential risks of adverse reactions in children less than 12 years of age were high relative to the limited benefits. This conclusion was supported by the historical profile of adverse reactions in children under the age of 12, which included deaths associated with respiratory depression.

The review showed that the risks associated with OTC cough and cold medicines are greater in children aged less than 6 years compared to children between 6 and 11 years. These medicines therefore should not be used for treating children less than 6 years of age, and should only be administered to children aged 6-11 years on the advice of a doctor or pharmacist. Furthermore, all of these medicines should be in child-resistant packaging and labelled accordingly. The scheduling status of these medicines in the Poisons Standard should also be examined in order to determine if any changes are needed to their availability.

The recommendations resulting from this safety review included the introduction of new Required Advisory Statements for Medicine Labels (RASML), which came into effect in December 2015. Oral preparations containing codeine or any other active component indicated for cough, cold or flu that do not include dosage instructions for children aged under 12 years will read 'Do not give to children under 12 years of age.' For example, oral preparations containing codeine indicated for cough, cold or flu will include dosage instructions for children aged from 'x' to 11 years (where 'x' is 6, 7, 8, 9, 10 or 11).

• When x = 11 'Do not give to children under 11 years of age, except on the advice of a doctor, pharmacist or nurse practitioner'
• When x < 11 'Do not give to children aged between 'x' and 11 years of age, except on the advice of a doctor, pharmacist or nurse practitioner.'

These requirements clearly indicate concern regarding the safety of codeine in OTC cough and cold preparations (Schedule 2) when given to children.

Subsequent to this initial review, two expert safety reports were commissioned by the TGA: Safety review on codeine use in children and ultra-rapid metabolisers (TGA, 2015) and Investigating the efficacy and safety of over-the-counter codeine-containing combination analgesics for pain and codeine based antitussives.^[11] The following provides the outcomes and recommendations concluded by these expert reviews.

Safety review on codeine use in children and ultra-rapid metabolisers (TGA, October 2015)

The TGA's second safety review of codeine use in children (and also included ultra-rapid metabolisers) was published on the TGA website in October 2015. [TGA Pharmacovigilance and Special Access Branch Safety Review: Codeine use in children and ultra-rapid metabolisers. October 2015.

This safety review considered the use of codeine-containing products in children and breastfeeding mothers, in the context of genetically determined ultra-rapid metabolism of codeine to morphine. Children who metabolise codeine to morphine ultra-rapidly are at a higher risk of accidental morphine overdose, which can lead to respiratory compromise and death. Children are more susceptible to respiratory problems than adults due to their immature airway anatomy. Children who have had an adenotonsillectomy for obstructive sleep apnoea may be particularly susceptible to opioid-induced respiratory depression in the post-operative period. Codeine that has been metabolised to morphine can also be ingested by infants through breast milk, causing risk of respiratory depression to infants of ultra-rapid metaboliser mothers who take codeine.

Internationally, deaths have been reported in children with ultra-rapid metabolism who were given codeine for analgesia post adenotonsillectomy, and for other indications. Deaths have also been reported internationally in breast-fed infants of mothers who are ultra-rapid metabolisers of codeine. However at the time of this review, there were no reported cases of respiratory compromise leading to deaths with paediatric codeine use in ultra-rapid metabolisers in the Australian post-market or coronial data.

The final recommendations of the safety review were:

• The use of codeine in children younger than 12 years of age for any indication, and in children 12-18 years post adenotonsillectomy for obstructive sleep apnoea should be contraindicated.
• Existing warnings contraindicating codeine use by breastfeeding mothers should be made consistent across all codeine-containing products.
• Warnings should be added to advise against using codeine if the individual is known to be an ultra-rapid metaboliser.
• Healthcare professionals, patients and caregivers should be educated regarding the variability of codeine efficacy, the possibility of ultra-rapid metabolism-related morphine overdose, and the signs of such, including respiratory depression.

These recommendations were supported by the TGA's Advisory Committee on the Safety of Medicines (ACSOM) at their meeting on 10 July 2015. ACSOM noted that the OTC availability of codeine-containing medicines supported a general perception in the community that codeine is safe and that there would need to be additional measures, such as education and possible up-scheduling, to achieve the desired outcome of risk reduction.

The independent expert safety committee emphasised the risks of respiratory depression and possible death in the context of ultra-rapid metabolism associated with codeine, with these risks outweighing the benefits of codeine use for all indications in children under the age of 12 years. Furthermore it is not possible to identify in advance the subgroup of children who are at increased risk of toxicity (e.g. through being an ultra- rapid metaboliser), and thus the risks relate to all children under the age of 12.

Other points made in the independent expert safety advice included:

• The risks associated with codeine outweigh the benefits for analgesia in children under the age of 18 years who have undergone tonsillectomy or adenoidectomy for sleep apnoea, for the same reasons as for children under the age of 12 years, as outlined above. This is consistent with both the FDA (USA) and EMA (Europe) positions, which contraindicate the use of codeine after adenotonsillectomy.
• That the risks to breastfed infants associated with ultra-rapid metabolism of codeine by their mothers outweigh the benefits of codeine for any indication by breastfeeding mothers. As a mother's knowledge of her own experience with codeine (and indirectly, metaboliser status) does not predict the infant's response, breastfeeding should be a contraindication for codeine.

