Methods To characterize the change in the dose of opioids over time, a retrospective cohort study using the PharMetrics Patient-Centric database for the years 1999 through 2008 was conducted. Access to the PharMetrics database requires a license agreement and the data are provided de-identified. Tabulations from these data do not require ethics approval. Inclusion and exclusion criteria Opioid-naive individuals exposed to opioids in 2000 who had 2 strong opioid dispensings at least 6 months apart

(to focus on subjects with long-term opioid exposure), regardless of the duration of the prescription, were included. Opioid-naive individuals were defined as subjects Inhibitors,research,lifescience,medical who did not receive any type of opioid for at least

6 months DAPT cell line before their first opioid dispensing in 2000. The date of the first dispensing of a strong opioid prescription in 2000 was defined as the index date. Inhibitors,research,lifescience,medical The dispensing at the index date had to be for a strong and full agonist opioid (e.g., morphine, hydromorphone), Table Inhibitors,research,lifescience,medical ​Table1.1. Oral, rectal, transdermal, subcutaneous, intramuscular or intravenous routes of administration and all forms of presentation (immediate release or controlled release) were included. A subject remained in the cohort even if after receiving a strong opioid at the index date, he or she subsequently received a weak, agonist antagonist, or partial agonist opioid. All opioid doses were converted into oral morphine equivalent doses. Table 1 Strong opioids dispensed at index date Patients who were receiving opioids for the treatment of opioid addiction were excluded. To determine presence of addiction before the index date, the International Statistical Inhibitors,research,lifescience,medical Classification of Diseases and Related Health

Problems, ninth edition (ICD-9) diagnostic codes for drug dependence or drug Inhibitors,research,lifescience,medical abuse were used. Pattern of exposure Exposure was classified as either continuous or intermittent. A subject was defined as “continuously exposed” if there were no time gaps between the dispensing of opioids, and “intermittently exposed” if there was a time gap between the dispensing of opioids. A gap was considered to occur when the number of days between 2 dispensings was more than 4 times the number of days supplied by the previous dispensing. Four times the days supplied was used to take Rolziracetam into account that some patients may have taken the medication less often than prescribed. Daily dose and dose over time Daily dose was calculated from the quantity dispensed and the days supplied. Daily doses were re-expressed as oral morphine equivalents using the conversion factors shown in Table ​Table22. Table 2 Morphine equivalent conversion factors To determine the behavior of opioid dose over time, mean, median dosage, interquartile range and 95th percentile of opioid dose over 6-month periods from the index date were calculated.