Serious morbidity associated with misuse of over-the-counter codeine–ibuprofen analgesics: a series of 27 cases

While extensive overseas evidence is accumulating about the non-medical use of prescription opioids1-5 and the serious consequences of such use,1-4,6,7 literature on non-prescribed or over-the-counter (OTC) opioids is mainly confined to case descriptions.8-11 This is despite indications, such as in the 2007 Australian National Drug Strategy Household Survey, that over half a million Australians used pain killers for non-medical purposes,12 the third most common category of substance use in Australia after cannabis and ecstasy.

Although codeine is often described as a weak opioid analgesic, codeine dependence is a well recognised complication of long-term use.13-15 Codeine-containing medications are available in Australia either through a doctor’s prescription or in combination OTC formulations with simple analgesics. Substance-dependent individuals who escalate their dose of medication above recommended amounts are at risk of harm from the accompanying simple analgesic,16 including toxicity from non-steroidal anti-inflammatory drugs (NSAIDs)17-19 such as ibuprofen.

We collected data on a series of 27 patients as a response to clinical interest in anecdotal reports of misuse of an OTC pharmaceutical product containing codeine phosphate 12.8 mg and ibuprofen 200 mg.

Clinicians in a network of specialist addiction treatment services (the Victorian Addiction Inter-hospital Liaison Association) in several Victorian health regions collected and submitted the cases for this study. These services cover nine hospitals across Melbourne metropolitan regions and rural Victoria. They range from small, specialist consultation–liaison teams to large, multidisciplinary suites, including alcohol and other drug outpatient treatment services. The 27 patients either presented for treatment of opioid dependence, or were inpatients referred to hospital addiction medicine services between May 2005 and December 2008.

A case report form was used to collect standardised information about OTC codeine–ibuprofen cases. The form included the following details: the harm experienced by the patient; the minimum and maximum doses of OTC codeine–ibuprofen consumed; the patient’s drug use history; the main brand of OTC codeine–ibuprofen used; the drug source; a description of the patient’s presentation; and patient outcomes.

Details of the study and the case report form were disseminated to participating addiction medicine clinicians. Addiction medicine specialists completed all but two of the case report forms, and two forms were received from specialist addiction medicine clinical nurse consultants. Four separate addiction services, from southern, eastern, western and central metropolitan Melbourne contributed cases.

Descriptive analysis was conducted with SPSS, version 14.0 (SPSS Inc, Chicago, Ill, USA). The study was approved by the Victorian Department of Human Services Human Research Ethics Committee.

Of the 27 patients in the cases collected, about half were male (sex was not reported in one case).

Most of the sample (17) did not report a history of injection drug misuse. Just over half the patients (14) reported only using pharmaceutical drugs (Box 1). Three patients had a history of alcohol use disorder.

Opioid dependence and gastrointestinal complications (attributed to ibuprofen) were the most common morbidities, with 10 cases of each. Three patients had hypokalaemia and one patient required dialysis. These complications (hypokalaemia and renal failure) are associated with use of high doses of NSAIDs such as ibuprofen. Four patients were admitted to a hospital intensive care unit, and 12 had documented anaemia.

However, 26 of the 27 patients reported prolonged use (longer than 6 months) of supratherapeutic doses of OTC codeine–ibuprofen, with a mean duration of use of 3.6 years (Box 1). In the 15 cases where the OTC codeine–ibuprofen source was documented, the patient reported using multiple pharmacies to acquire these medications.

A mean dose range of 34–47 tablets per day was reported in this case series. This number of tablets would provide a mean daily dose of 435–602 mg of codeine phosphate and 6800–9400 mg of ibuprofen. Most patients did not document a brand of OTC codeine–ibuprofen. Nurofen Plus was the brand specified by all nine patients who reported the brand.

A significant proportion of patients (n = 15) reported initiating use of OTC codeine–ibuprofen products for painful conditions, including back pain and headaches, and subsequently escalating the dose (Box 2).

Most patients (n = 16) were treated with some form of opioid pharmacotherapy, with three patients undertaking buprenorphine-assisted detoxification, and 13 were started on opioid substitution treatment (OST). Of those who received OST, most (n = 10) received sublingual buprenorphine–naloxone, and three received methadone solution.

To our knowledge, this is the largest collection of cases examining the complications of prolonged use of supratherapeutic doses of OTC codeine–ibuprofen. As with the published case studies on OTC analgesic misuse, we found serious morbidities consistent with NSAID toxicity20 including gastrointestinal disease, renal failure, anaemia and severe hypokalaemia.8,9 Many of our study’s patients differ from previously described opioid-using treatment populations,21 with most reporting no drug and alcohol treatment history, and around half having no history of other current or past illicit substance use. Despite this, more than half the patients described in this series received OST for opioid dependence.

As a case series relying on clinical data opportunistically collected by specialist hospital addiction medicine services, this study has limitations. Our study is not able to estimate the prevalence of codeine–ibuprofen misuse or associated morbidity. While our case series suggests an association between chronic use of supratherapeutic doses of OTC codeine–ibuprofen and medical complications, we have not looked at toxicity associated with therapeutic doses. It is unclear whether these cases represent a small proportion or a sentinel group of OTC codeine–ibuprofen misusers in the Australian community. Despite these limitations, this study is consistent with, and broader than, previously published reports.8,9,20

Information about morbidity resulting from misuse of OTC medications is scant, as comprehensive surveillance of adverse events associated with OTC medications relies on patient reporting and health professional documentation and submission of the event. Amounts of OTC medications purchased by individuals (eg, through “pharmacy shopping”) are also difficult to monitor in the absence of a routine recording system, such as that used to limit sale of pseudoephedrine, a methamphetamine precursor drug.22 At time of writing, pharmacists were only required to supervise dispensing of large pack sizes of OTC codeine–ibuprofen (more than 24 tablets). Due to concerns about harm from misuse of these preparations, rescheduling on 1 May 2010 requires that all OTC codeine–ibuprofen products be supplied directly by a pharmacist.

In many of these cases, serious morbidity resulted from use initiated for therapeutic reasons, such as persisting pain. Given that these drugs are likely to remain available without prescription in Australia, physicians should ask specifically about non-prescribed analgesics when taking a medication history, and pharmacy personnel should consider the risk of misuse when supplying these combination analgesic products. We believe the response of health professionals to opioid dependence from OTC codeine–ibuprofen misuse is an important area for future research.