Of the approximately 760,000 adults in Nova Scotia from 2005–2009, almost 60,000 (7.9%) adults, redeemed an out-of-hospital prescription for paracetamol/opioid combinations over a one-year period (July 2009/2010). Of this 60,000, almost 4,000 (6.7%) filled prescriptions at least once that provided daily doses exceeding the usual Health Canada recommended maximum (4.0
g). This finding is consistent with the findings of Mort et al. [41
] and Albertson et al. [32
] who report rates of 8.1% and 5.9% respectively, but lower than the rate (23.3%) observed in other studies [31
]. The Nova Scotia and other study findings are considered underestimates because they exclude medications dispensed in-hospital, non-prescription paracetamol containing products and paracetamol–only prescriptions. However, an advantage of the Nova Scotia study over previously published population studies is that this study includes virtually all persons in a geographic area and is not limited by the enrollment criteria of US-based health insurance programs.
One in five, more than 10,000 individuals, filled at least one prescription with a daily paracetamol dose greater than 3.25
g. Further, the number and percentage of adults redeeming out-of-hospital prescriptions for paracetamol/opioid combinations decreased in each year from 2005 through 2010, despite a slight population increase, but the numbers of prescriptions filled and tablets dispensed increased. This finding suggests that fewer individuals filled more prescriptions for more tablets over this period. Taken together, these findings raise concerns regarding the potential for a substantial number of adults to be at risk for paracetamol-induced hepatotoxicity due to the unintentional ingestion of high doses of paracetamol.
Certain sub-populations may be particularly vulnerable to accidental overdose. The findings suggest that older persons, i.e. those age 65 and over, may fill more prescriptions for these combinations than younger persons, and for larger quantities of tablets. Older persons may be particularly likely to consume paracetamol-containing medications long-term because of their high prevalence of painful conditions such as osteoarthritis.[42
] The finding that among those who filled prescriptions exceeding 4.0
g/day or 3.25
g/day, older persons were significantly more likely to do so multiple times raises concerns that they may be at increased risk of chronically consuming high-dose paracetamol.
Similarly, women may be at higher risk than men, given that a greater percentage of women than men filled any prescription and filled prescriptions that exceeded 4.0
g/day (7%) and 3.25
g/day (19%). Li and Martin  observed a higher rate of paracetamol overdose among females presenting in emergency departments that provide care to children, youth and adults. [43
] The authors speculated that compared with males, females use more non-prescription analgesics for longer durations, and are more likely to use these medications in suicide attempts.[43
] In contrast, Mort et al. [41
] observed a significantly higher rate of paracetamol use among male beneficiaries of three insurance programs. The possibility of an interaction between sex and age was not examined in any of these studies, and the population characteristics varied markedly.
More than one-quarter of women and one-quarter of persons age 65 and over who filled prescriptions that provided more than 3.25
g/day did so multiple times. These patterns of use, together with the widespread availability and use of non-prescribed paracetamol-containing products raise the potential for the unintentional consumption of high – and potentially hepatotoxic – doses of paracetamol. Individuals may take paracetamol-containing products such as a cough and cold preparation or plain non-prescription paracetamol in addition to their prescribed analgesic and be unaware of the actual amount of paracetamol that they are consuming.
The use of paracetamol/opioid compounds may place patients at increased risk of unintentional paracetamol overdose because they are fixed-dose combinations. Increasing the opioid dose – in order to achieve adequate analgesia - also increases the dose of paracetamol, possibly over the recommended daily maximum dose. In Canada, there is a high consumption of codeine-paracetamol compounds. [44
] The analgesic efficacy of codeine is potentially unreliable because of its unpredictable pharmacokinetics. [45
] Codeine is a prodrug that must be converted to morphine. This conversion depends on the polymorphic cytochrome P4502D6 (CYP2D6) pathway. Genetic polymorphisms result in three phenotypes, poor, extensive and ultra-rapid metabolizers. A poor metabolizer may receive almost no analgesic effect from a standard dose of codeine. [47
] Prescribers need to evaluate the role of these compounds compared with other analgesics and determine the risks and benefits for individual patients.
