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10 Articles in Volume 12, Issue #7
August 2012 Pain Research Updates
Cash Patient: A Clinical Dilemma
Common Opioid-Drug Interactions: What Clinicians Need to Know
Compliance in Pain Patients: Balancing Need to Test With Need to Treat
Cytochrome P450 Testing In High-dose Opioid Patients
Discharging a Patient Suspected of Diversion
Examining the Safety of Joint Injections In Patients on Warfarin
Genomic Medicine
Letters to the Editor from August 2012
Minimally Invasive Spine Surgery— Who Can it Help?

Cytochrome P450 Testing In High-dose Opioid Patients

Severe, chronic pain patients who seek opioid dosages above normal standards should now be tested for genetic cytochrome P450 deficiencies.

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

Table: Metabolism of opiods

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

Table: Opioid dosage and CYP enzyme deficiencies

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.

Table 3: CYP450 enzymes to be tested

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.

Since opioids clearly appear to use the CYP450 system, as opposed to a single enzyme, every enzyme need not be tested to detect an abnormal system.4-6 Based on the author’s experience, these three enzymes will identify a high percentage, if not the majority, of patients who have a defective opioid metabolizing system and require a high opioid dosage. Also, many high-dose opioid patients have multiple defects in their CYP450 opioid-metabolizing system, and testing of these three CYP450s can identify many of these individuals.

CYP-3A4, another major metabolic enzyme, is less likely to have variations than the three cited above. Although it is known to be involved in opioid metabolism, commercial testing is just becoming available and the quality of the testing is not yet clear.15-19 The author has used commercial testing of CYP-3A4, but has not yet found it to identify patients who have a defective CYP system that could not have been identified by testing 2D6, 2C9, or 2C19. Consequently, testing for 3A4 is not recommended at this time.

Test Results
A deficiency of any one of the three enzymes will require clinical interpretation and judgment as to which opioids should be prescribed. Most pain patients who have a CYP defect will require higher-than-normal opioid dosages or an opioid that does not use the CYP system.1,7

There are only a few basic guidelines regarding the selection of opioids. If a patient is a PM (90% to 100% reduced function) of CYP-2D6, for example, codeine, hydrocodone, tramadol, or low-dose oxycodone may not be as effective as other choices because this enzyme is required to activate or convert these four opioids to active metabolites.3,11 The opioids fentanyl and methadone can be affected at least to some degree by abnormalities of the CYP enzyme system and potentially require a higher-than-normal dosage.4,15,17-19

An IM designation usually means that the enzyme is functioning at a reduced capacity (about 50% reduced function). Individuals carrying the IM designation will metabolize opioids, but are underactive and require a high dose to prime or force metabolism. An individual who carries the UM gene is likely to metabolize opioids too quickly; thus, potentially requiring a higher dose.

Although in vitro or animal studies may suggest that an opioid is more prone to be metabolized by one of the three enzymes tested, clinical observations in patients suggest that these three enzymes interact with each other and any defect in any enzyme clinically appears to affect opioid metabolism. There is also great variability between patients. It is clear, however, that any defect in the CYP450 enzyme system may require high or altered opioid dosing, or consideration for alternative opioid or analgesic therapy.

More important than attempting to select an opioid in an uncertain CYP450 system is to always start opioids at a low dosage and titrate the dosage upward.

Genetic Characteristics And Diseases
One genetic defect tends to beget another. In my experience, patients with a genetic disease such as ankylosing spondylitis, Ehlers-Danlos syndrome, sickle cell anemia, and immunologic disorders seem to have a high prevalence of CYP450 deficiencies.24 (See Figures 1 and 2 for case examples.)

Patients with CYP450 defects tend to report that they have a history of requiring extra dental or surgical anesthesia.2 They may also shun alcohol as they may have a toxic reaction to it—alcohol requires the CYP450 system to convert to acetaldehyde, the non-toxic metabolite. Other patients with CYP450 defects report they must drink excessively to get “high” or they may become violently ill with vomiting and even black out.2

Figure: woman with congenital, severe elephantiasisFigure 2: Woman with systemic lupus erythematosus

Study Results
To help provide CYP450 testing guidelines, I studied 66 intractable pain patients who take at least 150 mg equivalent of morphine each day. An intractable pain patient is defined as one who has constant pain due to a condition that has no known cure, and has failed to respond to standard pain treatments including standard opioid dosages. These patients attended the author’s clinic on four consecutive days in May 2012. DNA samples were collected by use of a buccal swab and analyzed by one commercial laboratory (Genelex, Seattle, Washington).

