The Myth of Morphine Equivalent Daily Dosage

The Myth of Morphine Equivalent Daily Dosage | May 2016 | Michael E. Schatman, PhD; Jeffrey Fudin, PharmD

For far too many years, pain researchers and clinicians have relied on the concept of the morphine equivalent daily dosage (MEDD), or some variant of it, as a means of comparing the “relative corresponding quantity” of the numerous opioid molecules that are important tools in the treatment of chronic pain

researchers have relied on non-empirically derived “equivalent dosages” as a means to facilitate research in which opioid consumption serves as a dependent variable.

Clinically, opioid “conversion” tables have been routinely used when switching a patient from one opioid to another.

And, most unfortunately, opioid prescribing guideline committees have relied on this concept as a means of placing (usually arbitrary) limits on the levels of opioids that a physician or other clinician should be allowed to prescribe. 

Although these guidelines typically bill themselves as “voluntary,” their chilling effect on prescribers and adaptation into state laws[2] makes calling them “voluntary” disingenuous.

Although some scientists and clinicians have been questioning the conceptual validity of MEDD for several years, a recent study has indicated that the concept is unequivocally flawed—thereby invalidating its use empirically and as a tool in prescribing guideline development.

(See Rennick A, Atkinson TJ, Cimino NM, Strassels SA, McPherson ML, Fudin J. Variability in Opioid Equivalence Calculations. Pain Medicine. 2016;17: 892–898.)

This analysis determined that a fundamental inadequacy of the MEDD concept is the lack of a universally accepted opioid-conversion method.

Regarding the use of MEDD in research, our suspicion is that many pain investigators have known about the problems with this prodigiously flawed concept for many years.

For example, in a 1991 Australian review of the polymorphic metabolism of opioids, the authors concluded that “Pharmacogenetics may play an important role in explaining the wide variability of the clinical response to many opioid drugs.”

See Polymorphic metabolism of opioid narcotic drugs: possible clinical implications. 1991

The oxidative metabolism of many drugs is under genetic control. The enzyme responsible for this reaction for this group of drugs is cytochrome P-450IID6. Humans can be classified either as extensive metabolisers or, if lacking this enzyme, poor metabolisers

The hepatic O-demethylation of codeine to morphine, quantitatively a minor metabolic process, represents this type of genetic polymorphism and has been studied in human pharmacokinetic studies, human urinary recovery studies, and in human and rat liver microsome experiments.

The incidence of poor metabolisers in caucasian subjects is 7-10%.

one might anticipate that poor metabolisers would not obtain pain relief from codeine.

Others opioids (dihydrocodeine, hydrocodone, oxycodone, and thebaine) are structurally similar to codeine and their metabolism (O-demethylation at the 3 position) might also be under genetic control.

Pharmacogenetics may play an important role in explaining the wide variability of the clinical response to many opioid drugs.   

Yet, a quarter of a century later, MEDD remains routinely used in pain research worldwide. Given that invalid dependent variables in research result in invalid findings, our hope is that investigators will begin to conduct studies comparing morphine with morphine, hydrocodone with hydrocodone, and so on—as opposed to relying on the standard (and far more convenient) approach of MEDD.  

Implications in the Clinic

Clinically, prescribers need to use this information regarding the flawed MEDD concept to begin practicing dosage-switching and opioid rotation in a more thoughtful and scientific manner.

Furthermore, the evidence supporting pharmacogenomic differences among patients is mounting and needs to be carefully weighed before labeling a patient who requires 30 mg of morphine rather than the prescriber’s “standard” of 10 mg in order to achieve adequate analgesia as an “addict.”

Association Between Human Pain-Related Genotypes and Variability in Opioid Analgesia: An Updated Review. | 2015

On an individual level, there is a difference in the analgesic response to a given opioid.

Various factors such as gender, age, and genetic variation can affect the analgesic response.

The genetic variation can influence pharmacokinetics (eg drug transporters and drug-metabolizing enzymes) and/or pharmacodynamics (eg opioid receptor and catechol-O-methyltransferase enzymes)

We present recent experimentally induced pain, postoperative pain, and cancer pain and chronic non-malignant pain conditions studies in humans, focusing on the association between genetic variation and analgesic response assessed as opioid consumption or changes in pain scores

(Also see: Baber M, Bapat P, Nichol G, Koren G. The pharmacogenetics of opioid therapy in the management of postpartum pain: a systematic review. Pharmacogenomics. 2016;17:75-93. Abstract)

Although the use of MEDD in research and, to a greater extent, in practice, is probably due to unawareness of its inaccuracy, we posit that the use of MEDD by recent opioid guideline committees (eg, the Washington State Opioid Guideline Committee and the Centers for Disease Control and Prevention Guideline Committee) in the drafting of their guidelines is based more heavily on disregarding available evidence rather than ignorance.

See also:

Washington State Agency Medical Directors’ Group. Interagency guideline on prescribing opioids for pain. http://www.agencymeddirectors.wa.gov/Files/2015AMDGOpioidGuideline.pdf Accessed on May 11, 2016.

Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. MMWR Recomm Rep. 2016;65:1-49.

Furthermore, their misconduct in doing so has been more pernicious than the use of MEDD by researchers and individual clinicians, because these guidelines widely affect society as a whole as well as individual patients with persistent pain syndromes.

Although we emphatically agree that opioid analgesia should not be the first-line treatment for chronic noncancer pain, when other nonopioid treatments have either failed, are contraindicated medically or owing to behavioral and emotional factors, or are inaccessible because of the health insurance industry’s refusal to cover them (irrespective of their established evidence-bases), opioids should be considered.

Guidelines that contain language suggesting that alternative treatments are regularly available when this is not the case are shortsighted and troubling.

Recently, we published an article in the Journal of Pain Research titled “The MEDD Myth: The Impact of Pseudoscience on Pain Research and Prescribing-Guideline Development,”

This article goes into considerably more detail regarding the clinical and ethical imbroglio that we address in the current brief article, and as an open-access publication, the Journal of Pain Research encourages readers to access the full text at no cost.  

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