In light of these safety review recommendations, the TGA has commenced implementation of label warning statements for all Schedule 4 codeine-containing medicines. Implementation of the recommendations for the remaining Schedule 2 and Schedule 3 products is on hold pending the current re-scheduling decision. If the scheduling decision is to maintain codeine-containing products as OTCs, a consultation on the above recommended warning statements may take place concurrently with any new statements that would come out of the scheduling decision.

Investigating the efficacy and safety of OTC codeine-containing combination analgesics for pain and codeine based antitussives (March 2016; George Institute review)

The aim of this systematic review^[12] was to determine the efficacy and safety of OTC codeine combination analgesics for the treatment of any pain condition, or as an antitussive. A total of 14 randomised placebo-controlled trials of combination codeine analgesics or codeine based medicines [involving 788 participants] were included in this review. Ten of the trials evaluated the effects of codeine on various pain conditions and four trials evaluated codeine's antitussive effects. There is high quality evidence that combination codeine medicines provide clinically important pain relief in the immediate term (3 hours post ingestion), but it is unclear the level of incremental pain relief that was provided by the codeine component of these combination medicines.

In addition to the studies above, three trials compared combination codeine medicines with appropriate single ingredient comparators, two of which reported no statistically significant difference in analgesia, with one trial reporting a marked increase in analgesia attributable to codeine activity (refer to 'Morbidity and death' below for more details). Some of the trials however, did not use the same-drug comparisons, comparing codeine-containing combination medicines with single ingredient analgesia medicines such as an NSAID plus codeine or paracetamol. In these trials, no information was presented for codeine-only medicines compared to combination medicines (such as NSAIDs or paracetamol) which made it difficult to evaluate the incremental effectiveness of codeine or to attribute any findings involving the efficacy of codeine alone.

Furthermore, this review found that codeine-based medicines reduce cough severity, but not frequency; however the evidence for this is very low quality.

Morbidity and death

Morbidity

It is clear from publications, case studies, and anecdotal reports over the last couple of decades that morbidity from misuse of codeine-containing OTC products is a significant health problem, both internationally and in Australia. The misuse and abuse of codeine leads to the ingestion of excessive doses of the companion drugs (usually paracetamol or NSAIDs).

According to a recent survey from the National Drug Institute, the number of teenagers abusing medicines doubled between 2010 and 2013, with 41% of these teenagers reporting OTC codeine combination medicine misuse.^[13]

There are case reports of serious adverse effects and deaths from combination codeine medicines, particularly related to paracetamol-induced hepatotoxicity^[14] and NSAID-induced gastrointestinal (GI) ulceration.^[15,16] The TGA Database of Adverse Event Notifications^[17] (sourced in early 2014) contained 59 cases of gastrointestinal ulcer or bleeding related to codeine/NSAID combinations, and 57 cases of hepatotoxicity from combination codeine/paracetamol products.

Opioid withdrawal symptoms upon cessation appear to propagate the cycle of misuse and dependency as evidenced in some case studies where opioid withdrawal was of notable concern.^[18,19]

In a submission to the Department of Health in 2008, the Victorian Department of Health had identified 77 cases of codeine-ibuprofen analgesic misuse (50 tablets per day on average) over months to years (average 2.5 years) resulting in dependence and serious incidences of harm, including one death.^[20] The Department of Health then requested that all state and territory health departments provide information on the abuse or misuse of codeine and ibuprofen combinations. Significant morbidity associated with the misuse of codeine-containing combination products was subsequently reported by every Australian state and territory. However, the data were not comprehensive and could not be formally analysed.

Frei et al. ^[18] (2010) examined data on a series of 27 patients being treated for complications of prolonged use of supra-therapeutic (more than 6 months with a daily dose ranging between 34 and 47 tablets) OTC codeine-ibuprofen analgesics in Victoria between May 2005 and December 2008. Ten patients had GI complications attributed to ibuprofen, including one patient who required a gastrectomy; 4 patients had life threatening hypokalaemia and one patient had renal failure, requiring dialysis.

In a 2016 study by Hotham and co-workers,^[21] the number of patients hospitalised due to serious adverse effects relating to misuse of OTC codeine-containing analgesics, and the related cost of hospitalisation, was determined for one South Australian hospital over a 5-year period. There were 99 admissions related to OTC codeine-containing analgesic (pertaining to 30 individual patients), with most relating to GI morbidities secondary to ibuprofen/codeine misuse. Patients consumed a mean of 28 codeine-containing tablets per day, over a mean duration of 606 days prior to admission. The mean cost per hospital admission was $10,183.

Death

Substantial evidence from publications and case studies show that drug toxicity involving codeine contributes to both accidental and intentional deaths. Many of these deaths can be attributed to the misuse of combination codeine medicines.^{[20,22,23,24]}

In 2013, Pilgrim et al^[24] reported the outcome of Victorian coronial cases over a 10-year period from January 2001 to December 2011. There were 115 deaths in which codeine and ibuprofen were co-detected in post-mortem analyses or in which the misuse of codeine and ibuprofen was confirmed. In 7 of these deaths, NSAID-type pathology was recorded.