All the patients in the study were believed to have “centralized” their peripheral pain. All were initially referred to this specialty clinic after failing to respond to standard opioid dosages, as well as such ancillary measures as corticosteroid interventions, electromagnetic measures, surgery, physical therapies, and medical management with neuropathic agents. All patients enrolled have a primary care physician, and family members must be involved and attend office visits with the patient. All patients were on stabilized opioid dosages for at least three months. Patients and family members attested that every patient was functional, ambulatory, non–bed-bound, and able to carry out normal activities of daily living such as dressing, eating, and toiletry. At the time of testing, patients were asked if they had ever taken hydrocodone, codeine, or tramadol—three agents known to be metabolized by CYP450—and whether they experienced pain relief with them.

Of the 66 patients, 55 (83.3%) were found to have one or more CYP450 defects. This is a much higher prevalence of defects than found in the general population, which is estimated at 20% to 30%.25 An examination of the individual cases found that 21 of the 66 patients (31.8%) had two CYP450 defects, and an additional 6 patients (9.1%) had three CYP450 defects.

Table 4 provides the results for each individual patient. Please note that patients had widely varied responses to hydrocodone, codeine, and tramadol, despite having a defective CYP450 system. The literature states that CYP-2D6 is a significant component for the metabolism of these three drugs.6,9,11 This information, however, is primarily derived from in vitro or animal studies. Until there is more elucidation of enzyme specificity in humans, the author recommends that the three CYP450 enzymes tested here be viewed as one interconnected system. Any single defective CYP450 enzyme may disturb normal opioid dosing and metabolism. Put another way, any defect in CYP-2D6, 2C19, or 2C9 should prompt the practitioner to be prepared to use a non-standard and/or high-dose opioid regimen.

Table 4: CYP450 deficiencies in 66 patients who take high-dose opioidsTable 4: CYP450 deficiencies in 66 patients who take high-dose opioidsTable 4: CYP450 deficiencies in 66 patients who take high-dose opioidsTable: CYP450 Deficiencies in 66 Pain Patients Who Take High-dose OpioidsTable 4: CYP450 deficiencies in 66 patients who take high-dose opioids

Limitation of the Study
As noted in Table 4, some patients did not show a CYP450 defect in the three enzymes that were tested. This does not mean they do not have a genetic defect. Such defects that do not currently have a diagnostic test include abnormalities in glucuronidation, gastrointestinal absorption, and receptor-site density. Also, there are many gene polymorphisms related to neurotransmitters, non-opioid receptors, and nerve conduction that may influence pain sensitivity and analgesia.24

Centralized pain (defined as pain that starts in the periphery and later transforms into pain imprinted in the CNS) is likely present in most patients who require a high opioid dose.26 The mechanism is probably a loss of CNS opioid receptors. Centralized pain is produced by glial cell inflammation that leads to tissue destruction including opioid receptors. With fewer receptors available, a high opioid dosage may be necessary to continually bind to, and trigger, remaining receptors. It may well be that some patients require a high opioid dose due to centralized pain or other factors independent of, or in combination with, their CYP450 defect.12,24,26 It is probable that multiple factors prevail in many patients who require a high opioid dosage.24

It is important to point out that all patients who have a CYP450 abnormality do not require high opioid dosages. Also, the author has now observed many patients with CYP450 defects reduce their opioid dosage to low levels when the patient’s pain is adequately controlled. Pain severity and opioid dosage are separate biologic entities that must always be independently evaluated. The finding of a CYP450 abnormality simply tells all parties that a high opioid dose may be necessary and, at least partially, is the result of genetic deficiencies.

Summary
A high percentage of chronic pain patients who require a high opioid dosage of more than 150 mg of daily morphine equivalents have defects in their CYP450 system. Some patients have multiple CYP450 defects, as well as centralized pain, which may contribute to the necessity of a high opioid dosage.26 It is now possible to commercially access tests for three key CYP450 enzymes—2D6, 2C9, and 2C19—which are critical for opioid metabolism. Pain patients who don’t respond to standard opioid dosages and consequently demand a higher dose, as well as current patients who take above 150 mg per day of morphine equivalents, should be genetically tested. If CYP450 abnormalities are present, a clinical effort should be made to utilize hydromorphone, oxymorphone, or tapentadol as these opioids are primarily metabolized by glucuronidation, the alternate opioid metabolism system. Pain patients, particularly those with multiple CYP450 defects, may have to use non-oral administration routes such as injections, sublingual, buccal, or intrathecal routes to bypass liver metabolism. Since CYP450 testing is now available, no pain patient who seeks a higher opioid dosage should be pejoratively labeled as a drug seeker until testing is done. CYP450 testing should now be done routinely to help establish that a chronic pain patient may legitimately require a high opioid dose.

Last updated on: October 26, 2012
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