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Making Practical Sense of Cytochrome P450

Guidelines for the likely 20 to 30% of pain patients who have a genetic defect involving one of three major CYP450 enzymes and so cannot effectively metabolize certain opioids that must be converted to a metabolite to be effective.
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How Common Are GOMDs?

GOMDs are much more common than is realized (see Table 2). To date there are no wide-scale testing surveys involving the three CYP enzymes most critical to opioid metabolism. A number of investigators including the major genetic testing laboratories, however, provide estimates of prevalence. Quest Laboratories, which is a national leader in genetic testing publishes, with each CYP450 test result, some estimates of genetic defect prevalence. For example, if you order a CYP-2C9, one of the two major enzymes for opioid metabolism that can be tested, you will receive a report that states “Approximately one-third of Caucasians, 2.8% of Asians, and 3-13% of Africans carry one or both of the variant alleles.” The prevalence statement written on a CYP-2D6 report states that abnormal metabolism of this enzyme is “5-10% of Caucasian individuals, approximately 2% of Asians, and 2-17% of Africans carry loss of function that result in the poor metabolizer phenotype.” If you consider these statements in light of the fact that the CYP-3A4 gene is far more involved in opioid metabolism and that there are likely some genetic defects in the non-CYP opioid metabolism system, it is reasonable to assume that 20-30% of pain patients have a GOMD.

Table 2. Opioid dosage and CYP enzyme deficiences
Enzyme Variation Opioid Dosage Laboratory
Terminology
Normal Normal Extensive metabolizer
Overactive High or ultra high because the enzyme continuously deactivates the opioid and thus lowers serum levels Rapid metabolizer
Underactive CYP enzymes are slow or “lazy" thus needing extra opioid dosage to “force” metabolism Intermediate
metabolizer
Inactive or Absent Won’t process opioid thus causing serum levels to rise and produce toxicity Poor metabolizer
Table 3. Quick Reference Metabolism of Opioids by Class and System

Pro-opioids that require conversion to an active metabolite
Codeine ---------------------->Morphine
Hydrocodone----------------------> Hydromorphone
Dihydrocodeine ---------------------->Morphine
Tramadol ---------------------->O-desmethytramadol

These opioids primarily rely on the enzyme CYP-2D6 to make the conversion.

Opioids that act directly on opioid receptors without the necessity of metabolic conversion


Fentanyl
 

 

Morphine Levorphanol Oxycodone
Hydromorphone Oxymorphone Propoxyphene  
Methadone Meperidine Tapentadol  
These opioids primarily rely on CYP-3A4, CYP-2C9, or glucoronidation (non-CYP) for metabolism to an excretable, non-active metabolite.
Common opioids that primarily rely on the CYP450 enzyme system for metabolism
Codeine Methadone Fentanyl Oxycodone Hydrocodone Morphine
Common opioids that bypass the CYP450 enzyme system and use glucoronidation for metabolism
Oxymorphone Tapentadol Hydromorphone
Note: Some opioids are converted to active metabolites and/or metabolized by a combination of CYP450 enzymes and non-CYP metabolism.

What Does The CYP System Do?

The CYP450 system, depending on the opioid being administered, performs one or two actions:

Table 4. Opioid Toxicity Symptoms with a Genetic Opioid
Metabolic Defect
Allergic Manifestation
Itching
Edema
Angio-edema
Wheezing
Anaphylaxis
Respiratory Impairment
Breathless
Stands and walks
Hyperventilation
Sudden weakness
Collapse
Cardio-pulmonary shut down
Note: the above symptoms may present if a GOMD or drug inhibits a CYP450 enzyme system. Emergency treatment may necessitate naloxone, epinephrine, corticosteroids, and respiratory support.

Types of CYP450 Opioid Metabolic Defects

There are three types of GOMDs that may exist in any one of the three major opioid CYP450 enzymes (see Table 2). They are inactive or absent, underactive, or over-active.7,8

The first type of defect is an inactive or absent enzyme that simply won’t metabolize the opioid thus leaving the opioid to be excreted in an unchanged form. The danger here is that an opioid that can’t be metabolized in a timely manner builds up in the serum. If opioid dosages are repeated, particularly in a non-tolerant person, there is the danger of opioid toxicity which are, primarily, allergic manifestations or respiratory depression (see Table 4). This mechanism is undoubtedly responsible for some if not most, of the numerous overdose deaths that have occurred since opioid prescribing for pain became so popular in the last decade.

The second type of defect is an enzyme that is over-active.4,10 Laboratories refer to this GOMD as a “rapid metabolizer." Fundamentally, the enzyme clears opioids from the serum too fast thus lowering the serum opioid concentration. This leaves the patient in pain and constantly needing additional opioids for relief. Also, each opioid dosage lasts only a short time. For example, a long-acting opioid that is supposed to last 12 hours may only last 4 hours.

The third type of defect is an underactive enzyme and is the most common CYP-2C9 defect found by the author in high dose opioid-maintained pain patients.5 Laboratories refer to this GOMD as an “intermediate metabolizer" (see Table 2). Think of this situation as a slow or “lazy" enzyme. When this GOMD is present, opioids clear the serum slowly leaving a high serum concentration which can be toxic. Apparently a high serum opioid concentration is necessary when this GOMD is present, however, to “force" the “lazy" enzyme to work.

Last updated on: September 27, 2017
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