Roxburgh et al (2015)^[10] used data from the National Coronial Information System to examine trends in codeine-related deaths in all Australian states and territories between 2000 and 2013. It is likely that this data includes at least some of the data from Pilgrim et al.^[24] Codeine-related deaths were defined as deaths where codeine was detected and codeine toxicity contributed to death, including deaths attributed to multiple drug toxicity (including codeine). Codeine toxicity was a contributory factor in 1437 deaths between 2000 and 2013. The underlying cause of death was determined to be codeine toxicity in 7.8% of cases (113 deaths), and multiple drug toxicity (including codeine) in 83.7% of cases (1201 deaths). Approximately 24% (343 cases) of the deaths were related to a prescription codeine product (usually Panadeine forte), 16% (229 cases) included an OTC codeine product, and in the remaining 60% of deaths, there was no information about whether the codeine consumed before death was prescribed or OTC. The toxicology profile in approximately half of the deaths also involved paracetamol, ibuprofen or doxylamine. Importantly, regardless of the source of codeine or its direct relationship with mortality, codeine-related deaths (with and without other drug toxicity) increased from 3.5 to 8.7 deaths per million persons between 2000 and 2009. Just under half of the deaths were attributed to accidental overdose, and the rate of these deaths also increased significantly by 9.3% each year, from 1.8 to 5.1 deaths per million persons.

In addition to morbidity and deaths associated with the misuse of combination products and opioid dependence, deaths have been reported in young children given codeine post-operatively and in babies of breast-feeding mothers given codeine. The risk of severe respiratory depression is much higher in children and ultra-rapid metabolisers because of the higher rate of conversion of codeine to morphine in these individuals. Extensive metabolisers may have up to 30-fold higher blood morphine concentrations than poor metabolisers, resulting in greater respiratory depression and sedation. In one study in 156 Caucasians given 25 mg codeine, ultra-rapid metabolisers had up to 45-fold higher concentrations of codeine metabolites than poor metabolisers.[26]

The risks of respiratory depression, morbidity and death associated with codeine use in children under the age of 12 is of great concern, both internationally (US and the EU) and within Australia. Further, there is an increased risk of morbidity and death associated with codeine use in children under the age of 18 years, who have undergone tonsillectomy or adenoidectomy for sleep apnoea (see previous section).

A TGA literature search covering the period 2015 to 2016 has not found any clinical studies or systematic reviews of codeine safety published in this period. Other than the Roxburgh^[10] paper (discussed above under 'Death') which provides evidence of increasing rates of fatal codeine-related overdoses in Australia, no new codeine safety issues have been identified since 2015.

Dependence and addiction

Early reviews published in the 1970s and 1980s concluded that addiction^[27] to codeine is rare.^[28,29] However several other reports, including those published more recently, describe individuals who misuse or regularly use codeine.^{[30,31,32,33,34]} Anecdotal evidence suggests that some individuals may not be aware of a drug use problem until there are serious health harms (see 'Morbidity and death' above). It is this lack of awareness that highlights the need to educate consumers about the potential for codeine to cause dependency.

The risk of codeine abuse relates to the development of opioid dependence which causes significant social disadvantage. This stems from the need to acquire large quantities of OTC codeine-containing analgesics on a daily basis, and from the need to access opioid substitution therapy with methadone or similar drugs.

At a single drug dependence unit in South Australia, there has been a progressive increase in the annual incidence of codeine as the drug of dependence leading to a need for intervention, increasing from 31 in 2002-2003 to 174 by 2013-14.

In 2013, data from the national opioid pharmacotherapy statistics showed that codeine was the opioid drug of dependence for 1,038 clients receiving opioid substitution pharmacotherapy. Another recently published study of 902 people who inject illicit drugs, found that approximately one-third had also misused OTC codeine during the preceding six months. Furthermore, the presence of codeine in OTC combination analgesics contributes to severe adverse outcomes associated with overdosage of the paracetamol31 or ibuprofen^[35] component (see above 'Morbidity and death'). Anecdotally some abusers of OTC codeine medicines are consuming between 30 to 70 tablets or capsules per day of codeine-containing analgesics. A majority of people with codeine-dependent behaviours purchase their codeine-based medicines from multiple pharmacies. ^[18,36]

International regulation of codeine

Due to harm from abuse or misuse of codeine, including dependency and death, medicines containing codeine are specifically regulated in many countries. Regulatory controls include limits on pack sizes, label warnings on packaging, warnings in consumer information leaflets, and availability of codeine-containing medicines by prescription only.

United States of America (USA)

In the USA, under Food and Drug Administration (FDA) regulation all codeine products are available by prescription only. However some states follow an exemption (21 CFR 290.2) from prescription requirements for low-dose codeine mixed with a cough syrup, which may be dispensed by a pharmacist if the preparation contains not more than 200 mg codeine per 100 g of syrup and also includes one or more non-narcotic active ingredients.

In 2013, the FDA issued a warning that codeine is contraindicated in post-operative pain management of children under 12 following tonsillectomy and/or adenoidectomy, due to rare life-threatening adverse events or death, due to rapid metabolism of codeine to morphine.

In 2015, the FDA initiated a review into the possible risks of using codeine-containing medicines to treat coughs and colds in children less than 18 years of age because of the potential for serious side effects, including slowed or difficult breathing. This review is ongoing.

