Inches, Centimeters, and Yards: Overlooked Definition Choices Inhibit Interpretation of Morphine Equivalence

Abstract

Objective: Morphine-standardized doses are used in clinical practice and research to account for molecular potency. Ninety milligrams of morphine equivalents (MME) per day are considered a "high dose" risk threshold in guidelines, laws, and by payers. Although ubiquitously cited, the "CDC definition" of daily MME lacks a clearly defined denominator. Our objective was to assess denominator-dependency on "high dose" classification across competing definitions.

Methods: To identify definitional variants, we reviewed literature and electronic prescribing tools, yielding 4 unique definitions. Using Prescription Drug Monitoring Programs data (July to September 2018), we conducted a population-based cohort study of 3,916,461 patients receiving outpatient opioid analgesics in California (CA) and Florida (FL). The binary outcome was whether patients were deemed "high dose" (>90 MME/d) compared across 4 definitions. We calculated I2 for heterogeneity attributable to the definition.

Results: Among 9,436,640 prescriptions, 42% overlapped, which led denominator definitions to impact daily MME values. Across definitions, average daily MME varied 3-fold (range: 17 to 52 [CA] and 23 to 65 mg [FL]). Across definitions, prevalence of "high dose" individuals ranged 5.9% to 14.2% (FL) and 3.5% to 10.3% (CA). Definitional variation alone would impact a hypothetical surveillance study trying to establish how much more "high dose" prescribing was present in FL than CA: from 39% to 84% more. Meta-analyses revealed strong heterogeneity (I2 range: 86% to 99%). In sensitivity analysis, including unit interval 90.0 to 90.9 increased "high dose" population fraction by 15%.

Discussion: While 90 MME may have cautionary mnemonic benefits, without harmonization of calculation, its utility is limited. Comparison between studies using daily MME requires explicit attention to definitional variation.

FIGURE 1

Inconsistency in identifying “high dose” patients on opioids. The proportion of patients on opioids considered “high dose” (>90 mg of morphine equivalents [MME]/day) varies by definition alone, from July to September 2018. Four definitions were identified from the literature and clinical tools. Total days supply (D1) divides the sum of MMEs by the sum of days supply, allowing the denominator to be longer than the prescribed duration. On-therapy days (D2) divides total MME by the number of calendar days. Fixed observation window (D3) uses a fixed denominator, typical 30 to 90 days in research studies. Maximum daily dose (D4) identifies the day with the highest total possible exposure.