(P-027) Four Competing Definitions of Morphine Equivalence Insidiously Inhibit Evidence Synthesis

Background: Morphine-standardized analgesic doses are used in clinical practice and research to account for molecular potency. 90 milligrams of morphine equivalents (MME) per day are considered a “high dose” risk threshold in guidelines and laws. Theoretically total MME (numerator) is divided by days supply (denominator) to calculate daily MME. Although ubiquitously cited the “CDC definition” of daily MME lacks a clearly defined denominator.

Objectives: To assess the sensitivity of denominator-dependency on “high dose” classification across 4 competing definitions of daily MME.

Methods: To identify definitional variants, we examined text descriptions from 27 studies cited in the 2016 CDC Pain Management Guideline, literature, and electronic prescribing tools; our review yielded 4 unique definitions. Using Prescription Drug Monitoring Programs data (Jul-Sep 2018), we conducted a population-based cohort study of 3,916,461 patients who received outpatient opioid analgesics in California (CA) and Florida (FL). The binary outcome was whether patients were deemed “high dose” (>90 MME/day), which we compared across the 4 definitions. We calculated I^2 for heterogeneity attributable solely to definition, and stratified by extended/immediate release.

Results: In a simple example, a 30-day supply of 2 partially overlapping oxycodone prescriptions have daily MME varying across 4 definitions: 76mg (total days supply); 93mg (on-therapy days); 31mg (fixed observation window); or 105mg (maximum daily dose). 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: 17-52 (CA) and 23-65 mg (FL)]. Across the definitions, prevalence of “high dose” individuals ranged 5.9%-14.2% (FL) and 3.5%-10.3% (CA). Definitional variation would impact a hypothetical surveillance study trying to establish how much more “high dose” prescribing was present in FL than CA: from 34% to 79% more. Meta-analyses revealed strong heterogeneity (I^2 range 86%-99%) based solely on MME definition, impacting immediate- and extended-release differentially. In the sensitivity analysis, including unit interval 90.0-to-90.9 in the boundary increased the “high dose” population fraction by 15.4%.

Conclusions: Previously unrecognized definitional variation confounds surveillance metrics and constrains real-world applicability of observational studies. 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 for validity.