In addition, products containing codeine with paracetamol (acetaminophen) have black box warning labels regarding both hepatotoxicity and codeine metabolism:

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product.

WARNING: Death Related to Ultra-Rapid Metabolism of Codeine to Morphine.

Europe and Asia

Medicines containing codeine are available only with a prescription in Hong Kong, Iceland, India, Japan, the Maldives, Romania, Russia, and the United Arab Emirates.

Of the 28 European Union (EU) member states (including the United Kingdom (UK)), 15 countries require a prescription (Austria, Belgium, Croatia, the Czech Republic, Finland, Germany, Greece, Hungary, Italy, Luxembourg, Netherlands, Portugal, Slovakia, Spain and Sweden), two countries permit OTC sale of cough linctus only (Hungary and Netherlands), and 13 countries allow the sale of OTC codeine solid dosage forms.^[37] Of the countries that permit codeine over the counter, all except Denmark require the sale to be under the supervision of a pharmacist. Five countries have limits on the quantity of tablets sold, and five countries contain a warning label relating to addiction on the pack. The permitted maximum allowable amount of codeine per preparation is 30 mg in Bulgaria, 20 mg in France, 15 mg in Poland, and 12.8 mg or less in the remaining countries.

Like the FDA, the European Medicines Agency (EMA) has issued recommendations to prevent the use of codeine-based preparations in children under 12 and to carefully consider the use of these medicines in children aged 12-18 years with breathing problems.

United Kingdom

Under the Misuse of Drugs Act and the Prescription Only Medicines (Human Use) Order 1997, there are provisions for small quantities of the controlled drugs, codeine and dihydrocodeine (DHC), to be available in non-prescription medicines in combination with non-opioid analgesics (paracetamol, aspirin and ibuprofen). They may include doses of up to 25.6 mg of codeine phosphate (i.e. 2 tablets/dose of 12.8 mg/tablet) and up to 14.92 mg of DHC tartrate (i.e. 2 tablets/dose of 7.46 mg/tablet). All non-prescription medicines containing codeine or DHC are classified as Pharmacy (P) medicines (equivalent to Schedule 3 in Australia).

Oral liquid products containing codeine for the symptomatic treatment of dry cough are also available with a prescription and classified as P medicines in strengths of up to 15 mg/5 ml. Before 2010 they were available in paediatric as well as adult formulations. Now they are available for use in adults over 18 years only.

In February 2005, following a review of the abuse and misuse of OTC medicines containing codeine or DHC, the MHRA implemented the following risk minimisation measures:

• Stronger warnings on the Summary of product characteristics (SmPC), Patient Information Leaflet (PIL) and label to reflect the importance of not taking the medicines for more than three days continuously without medical review, and to warn about the risks of addiction and headache from overuse.
• The PIL and labels state that products containing codeine can cause addiction if used continuously for more than three days. The outer pack is labelled 'For three days use only. Can cause addiction.'
• Limiting the pack size to 32 tablets (4 days' supply) by voluntary agreements with companies, with any pack sizes available above 32 tablets labelled as 'dispensing only'.
• Agreeing with companies, a responsible approach to promotional activities.

In July 2009, the Medicines and Healthcare products Regulatory Agency (MHRA) undertook a further review of risk minimisation measures in relation to codeine and dihydrocodeine-containing analgesics and implemented the following measures:

• Further strengthening the warnings on PILs, labels and advertising about the risk of addiction, the importance of not taking the medicine for more than three days consecutively and the need to seek advice from a doctor if painkillers are needed for longer than three days.
• Limiting the indications for non-prescription use to the short term treatment of acute, moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone.
• Removing all indications related to colds, flu, coughs and sore throats for OTC codeine.
• Reducing the pack size of all codeine and dihydrocodeine-containing non-prescription medicines, including effervescent forms to 32.
• Providing more information in the PIL about the signs and symptoms of addiction.

In 2010 the MHRA undertook a benefit risk review of OTC oral liquid cough medicines containing codeine, in children younger than 18 years. The review revealed a lack of robust evidence supporting the efficacy of codeine in treating cough in children. The conclusion was that the risks associated with OTC oral liquid medicines containing codeine for the treatment of cough outweighed the benefits in children and young people under 18 years. The following measures were implemented:

• the indication for children and young people under 18 years was removed from OTC oral liquid cough medicines containing codeine
• making it compulsory for all oral liquid codeine medicines to be supplied in child-resistant containers to minimise the risk of accidental ingestion by children
• updating of the packaging and leaflets for OTC liquid cough medicines that contain codeine to reflect the new advice that they are not for use in children and young people under 18 years.

A personal communication with MHRA in early 2016, indicated that there had been a drop in sales of OTC codeine combination analgesics in the UK post these regulatory reforms, however literature suggests that the UK has actually observed an increase in overall opioid use for pain management over the 2011-2013 period.^[38]

Canada

In Canada, under Section 36 of the Narcotic Control Regulations, products containing codeine are exempted from prescription if they:

• contain not more than 8 mg codeine in solid form; (for reference, in Australia Schedule 2 permits 10 mg or less, and Schedule 3 permits 12 mg or less) or
• not more than 20 mg codeine per 30 mL in liquid form and
• if the preparation contains at least two additional medicinal ingredients other than a narcotic.

