Cytochrome P450 Testing In High-dose Opioid Patients
While it is common knowledge that the cytochrome P450 (CYP450) enzyme system is critical for the metabolism of some opioids, genotype testing of pain patients for CYP450 polymorphism has not been generally recommended.1,2 This situation, however, may change as pain specialists begin to recognize that patients who require high doses of opioids may have a genetic defect that may affect their ability to metabolize these agents.
In the past, genotyping for CYP450 polymorphisms was not cost effective or convenient. However, testing technology, commercial availability, third-party reimbursement, and most of all, clinical understanding, have recently coalesced to make CYP450 genetic testing an essential component of high-dose opioid therapy. It is my recommendation, therefore, that patients who require more than 150 mg per day of morphine equivalents be tested for three specific CYP defects—2D6, 2C9, and 2C19.
To study the validity of genotype testing, I prospectively studied 66 patients on high-dose opioids in my pain clinic. The study found that the vast majority of these patients had CYP450 defects.
What Is CYP450?
Although the name cytochrome P450 is somewhat unfortunate—perhaps a better name would have been “drug metabolizing enzyme system”—the enzyme derives its name from the heme pigment (deep red color), which absorbs light at a characteristic wavelength of 450 nanometers. CYP450 enzymes are primarily found in the liver, but can exist in the intestine, lungs, brain, and kidney. The CYP450 system consists of 481 separate genes that code for 74 unique families. A family name is denoted by an Arabic number, the subfamily by a Roman uppercase letter, and the individual enzymes by another Arabic number following the letter indicating the subfamily (ie, CYP-2D6).3-5
Why Is CYP450 Important?
There are a number of opioids that are affected by CYP450 (Table 1).6-20 Those that are metabolized via CYP enzymes include codeine, hydrocodone, oxycodone, tramadol (Ultram), fentanyl, and methadone. Some of these opioids are metabolized to metabolites for analgesic effectiveness and for elimination from the body to prevent a toxic build-up of opioids. Those opioids that are unaffected or mildly affected by CYP450 include morphine, hydromorphone, oxymorphone (Opana), and tapentadol (Nucynta).6-19 Three opioids—hydromorphone, oxymorphone, and tapentadol—primarily use the alternate system, glucuronidation, for metabolism, so they may be used as therapeutic alternatives for clinical trials in patients who have defective CYP450 metabolism.1,20
Patients vary in their CYP enzyme expression and function, which leads to distinct phenotypes. Genetic CYP testing has a terminology that may be unfamiliar to some medical practitioners.4 Laboratory results will list patient results as extensive metabolizer (EM; normal enzyme), rapid or ultrarapid metabolizer (UM; overactive enzyme), intermediate metabolizer (IM; underactive), or poor metabolizer (PM; inactive or minimally active). The latter two, IM and PM, mean the enzyme has decreased function (Table 2).21
It is also important to point out that most opioids will act without biotransformation at the opioid receptor, and provide pain relief without being metabolized by the CYP or glucuronidation system. However, some opioids are robustly metabolized in first-pass effect. This explains the increasing utilization of sublingual, buccal, patch, subcutaneous and intravenous injection, and intrathecal routes for opioid administration, since these non-oral routes allow either greater opioid effect or reach the central nervous system (CNS) prior to entering the liver.
Who Should Be Screened?
No published guidelines yet exist for generalized testing of the CYP system outside of certain populations (specific cancers, patients requiring anticoagulation, and human immunodeficiency virus patients). A major reason to perform CYP450 genetic testing is to identify pain patients who legitimately require a high-dose, or unusual, opioid regimen.2,22 This includes patients who continually complain of inadequate pain relief despite standard opioid dosages, identify drugs that are more effective, or describe medicines that do not work well. Patients with a daily morphine equivalent dosage requirement of more than 150 mg per day should be tested to help validate that a high opioid dosage is needed. Caution must be exercised, however. All too often, these patients may be erroneously labeled as drug seekers or addicts. Before these labels are applied to a patient in pain, CYP450 testing should be considered.
Another reason to consider testing is the risk of drug–drug interactions (DDIs). A significant number of drugs may inhibit or enhance (induce) the activity of certain agents, thereby increasing or reducing clinical effects of drugs. Most DDIs involving opioid medications involve CYP450 inhibitors, which cause an increased level of opioids in the system—thus, placing a patient at risk of sedation, respiratory depression, and possible toxic effect.1,10,13
CYP450 testing also may guide the practitioner in the selection of opioids that are compatible with a patient’s genetic status. For example, a patient with a CYP-2D6 defect may not respond well to codeine, which is considered a prodrug with the active metabolite morphine. Therefore, the efficacy and safety of codeine as an analgesic are governed by CYP-2D6 polymorphisms. Codeine has little therapeutic effect in patients who are CYP-2D6 PMs, whereas the risk of morphine toxicity following codeine administration is higher in UMs.23
Since the CYP450 system is primarily liver-based, routes that avoid oral administration and first-pass liver metabolism may be an option in certain populations. This is particularly true in patients who demonstrate multiple CYP defects. Non-oral routes include sublingual, buccal, suppository, injection, topical (patches), and intrathecal.
Three CYPs to Test
Of all the enzymes in the CYP family, researchers have identified three that account for a significant amount of opioid metabolism and may currently be tested—2D6, 2C9, and 2C19 (Table 3).1,3,12 These three enzymes have been intensively studied and there are now data detailing their interactions with numerous drugs.1,4 Laboratory testing technology is reliable for these three enzymes, and third-party carriers, including Medicare, are now paying for these tests. Biologic samples for analysis can be taken from saliva, blood, or a buccal swab.