Regulatory responses to over-the-counter codeine analgesic misuse in Australia, New Zealand and the United Kingdom
Correspondence to: Ms Claire L. Tobin, School of Public Health and Preventive Medicine, Monash University, Level 3 Burnet Building, 89 Commercial Road, Melbourne, Victoria 3004; e-mail: Claire.Tobin@monash.edu
Objective: Analysis of the policy response by Australia's National Drugs and Poisons Schedule Committee (NDPSC) and comparison with recommendations by expert advisory committees in New Zealand and the United Kingdom.
Methods: Analysis of public policy documents of relevant regulatory authorities was conducted. Data were extracted regarding changes to over-the-counter (OTC) codeine analgesic scheduling, indications, maximum unit dose, maximum daily dose, maximum pack size, warning labels, consumer medicine information and advertising. Where available, public submissions and other issues considered by the committees and rationale for their recommendations were recorded and thematically analysed.
Results: Expert advisory committees in Australia, NZ and the UK defined the policy problem of OTC codeine misuse and harm as small relative to total use and responded by restricting availability. Pharmacist supervision was required at the point-of-sale and pack sizes were reduced to short-term use.
Conclusions: Comparison with recommendations by expert advisory committees in NZ and the UK suggests the NDPSC's actions in response to OTC codeine misuse were appropriate given the available evidence of misuse and harm, but highlights opportunities to utilise additional regulatory levers.
Implications: Framing policy problems as matters of public health in the context of limited evidence may support decision makers to implement cautionary incremental policy change.
At its February 2008 meeting, Australia's National Drugs and Poisons Schedule Committee (NDPSC) foreshadowed that existing controls on accessibility of over-the-counter (OTC) codeine analgesics would be examined at its next quarterly meeting as a matter of public health concern.1 At the same time, New Zealand's Medicines Classifications Committee (MCC) was considering its controls on codeine analgesics, and a parliamentary inquiry into dependence on prescription and OTC medication was under way in the UK, suggesting that the emergence of OTC codeine analgesic misuse was not a localised phenomenon.2,3
Codeine phosphate is a weak opioid analgesic, which is widely available in Australia in combination with other non-opioid analgesics such as aspirin, ibuprofen and paracetamol for the treatment of mild to moderate pain. Commonly used OTC combination analgesic preparations contain codeine in unit doses ranging from 8 mg to 15 mg (Table 1), even though doses below 30 mg of codeine are unlikely to produce any additional pain-relieving benefit than the non-opioid analgesic alone.4 Codeine is a pro-drug of morphine, hence it may produce euphoria at high doses and dependence may occur with regular use.4 Ibuprofen belongs to the non-steroidal anti-inflammatory class of drugs (NSAID), which are associated with a risk of dose-related gastrointestinal adverse effects, and renal impairment.4 Codeine phosphate-ibuprofen combined analgesics became available OTC in Australia in 2002.5
Table 1. OTC codeine analgesics commonly used in Australia.
|Panadeine Extra||15 mg||Paracetamol 500 mg|
|Nurofen Plus, Panafen Plus, Advil Plus||12.8 mg||Ibuprofen 200 mg|
|Chemmart Strong Pain Relief, Chemists’ Own Pain Tablets||10 mg||Paracetamol 500 mg|
|Disprin Forte||9.5 mg||Aspirin 500 mg|
|Panadeine||8 mg||Paracetamol 500 mg|
|Aspalgin||8 mg||Aspirin 300 mg|
Codeine phosphate 12.8 mg/ibuprofen 200 mg products combine a sub-therapeutic dose of codeine, an addictive substance, with an NSAID that has serious adverse effects at high doses. It is believed that these products are particularly sought for misuse because of the high codeine dose per tablet, relative to other OTC codeine analgesics, and the absence of acute toxicity in overdose that is associated with paracetamol.6 A consequence of the inability to separately titrate the doses of drugs combined in OTC codeine analgesics is that an individual escalating their codeine dose above recommended levels risks secondary harm from the non-opioid analgesic it is combined with.
