A total of 9940 people initiating chronic opioid therapy were included in the cohort. They were followed for a mean of 42 months (range <1 to 119 months) from their initial 90-day exposure window. Of the total cohort, 61% had complete follow-up (from entry into the cohort until the end of the study period, or until an event), 32% left GHC during the study period and 7% died. The characteristics of the cohort are shown in . Around 60% was female, with a mean age of 54 years. Two thirds of the cohort received a diagnosis of back pain or extremity pain at the index visit (38% and 30% respectively). The mean daily dose of opioids prescribed was 13.3 mg (morphine equivalents). Among 46% of the cohort, hydrocodone was the opioid they were most commonly prescribed, and 10% of the cohort received predominately long-acting opioids. Cohort patients were using opioids during 51.2% of the follow-up time: with 40.1% of observation time at the lowest dosage level (1 to <20 mg. morphine equivalents); 6.7% at 20 to <50 mg.; 2.6% at 50 to <100 mg., and 1.8% was at 100 mg. or greater. Three quarters (74%) of the cohort was also prescribed sedative-hypnotics at some point.
Clinical description of identified opioid overdoses
During the study period, 6 fatal opioid-related overdoses and 74 non-fatal events were identified, of which 13 were classified as definite non-fatal opioid overdoses and 32 as probable non-fatal opioid overdoses (10 were uncertain, 17 probably not, and 2 definitely not opioid overdoses). Using a definition of death, definite or probable non-fatal overdose for an opioid-related overdose, we identified 51 patients who experienced one or more overdose events. Of these, 40 (78.4%) experienced a fatal or otherwise serious overdose, and 11 (21.6%) had only non-serious overdose events. Common clinical contexts for overdose were varied and included accidental excess ingestion of opioids (n=8) and suicide attempt (n=6). Additional opioids obtained from non-medical sources were noted for three people and drug abuse was mentioned for four. Four patients had notes indicating overdoses associated with applying extra Fentanyl patches or sucking on a patch. The largest category of noted clinical effects of the overdose was delirium, loss of consciousness or confusion (n=23), followed by respiratory problems (n=15) and falls (n=4). The most common initial care settings identified for overdose events were the emergency room (n=23), inpatient care (n=14), urgent care (n=2) or other ambulatory care (n=6).
The annual rate of overdose for the total sample was 148 per 100,000 person years overall, and 116 per 100,000 for serious overdose (). The overdose rates were somewhat higher among persons age 65+ than among persons in the two younger age groups, and were similar in men and women. Overdose rates were elevated among those with a history of depression or substance abuse treatment (). The overall rate of overdose mortality (n=6 deaths) was 17 per 100,000 person years, so there were over seven times as many non-fatal overdoses as fatal overdoses in this cohort. When stratified by recent receipt of opioids, the annual overdose rate was 256 per 100,000 person years among patients recently receiving medically prescribed opioids, compared to 36 per 100,000 person years among the sub-sample not recently receiving medically prescribed opioids (). We examined overdose events by clinic and did not observe notable clustering of overdose within any of the 29 clinics included in this study (data not shown).
Hazard ratios for the relationship between recent opioid dosage level and overdose
Relationship between opioid dose dispensed and overdose
Hazard ratios for the relationship between recently prescribed opioid dosage level and opioid-related overdose, adjusted for potential confounders, are shown in . People receiving the lowest opioid dosage levels (<20mg per day) had an annual overdose rate of 160 per 100,000 person years. The risk of overdose increased with increasing opioid dosage level. Among persons receiving an opioid dose of 100mg or more per day, the annual overdose rate was 1791 per 100,000 person years, a nine-fold increase in overdose risk [8.87 (95% C.I. 3.99, 19.72)] compared to those receiving the lowest doses. When analysis was restricted to serious events, the hazard ratios were of a similar magnitude, and demonstrated a comparable difference by dose (). Persons recently receiving sedative-hypnotic medications were also at increased risk of opioid overdose, but risk did not increase with the frequency of receiving sedative-hypnotic medications. Relative to persons not receiving any sedative-hypnotic medications in the 90 days prior to opioid overdose, the overdose hazard ratios were as follows: 3.4 [1.6–7.2] for 1-22 days supply; 0.9 [0.2-4.0] for 23-44 days supply; 3.7 [1.6-8.9] for 45-71 days supply; and 2.7 [1.2-6.0] for 72+ days supply. In multivariate analyses, recent initiation of opioid use (starting or restarting) was not associated with either increased or reduced risk of opioid overdose (data not shown).
We assessed patient differences by the maximum opioid dose received over the follow-up period. Patients receiving the highest opioid doses (relative to those in the lowest dose group) more often: were male (48.4% vs. 39.5%); were current smokers (40.0% vs. 28.0%); had a history of depression treatment (32.0% vs. 25.9%); had a history of substance abuse treatment (13.7% vs. 5.3%); and had higher Charlson comorbidity scores (mean =0.93 SD=1.61 vs. mean=0.63 SD=1.40), but did not differ in age. The intermediate dosage groups were generally similar to the lowest dose group on these variables.
Persons who had not recently received opioids had lower risk of overdose than patients receiving opioids at low dosage levels (). In covariate stratified analyses, the consistency of differences in overdose risk was compared for persons recently receiving opioids and persons not recently receiving opioids. Elevated overdose risk was observed among those recently receiving prescribed opioids in all sub-groups (data not shown).