In February 2016, all non-prescription codeine was banned in the province of Manitoba. Interestingly, in an online poll which asked whether other provinces should follow Manitoba's lead and switch low-dose codeine products to a prescription-only status, 79% said yes.^[39] Some comments in resonse to this poll included:

• 'Most cases of opioid addiction start with abuse of xxx [OTC codeine-containing medicine]'
• 'It is incomprehensible that we still have an opioid available for self-selection (with the approval of the pharmacist) when we are battling an opioid crisis. Low-dose codeine has next to no place in treatment and the risk of harm is much higher than any potential benefit' –Pharmacist
• 'As a Manitoba pharmacist, I think that the results have been very positive' – Pharmacist
• 'These products gives the pharmacist an alternative when nothing else seems to work to relieve pain'
• 'Needed for short-term emergency pain. Package offered for sale should be smaller'.

In November 2016, a national report was released by the Canadian Institute for Health Information and the Canadian Centre on Substance Abuse.^[40] The report provides figures on how often opioid overdoses, accidental or deliberate, send people to hospitals across the country and 'illuminates the toll of the escalating opoid crisis on the [Canadian] Health Care System'.^[41]

Summary of international regulation of codeine and implications for Australia

While the list of countries discussed above is not exhaustive, it is apparent that there is wide variability in the way codeine-containing medicines are regulated overseas. Furthermore, growing evidence suggests that countries with less strict regulations around codeine availability generally see more abuse and misuse of the low-dose OTC codeine medicines. ^{[37,42,43,44,45]}

Figure 1: Mean availability of opioids for pain management in 2001-2013. ^[38]

Concerningly for Australia, a recent 2016 study indicates that the use of opioid analgesics increased considerably over a decade (2001-2013), with Australia showing some of the most significant increases in opioid consumption for pain management behind Germany, North America, Austria and Gibraltar (Figure 1). ^[38,46] While the reasons behind this increase were not specifically identified in the study, authors speculated that physical availability, practical accessibility and affordability could be main driving factors. ^[38] This suggestion is not unreasonable given that Australia is in the minority of countries to sell codeine-containing medicines OTC.^[47]

Australian risk management framework

Standard for the Uniform Scheduling of Medicines and Poisons

Scheduling is a national classification system that enables states and territories to uniformly control how medicines and chemicals are made available to the public. Medicines and chemicals are classified into Schedules according to the level of regulatory control over the availability of the medicine or chemical required to protect public health and safety. The Schedules are published in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) and are given legal effect through state and territory legislation. The SUSMP is legally referred to as the Poisons Standard.

Scheduling decisions are made by the Secretary of the Department of Health or their delegate according to subsection 52D(2) of the Therapeutic Goods Act 1989 (TG Act) taking into account relevant matters of public health as set out under section 52E of the Act. These matters include the risks and benefits of the use of a substance, the purposes for which a substance is to be used, the substance's toxicity, dosage, formulation, labelling, packaging, presentation and any potential for abuse.

The Scheduling Policy Framework (SPF) is currently maintained by the Australian Health Ministers' Advisory Council (AHMAC) and provides the policy underpinning the mechanism for scheduling decisions. This policy guideline, together with the TG Act, sets out the scheduling process, guidance for amending the Poisons Standard, the classification system for medicines and chemicals, as well as guidelines for applications, public consultation and confidential information as these relate to scheduling applications.

The extensive public consultation associated with scheduling decisions and proposals to change the Poisons Standard is a critical component of this transparent regulatory framework to ensure that procedural fairness and natural justice are provided to those stakeholders that may be impacted by any scheduling decisions. In relation to codeine several calls for public submissions have been held in addition to those required by legislation.

Scheduling of medicines

Scheduling is the national classification system that controls how medicines and chemicals are made available to the public. Medicines and chemicals are classified into Schedules according to the level of regulatory control required to manage the availability of the medicine or chemical, and therefore protect public health and safety. The Schedules are published in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) and are given legal effect through state and `territory legislation. The SUSMP is legally referred to as the Poisons Standard.

Scheduling decisions take into account relevant matters of public health as set out under section 52(E) of the Act. These matters include:

1. (1) In exercising a power under subsection 52D(2), the Secretary must take the following matters into account (where relevant):
   1. (a) the risks and benefits of the use of a substance
   2. (b) the purposes for which a substance is to be used and the extent of use of a substance
   3. (c) the toxicity of a substance
   4. (d) the dosage, formulation, labelling, packaging and presentation of a substance
   5. (e) the potential for abuse of a substance, and
   6. (f) any other matters that the Secretary considers necessary to protect public health.

In addtion to the matters prescribed under subsection 52E (1) of the Therapeutic Goods Act 1989 (above), the scheduling delegate must also consider the factors described in the SPF.

Scheduling factors

The Schedules and corresponding scheduling factors relevant to scheduling of codeine are described in the following sections. The factors are set out in the AHMAC Scheduling Policy Framework (SPF) document.