Cases of misuse and dependence on OTC codeine-ibuprofen resulting in life-threatening morbidity including gastric ulceration and haemorrhage, renal tubular acidosis and severe hypokalaemia have been reported in Australia,6–13 NZ14–16 and the UK.17–22 A common pathway to high dose dependence on OTC codeine analgesics is by commencement at therapeutic doses for pain treatment (recommended maximum daily dose six tablets), then gradual escalation to higher-than-recommended doses to achieve effective analgesia or euphoric effects.11,19,23 Doses of up to 100 tablets daily, the equivalent of 16 times the recommended OTC maximum daily dose of ibuprofen, have been recorded.7,14
Non-medical use of analgesics was the fourth most frequently reported drug recently used by Australians in the 2010 National Drug Strategy Household Survey, behind alcohol, tobacco and cannabis, and equal with ecstasy.24 Among those reporting recent misuse of analgesics, most reported misusing OTC analgesics (72.7%) rather than prescription analgesics (27.3%).25 Globally, pharmaceutical opioid misuse is increasing, particularly in developed countries. In some, misuse of licit drugs is predicted to exceed use of illicit drugs.26,27 Balancing availability of pharmaceuticals to prevent misuse, while ensuring access for rational medical use, presents a challenge for policy makers.28
The availability of medicines in Australia is controlled through a national classification system where medicines are scheduled according to the level of control required to protect consumers; from general sales medicines (not listed in the schedule), to pharmacy medicines (Schedule 2), pharmacist-only medicines (Schedule 3), prescription medicines (Schedule 4), or controlled drugs (Schedule 8). In 2008, when scheduling of OTC codeine analgesics came under review by the NDPSC, these medicines were available to Australian consumers through self-selection from pharmacies without interaction with a pharmacist, in packets of up to 100 tablets, with little clear or readily accessible information about the risks of addiction or exceeding recommended doses. They were heavily advertised directly to consumers. Very similar controls were in place in NZ and the UK, where these products were also available as pharmacy medicines. While OTC drug availability is favoured in many Western countries because it enables timely access to medicines without need for a doctor's prescription, some argue that these benefits may be offset by problems due to inappropriate use or suboptimal therapy.29
Structures to determine the scheduling of medicines are similar in Australia, NZ and the UK. Expert advisory committees established under Acts of Parliament are empowered to make decisions (the NDPSC at that time in Australia), or advise health ministers on medicine scheduling decisions (the MCC in NZ and Committee on Human Medicines [CHM] in the UK).30–32 The committees consider the balance of available evidence, weighing potential benefits against risks of harm, taking into account purposes of use and need for access, toxicity, safety and potential for abuse. By statutory requirement, the committees publicly foreshadow potential medicines scheduling changes and consider any public submissions by interested parties.
With limited published evidence about the prevalence and nature of OTC codeine analgesic misuse and associated harms available at the time these medicines were under review, the arguments submitted through public consultation had the potential to greatly influence how the committees defined and responded to the policy problem. Comparative analysis of the NDPSC's regulatory response, with expert advisory committee's responses in NZ and the UK, to the emerging problem of OTC codeine analgesic misuse may provide an early indicator of whether the action taken was appropriate and adequate.
This study analyses public submissions and other evidence informing the NDPSC's definition of and response to the problem of OTC codeine analgesic misuse, and compares Australia's reaction with regulatory responses in NZ and the UK.
Public documents of medicine regulators and their expert advisory committees in Australia, NZ and the UK were reviewed to identify regulatory responses to OTC codeine analgesic misuse. The search was restricted to the period when controls on these analgesics were under consideration by regulatory authorities: February 2008 to June 2009 in Australia; December 2007 to November 2009 in NZ; and July to September 2009 in the UK.
Data were extracted and tabulated regarding controls on OTC codeine scheduling, indications, maximum unit dose, maximum daily dose, maximum pack size, warning labels, consumer medicine information and advertising. Where available, public submissions and other issues considered by the committees and rationale for their recommendations were recorded and thematically analysed.
Submissions were categorised as supportive, neutral or opposed to scheduling change, then examined for emerging themes in how the problem was defined, causation interpreted and solution recommended. Arguments, considerations and recommendations regarding compounding of codeine, which was also under consideration by the NDPSC at that time, but treated as a separate issue, were excluded from analysis.
Policy responses to OTC codeine analgesic misuse are summarised in Table 2. Across all three countries, the problem emerged as a particular concern with OTC codeine-ibuprofen, but was responded to as a class issue for all OTC codeine analgesics. The rationale for this decision was best explained by the NDPSC who noted that differentiation in scheduling by analgesic would likely result in a shift in the patterns of misuse, potentially creating a dangerous situation if misusers shifted suddenly to OTC codeine-paracetamol that may be lethal in acute overdose.33
Table 2. Controls on OTC codeine analgesics, pre (unshaded) and post (shaded) regulatory review.
