Genetic Screening for Defects in Opioid Metabolism: Historical Characteristics and Blood Levels
There continues to be great interest in the study of genetic defects of chronic pain patients who have difficulty metabolizing opioids. This is especially true as more and more pain patients are requiring high opioid dosages
and/or an unusual regimen.1,2
According to one report, one-third of the Caucasian population in the United States has a genetic defect in the cytochrome P450(CYP450) enzyme system.3 Even if this figure is high, the pain practitioner must suspect that a high percentage of their patients will have a genetic defect in opioid metabolism. These patients will, therefore, require high doses of opioids and/or an “odd” regimen of drugs, which will inevitably include an opioid combined with at least one other drug class, such as benzodiazepines, stimulants, or anti-depressants.
Due to the high cost of analyzing blood for CYP450 abnormalities, routine blood testing is not a practical clinical tool at this time. Therefore, I’ve developed a simple screening tool to help identify patients with possible CYP450 abnormalities. This screening tool is based on the study of 9 intractable pain patients with laboratory-confirmed CYP450 defects. Although imperfect, these simple tools may give pain practitioners a better idea whether a patient has a genetic defect in opioid metabolism. With this information, the physician will know to be cautious when initiating a new drug or will be prepared to use high-opioid dosages and/or a one-of-a-kind treatment plan for the patient.
Screening for Genetic Abnormalities
There are many reasons to screen for genetic abnormalities in chronic pain patients. First, drug-drug interactions are extremely common.1 Opioid use has been highly associated with cardiac arrhythmias and death due to overdose.2 These serious interactions usually occur within 72 hours after a physician initiates an opioid in a patient who is already taking an anti-depressant, benzodiazepine, anti-seizure medication, anti-histamine, or another substance. Having a suspicion that a patient may have a genetic defect of metabolism can be helpful when initiating an opioid, thus avoiding a potential drug interaction. The guide is to start with the lowest dosage of opioid as possible and gradually increase the dosage over time. (Start low, go slow.)
Second, physicians are continually asked to justify to third-party payers as to why a patient may need a high opioid dose or an odd or expensive regimen. Although we can’t tell whether a patient has a genetic metabolic defect unless he or she has a laboratory test that confirms a CYP450 defect, it’s recommended that a diagnosis of “Pre-sumptive Genetic Metabolism Defect” is stated on a patient’s chart.
Third, and most important to many physicians, it’s vital to identify patients with likely genetic defects and refer that patient, and/or consult with physicians who regularly deal with these individuals. These patients are often labeled as addicts, drug seekers, deviants, or pseudo-addicts. Unfortunately, these patients may require extraordinary amounts of clinical time to manage, and not all physicians are prepared to deal with these special issues. (See Table 1.)
Table 1. Why Screen for Genetic Metabolic Defects?
1. Avoid drug interactions.
2. Prepare for a regimen of high-dose opioids or an unusual
3. Educate third parties on the need for a high-dose, unusual, or
Screening for Cytochrome P450
Screening for cytochrome P450 shouldn’t routinely be done for 2 reasons: 1) The tests are extremely expensive, and 2) There are 3 different CYP450 defects that significantly alter opioid metabolism.1 Unfortunately, only 2 of the 3 defects have a commercially available test (CYP2D6 and CYP2C9).The most common CYP450 defect, however, is believed to be the CYP3A4, and because this test is still in the research stage, it’s not yet commercially available.4,5
Therefore, my recommendation is to screen for CYP2D6 and CYP2C9 defects only if there is historical evidence and/or abnormal opioid blood levels that suggest the presence of a CYP450 defect. Furthermore, there is no clinical reason to go to such expense unless a health plan, family member, or other third-party wants to know why the patient needs a high-dose, expensive treatment regimen. If testing is done, the third party needs to be informed that a negative finding for the 2 currently available CYP450 tests does not rule out the presence of a genetic defect or the need for an expensive, unusual, or high-dose opioid regimen.
Genetic Screening Tool
To develop a practical screening tool, I asked 9 patients with laboratory-documented CYP2C9 or CYP2D6 genetic defects a few questions. (See a brief profile of each patient, which is outlined in Table 2.) All patients required an unusual and/or high-dose opioid regimen for pain control. What was especially interesting was that all 9 patients gave essentially identical answers to 3 historical questions. (See Table 3.)
There may be other screening questions that are more specific when more patients are studied. These inquiries emerged from a written questionnaire survey, which covered more than a dozen topics, including allergies, family history, and genetic disease. The survey also covered adverse reactions to drugs, including opioids, anti-inflammatory agents, anti-depressants, and anti-histamines.
Table 2. Case Descriptions