TABLE 4.

Recommendations on Equianalgesic Definitional Variants

1. Total days supply: The least complicated calculation appears best suited when immediate-release opioids are prescribed for short discrete times. It consistently underestimated MME per day when overlapping prescriptions were present or when immediate-release and extended-release opioids were prescribed concurrently, as with 78% of patients with chronic opioid use

2. On-therapy days: Provides a smoothed measure useful in studies of dose-dependent adverse effects, including opioid-induced constipation or overdose in patients with opioid tolerance or who have been stable on opioids. The metric is time-varying and affords the greatest flexibility to define medication gap periods and leftover/unused medications to improve pharmacoepidemiologic studies

3. Fixed observation window: Most suitable for studies with a known or suspected duration of risk during which adverse events are expected to occur, such as incidence of opioid use disorder. This definition may be useful when prescriptions are filled at irregular time intervals on a as-needed basis (pro re nata). The definition consistently had the lowest milligrams per day for immediate-release opioids. This is the definition recommended by the Department of Health and Human Services Office of the Inspector General.43 It is the most robust to misspecification, amenable to transformations, and has the least noise when constructing continuous functions.40 However, since it assumes uniform exposure/risk within a window, there is less scope for time-varying adjustment

4. Maximum daily dose: A toxicological perspective may be appropriate for opioid naive patients with no tolerance and in the presence of comorbidities for respiratory depression. It appears to be best suited for immediate dose-dependent toxic effects, such as respiratory depression in opioid naive patients. This definition may have limited use if it includes opioids where fatal toxicity does not involve respiratory depression (eg, tramadol) or have atypical mu-opioid receptor agonism (eg, tapentadol, buprenorphine). The definition assumes uniform risk of adverse outcomes regardless of time on-therapy. More so than the others, this definition is prone to influence from early refills, unused medication, and how the 90 MME threshold is operationalized. This definition underlies the algorithm embedded in the CDC Opioid Guideline mobile app.51 There may be difficulty reconciling findings with studies using the other definitions because it returns a MME per day that is significantly higher

CDC indicates US Centers for Disease Control and Prevention; MME, milligrams of morphine equivalents.