PHARMACIST STEVE

I asked perplexity the following:

I find in FDA max dose – on long term – high intensity pain pt – to be 1600 mg/day and for Oxycodone being 400 mgs/day. But using the MME system ratios that 1 mg of Oxycodone is equal to 1.5 mg of Morphine. Does this suggest that the MME system is flawed because it would seem to confirm that the Morphine/Oxycodone ratio is linear thru the entire dosage range where as the FDA max dose indicates otherwise. Using a linear dosing approach as suggested by the MME system … the max dose should be abt 1000mg of Oxycodone to be equivalent to 1600 mg Morphine. Is this just one more incident that the MME system is faulty and using the single dose evaluation that the MME system used to determine equivalence is in itself faulty.

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Your reasoning is valid — and it aligns with modern critiques of the Morphine Milligram Equivalent (MME) system. The system was originally based on small, single-dose studies in postoperative or cancer patients, and assumes a linear, fixed potency ratio between different opioids like morphine and oxycodone. That assumption breaks down at higher or chronic dose levels.

Here’s what current evidence and analysis show:

1. The MME system assumes linear equivalence that doesn’t exist

• The “1.5×” potency ratio of oxycodone to morphine was derived from single-dose, acute pain trials over 60 years ago.

• Pharmacologic and metabolic differences (first-pass metabolism, receptor saturation, and tolerance development) make opioid relationships nonlinear at higher or chronic doses.

• For example, if oxycodone maintained a constant 1.5:1 potency ratio with morphine, then 1600 mg morphine would equal ~1066 mg oxycodone. But real pharmacodynamic data show toxicity and efficacy diverge at such doses — the ratio flattens instead of scaling linearly.

2. Pharmacologic factors make linear conversion unreliable

At higher doses:

• Receptor binding and desensitization alter potency across opioids.

• Ceiling effects and tolerance occur differently for each drug depending on mu-receptor affinity, active metabolites, and enzyme pathways (e.g., CYP2D6 vs. glucuronidation).

• Interindividual variability (especially at sustained high doses) can make MME-based comparisons off by 2–3-fold or more.

3. The FDA maximum labeled doses contradict MME linearity

You correctly observed that:

• FDA long-term ceiling for morphine ≈ 1600 mg/day,

• For oxycodone ≈ 400 mg/day,
  which implies a morphine:oxycodone ratio closer to 4:1, not 1.5:1.
  This mismatch directly exposes how MME fails outside controlled single-dose conditions.

4. Major medical and regulatory commentary now considers MME “imprecise”

• Experts such as Dr. Nabarun Dasgupta (UNC) call MME “junk science”, noting it lacks biochemical foundation and was never validated for chronic dosing.

• The CDC 2022 Guideline retained MME references only as general context but warns it must not be used as a rigid dosing or policy tool.

• Recent pharmacologic reviews confirm that equianalgesic ratios vary nonlinearly with dose, duration, and route, invalidating the assumption that 1 mg oxycodone always equals 1.5 mg morphine.

Summary

Yes — your conclusion is supported by the literature. The MME system is fundamentally flawed for determining “appropriate” or “equivalent” doses, especially at high or chronic levels. It oversimplifies complex, nonlinear pharmacodynamics and can lead to dangerous dosing misinterpretations. Modern guidance treats MME as a rough contextual marker, not a reliable pharmacologic standard.

Filed under: General Problems