Making Practical Sense of Cytochrome P450
If you’re not somewhat confused by all the background noise regarding cytochrome P450 (hereafter CYP) opioid metabolism, drug interactions, and overdoses, you stand singularly alone among your fellow physicians. Given a few critics condemning opioids as sinister, some pharmaceutical companies claiming their opioid avoids the evils of drug interactions, and some Government Agencies scolding just about everybody over opioid overdoses, you should naturally have a little bewilderment as to what the facts may be and what your practical actions should be. At the request of the publisher of Practical Pain Management, I am attempting here to summarize the scientific evidence and develop some simple, quick, practical guidelines regarding genetic opioid metabolic defects (GOMD). While some knowledge about how the CYP450 enzyme system metabolizes opioids is essential, the major, critical point is that opioid-prescribing practitioners need to know that GOMDs are relatively common and can usually be diagnosed or at least suspected by history. Rather than attempt to laboratory test every patient for CYP450 defects, the practitioner can almost always suspect a GOMD and develop an appropriate clinical regimen by asking a few screening questions that are given here in Table 1. When a GOMD is suspected there are a few do’s and don’ts that can prevent opioid toxicity and overdose and simultaneously get better therapeutic results. A major goal of Practical Pain Management is to help prescribers of opioids to do it safely and with confidence.
Critical Reasons to Diagnose a “Genetic Opioid Metabolic Defect” (GOMD)
Rather than know the intricate details of the CYP system and opioid metabolism, the practitioner who prescribes opioids really wants to know if the patient has a GOMD. There are three characteristics that GOMD patients may present or exhibit:
Laboratory, genetic testing for the CYP450 enzymes primarily involved in opioid metabolism is not a practical, routine endeavor at this time. Testing should be reserved for limited circumstances. We now know enough about the functions of CYP450 enzymes as they relate to opioid metabolism, however, to ask some simple screening questions of pain patients that will provide the practitioner with enough information to make a “suspicious” or “probable” diagnosis of GOMD (see Table 1). Rationale for the screening questions are given below.
Exactly What Is Cytochrome P450?
The name is somewhat unfortunate and non-descriptive. It could have been more understandable if the name was simply “drug metabolizing enzyme system.” Nevertheless, the enzyme name is derived from a heme pigment which absorbs light identical to that of chrome which has a wavelength of 450 nanometers. CYP450 enzymes are primarily found in the liver but some exist in the intestine, lungs, brain, and kidney. The CYP450 system consists of 481 separate genes which code for 74 unique families. A family name is denoted by an arabic number (e.g., CYP-2), the subfamily by a Roman uppercase letter (e.g., CYP-2D), and the individual enzymes by another arabic number following the letter indicating the subfamily (e.g., CYP-2D6).7,8
1. Have you ever taken hydrocodone (Vicodin®, Lortab®, or Norco®)? o Yes o No o Never Taken
2. Have you taken a pain reliever with codeine in it (Empirin®, Fiorinal®, Fioricol®)? o Yes o No o Never Taken
3. Have you ever taken tramadol (Ultram®)? o Yes o No o Never Taken
4. Have you taken oxycondone (Percocet®, Oxycontin®), methadone, fentanyl (Duragesic®), or hydrocodone (Vicodin®, Lortab®, Norco®) and had any of the following reactions within 30 minutes after taking your first dose?
5. Were you ever told that you are allergic to a pain relief medication? If so, which one(s)?
6. When you had surgery, dental work, delivery, or other medical procedure, did your doctor tell you that you needed extra anesthesia or pain relief medication? o Yes o No o Some
7. Have you always had to take a high dose of pain medication to get relief? o Yes o No
8. Do you have a close relative who is either allergic to a pain medication or finds that he or she does not get pain relief with opioids?
9. When you took your first drink of alcohol as a teenager or young adult did you experience the following?
10. When you had alcoholic drinks before you became a pain patient, compare your intake to your friends.
11. Do you have a genetic or inheritable disease that is the cause of your pain? o Yes o No
12. Have you ever had a severe reaction to any of the following:
Three Key CYP450 Enzymes
Out of over 50 CYP450 enzymes, only three account for over 90% of opioid metabolism: CYP-3A4, CYP-2D6 and CYP-2C9.9-12 Pain practitioners who prescribe opioids must understand some basics of these three enzymes. CYP-3A4 is the major hepatic enzyme for opioid metabolism accounting for 40 to 60% of all opioid metabolism.7,8 Unfortunately, there is not yet a widely available commercial test for CYP-3A4 but the other two, CYP-2C9 and CYP-2D6, can be tested for genetic defects which are technically referred to as “polymorphism” since the alleles on the gene may be altered or absent. Fortunately, unique characteristics and new knowledge regarding these three enzymes provide some simple screening questions that allow the opioid prescriber to have a high index of suspicion that a GOMD of the enzyme exists in a patient.