| Scheduling ||Pharmacy Medicines (S2) if <25 tabs packet||Pharmacy Only Medicine||Pharmacy medicines (P)|
| ||Pharmacist Only Medicines (S3) if ≥25 tabs packet|| || |
| ||Pharmacist Only Medicines (S3)||Restricted (Pharmacist Only) Medicine||Pharmacy medicines (P)|
| Indications ||Short-term treatment of acute pain||For use as an analgesic||Colds, influenza, coughs, sore throats, minor and moderate pain.|
| ||Short-term treatment of acute pain||For use as an analgesic||Short-term treatment of acute, moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone|
| Max. unit dose codeine ||≤10 mg||≤100 mg||≤12.8 mg (codeine phosphate)|
| ||≤12 mg||≤15 mg||≤12.8 mg (codeine phosphate)|
| Max. daily dose codeine ||≤60 mg||No limit||No limit|
| ||≤100 mg||≤100 mg||No limit|
| Max. pack size ||Up to 100 tablets||No limit||≤ 32 tablets (voluntary agreement)|
| ||≤5 days supply||≤5 days supply||≤ 32 tablets (statutory requirement)|
| Warning labels ||Codeine warnings not required||Codeine warnings not required||Warnings about the potential for dependency and medicine overuse headache with prolonged use (voluntary agreement)|
| ||Referred to TGA – no action taken||“Codeine is an addictive substance.”||Front of pack: “Can cause addiction. For three days use only.”|
| || ||“Do not use for more than three days.”||Back of pack: “This medicine contains codeine which can cause addiction if you take it continuously for more than three days. If you take this medicine for headaches for more than three days it can make them worse.” (Statutory requirement)|
| Consumer medicine information (CMI) leaflets ||CMI not included in packs. Codeine warnings not required.||CMI not required||Warnings about the potential for dependency and medicine overuse headache with prolonged use. (Voluntary agreement)|
| ||CMI not included in packs. Template CMI developed with warning: “This medicine may be addictive if taken for more than a few days at a time” Existing drug sponsors are not required to update their CMI, but any new products in this class must develop CMIs consistent with these templates.||CMI not required||Several prominently displayed warnings of the risk of addiction or overuse headache if used continuously for more than three days; and information about warning signs of addiction. (Statutory requirement)|
| Advertising ||Permitted (Appendix H listing)||Direct to consumer advertising permitted – Must state “incorrect use could be harmful”||Permitted (voluntary agreement to take a “responsible” approach to promotional activities)|
| ||Not permitted||Direct to consumer advertising permitted – Must state “incorrect use could be harmful”||Permitted (PAGB Advertising Code must be updated to reflect new indications and warnings, and must not contain references to painkilling power and strength)|
The NDPSC deliberated the scheduling of codeine combination analgesics over 17 months before reaching a resolution, even though when the issue was first raised with the Committee in February 2008 it was deemed a “matter of public health”, which typically is a trigger for prompt action.1 Lack of data to accurately quantify the magnitude and severity of the suspected problem of OTC codeine misuse and associated harms meant the Committee was reliant on reports from jurisdictional members and public submissions from interested parties to inform their decision making.
Detailed minutes of the NDPSC meetings included de-identified summaries of 96 public submissions regarding OTC codeine scheduling received by the Committee during the time this matter was under consideration.1,33–36 More submissions supported maintaining the status quo (n=60) than were in favour of scheduling reform (n=34).
Submissions arguing for scheduling reform defined OTC codeine analgesic misuse as a significant problem, describing cases of dependence and serious and life-threatening injuries associated with ibuprofen-codeine misuse as the “tip of the iceberg”.34 The medicines themselves and inadequate controls over supply were identified as the cause of the problem. Multiple submissions highlighted that codeine is addictive and has questionable analgesic efficacy at low doses. The Faculty of Pain Medicine of the Australian and New Zealand College of Anaesthetists suggested that codeine in OTC combination analgesics had “no analgesic purpose but increased the risk of physiological and psychological dependence and, consequently, morbidity”.33 Despite many submissions identifying these products as the cause of the problem, the most commonly suggested policy response was restricting availability of OTC codeine analgesics rather than altering or removing them from supply.
The submissions opposing changes to the existing scheduling of OTC codeine analgesics argued that the few cases of misuse identified were not indicative of a wider problem and were low in comparison to total use. Some submissions argued that the potential for misuse was not limited to ibuprofen-codeine, but included all OTC codeine analgesics. The submissions implied that the cause of the problem was not these medicines, which were described as safe and effective when taken as directed by the “vast majority” of “legitimate” and “responsible” consumers,34,35 but with the small minority of consumers who misused them. It was suggested that the response should be commensurate with the scale and nature of the problem and targeted towards those who misused the medicines. Education and awareness-raising campaigns were recommended and real-time monitoring of supply was proposed as an alternative to restricting availability.