Schedule 2: Pharmacy medicines

1. The quality use of the medicine can be achieved by labelling, packaging, and/or provision of other information; however access to advice from a pharmacist is available to maximise the safe use of the medicine.
2. The use of the medicine is substantially safe for short term treatment and the potential for harm from inappropriate use is low. Suitable for diagnosis and treatment by the consumer in the management of minor ailments.
3. The use of the medicine at established therapeutic dosage levels is unlikely to produce dependency and the medicine is unlikely to be misused, abused or illicitly used. Medicines which do not meet this factor are not suitable to be classified as Schedule 2 Pharmacy Medicines, irrespective of any other applicable factors.
4. The risk profile of the medicine is well defined and the risk factors can be identified and managed by a consumer through appropriate packaging and labelling and consultation with a medical practitioner if required. There is a low and well-characterised incidence of adverse effects; interactions with commonly used substances or food and contra-indications.
5. The use of the medicine at established therapeutic dosage levels is not likely to mask the symptoms or delay diagnosis of a serious condition. Appropriate labelling and packaging can manage any risks.

Schedule 3: Pharmacist Only medicines

1. The medicine is substantially safe with pharmacist intervention to ensure the quality use of the medicine. There may be potential for harm if used inappropriately. The consumer can identify the ailments or symptoms that may be treated by the medicine but counselling and verification by a pharmacist is required before use. Pharmacist-consumer dialogue is necessary to reinforce and/or expand on aspects of the safe use of the medicine.
2. The use of the medicine at established therapeutic dosages is not expected to produce dependency. Where there is a risk of misuse, abuse or illicit use identified, the risk can be minimised through monitoring by a pharmacist.
3. The risk profile of the medicine is well defined and the risk factors for adverse effects and interactions are known, identifiable and manageable by a pharmacist.
4. Where the medicine is intended for recurrent or subsequent treatment of a chronic condition, pharmacist intervention is required to monitor safe use of the medicine following recommendation by a medical practitioner or a pharmacist. The consumer may not be able to self-monitor the safe ongoing use of the medicine. The condition does not require medical diagnosis or only requires initial medical diagnosis, and the consumer does not require close medical management.
5. The use of the medicine at established therapeutic dosage levels may mask the symptoms or delay diagnosis of a serious condition. Pharmacist-consumer dialogue is required to detect the risk of masking a serious disease or compromising medical management of a disease, and to deal with it appropriately.

Schedule 4: Prescription Only medicines

1. The ailments or symptoms that the substance is used for require medical intervention. Diagnosis, management or monitoring of the medical condition is such that it requires medical intervention before the substance is used.
2. The use of the substance requires adjunctive therapy or evaluation. Adjunctive therapy could include other medicines, non-pharmacological measures, or specialised medicine delivery devices. Evaluation could include laboratory tests or additional clinical assessments.
3. The use of the substance at established therapeutic dosage levels may produce dependency but has a moderate propensity for misuse, abuse or illicit use. Control of access and duration of therapy by a medical, veterinary or dental practitioner is required.
4. The seriousness, severity and frequency of adverse effects are such that monitoring or intervention by a medical practitioner is required to minimise the risk of using the substance.
5. The margin of safety between the therapeutic and toxic dose of the substance is such that it requires medical intervention to minimise the risk of using the substance.
6. The seriousness or severity and frequency of the interactions of the substance (medicine-medicine, medicine-food, or medicine-disease) are such that monitoring or intervention is required by a medical practitioner.
7. The use of the substance has contributed to, or is likely to contribute to, communal harm. For example the development of resistant strains of microorganisms. Appropriate use, and/or the decision to continue treatment, requires evaluation by a medical practitioner.
8. The experience of the use of the substance under normal clinical conditions is limited. Unexpected effects of the substance may only become evident after widespread use. Close monitoring of the patient is required by a medical, veterinary or dental practitioner to monitor for unanticipated effects.

Schedule 8: Controlled medicines

1. The substance is included in Schedule I or II of the United Nations Single Convention on Narcotic Drugs 1961 or in Schedule II or III of the United Nations Convention on Psychotropic Substances 1971.
2. The substance has an established therapeutic value but its use, at established therapeutic dosage levels, is recognised to produce dependency and has a high propensity for misuse, abuse or illicit use.
3. The substance has an established therapeutic value but by reason of its novelty or properties carries a substantially increased risk of producing dependency, misuse, abuse or illicit use.

Current scheduling status of codeine

Codeine is currently listed in Schedules 8, 4, 3 and 2 of the Poisons Standard (see below), and thus has various controls and restrictions placed over its availability in order to protect public health. Low-dose codeine (8-15 mg/dose unit; Schedule 2 and Schedule 3) is currently available in cough and cold medicines and in combination with other analgesics OTC in pharmacies. High dose codeine (>30 mg/dose unit) and other opioids such as morphine, pethidine, tramadol and oxycodone are either available only by prescription (Schedule 4) or are controlled drugs (Schedule 8).

The schedule entries for codeine in the Poisons Standard are as follows:

Schedule 8

CODEINE except when included in Schedule 2, 3 or 4.

Schedule 4

CODEINE when compounded with one or more other therapeutically active substances:

1. a) in divided preparations containing 30 mg or less of codeine per dosage unit; or
2. b) in undivided preparations containing 1 per cent or less of codeine,

except when included in Schedule 2 or 3.

