Defective Opioid Metabolism in Pain Patients

Here are two more articles about the great variety in individuals’ ability to metabolize opioids (and a list of 6 previous posts about this), which leads to great variety in the pain relief they achieve from opioids.

This is the scientific arguments against the CDC opioid guidelines and other such “standards” limiting opioid doses to some arbitrary standard.

Genetic Mutations in Cytrochrome P 450 2D6 – P1 – Practical Pain Management – March 2014

The majority of opioid medications are metabolized by one or more of the CYP450 isozymes.  

In terms of CYP 450-related drug metabolism, there are 9 CYP isoenzymes of known clinical importance and they are referred to as CYP-1A2, CYP-2B6, CYP-2C9, CYP-2C18, CYP-2C19, CYP-2D6, CYP-2E1, and CYP-3A4.

Of those drugs that undergo liver metabolism, a specific CYP enzyme (or a combination of enzymes) is responsible for each drug’s metabolism. Pharmacogenomic testing can be used to assess the activity of CYP450 isozymes (3A4, 2C9, 2C19, 2D6) prior to administration of an agent to predict a patient’s response

A poor metabolizer of CYP2D6 will not be able to metabolize certain opioids in the liver, resulting in an increase in the blood level of the parent drug and a decrease in its metabolites. These individuals have a tendency to become toxic on the “usual” doses of medications.

Opioid drugs most affected by CYP2D6 include:

  • codeine,
  • hydrocodone, and
  • tramadol.

The following opioids are also affected by CYP2DC, but may provide some pain relief when given at higher dosage:

  • oxycodone,
  • meperidine, and
  • methadone.

Many patients with cytochrome P450 defects must resort to opioid drugs that do not utilize the cytochrome system for drug metabolism, but use an alternative system referred to as Phase-2 metabolism, or glucoronidation.

There are 4 opioid drugs that do not use the cytochrome system:

  • morphine,
  • hydromorphone,
  • oxymorphone, and
  • tapentadol.

Another option is to use an alternative route of administration, such as transdermal patch (ie, fentanyl and buprenorphine), which bypass the first pass (Phase One) effect and generate significantly fewer metabolites. Metabolite levels can rise, however, with long-term application of patches.

The major message about cytochrome P450 genetic testing is that patients who are not getting good pain relief should be tested.

Remember, genetic testing need only be done once. With the test results in hand, a knowledgeable pain practitioner can select a pain reliever that is effective.

Forest Tennant, MD, DrPH

Need for High Opioid Dose Linked to CYP450 – Practical Pain Management – September 25, 2012

Patients with chronic pain who require high doses of opioids to achieve pain relief show exceptionally high rates of defects of the cytochrome P450 (CYP450) enzyme system compared with the general population.

The CYP450 enzyme system is known to play an important role in the metabolism of opioids, and recent advances in genetic testing allow for the easy detection of defects to the enzymes.

We’ve known for years that among patients with the exact same pain conditions one may need 500 mg of morphine a day while the other may need only 50 mg, but we’ve always wondered why,” lead author Forest Tennant, MD, told Medscape Medical News.

“It turns out that among high-dose patients, about 85% have these defects in 1 or more of their CYP450 enzymes.” In the general population, only about 20% to 30% of people have CYP450 defects, he said.

To evaluate patterns among his own patients with intractable pain, Dr. Tennant tested 66 patients attending his clinic in West Covina, California, who required more than 150 mg equivalence of morphine a day for pain relief.

The patients were tested specifically for the CYP2D6, CYP2C9, and CYP2C19 enzymes. The results showed that 55 (83.3%) of the 66 patients had 1 or more CYP450 defects, 21 (31.8%) had 2 defects, and 6 (9.1%) had 3 defects.

“Pharmacogenomics represents the emerging frontier for understanding interindividual variability in opioid efficacy and toxicity, and in guiding safe and effective opioid pharmacotherapy

With regard to opioid response, the mu-opioid receptor, the ATP [adenosine triphosphate]-binding cassette subfamily B, and other genes are believed to play significant roles,” he explained.

With CYP450, a “superfamily” of enzymes responsible for the metabolism of most opioids, various polymorphisms and variables in activity can have clinical significance the agency said. “The three children who died after taking codeine exhibited evidence of being ultra-rapid metabolizers.”

The enzymes, for instance, have been implicated as playing a role in the overactive metabolism of codeine. In a recent case, the US Food and Drug Administration (FDA) in fact issued a warning about the risks associated with codeine after 3 children died and a fourth child nearly died after having been administered codeine following tonsillectomy and adenoidectomy.

“Once in the body, codeine is converted to morphine in the liver by an enzyme called cytochrome P450 isoenzyme 2D6 (CYP2D6) (and) some people metabolize codeine much faster and more completely than others,” the FDA wrote in a statement.

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