Maximum Opioid Doses are an Abomination

Maximum Opioid Doses: A Pharmacological Abomination – By Josh Bloom — June 22, 2020

Despite irrefutable pharmacological evidence of the wide range in individuals’ metabolism of opioid drugs, states continue to impose “one-size-fits-none” laws.

It’s safe to say that no one is really paying attention to the science. So, here it is. Again.

The American Medical Association was two years late to the party when it issued its first statement (1) about the inappropriate use of CDC Guidelines to establish, among other things, laws that define a dose and duration limits for opioid analgesics. No one was listening. Since then things have gotten worse, not better, for pain patients.  

Fortunately, the AMA has given it another shot. A June 16th, 17-page letter from AMA Executive Vice President and CEO Dr. James L. Madara to Dr. Deborah Dowell, the Chief Medical Officer National Center for Injury Prevention and Control (part of the CDC) has some real oomph to it (emphasis mine.)

States Continue to Ignore Science

Pharmacy Benefits Managers Kick Pain Patients When They’re Down

Madara points out that prescription drug providers (PBMs) have stuck their balance sheets where they’re not welcome.

• Walmart’s policy includes a 50MME or 7-day hard threshold for opioid prescribing.
• CVS Caremark’s policy has multiple restrictions, including a 7-day hard threshold for opioid prescribing •
• OptumRx’s policy is aligned with 2016 Guidelines”
• Drug stores telling doctors how much medicine the can prescribe? Madness.

here is an abridged version of “Opioid Policies Based On Morphine Milligram Equivalents Are Automatically Flawed.”

Maximum daily doses, recommended by the CDC in 2016 have been enacted as law. The maximum dose is based on a ridiculous concept called morphine milligram equivalents (MME) – the ratio of the “power” of the drug compared to that of morphine. This may sound reasonable (assuming that you think that the government should be allowed to dictate to physicians the amount of only one class of drugs – opioid – that they are allowed to prescribe. While MME values are touted as useful predictors of the total “opioid load” that a patient can receive, they are nothing of the sort.

Flawed science,  meaningless results

Below is a chart published by the CDC, a “guide” (2) for physicians who prescribe pain drugs. It is a god-awful mess but is used nonetheless.

Although the conversion table seems to be straightforward enough, it is based on an assumption that all opioids behave similarly in the body. But this assumption could not be less accurate.

Once the profound differences in the properties of the drugs and the difference between individuals who take them are taken into account it becomes clear that the CDC chart flawed and the MME is little more than a random number.

Table 1. MME equivalents. Source:CDC

Not all opioids are created equal, especially in the body

Anyone with even a passing knowledge of pharmacology would immediately be skeptical of the chart.

does not take into account a number of critical properties that paint a more complete picture of the fate of the drug once swallowed

Bioavailability

Bioavailability is a measure of the how well a pill will be absorbed in the gut and subsequently enter the bloodstream.

Furthermore, drugs with low bioavailability have a greater variation from one individual to the next, making the pharmacology of a drug like oxymorphone even less predictable.

Half-life and metabolism

bioavailability is far from the only measure of an oral drug’s effect on people or animals.

Two of these are the crucial parameters half-life and metabolism.

Oxymorphone, even though it is twice as potent as oxycodone (Table 1), is metabolized much faster; its half-life (5) is 1.3 hours, while oxycodone, although less potent, stays in the blood much longer (its half-life is 4.5 hours).

The difference in metabolizing enzymes itself is a substantial concern when comparing two different drugs, but it becomes even more so when other drugs are part of the picture.

The only certainty is uncertainty

So, which drug is better for a pain patient? Do the MME values really reflect the drugs’ relative ability to relieve pain? Do half-life and bioavailability matter? Does the fact that different types of enzymes are involved in metabolism make a difference?

The answer to all of these questions is “who knows?” All we are told is that patients cannot be prescribed more than 60 mg of oxycodone or 30 mg of oxymorphone per day.

It becomes patently obvious that the simple CDC chart provides us with numbers that are probably more artifactual than real. The chart tells us little about which opioid drug might the best for a single person or its optimal dose, let alone a diverse population.

Polypharmacy: Drug-drug interactions

Genetics: Abundant differences in human metabolism of opioids

Perhaps the most important factor in determining the optimal dose of an opioid is the profound difference in the genetic makeup of individuals; some people may metabolize opioids 100-times that of others simply because of the impact of genetics on CYP function. Table 3 shows the range of variation of the rate of metabolism of four CYP enzymes.

Given the wide range of CYP activity variability from individual to individual, it should come as no surprise that this difference profoundly affects opioid users, especially since CYP3A4 and CP2D6 are responsible for much of metabolism of these drugs. It is this genetic variability that is responsible for both poor metabolizers and rapid metabolizers of opioids.

Problems and more problems:

Even under ideal conditions – two people taking the same opioid drug at the same dose, at the same interval, and taking no other drug – huge variations of innate metabolism from one individual to another will necessarily result in a wide range in clinical response to that drug.

Conclusion

The CDC MME chart, in fact, the entire concept of morphine milligram equivalents may be convenient for bureaucrats but because of differences in the absorption of different drugs into the bloodstream, half-life of different drugs, the impact of one or more other drugs on opioid levels, and large differences of the rate of metabolism caused by genetic factors, is not only devoid of scientific utility, but actually causes far more harm than help by creating “guidelines” that are based upon a false premise.

When a policy is based on deeply flawed science, the policy itself will automatically be fatally flawed. It cannot be any other way.