Several submissions were critical of the quality of evidence informing the Committee's decisions. Some submissions claimed that there was “little solid evidence” and “no hard data” to demonstrate the magnitude or nature of misuse, justify rescheduling or even warrant continued inquiry.34 The case reports submitted to the Committee were described as “anecdotal”, “untested” and “hearsay at best”.35 Several submissions urged the Committee to delay decision making until further research was available.
The NDPSC established a Codeine Working Party (CWP), including jurisdictional, regulatory, pharmacy and industry representatives, to review the scheduling of all codeine combination products, delaying a decision on the scheduling of ibuprofen-codeine combinations until the CWP's findings were available. A literature review conducted by the CWP did not uncover any more “rigorous” data36 than had already been considered by the Committee. An external evaluator concluded that while it was impossible to quantify the risk of harm associated with these products with available data, the case reports and information provided to the Committee collectively painted a “compelling picture of the potential harm associated with OTC combination analgesics containing codeine”.36 The evaluator reasoned that the proportion of all users that abuse OTC codeine analgesics and the risk of harm to all users of OTC codeine analgesics is low, but the risk of significant harm and even death from abuse is high.
The Committee agreed that of the matters set out in section 52E(1) of the Medicines Act 1989: risks and benefits; extent and patterns of use; dosage and formulation; need for access; and potential for abuse; were relevant to their decision in this instance.33 Although some Committee members voiced concerns that the public was exposed to risks of addiction and harm from these medicines with little evidence to demonstrate they are more effective at relieving short-term pain than non-codeine analgesics, the issue of efficacy fell outside their remit and was instead referred to the Therapeutic Goods Administration (TGA). Although having the power to re-assess the efficacy of registered medicines, the TGA has taken no further action on this issue to date.
The NDPSC decided there was “significant justification” for the removal of codeine from Schedule 2 (pharmacy only), however, was of the view that removal of all codeine analgesics from the OTC market to Schedule 4 (prescription only) was not warranted.33 The Committee reasoned that a Schedule 3 listing, resulting in these products being available OTC only upon the advice of pharmacists, would provide an opportunity for pharmacists to detect signals of misuse or abuse, while maintaining access for legitimate users without need for prescription.33 The Committee limited pack size to no more than a five-day supply, citing that most conditions requiring the treatment of short-term pain should resolve in this period.33
The Committee resolved not to permit advertising of OTC codeine analgesics, stating that the “public benefit” from advertising could not be demonstrated.33 Decisions regarding consumer information and label warnings also fell outside the jurisdiction of the NDPSC, however they referred related submissions on to the TGA for their consideration. In response, the TGA collaborated with the Australian Self Medication Industry (ASMI) to develop new Consumer Medicine Information (CMI) templates, which include one statement that “codeine may be habit forming”.37 No warnings regarding codeine were required on package labels.
In 2005, the predecessor to the CHM acted to minimise the risk of addiction to OTC codeine through strengthened consumer warnings on labels and inside packs and a voluntary agreement with drug companies to reduce pack sizes to 32 tablets and take a responsible approach to promotion.38 The All Party Parliamentary Group on Drug Misuse (APPGDM) inquiry, and continued media reporting of OTC codeine addiction, prompted the UK medicine regulator in 2008 to ask the CHM to again consider if these levers had been adequately utilised, however, their remit did not extend to scheduling.
The CHM considered the evidence and recommendations presented in the APPGDM report, new sales data and information from self-help groups. The view expressed by the CHM was that the incidence of misuse or addiction to OTC codeine products was low and little evidence was available to suggest it was increasing, but these medicines did pose an indirect danger to health through their potential for misuse.38 Accordingly, they did not agree that availability of these products should be restricted by a further reduction in maximum pack size (as recommended by the APPGDM).38 However, as data indicated that sales of large packs had increased following a voluntary reduction in maximum pack size to 32 tablets in 2005, this control was enforced through regulation.39
The CHM reasoned that feedback from patient groups had indicated that existing voluntary warnings on addiction and overuse had not proved effective, and so required by regulation the inclusion of prominent warnings on the front and back of packaging and in patient information leaflets.39 They did not adopt the APPGDM recommendation to ban advertising of these medicines, because they stated there was no clear evidence to link advertising with addiction or misuse.38
In December 2007, New Zealand's medicines regulator asked the MCC to consider limits to OTC codeine combination unit dose and pack size after observing codeine levels in Pharmacy-Only combination products rising.40 The MCC acted quickly to revise the scheduling of codeine combination analgesics containing more than 15mg of codeine per unit dose from Pharmacy-Only to Prescription, stating that medicines above that strength of codeine were not suitable for self-selection, then undertook further consultation to inform their consideration of appropriate pack size limits.41 All four of the public submissions received by the Committee in response to their forecasted consideration of suitable codeine cut-off points and pack sizes for OTC sale argued for no change to the current controls on OTC codeine, noting that the vast majority of consumers used these medicines responsibly.42
The MCC agreed that NZ and Australia's controls on these medicines should be harmonised where possible and postponed their recommendation until the NDPSC's position was resolved.43 Like Australia, they restricted the scheduling of these medicines to require supply by a pharmacist, set a maximum daily dose of 100mg codeine, and limited pack size to no more than a five-day supply. The MCC supported the UK's approach to warning statements regarding addiction, believing they would further discourage the long-term use of these products, and required a warning statement on all OTC codeine analgesic labels that codeine is an addictive substance.42
After considering the limited evidence available to them, expert advisory committees in Australia, NZ and the UK defined the policy problem of OTC codeine analgesic misuse and harm as small – relative to total use – and responded to minimise harm by using regulatory levers to restrict availability.
