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A conversation with Dr. Nabarun Dasgupta, Gillings Innovation Fellow, and Senior Scientist at the UNC Injury Prevention Research Center
February 6, 2022 – 2:46 pm
Daily Remedy discusses with Dr. Naburun Dasgupta’s research paper, Inches, Centimeters, and Yards, to learn about inconsistencies in the definition of Morphine Milligram Equivalents (MME) and how they have led to clinically harmful policies.
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A conversation with Dr. Nabarun Dasgupta
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Inches, Centimeters, and Yards
Overlooked Definition Choices Inhibit Interpretation of Morphine Equivalence
Dasgupta, Nabarun PhD*; Wang, Yanning MS†; Bae, Jungjun BS‡,§; Kinlaw, Alan C. PhD∥,¶; Chidgey, Brooke A. MD#,**; Cooper, Toska MPH*; Delcher, Chris PhD‡,§
The Clinical Journal of Pain: August 2021 – Volume 37 – Issue 8 – p 565-574
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.
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.
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%.
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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.
Morphine-standardized analgesic doses are calculated in clinical practice and research routinely. And, in support of safer opioid prescribing, clinical guidelines suggest limits or cautions above 90 mg of morphine equivalents (MME) to prevent respiratory depression. Yet, subtle variations in MME per day calculations have been overlooked.1 Therefore, we sought to quantify the practical impact of definitional variants to provide clarity.
Equianalgesic conversion factors between opioids were intended to guide dosing when switching patients by accounting for potency.2,3 Conceptually, an equianalgesic dose is that at which 2 opioids provide the same pain relief. Contrary to conventional wisdom, conversion values are not based on pharmacologic properties. Instead, they arose 60 years ago from small single-dose clinical studies in postoperative or cancer populations with pain score outcomes; toxicologic effects (eg, respiratory depression) were not evaluated.4
Amid concerns about opioid overdose, the concept of equianalgesic potency resurfaced.5 In 2016, the US Centers for Disease Control and Prevention (CDC) issued a guideline for chronic noncancer pain management including strong cautions above 90 daily MME based on population-level mortality studies.6 The CDC Guideline formalized a shift in the MME concept from antinociception to toxicology. The 90 daily MME recommendation was not absolute; however, some state laws, policies, and insurance requirements now invoke the threshold explicitly. For example, the State of Maine prohibits “any combination of opioid medication in an aggregate amount in excess of 100 MME of opioid medication per day.”7 CDC recognized this misapplication with a statement softening the “hard limits” inferred.8 The American Medical Association has expressed similar concerns.9
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