Predictors such as First Prescription Duration Affect Long-Term Opioid Use

On March 17, 2017, the CDC published a report that found people were more likely to use opioid pain relievers for a year or more when their first prescription supply exceeded 10 or 30 days, when a patient received a third prescription, or when the cumulative dose over the first episode of opioid use was 700 morphine milligram equivalents or more. People were substantially more likely to use opioid pain relievers for a year or more when the initial duration of opioid therapy reached 6 and 31 days.


Because long-term opioid use often begins with treatment of acute pain, in March 2016, the CDC Guideline for Prescribing Opioids for Chronic Pain included recommendations for the duration of opioid therapy for acute pain and the type of opioid to select when therapy is initiated. However, data quantifying the transition from acute to chronic opioid use were lacking.


Patient records from a database of commercial health plan information from a large number of managed care plans representative of the U.S. commercially insured population were analyzed to characterize the first episode of opioid use among commercially insured, opioid-naïve, cancer-free adults and quantify the increase in probability of long-term use of opioids with each additional day supplied, day of therapy, or incremental increase in cumulative dose. The largest increments in probability of continued use were observed after the fifth and thirty-first days on therapy; the second prescription; a cumulative dose of 700 morphine milligram equivalents (a conversion factor to convert different opioids into an equivalent dose of morphine); and first prescriptions with 10- and 30-day supplies. By providing quantitative evidence on risk for long-term use based on initial prescribing characteristics, these findings might inform opioid prescribing practices.


A random 10% sample of patient records during 2006–2015 was drawn from the database. Records were selected of patients 18 or older who had at least one opioid prescription during June 1, 2006–September 1, 2015, and at least six months of continuous enrollment without an opioid prescription before their first opioid prescription. Patients excluded were those who had any cancer (other than nonmelanoma skin cancer) or a substance abuse disorder diagnosis in the six months preceding their first opioid prescription, or whose first prescription was for any buprenorphine formulation indicated for treatment of substance abuse.


Patients were followed from the date of their first prescription until loss of enrollment, study end date, or discontinuation of opioids, which was defined as 180 days or more without opioid use. The duration of use, number of prescriptions, and cumulative dose (expressed in morphine milligram equivalents) for the first episode of opioid use (defined as continuous use of opioids with a gap of no greater than 30 days) were calculated. The number of days’ supply and average daily dose in morphine milligram equivalents for the first prescription were also calculated. The first opioid prescription was categorized into six mutually exclusive categories: (1) long-acting: buprenorphine, fentanyl, morphine, oxycodone, oxymorphone, and tapentadol; (2) other Schedule II short-acting: fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxymorphone and tapentadol; (3) oxycodone short-acting; (4) hydrocodone short-acting; (5) Schedule III–IV and nalbuphine: codeine, dihydrocodeine, butorphanol, nalbuphine, pentazocine and propoxyphene; or (6) tramadol.


Researchers estimated (1) median time to discontinuation of opioid use; (2) probability of continued opioid use at 1 year and 3 years for different treatment duration thresholds (daily for 1–40 days and weekly for 1–26 weeks); (3) number of prescriptions (1–15); and (4) cumulative dose of the first episode of opioid use (50–2000 morphine milligram equivalents). Similarly, the relationship between the number of days’ supply, choice of first opioid prescription, and probability of continued opioid use at 1 and 3 years was also examined. Sensitivity analyses were conducted by (1) modifying the discontinuation definition from 180 or more opioid-free days to 90 ore more opioid-free days; (2) changing the allowable gap in the first episode of opioid use from 30 days to 7 days; and (3) excluding patients whose average daily dose of the first prescription exceeded 90 morphine milligram equivalents.


A total of 1,294,247 patients met the inclusion criteria, including 33,548 (2.6%) who continued opioid therapy for a year or more. Patients who continued opioid therapy for a year or more were more likely to be older, female, have a pain diagnosis before opioid initiation, initiated on higher doses of opioids, and publically or self-insured, compared with patients who discontinued opioid use in under a year. Among persons prescribed at least 1 day of opioids, the probability of continued opioid use at 1 year was 6.0% and at 3 years was 2.9% with a median time to discontinuation of 7 days. Approximately 70% of patients had an initial duration of opioids of a week or less. Approximately 7.3% of patients were initially prescribed opioids for 31 days or more.


