They are the foundation of the CDC’s 2016 opioid guidelines, resulting in legislation limiting opioid prescribing in 36 states. Morphine milligram equivalents, or MMEs, are used to set arbitrary prescribing limits for opioids by physicians since many state legislators fail to understand — and translate into policy and law — the ’16 guidelines. If we had all known the history of MMEs, perhaps we would not have been so eager to embrace them.

What exactly is a Morphine Milligram Equivalent (MME)? The CDC defines it as: “The amount of milligrams of morphine an opioid dose is equal to when prescribed. Calculating MME accounts for differences in opioid drug type and strength.”

MMEs are used in pain management. Clinically, to help transition patients from an ineffective treatment choice to a more effective dosage, form or medication. Researchers have also used MMEs to standardize data on medications and prescribing habits when using varying datasets.

The source of MMEs: It’s not at all what you’d think

The origin of MMEs seems to be shrouded in the mists of history. The earliest reference to comparing one opioid to another was in a 1974 JAMA article treating the acute pain of myocardial infarction, “Meperidine hydrochloride in parenterally administered doses of 75 mg provides effective analgesia of the same duration as does 10 mg of morphine sulfate.”

Two months later, that view of equivalence was rebutted as:

“… counter to that of standard texts and journals of pharmacology and is not consistent with our own experience. While it is accepted that the meperidine dose equivalent to 10 mg of morphine is 75 to 100 mg, duration of analgesia by meperidine may be as little as 50% that of morphine … in chronic or sustained pain, such as occurs in malignant invasion of bones or in sickle cell crisis, the difference is readily apparent to the alert physician and nurse. It has been suggested that physicians are undertreating patients in pain.”

All the hallmarks of today’s concerns were there:

• Clinical experience
• Equianalgesic dosage (the amount to provide the same level and duration of pain relief)
• The distinction between acute and chronic pain
• Undertreatment of patients in pain

The next reference I found was published in 1984, coming from a study of 38 patients receiving opioids for chronic, non-malignant pain at Memorial Sloan Kettering’s pain clinic.

“A 25-year-old man developed severe left calf pain associated with swelling and tenderness. He was admitted to hospital in June 1975, taking approximately 28 morphine equivalent mg/24 h for pain.”

There was no citation. The authors relied on their expertise or some unreferenced work to draw that equivalence.

A paper in the journal Pain from 1996 begins to unravel the underlying scientific studies performed in 1936.

“The morphine dose equivalents for hydromorphone and other opioids derive from single-dose studies, all of which involved intramuscular or oral administration and measured pain reduction as the therapeutic endpoint.”

But the authors settle for an even more unsettling definition, based on a 1975 paper in the journal Anaesthesiology. The use of this paper to define MMEs is nothing short of astounding:

“Subjective responses to nurse-observer questions were used to quantitate analgesia for postoperative pain. Hydromorphone is more potent than commonly believed: approximately 0.9 to 1.2 mg is equianalgesic with 10 mg of morphine, with a similar incidence of side effects.”

It is scientifically illiterate to use this subjective casual observation to form the basis of policy. Yet, this paper is used as a reference by the CDC in its 2016 Opioid Prescribing Guide.

The CDC’s MMEs: lost in translation

The CDC explanation of their MME conversions references this paper, “Defacto Long-term Opioid Therapy for Non-Cancer Pain,” so let’s take a brief look at this study.

It looked at opioid use of adults in two health care plans, between 1997 to 2005, reflective of their regional demographics. There is exactly one sentence in the paper that you need to pay attention to:

“The conversion factors were based on information from multiple sources. After reviewing published conversion factors, consensus was reached among two physicians with clinical experience in pain management and a pharmacist pharmacoepidemiologist.”

The basis of the CDC recommendations comes down to two physicians and a pharmacoepidemiologist. Not overwhelmingly “established” science. Let’s leave those subjective MME conversions to the side for a moment and consider the researchers’ quest to identify a “threshold” to long-term opioid therapy.

In their study, the overwhelming majority of patients took them for less than a month; 80% used opioids for less than a week, 14% took opioids, on average, for only a month. Only 5.5% of the patients receiving opioids took them for longer than a year; they became the focus. In searching for even longer-term use, a possible marker of “addiction,” the researchers found that half of those patients continued therapy into the next year – they were those most likely “to continue frequent use of opioids in future years.” [1] They identified a boundary or signal that an individual’s opioid use might be problematic.

“By setting a clear boundary between acute and episodic use on the one hand, and long-term use on the other, it may be possible for physicians and health plans to establish a checkpoint …”

There is no mention of MMEs. The variation in the amount of MMEs prescribed or taken among that 6% was too variable to be a threshold — not surprising, given the subjective nature of their calculation. The researcher’s boundary line was the duration of prescribing — a year, the point that would identify that half of the 5.5% they felt to be “at risk.” Most importantly, their boundary was a call to reconsider therapy, not a limit on MME.

Other researchers with similar studies sought their bright line defining those at risk. But quietly, the risk changed from a concern over addiction, as a threshold based on length of treatment would suggest, to a concern over the risk of “overdose.” See the difference in the focus of a 2016 review which concluded:

“A clear cut-point in opioid dosage to distinguish between overdose cases and controls was not found. However, lowering the recommended dosage threshold below the 100 MME used in many recent guidelines would affect proportionately few patients not at risk for overdose while potentially benefiting many of those at risk for overdose.”

Somewhere along the way, lost in translation, the concern of addiction morphed to concern over overdose. Despite a lack of “a clear cut-point in opioid dosage,” MMEs replaced fuzziness with pseudo-certainty.

If the ambiguity of what a threshold MME means is insufficient, MME suffers from two additional problems: its calculation and what is being measured. Topics we will address another day.

Charles Dinerstein is a surgeon.

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