Opioid Policies Based On Morphine Milligrams

Opioid Policies Based On Morphine Milligram Equivalents Are Automatically Flawed – By Josh Bloom — October 23, 2018

  • Calhoun, who died in 1989 at age 55, was 6’4″ and weighed 601 pounds
  • Dinklage, who is 4’5″ tall, weighs 110 pounds.

Now imagine that both Dinklage and Calhoun have headaches and need aspirin. The recommended adult dose for Bayer Aspirin is two 325 mg tablets every four hours.

Will this dose be suitable for both men?  

A website called Omni Calculator makes it possible to estimate the volume of blood in a person based on gender, height, and weight.

  • Plug in Haystacks and you’ll see that he had 12,019 mL (12.7 quarts) of blood in his body.
  • Do the same for Dinklage, and the number is quite different – 3,105 mL (3.3 quarts).

All things being equal, the concentration of aspirin in Dinklage’s blood would be four-times that in Calhoun’s from the same two aspirin tablets.

it is all but certain that two aspirin tablets are going to elicit very different physiological responses in each man.

While the comparison may seem silly, in today’s anti-opioid “one-size-fits-all” climate such a mindset has become the foundation for government-dictated medicine. And it’s very bad medicine.

The deeply flawed policies that are being enacted as law all over the country are based on the “one-size-fits-none” concept of morphine milligram equivalents (MME) – the maximum amount of an opioid medication than is permitted per patient per day.

While MME values are touted as useful predictors of the total “opioid load” that a patient can receive, they are nothing of the sort. And MME-based policies don’t just fail because of differences in the size of patients; they fail for multiple reasons.

Flawed science yields meaningless results

Although the conversion table seems to be straightforward enough, it is based on an assumption that all opioids behave similarly in the body.

But they don’t.

Once we see the profound differences in the properties of the drugs and the difference between individuals who take them it becomes clear that not only is the CDC chart flawed, but the MME is little more than a random number.

Not all opioids are created equal, especially in the body

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

Let’s take, for example, the two drugs at the bottom. Although Table 1 tells us that oxymorphone is twice as “strong” as oxycodone it does not take into account a number of critical properties that paint a more complete picture of the fate of the drug once swallowed. In other words, there is no information about pharmacokinetics –  the effect of the body on the drug.

Bioavailability

One of the many pharmacokinetic properties required to establish how a drug will fare within the body is called bioavailability – a critical determinant for whether a drug will be effective if taken orally.

Bioavailability is a measure of the how well an oral drug will be absorbed in the gut and subsequently enter the bloodstream

Conversely, when a drug has poor bioavailability, for example, 10%, then most of the drug will either pass through the intestinal tract unchanged or be absorbed but then rapidly metabolized.

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

Although critical, bioavailability is far from the only measure of an oral drug’s effect on people or animals. Table 2 shows three of the most common pharmacokinetic properties of oxycodone and oxymorphone.

Two other critical parameters are half-life and metabolism.

Table 2. Three pharmacokinetic parameters of oxymorphone (right) and oxycodone (left). Source: Ref. (a). Ref. (b).

Table 2 clearly shows that oxycodone and oxymorphone, although putatively similar, will behave very differently in people.

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).

Additionally, there are differences which liver enzymes carry out the metabolism.

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?”

When other drugs and other pharmacokinetic properties are added to the mix It becomes patently obvious that the simplistic CDC chart provides us with numbers that are little more than artifacts.

Polypharmacy: People take more than one medication

The primary site of drug metabolism is the liver. Within the liver, there are different families of metabolizing enzymes.

By far, the most important class in humans is the CYP450 family (6) of enzymes. There are about 60 members in this class and these account for about 75% of the metabolic processes that occur within our bodies.

Two of the most important members (also called isozymes) of this family are called CYP3A4 and CYP2D6. These two are responsible for metabolizing many common drugs, including opioids.  

