The mean (approximately 60 mg), twenty-fifth percentile (approximately 30 mg), selleck kinase inhibitor seventy-fifth percentile (approximately 60 mg) and ninety-fifth percentile (approximately 120 mg) doses were also stable over time (Table

​(Table33). Table 3 Morphine equivalent daily dose by time in subjects with intermittent exposure Six hundred and nineteen subjects were continuously exposed to moreover opioids for at least Inhibitors,research,lifescience,medical 6 months, and 6 years after the index day, only 9 subjects were continuously exposed to opioids. The daily morphine equivalent dose in subjects with continuous exposure and no cancer diagnosis remained stable for the first two years, as measured by mean (approximately 70 mg), median Inhibitors,research,lifescience,medical (approximately 50 mg), twenty-fifth (approximately 30 mg) or seventy-fifth percentiles (approximately 75 mg), but the 95th percentile dose rose from 143 mg to 185 mg. After the second year of continuous exposure, although the median dose remained stable, the mean, seventy-fifth percentile and ninety-fifth percentile doses rose gradually. After the fourth year of continuous exposure the median opioid dose increased as well, though it should be noted Inhibitors,research,lifescience,medical that the number of subjects was small. The daily morphine equivalent dose in subjects with continuous exposure and a cancer diagnosis increased earlier

than in subjects without cancer diagnosis (Tables ​(Tables44 and ​and55). Table 4 Morphine equivalent daily dose by time Inhibitors,research,lifescience,medical in subjects with continuous exposure without cancer diagnosis Table 5 Morphine equivalent daily dose by time in subjects with continuous exposure with cancer diagnosis The opioid dose among subjects whose exposure ended in a given 6-month time period was similar

to the opioid dose among subjects who remained exposed in the next 6-month time period (Table ​(Table66). Table 6 Morphine equivalent median daily doses in subjects continuously Inhibitors,research,lifescience,medical exposed to opioids by time and by permanence in the cohort Exposure to high doses of opioids In subjects who were intermittently exposed to opioids exposure to high doses (180 mg or more of oral morphine equivalent) occurred at some point in 2,095 (4%) subjects and 1,257 (2.6%) were exposed to very high doses (300 mg or more of oral morphine equivalent). In subjects who were continuously exposed to opioids, 7.6% were exposed to high doses of opioids and 2.9% GSK-3 were exposed to very high doses of opioids at some point. Ten percent of subjects who were continuously exposed to opioids with a cancer diagnosis were exposed to high doses of opioids compared with 7% of subjects who were continuously exposed to opioids without a cancer diagnosis. In subjects intermittently exposed to opioids, 18.7% reached doses of 100 mg or more of oral morphine equivalent. In subjects continuously exposed to opioids, 19.9% reached doses of 100 mg or more of oral morphine equivalent.