Prescribing of opioid analgesics
From January 1991 to May 2007, the prescribing of opioid analgesics in Ontario increased by 29%, from 458 to 591 prescriptions per 1000 individuals annually (). Codeine was the most frequently prescribed agent, although the number of prescriptions for the drug declined gradually during the study period. In contrast, the number of oxycodone prescriptions rose more than 850% during the same period, from 23 per 1000 individuals in 1991 to 197 per 1000 in 2007. The prescribing of hydromorphone, fentanyl and morphine also increased considerably over the same period, although the total number of prescriptions for these drugs was far lower than that for oxycodone-containing products (). By 2006, oxycodone accounted for 32% of the almost 7.2 million prescriptions for opioids dispensed that year. Of the 2.3 million oxycodone prescriptions dispensed in 2006, 28% were for the long-acting formulation.
Annual number of opioid analgesics prescribed on an outpatient basis in Ontario from 1991 to 2007.
From January 2001 to May 2007, the period during which we had detailed population-level prescribing data, the average amount of long-acting oxycodone dispensed per prescription increased by 24%, from 1830 mg to 2280 mg. The amount of long-acting morphine dispensed per prescription increased by 3%. During this period, the correlation between prescription counts of oxycodone and total mass of drug dispensed was exceptionally high (r = 0.996), which validates the use of prescription counts as a measure of prescribing before 2001.
Between 1991 and 2004, the Office of the Chief Coroner of Ontario classified 7353 deaths as involving alcohol, drugs or both. Of these, the files of 254 individuals (3.5%) were unavailable for study; approximately 180 of the missing files were for deaths during 1993. We examined the remaining 7099 records individually. In 3406 of these, opioids were implicated as a cause of death ().
Characteristics of 3406 people whose deaths were related to opioid use in Ontario between 1991 and 2004
Most of the 3406 deaths (2108 [61.9%]) involved a single opioid (or possibly morphine and heroin together, since morphine is the only detectable metabolite in many heroin-related deaths). Morphine or heroin (or both) were involved in 761 of these deaths, of which 49 were confirmed to involve heroin based on the presence of the 6-monoacetylmorphine metabo-lite. The next most common opioids involved in single-opioid deaths were codeine (n = 431), methadone (n = 304) and oxycodone (n = 234).
The majority of opioid-related deaths also involved at least 1 non-opioid central nervous system depressant. This was the case in 425 (91.6%) of the 464 deaths involving oxycodone, for example. The most commonly implicated non-opioid central nervous system depressants in deaths related to oxycodone use were benzodiazepines (n = 276 [59.5%]), alcohol (202 [43.5%]) and cyclic antidepressants (n = 122 [26.3%]).
Opioid-related mortality doubled, from 13.7 per million in 1991 to 27.2 per million in 2004. The median age at death was 40 years (interquartile range 34–48 years); 67% of the deaths occurred in men. The manner of death was deemed by the coroner to be unintentional in 1847 cases (52.4%), suicide in 803 (23.6%) and undetermined in 745 (21.9%).
We observed a substantial increase in overall opioid-related mortality following the addition of long-acting oxycodone to the provincial drug formulary in January 2000. Between 1999 and 2004, the annual number of opioid-related deaths increased by 41% (p = 0.02), from 19.4 to 27.2 per million annually (, top panel). The number of oxycodone-related deaths increased by 416% (p < 0.01) during the same period, from 1.39 per million to 7.17 per million annually (, bottom panel). The rise in opioid-related deaths was due in large part to inadvertent toxicity; there was no significant increase in the number of deaths from suicide involving opioids over the study period ().
Deaths related to the use of opioid analgesics (top) and long-acting oxycodone (bottom) in Ontario, 1991 to 2004. *The value for 1993 is an underestimate owing to missing data (see text for details).
Deaths related to the use of opioid analgesics from 1991 to 2004, by manner of death. *The value for 1993 is an underestimate owing to missing data. (See text for details.)
Health care utilization before death
We linked coroner’s data to existing health care databases for 3271 (96.0%) individuals who died of opioid-related causes. We included 3066 deaths that occurred on or after July 1, 1992. Most of the patients (2037 [66.4%]) were seen by a physician in an outpatient setting at least once in the 4 weeks before death. The median number of outpatient physician visits per individual in the 52 weeks before death was 15 (interquartile range 6–29). Emergency department visits were also common, with 1807 (58.9%) of the individuals having at least 1 visit in the year before death.
The final encounter with a physician before death was an office visit for 2476 patients and an emergency department visit for 378 patients. The median number of days (and interquartile range) between the visit and death was 11 (4–34) for those who made an office visit and 9 (2–37) for those who went to an emergency department. Analysis of physician claims for these visits revealed that diagnoses of mental health problems (e.g., anxiety, depression or drug dependence) and pain-related complaints (e.g., joint pain or back pain) comprised the most common reasons for medical attention, which suggests that opioids prescribed to patients with these conditions may have contributed to death.
Of the 1095 patients for whom we had individual-level prescribing data, 897 (81.9%) received at least 1 prescription for an opioid in the year before death; 614 (56.1%) received at least 1 opioid prescription in the month before death. The median number of opioid prescriptions dispensed in the year before death was 10 (interquartile range 2–28). Many patients who were dispensed an opioid or other central nervous system depressant following their final physician visit had the same pharmaceutical identified on post-mortem toxicological analysis. For example, of the 75 individuals who were dispensed oxycodone following their last physician visit, 50 (66.7%) had oxycodone present on post-mortem toxicological analysis.