An American, multicentre, prospective study of 275 identified paracetamol-induced cases of acute liver failure, 48% of cases were unintentional or ‘therapeutic misadventures’.[4
] Most (79%) of these individuals reported taking paracetamol for pain, almost two-thirds (63%) reported taking a prescription paracetamol/opioid combination and 38% were consuming two paracetamol-containing products concurrently. Of particular concern was the fact that these persons have poorer outcomes than those with intentional overdoses; a significantly greater percentage presented with severe (grades 3 and 4) hepatic encephalopathy, possibly because of a delay in seeking medical care.[4
] Two Canadian studies found lower proportions of unintentional overdoses, 25% [14
] and 13% [13
] respectively. However, while paracetamol overdose-related hospitalisations declined from 1995 to 2004 among persons younger than 50
years, the rate increased for those ages 50 and over, as did their rate of hospitalisation.
Various strategies have been proposed or implemented in an effort to reduce paracetamol-related harms. The UK introduced legislation that limits the quantity of paracetamol sold without prescription and required these products to be blister-packed. In 2009, the US Food and Drug Administration (FDA) convened an internal working group from the Center for Drug Evaluation and Research (CDER) to prepare a report on the issue of paracetamol-related hepatotoxicity in preparation for the joint meeting of three Advisory Committees: Drug Safety and Risk Management; Nonprescription Drug; and Anesthetic and Life Support Drugs.[29
] Upon discussion of the working group’s report, the Advisory Committees accepted some, but not all, of the working group’s recommendations. The Committees recommended: the elimination of prescription paracetamol combinations; reduction of the maximum daily dose to 3.25
g and the maximum individual dose to 650
mg; designating 500
mg tablets as prescription-only; and a single concentration for all liquid products. The Committees also voted to encourage the FDA to promote awareness among health professionals by including a black box warning in product information and to encourage patient-education regarding the potential risks.[29
] In Canada, the National Opioid Guideline Group recommends that paracetamol doses not exceed 3.20
g/day for the management of chronic non-cancer pain.[50
] Health Canada issued an advisory in January 2011 reminding Canadians about using paracetamol wisely [52
] and referencing the labelling requirements for over-the-counter products that include a maximum daily dose of 4.0
g for adults and children 12
years and older [2
Healthcare professionals must be vigilant when prescribing and dispensing paracetamol/opioid combinations and educate their patients about paracetamol-containing products and their potential toxicity. The need for greater public education has been recognized.[41
] Persons who receive care from multiple health care prescribers such as physicians (primary care and specialists), dentists, pharmacists and nurse practitioners may be particularly at risk. In the future, computer generated alerts in decision support systems might be helpful in determining maximum doses for over-the-counter and prescription paracetamol-containing medications.
A limitation to our study is that patient level information was not available. For example, data were not available regarding patient weight, ethnicity, type and severity of pain or adequacy of pain control, comorbidities, patient preferences or specific risk factors for hepatotoxicity such as the presence of non-alcoholic fatty liver disease, or the concomitant use of other drugs or herbal therapies.[3
] In addition, we were unable to determine the rates of genetic polymorphisms of the CYP2D6 pathway in our population.[45
] Further, the extent to which the population was at a palliative stage is unknown; stratified analysis by this time period of need for increased pain management is warranted.
Research is required to provide a more extensive understanding of the number of high risk individuals, treatment appropriateness and methods employed to optimize treatment, and the relationship between therapeutic doses of paracetamol and acute liver failure. In addition, investigation of the sex-based differences in patterns of use is warranted. Further, as government regulators and clinical practice guidelines adopt lower maximum doses, it will be important to determine if the application of these guidelines results in increased use of non-steroidal anti-inflammatory drugs (NSAIDS) and increased NSAID-related adverse events [28
Comprehensive evidence on the extent of paracetamol use and the relationship between therapeutic doses of paracteamol and acute liver failure is sparse as yet, as is the value of interventions that attempt to reduce harm [57
]. Further population-based studies are needed to better understand the role of paracetamol in the etiology of acute liver failure and to monitor changes over time as multi-faceted interventions are introduced in an attempt to limit harm from pain medications.