The highest probabilities of continued opioid use at 1 and 3 years were observed among patients who initiated treatment with a long-acting opioid (27.3% at 1 year; 20.5% at 3 years), followed by those whose initial treatment was with tramadol (13.7% at 1 year; 6.8% at 3 years) or a Schedule II short-acting opioid other than hydrocodone or oxycodone (8.9% at 1 year; 5.3% at 3 years). The probabilities of continued opioid use at 1 and 3 years for persons starting on hydrocodone short acting (5.1% at 1 year; 2.4% at 3 years), oxycodone short-acting (4.7% at 1 year; 2.3% at 3 years), or Schedule III–IV (5.0% at 1 year; 2.2% at 3 years) opioids were similar.


As expected, patients initiated on long-acting opioids had the highest probabilities of long-term use. However, the finding that patients initiated with tramadol had the next highest probability of long-term use was unexpected; because of tramadol’s minimal affinity for the μ-opioid receptor, it is deemed a relatively safe opioid agonist with lower abuse potential than other opioids. However, a report by the Substance Abuse and Mental Health Services Administration determined that emergency department visits associated with tramadol-related adverse events increased by 145% during 2005–2011. Long-term data on tramadol for pain management are sparse, with only one trial exceeding 12 weeks in duration. Despite this, among patients initiated with tramadol, over 64% of patients who continued opioid use beyond 1 year were still on tramadol, suggesting that tramadol might be prescribed intentionally for chronic pain management.


The probability of long-term opioid use increased most sharply in the first days of therapy, particularly after 5 days or 1 month of opioids have been prescribed, and levels off after approximately 12 weeks of therapy. The rate of long-term use was relatively low (6.0% on opioids 1 year later) for persons with at least 1 day of opioid therapy, but increased to 13.5% for persons whose first episode of use was for 8 or more days and to 29.9% when the first episode of use was for 31 or more days. Although 31 or more days of initial opioid prescriptions are not common, approximately 7% do exceed a 1-month supply. Discussions with patients about the long-term use of opioids to manage pain should occur early in the opioid prescribing process, perhaps as early as the first refill, because approximately 1 in 7 persons who received a refill or had a second opioid prescription authorized were on opioids 1 year later.


The findings in this report are subject to at least five limitations. First, although the cumulative dose of the first episode of opioid use is described, the likelihood of long-term use when the prescriber was titrating the dose was not determined. Rather, the total cumulative dose was calculated, which might have been increasing or decreasing over time. Second, the extent to which chronic opioid use was intentional versus the outgrowth of acute use is not known. Less than 1% of patients in this analysis were prescribed Schedule II long-acting opioids at the outset, so intentional chronic opioid prescribing might be uncommon; however, approximately 10% of patients were prescribed tramadol, which might indicate intentional chronic opioid prescribing. Third, information on pain intensity or duration were not available, and the etiology of pain, which might influence the duration of opioid use, was not considered in the analysis. Fourth, the frequency of prescriptions having certain days’ supplied (e.g., prescriptions with a 7-day supply would be more frequently observed than those with an 11- or 13-day supply) was not considered. The variability in the relationships between days’ supply, the cumulative dose, and duration of first episode and the probability of long-term use could be affected. Finally, prescriptions that were either paid for out-of-pocket or obtained illicitly were not included in the analysis.


Transitions from acute to long-term therapy can begin to occur quickly: the chances of chronic use begin to increase after the third day supplied and rise rapidly thereafter. Consistent with CDC guidelines, treatment of acute pain with opioids should be for the shortest durations possible. Prescribing less than 7 days (ideally 3 or fewer days) of medication when initiating opioids could mitigate the chances of unintentional chronic use. When initiating opioids, caution should be exercised when prescribing greater than 7 days of opioids or when authorizing a refill or a second opioid prescription because these actions approximately double the chances of use 1 year later. In addition, prescribers should discuss the long-term plan for pain management with patients for whom they are prescribing either Schedule II long-acting opioids or tramadol.


See the CDC Report


See the CDC Guideline for Prescribing Opioids for Chronic Pain


See also Medical Law Perspectives, January 2014 Report: Prescription Painkillers: Risks for Patients, Pharmacists, and Physicians


See the Medical Law Perspectives February 16, 2015, Blog: Pharmacy Owes Duty To Patient Not To Fill Excessive Prescriptions for Opioids


See the Medical Law Perspectives October 8, 2014, Blog: Opioid Pain Pill Abusers Switch to Heroin; Heroin Overdose Deaths Double