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9 Articles in Volume 10, Issue #4
Chaos (Nonlinear Dynamics) and Migraine
Enhancement of Nerve Regeneration by Therapeutic Laser
Functional Capacity Evaluation (FCE)
Making Practical Sense of Cytochrome P450
Non-pharmacologic Treatment of Shingles
Pain, Neurotechnology, and the Treatment-enhancement Debate
The New Age of Prolotherapy
Treating Myofacial and Other Idiopathic Head and Neck Pain
Treatment of Painful Cutaneous Wounds

Making Practical Sense of Cytochrome P450

Guidelines for the likely 20 to 30% of pain patients who have a genetic defect involving one of three major CYP450 enzymes and so cannot effectively metabolize certain opioids that must be converted to a metabolite to be effective.
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Laboratory Testing For CYP450 Defects

Until CYP-3A4 becomes widely available as a commercial test, CYP450 enzyme testing is not recommended in usual clinical practice (see answers to typical questions in Table 6). Not only is it expensive, testing for CYP-2C9 and CYP-2D6 may give an incomplete or false picture because it is the CYP-3A4 enzyme that is responsible for 40 to 60% of opioid metabolism. Also, there is no commercial testing for metabolic defects of glucoronidation or other non-CYP metabolism. About the only indication to test for CYP-2C9 and/or CYP-2D6 is if the patient needs to justify a high, expensive opioid dosage regimen for insurance payment or other non-clinical purpose. It is instructive to note that a series of CYP-2D6 cases over a long period were identified by patients all giving a history of non-responsiveness to hydrocodone, codeine, tramadol, or oxycodone.

Before you embark on genetic testing for either CYP-2D6 or CYP-2C9, screen the patient with some questions of which some are listed in the Table of Screening Questions (see Table 1). Even without a laboratory confirmation, all opioid- treated pain patients should be screened for GOMD by simple questions and given a diagnosis of “Presumed” or “Suspicious” GOMD.

“...practitioners who prescribe opioids should screen for a GOMD by simple historical questions and educate opioid-maintained patients on the hazards of non-opioid drugs that may suddenly and unexpectedly cause CYP enzyme inhibition and opioid toxicity.”

Guidelines to Prevent Opioid Toxicity

The old admonition “start low and go slow” should be the golden rule of opioid prescribing (see Table 7). Screen every patient who will need opioids with some screening questions for a possible GOMD. If the patient gives some answers suggesting that a GOMD may be present, initially use opioids that mostly bypass the CYP450 enzyme system. Included here are oxymorphone, hydromorphone, and tapentadol. Always remember that even if the patient may not have a GOMD they may be taking a substance which may inhibit or retard a normal CYP450 enzyme system and create an “artificial GOMD” that may produce opioid toxicity which, in its severe form, may cause death. To help avoid this unexpected and unforeseen consequence, the author recommends that the initial opioid in a patient who has not previously taken opioids or is new to the practitioner, should be a low dose of a short-acting opioid. In the event that, unknown to the practitioner, a CYP450 enzyme is genetically deficient or inhibited by some non-opioid drug, the low dose, short-acting opioid will only remain in the serum one to three hours and not be able to reach a serum opioid concentration that will produce toxicity. Long acting opioids are all hazardous and shouldn’t be used until the prescriber has observed the patient over time to be tolerant to opioids and have a CYP450 system that will appropriately metabolize opioids. Methadone, a long-acting opioid, is particularly problematic. It is the only opioid that requires at least five CYP450 enzymes for metabolism. Consequently, it is the opioid most susceptible to enzyme inhibition or shut-down by a benzodiazepine, anti-histamine, antidepressant, or anti-infective. Some other inhibitory drug classes are presented in Table 5.


It appears that 20 to 30% of pain patients who require opioids likely have a genetic opioid metabolic defect involving one of three major CYP450 enzymes. Some opioids are “pro” drugs that must be converted to a metabolite to be effective. The most notable are hydrocodone, codeine, tramadol and, to a lesser extent, oxycodone. Some common opioids—including morphine, fentanyl, metha-done, oxymorphone, and hydromorphone—do not have to be converted to a metabolite to be effective as they act directly on opioid receptors to provide pain relief. Some opioids, including tapentadol and oxymorphone, mostly bypass the CYP450 system and are metabolized by glucoronidation. At this time, it is possible to obtain a commercial laboratory test to detect genetic abnormalities only in the CYP-2D6 and CYP-2C9 enzymes. Unfortunately, no commercial laboratory test is yet widely available to quantitate the activity of CYP-3A4 which is the most important enzymes for opioid metabolism and accounts for 40 to 60% of all opioid metabolism. Until all three CYP enzymes can be tested collectively and commercially, it is not recommended that CYP enzymes be routinely tested. Rather, prior to opioid prescribing, the practitioner should screen patients for a possible GOMD by some simple questions which give rise to a suspicion of GOMD.

It is now known that such common therapeutic agents as benzodiazepines, antihistamines, and antidepressants may inhibit any of the opioid-metabolizing enzymes and produce the same inhibition or shutdown caused by a genetic defect. This inhibition may result in failure to clear opioids from the serum resulting in elevated opioid serum levels which produce opioid toxicity even to the point of respiratory depression and death. For this reason, practitioners who prescribe opioids should screen for a GOMD by simple historical questions and educate opioid-maintained patients on the hazards of non-opioid drugs that may suddenly and unexpectedly cause CYP enzyme inhibition and opioid toxicity.

  • 1. Patients will not respond or achieve pain relief with certain opioids.1-3
  • 2. Patients will require a high opioid dosage or an unusual opioid regimen.4,5
  • 3. Patients may overdose and even die if certain opioids are prescribed to a GOMD patient (and possibly a normal patient) who is taking an inhibitor or blocker of the CYP450 system. This includes such common drugs as benzodiazepines and antidepressants.6,7
    • 1. metabolizes some opioids (hydro-codone, codeine, oxycodone, tramadol which are considered “pro” or “parent” compounds) to active metabolites which provides pain relief; and
    • 2. metabolizes some opioids (e.g., methadone, fentanyl) to inactive compounds that can be excreted in the urine and other body fluids (see Table 3).7,8
Last updated on: September 27, 2017