Some public submissions to the NDPSC argued that, based on the limitations of the evidence available to the Committee, they should take no further action. However, the Committee determined that the case reports and case series presented to them collectively showed that there was a public health problem requiring action. In the spirit of the precautionary principle,44 the committees acted despite lack of scientific certainty, recognising the few detected cases of addiction and serious morbidity as a threat to public health. Estimates that 55% of the adult population in Australia regularly use OTC analgesics45 mean that even a low rate of misuse of OTC codeine analgesics may result in a large number of serious adverse events. The response taken by the committees was cautious and incremental, commensurate with the evidence of misuse and harm available to them. Availability was restricted by increasing pharmacist supervision and decreasing pack sizes, but not so far as to remove the products from OTC.
In restricting the availability of these products to Pharmacist Only, the committees placed great responsibility for prevention and control of drug misuse with pharmacists, indicating an assumption that pharmacists are well placed to detect and respond to misuse. However, research suggests that identifying inappropriate requests for OTC codeine analgesics, discussing the risk of addiction and screening for misuse is a challenge for some pharmacists.46,47
Variable responses to controlling advertising of OTC codeine analgesics highlighted opposing positions on where the burden of proof rests for regulatory change. While the CHM did not revise existing controls that permitted advertising of OTC codeine analgesics, on the basis there was no evidence to link this to addiction or misuse, the NDPSC did not permit advertising because its public benefit could not be demonstrated. Decision-making frameworks that include as default a more cautious stance (until benefit or no harm can be proven) assist regulators to give primacy to public health over commercial considerations.
The evidence that the NDPSC excluded from their considerations was as important as that which was included. The Committee noted several submissions highlighting the paucity of evidence to demonstrate analgesic effectiveness of codeine at OTC doses. However, the Chairman instructed the Committee that efficacy fell outside their remit of considerations according to the Act. Therefore it is likely that the Committee, when balancing the risks and benefits of maintaining OTC access to codeine analgesics, overestimated the benefits.
Australia acted to minimise harm using similar strategies to New Zealand and the UK, however, comparison with these countries highlights that not all available regulatory levers were utilised. Addiction warnings were prominently displayed on the front of packs and included in patient information leaflets in the UK. New Zealand also required warning labels that codeine is an addictive substance. However in Australia, the TGA's use of consumer warnings and information to improve consumers’ awareness of risks was weak.
Further insight and analysis into the policy considerations and processes of expert advisory committees in New Zealand and the UK was limited by commercial-in-confidence restrictions and freedom of information exemptions that prevented release of more detailed minutes for public access.
It is difficult to ascertain whether the policy response of the NDPSC has been effective at minimising harm associated with OTC codeine misuse in Australia. Several challenges preclude accurately capturing the prevalence and consequences of OTC drug misuse: there are no real-time mechanisms to monitor OTC sales; drug-seeking and misuse at the point-of-sale is difficult to identify due to covert behaviour and likelihood that OTC misusers do not fit the typical profile of illicit drug dependents;7,46 and adverse outcomes are underreported.48 Since the scheduling changes took effect on 1 May 2010, codeine-combination analgesics have continued to feature in reports to the TGA's Database of Adverse Event Notifications. However, with no accurate baseline data for comparison, it is unclear whether misuse and harm is increasing or decreasing. There is a need to develop monitoring systems and increase research in this area to better understand levels and patterns of misuse and the scale and nature of harms. As new evidence emerges on the risks and benefits of OTC codeine combination analgesics, their place in the market warrants re-evaluation.
Conflict of interest declaration
MD and CT co-authored a submission to the NDPSC during its consideration of OTC codeine analgesic scheduling.