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8 Articles in Volume 11, Issue #2
Preventive Therapies for Cluster Headaches
The Pain of Multiple Sclerosis: Is it Real and Is it Treatable?
Antidepressants in the Treatment of Chronic Pain
Genetic Screening for Defects in Opioid Metabolism: Historical Characteristics and Blood Levels
Post-operative Patient-controlled Analgesia in Pediatric Patients
Pharmacogenetics in Pain Care: Consideration of Economic Impediments and Ethical Imperatives
Are Opioids More Harmful Than NSAIDs for Elderly Patients?
How Genetics Can Complicate Pain Treatment

Genetic Screening for Defects in Opioid Metabolism: Historical Characteristics and Blood Levels

Some simple historical questions about a patient’s response to dental anesthesia, opioids, and alcohol can suggest to the pain practitioner that a genetic defect in opioid metabolism is likely present.

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
combination of agents.

3. Educate third parties on the need for a high-dose, unusual, or
expensive opioid regimen.


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

  1. A 39-year-old male, veteran weighs 292 pounds and works full-time as an electrician. He has severe knee and ankle arthritis that have been treated with 5 prior surgeries. He has a CYP2C9 defect. Daily opioid dosages are methadone 160 mg, oxycodone 540 mg, and hydrocodone 80 mg.
  1. A 62-year-old female has severe degenerative and osteoarthritic disease of the spine, hips, and knees. She has a CYP2C9 defect and works full time. Daily opioid and stimulant dosages have lowered significantly over the past year and now include fentanyl 15,200 µg, oxycodone 140 mg, modafinil 200 mg, phentermine 75 mg. Fentanyl blood level is 26 ng/mL (usual pain level is less than about 8 ng/mL),5 and oxycodone is 219 ng/mL (usual pain range is about 100-300 ng/mL).6
  1. A 51-year-old, disabled female has severe cervical and lumbar spine degeneration with radiculopathies. She has a CYP2C9 defect. Daily opioid dosages are hydromorphone 160 mg, fentanyl transmucosal 22,400 µg, fentanyl transdermal 4,800 µg, and oxycodone 720 mg. Blood level of fentanyl is 36 ng/mL (fentanyl should be no higher than about 8 ng/mL)5 and hydromorphone and oxycodone are zero. However, all 3 opioids are present in her urine.
  1. A 37-year-old male was in a motor cross accident and suffered a fractured right shoulder. He was left with arthritic changes and severe neuropathies of his shoulder, arm, and chest wall. He works full time, and he has a CYP2C9 metabolic defect. His daily opioid dosages are methadone 60 mg and oxycodone 2,400 mg.
  1. A 57-year-old, disabled male has arachnoiditis and a CYP2C9 metabolic defect. His daily opioid dosages are fentanyl transdermal 4,800 µg, fentanyl transmucosal 3,600 µg, hydromorphone 144 mg, and oxycodone 240 mg.
  1. A 32-year-old Vietnamese woman has cervical and lumbar spine degeneration. She has had fusions with metal screws and plates at both sites. She has a documented CYP2C9 metabolic defect and takes the following dai ly dose of opioids: oxycodone extended-release 640 mg and oxycodone short-acting 1,000 mg.
  1. A 31-year-old female developed intractable headache and hypopituitarism following multiple concussions. She is disabled, has a CYP2C9 metabolic defect, and gastrointestinal malabsorption that prohibits the use of oral opioids. In addition to multiple hormone replacements, her daily opioid dosages are hydromorphone injectable 350 mg and fentanyl sub-lingual drops 3,300 µg.
  1. A 46-year-old male has degenerative lumbar spine and hip disease caused by an industrial accident. He works full time, and he has a CYP2C9 defect. His daily opioid dosages are methadone 200 mg, fentanyl transmucosal 2,400 µg, and fentanyl transdermal 2,400 µg. His fentanyl blood level was 16.4 ng/mL, and methadone blood level was 347 ng/mL, which is in the expected range.5
  1. A 32-year-old female of Hawaiian descent has fibromyalgia and lumbar spine degeneration. She has a CYP2D6 metabolic defect. Her current daily opioid dosage, which is markedly reduced from one year ago, is oxycodone 420 mg and fentanyl transmucosal 6,000 µg. A blood test taken 1 to 2 hours after administration, revealed a oxycodone level of zero. On another occasion, oxycodone blood level was 591 ng/ml.


Opioid Blood Screening

Because the purpose of around-the-clock treatment with opioids is to maintain a steady level of opioids in the blood, a blood specimen taken any time of day or night should show a reasonable therapeutic level. If a patient’s opioid blood level is too high or too low, a genetic opioid metabolism defect may be present.

There are 2 types of patients with metabolic defects—the fast metabolizers and the slow or “lazy” metabolizers. The fast metabolizer will cause a rapid clearing of opioids from the blood. These patients will show a very low or even negative opioid blood level as soon as 1 to 2 hours after they take their regular dosage. With slow metabolizers, patients may require a very high opioid blood level to force or “prime” the defective enzyme to metabolize.


As many as one-third of the Caucasian population may have a genetic metabolic defect of the cytochrome P450 enzyme system, which could adversely affect opioid metabolism. At this time, there is no commercial laboratory blood test for this genetic defect. To raise the possibility that a genetic defect may be present, you should screen patients by asking them simple historical questions involving their need for dental anesthesia and opioids. Many patients report that short-acting opioids only provide 1 to 2 hours of pain relief.

If you suspect that a genetic defect is present, you should prescribe an opioid at a low dose and monitor the patient closely for 72 hours as most severe toxic drug interactions between an opioid and another drug—such as an anti-depressant—will occur during this time period. Gradually increase the dose. Patients with severe pain who have genetic defects in opioid metabolism may require an extremely high dosage of opioids to control their pain.


Table 3. Characteristics of Patients with Genetic Defects in Opioid Metabolism?

1. Require a high dosage of dental anesthesia.

2. Short-acting opioids only provide relief for 1 to 2 hours. Only a high opioid dosage provides pain relief.

3. Non-drinker—previous adverse reactions to alcohol when the patient drank or needed extra
intake to feel “high.”


Last updated on: October 27, 2015
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