Schedule 3

CODEINE when:

1. a) not combined with any other opiate substance;
2. b) compounded with one or more other therapeutically active substances, of which not more than one is an analgesic substance:
   1. i) in divided preparations containing 12 mg or less of codeine per dosage unit; or
   2. ii) in undivided preparations containing 0.25 per cent or less of codeine;
3. c) labelled with a recommended daily dose not exceeding 100 mg of codeine; and
4. d) in packs containing not more than 5 days' of supply at the maximum dose recommended on the label,

except when included in Schedule 2.

Schedule 2

CODEINE in preparations for the treatment of coughs and colds when:

1. a) not combined with any other opiate substance;
2. b) compounded with one or more other therapeutically active substances, of which at least one is phenylephrine and not more than one is an analgesic substance:
   1. i) in divided preparations containing 10 mg or less of codeine per dosage unit; or
   2. ii) in undivided preparations containing 0.25 per cent or less of codeine;
3. c) labelled with a recommended daily dose not exceeding 60 mg of codeine; and
4. d) in packs containing not more than 6 days' supply at the maximum dose recommended on the label.

Delegate's decision

The delegate's decision is primarily based on the protection of public health. The delegate considers advice from ACMS and all of the public submissions made in response to a public notice.

In making a decision to amend the Poisons Standard to protect public health, the delegate does not need to consider financial impacts to industry or the government. Often however, these considerations play a role in determining the implementation date for the scheduling decision.

Historical scheduling of codeine

The current scheduling of codeine in the Poisons Standard has been reviewed a number of times by the National Drugs and Poisons Schedule Committee (NDPSC) or the Advisory Committee on Medicines Scheduling (ACMS). The reviews were undertaken to follow up on concerns that have been raised regarding the abuse of codeine and the availability of all OTC combination analgesics containing codeine (e.g. paracetamol and ibuprofen products containing codeine).

Beginning in 2008, the NDPSC agreed to foreshadow a proposal (for consultation) to re-schedule all OTC codeine to Schedule 3 (with suggestions to limit the maximum daily dose to 100 mg codeine, limit the maximum pack size to 5 days' supply, restrict divided preparations to 12 mg of codeine per dosage unit and restrict undivided preparations to 0.25% codeine). In addition, the Schedule 2 entry for combination products containing codeine, phenylephrine and other cough and cold products was considered appropriate (with an amendment to the maximum of 6 days' supply), if all other OTC codeine were included in Schedule 3. A Codeine Working Party assessed these proposals (which were considered at all subsequent NDPSC meetings until June 2009) when several amendments were made, including the up-scheduling of combination analgesics containing codeine (CACC) from Schedule 2 to Schedule 3. The implementation date was May 2010.

The final decision currently under consideration involved either making a change to the scheduling of codeine or leaving the scheduling unchanged. Either way, this decision will have an effect on multiple sectors of the community. To better understand the potential impacts of any codeine scheduling decision on stakeholders - including industry, consumers, government and healthcare professionals - the Department of Health is undertaking this Regulation Impact Review.

How effective were the scheduling changes for codeine in 2010?

Codeine-containing analgesics were up-scheduled in 2010 from Schedule 2 to Schedule 3; nevertheless, this change did not achieve the required reduction in harm to affected individuals.^{[48,49,50,51,52,53,54,55,56]}

In recognition of the potential for harm arising from inappropriate use, the aim of this scheduling change was to provide increased surveillance of these medicines by a pharmacist to ensure quality use. Unfortunately, as indicated in the post 2010 health and safety reports (pp. 19 & 20), the re-scheduling has not been effective in reducing the adverse outcomes and opioid dependence. This therefore raises questions regarding the likely success of preventing further misuse and dependence of codeine-containing medicines by decreasing the pack size to 3 days supply and mandating warning statements on package labels. Changing the packaging of these medicines may not adequately address the problem of misuse and dependence; it may instead lead to a change in behaviour with dependent users sourcing codeine-containing analgesics elsewhere. Current labelling and packaging appear to be insufficient to warn individuals of potential adverse effects. As noted in the level of dependence, morbidity and deaths associated with codeine use (p. 17, What are the health concerns with codeine use?).

Is the current scheduling of codeine best practice?

When considering the scheduling factors in the current SPF, together with the scientific information highlighting the public health concerns for rapid metabolisers of codeine, the codeine dependency that can result from therapeutic doses of codeine, and the significant health risks associated with the misuse of OTC medicines containing codeine, codeine clearly meets the criteria for a Schedule 4 (or higher) medicine.

In October 2015 the medicines scheduling delegate announced the interim decision to up schedule all current Schedule 2 and Schedule 3 entries for codeine to Schedule 4 prescription only medicines. Due to extensive public comments, both in favour and opposed to re-scheduling, the delegate deferred making a final decision. Further public consultation was invited on several other options relating to the use of codeine.

The scheduling delegate sought public comment on a range of possible re-scheduling options on three occasions (see p. 96 'Formal consultation periods regarding the re-scheduling of codeine'). In general, the up-scheduling of codeine to prescription only is supported by submissions from pharmacists, many medical practitioners and their associated medical organisations. Submissions opposing up-scheduling of codeine largely came from OTC industry associations and individual pharmaceutical companies, the Pharmacy Guild of Australia (PGA) and a number of pharmacists and members of the public.