While Table 2 showed that even two very similar drugs will behave differently in the body when other common drugs are thrown into the mix the variability of opioid blood levels becomes even greater; opioid-metabolizing enzymes are affected by other drugs.

Figure 3. Drug-drug interactions of selected opioids with some common drugs. Source: J. Pruskowski and R. Arnold, Opioid Pharmacokinetics #307, Journal of Palliative Medicine Vol. 19, No. 6 (2016). doi.org/10.1089/jpm.2016.0024

Some highlights from Figure 3 include:

  • Of the six opioids listed, five of them are metabolized by both 3A4 and 2D6. Morphine is not metabolized by 3A4.
  • The 3A4 isozyme is inhibited by many drugs, including antibiotics, antifungals, antidepressants. blood pressure drugs, and HIV antivirals. The presence of any of these drugs will either result in higher than expected opioid blood levels, an increased half-life, or both. Inhibitors of 3A4 will increase blood levels of the opioid (except for morphine – it is not metabolized by 3A4), sometimes causing dangerously elevated levels of the opioid.
  • The 3A4 isozyme is also induced by other common drugs, such as anti-inflammatory steroids, HIV antivirals, anti-seizure drugs, and a tuberculosis drug. The presence of any of these drugs will either result in lower than expected opioid blood levels, a decreased half-life, or both. This can result in opioid levels that are inadequate for pain relief.
  • The 2D6 isozyme is inhibited by many of the same drugs that also inhibit 3A4 but also others, including those for allergies, malaria, and schizophrenia.
  • But the 2D6 isozyme is not induced by any of these commonly used drugs.

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. Table 3 shows the range of variation of the rate of metabolism of four CYP enzymes between individuals.

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 the drugs.

It is this genetic variability that is responsible for both poor metabolizers and rapid metabolizers of opioids.

For example, if the rate of metabolism by CYP34A of Patient A is 100-fold greater than that of Patient B, it is impossible to define a standard dose, such as those in Table 1, which would be therapeutically correct for either A or B and probably both.

Patient A will appear to have developed a tolerance for the opioid while Patient B will be far more sensitive to the drugs.

A standardized dose will be too low for Patient A and too high for Patient B.

Problems and more problems:

the following are obvious:

  • Some opioid drugs will be absorbed and pass to the bloodstream very well and some will do so very poorly.
  • Even opioids that appear to be structurally and functionally similar will be metabolized at very different rates.
  • Other drugs can drastically alter the physiological response of a pain patient to a given opioid; the second drug may increase a person’s response to the opioid or it may decrease it.
  • Even under ideal conditions – two people taking the same opioid drug at the same dose, at the same interval, and take 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 convenientfor bureaucrats

All the people in all the agencies are using

Milligrams of medication is the only objectively measurable value in pain management, while the reason for prescribing those milligrams is lost.

…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.

Policy Recommendations:

The author lists 10 very sensible policy recommendations – here are only the first four:

  1. The 2016 CDC Guideline for Prescribing Opioids for Chronic Pain and all its findings should be immediately withdrawn.
  2. A new set of guidelines must not be unilaterally formed by a single agency, especially the CDC, which lacks the chemical and pharmacological insight and knowledge to formulate a policy regarding drug use.
  3. The FDA has a far greater knowledge base about drugs and pharmacology and should form a task force composed of in- and outside pharmacologists, chemists, pain management physicians, neurologists, primary care physicians, surgeons, and pain patients.
  4. The task force should formulate a science- and medicine-based set of recommendations that are focused on treating and preventing pain, not stopping addiction – an endeavor that been shown time and time again to make matters only worse.

I think this was the fundamental problem with the CDC guideline: its purpose was to prevent addiction, not pain.

Though opioids are medically necessary for pain control, the guideline to using them was created by people and groups whose only goal was to reduce (and even eliminate) opioid prescribing, even though the overdoses were and are from the addition of other drugs contaminated with fentanyl.

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