…and there is good reason for this. To believe otherwise is indeed credulous. Although I will introduce scientific reasons to support that one person’s 100mg morphine equivalent dose is another person’s 200mg morphine equivalent dose, I will start by looking at it in simplest terms.
In the most straightforward example, consider that a single opioid dose in a 150 pound person may not achieve the same benefit or toxicity as it would in a 300 pound person – and believe me, I have plenty of patients in each of these categories. By example, consider the sweet taste of 1 teaspoonful of sugar in a 4 ounce cup of coffee versus 1 teaspoonful in an entire pot. Surely the least concentrated pot with just 1 teaspoonful of sugar will be bitterer (more pain for the heavier patient).
From a scientific perspective, the amount of active drug in the blood may be more or less, depending on how the body processes or metabolizes the drug. This is not the same from patient to patient, and in fact can be explained by various patient phenotypes. This is something that can be easily determined in patients by employing pharmacogenetic testing. In fact, an entire science known as pharmacogenomics has evolved that helps explain why some patient might respond better or worse to one drug (or a particular dose) compared to another drug. In short, pharmacogenetics variability could explain why a single drug could cause different patients on the same dose of the same drug (identical height, weight, and gender) to have efficacy with toxicity; efficacy with no toxicity; no efficacy and no toxicity; or no efficacy and significant toxicity. Seems crazy right? Not really, especially if you’re the patient or the clinician trying to justify an unusual dose or third tier drug option!
Different opioids undergo different metabolic pathways. Some are metabolized to more active drugs, some are metabolized to less active drugs, some are metabolized to inactive drugs, and others are metabolized to all or some of the above. There are individual enzymes in the liver known as cytochrome P450 enzymes, abbreviated CYP 450. The most common of the enzymes for opioid metabolism are 2D6, 3A4, and 2B6.
Select examples of liver enzyme Phase I metabolism:
Codeine (no activity) (2D6) –> morphine (more potent and active)
Codeine (no activity) (3A4) –> norcodeine (inactive)
Hydrocodone (active) (2D6)–> hydromorphone (more potent and more active)
Hydrocodone (active) (3A4) –> norhydrocodone (far less potent and less active)
Oxycodone (active) (2D6)–> oxymorphone (more potent and more active)
Oxycodone (active) (3A4) –> noroxycodone (inactive)
Patients may be one of the various phenotypes for each of these enzymes (2D6, 3A4) above and they can be a different type for each enzyme:
Poor metabolizer – Intermediate metabolizer = Extensive metabolizer (considered normal, with two wild type alleles) – Ultra-rapid metabolizer
- Imagine then what could happen if a patient was an ultra-rapid metabolizer of 2D6 and given codeine. They would convert the codeine rapidly to morphine and in fact this has been responsible for deaths in infants that ingested breast milk from an ultra-rapid 2D6 metabolizing mom.
- Imagine what would happen if a patient was a poor 2D6 metabolizer and couldn’t convert oxycodone to its more active form of oxymorphone (it wouldn’t work as well).
- Imagine then what could happen if a patient was an ultra-rapid metabolizer of 2D6 and given oxycodone, and at the same time was prescribed erythromycin which is a potent inhibitor of 3A4 – this would result in much higher levels of oxymorphone that could be toxic because degradation to the less active oxycodone metabolite, noroxycodone is blocked.
Aside from all this, the drug needs to combine to an opioid receptor. OPRM1 (Opioid Receptor Mu-1) is a gene that codes for the mu opioid receptor which is where endorphins and opioids combine to cause analgesia and euphoria. Depending on the patient’s genotype or OPRM1 variability, this too could affect one’s ability to respond to opioid therapy. If there’s minimal OPRM1, the patient will be a poor responder; if there’s an overabundance, the patient will respond to a lower opioid dose or could overdose more easily.
There are many more enzymes involved and various phases to opioid metabolism. In fact, the oral absorption or lack thereof is often dependent on yet another enzyme known as abcb1 (p-glycoprotein). This same enzyme is responsible for carrying some opioids across the blood brain barrier. Not only is this variable among patients, but like the CYP 450 enzymes outlined above, it is variable among patients. Even more of an issue is that production or inhibition of these enzymes occurs with certain drugs. For example, the Hepatitis C drug telaprevir can enhance methadone absorption from the gastrointestinal tract and also enhance absorption into the brain. This could happen within 48 hours of taking a single dose of newly prescribed telaprevir. And we wonder why so many people die from methadone – it is not just about “overdosing” by taking too much. It is far more complex!
So there you have it. Although this is a very narrow and simplistic overview, it is intended to demonstrate reasons why not everybody responds to or tolerates the same drugs or the same dose. There are of course many other factors related to the drug chemistry, type of pain, and much more. But the drug interactions and pharmacogenetics variability described herein is at least a starting point for our blog followers.
As always, comments are welcome!