The specific reasons for the recommendation to up-schedule codeine includes matters relevent under section 52E of the TG Act (see p 29 'Scheduling of medicines') and are outlined under the following headings:

• codeine as a prodrug and its metabolism;
• codeine toxicity and the availability of safer, more effective products;
• codeine use, misuse and abuse;
• current scheduling inconsistencies; and
• international scheduling considerations.

Each of these factors are detailed below.

Codeine as a prodrug and its metabolism

As a prodrug codeine causes direct toxicity primarily through its biotransformation into morphine. Metabolic polymorphism (as discussed on p. 15 'What is codeine?') leads to major variability within the population in terms of the extent and speed of this conversion to morphine. Ultra-rapid metabolisers, who have an accelerated rate and higher extent of conversion, are exposed to morphine concentrations that are 30 to 45-fold higher than those reached in poor metabolisers. High morphine plasma concentrations can lead to deep sedation, respiratory depression and death. This potential for severe adverse effects at therapeutic doses in ultra-rapid metabolisers suggests that codeine is an unsuitable OTC candidate. To limit excessive morphine concentrations following ingestion of recommended doses of codeine for any indication, some sources (including the Panadeine® Product Information packet) suggest that before taking codeine, the individual should know their particular CYP2D6 status. An individual would only know their CYP2D6 status after a specific blood test recommended or prescribed by their medical practitioner. Given that very few individuals are aware of their own metaboliser status, it would be very difficult to protect ultra-rapid metabolisers by way of label warnings.

Codeine toxicity and alternative products

Codeine shares the properties of other opioid analgesics (which are included in Schedule 4 or Schedule 8) and is potentially capable of producing dependence and in overdose, respiratory depression and reduced level of consciousness. There is also a greater risk of medication misadventure with codeine's relative lack of efficacy compared to safer products. From an efficacy prespective, there is no evidence that low-dose codeine combination analgesics provide any additional pain relief over optimal dosing of paracetamol, aspirin or ibuprofen (TGA Safety Review, March 2016 and references therein).

There are also a range of alternative analgesics for mild to moderate pain (e.g. Diclofenac/Voltaren or combination medicines such as ibuprofen plus paracetamol) that can fill the gap in the OTC market created by the re-scheduling of codeine. On the other hand, where strong pain relief is required, safer alternatives to codeine may be prescribed under doctors supervision. These may include medicines such as oxycodone or morphine, the correct doses of which can be accurately determined to manage pain due, unlike codeine, to their lack of metabolism variability in vivo.

Furthermore, reviews of the medical literature^[57,58] and advice from Australian pain specialists indicate that OTC combination analgesics containing codeine plus either paracetamol or ibuprofen, show little or no additional analgesic benefit compared to analgesics without opioids (e.g. paracetamol, ibuprofen, other non-steroidal anti-inflammatories (NSAIDs), or aspirin).

Codeine use, misuse and abuse

As outlined in 'Analgesia' (p. 17), although the approved indication for Schedule 3 codeine products is for the temporary relief of strong pain and discomfort associated with a number of different medical conditions, the medical literature ^{[18,59,60,61,62,63,64,65,66,67]} and consumer submissions received in 2015 indicate that the use of Schedule 3 codeine products for long term relief of chronic pain is significant.

The genetic influence on the metabolism of codeine, and thus its risk verus benefit for some individuals is small, raising questions regarding the role of codeine in clinical practice. This suggests that an appropriately qualified practitioner should be involved with assessing risk before prescribing codeine. Rather than self-treating with long term OTC codeine-containing analgesics, the management of chronic pain would be better achieved through medical practitioner input, with advice on appropriate non-pharmacological treatments and alternative pharmacological treatments.

Current scheduling inconsistencies

There are significant inconsistencies in the restrictions on codeine availability between Schedules 2, 3, 4 and 8.

Codeine is available OTC as a Schedule 3 medicine (Pharmacist Only) in packs of up to 40 tablets (e.g. Panadeine Extra®) containing 15 mg each, totalling 600 mg codeine (in combination with paracetamol) per pack.

Paradoxically, the same total pack quantity of 600 mg codeine (single active ingredient) is also available as a Schedule 8 (Controlled Drug) medicine in packs of 20 tablets containing 30 mg each. A Schedule 8 substance is recognised to have potential for abuse or addiction.

Similarly, an even higher quantity of 1500 mg codeine per pack is available as a Schedule 4 medicine (Prescription Only) in packs of up to 50 tablets (e.g. Panadeine Extra®) containing 30 mg each (in combination with paracetamol) per pack.

The availability of codeine-containing medicines in the lower schedules of 2 and 3 of the Poisons Standard is also inconsistent with the known risk of developing codeine dependence associated with these medicines. Codeine dependency is a major public health concern, that in some cases requires opioid substitution therapy with methadone or similar drugs to overcome dependence (see previous section 'Codeine use, misuse and abuse'). The intentional misuse and abuse of codeine leads to the ingestion of excessive doses of the companion drugs (usually paracetamol or NSAIDs) resulting in morbidity and/or death. ^[31,68]

International scheduling considerations

See 'International regulation of codeine' above.