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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.

If you’re not somewhat confused by all the background noise regarding cytochrome P450 (hereafter CYP) opioid metabolism, drug interactions, and overdoses, you stand singularly alone among your fellow physicians. Given a few critics condemning opioids as sinister, some pharmaceutical companies claiming their opioid avoids the evils of drug interactions, and some Government Agencies scolding just about everybody over opioid overdoses, you should naturally have a little bewilderment as to what the facts may be and what your practical actions should be. At the request of the publisher of Practical Pain Management, I am attempting here to summarize the scientific evidence and develop some simple, quick, practical guidelines regarding genetic opioid metabolic defects (GOMD). While some knowledge about how the CYP450 enzyme system metabolizes opioids is essential, the major, critical point is that opioid-prescribing practitioners need to know that GOMDs are relatively common and can usually be diagnosed or at least suspected by history. Rather than attempt to laboratory test every patient for CYP450 defects, the practitioner can almost always suspect a GOMD and develop an appropriate clinical regimen by asking a few screening questions that are given here in Table 1. When a GOMD is suspected there are a few do’s and don’ts that can prevent opioid toxicity and overdose and simultaneously get better therapeutic results. A major goal of Practical Pain Management is to help prescribers of opioids to do it safely and with confidence.

Critical Reasons to Diagnose a “Genetic Opioid Metabolic Defect” (GOMD)

Rather than know the intricate details of the CYP system and opioid metabolism, the practitioner who prescribes opioids really wants to know if the patient has a GOMD. There are three characteristics that GOMD patients may present or exhibit:

Laboratory, genetic testing for the CYP450 enzymes primarily involved in opioid metabolism is not a practical, routine endeavor at this time. Testing should be reserved for limited circumstances. We now know enough about the functions of CYP450 enzymes as they relate to opioid metabolism, however, to ask some simple screening questions of pain patients that will provide the practitioner with enough information to make a “suspicious” or “probable” diagnosis of GOMD (see Table 1). Rationale for the screening questions are given below.

Exactly What Is Cytochrome P450?

The name is somewhat unfortunate and non-descriptive. It could have been more understandable if the name was simply “drug metabolizing enzyme system.” Nevertheless, the enzyme name is derived from a heme pigment which absorbs light identical to that of chrome which has a wavelength of 450 nanometers. CYP450 enzymes are primarily found in the liver but some exist in the intestine, lungs, brain, and kidney. The CYP450 system consists of 481 separate genes which code for 74 unique families. A family name is denoted by an arabic number (e.g., CYP-2), the subfamily by a Roman uppercase letter (e.g., CYP-2D), and the individual enzymes by another arabic number following the letter indicating the subfamily (e.g., CYP-2D6).7,8

Table 1. Twelve Screening Questions to Make You Suspicious of a Genetic Opioid Metabolic Defect

1. Have you ever taken hydrocodone (Vicodin®, Lortab®, or Norco®)? o Yes o No o Never Taken
Did you get pain relief from it? o Yes o No o Some

2. Have you taken a pain reliever with codeine in it (Empirin®, Fiorinal®, Fioricol®)? o Yes o No o Never Taken
Did you get pain relief from it? o Yes o No o Some

3. Have you ever taken tramadol (Ultram®)? o Yes o No o Never Taken
Did you get pain relief from it? o Yes o No o Some

4. Have you taken oxycondone (Percocet®, Oxycontin®), methadone, fentanyl (Duragesic®), or hydrocodone (Vicodin®, Lortab®, Norco®) and had any of the following reactions within 30 minutes after taking your first dose?
o Vomiting o Headache o Breathlessness o Flushing o Itching o Dizzyness o Allergic reaction
Which drugs gave you the reaction? (list)_________________________________________________________________

5. Were you ever told that you are allergic to a pain relief medication? If so, which one(s)?

6. When you had surgery, dental work, delivery, or other medical procedure, did your doctor tell you that you needed extra anesthesia or pain relief medication? o Yes o No o Some

7. Have you always had to take a high dose of pain medication to get relief? o Yes o No

8. Do you have a close relative who is either allergic to a pain medication or finds that he or she does not get pain relief with opioids?
o Yes Which relative? ________________ What medication? ________________
o No

9. When you took your first drink of alcohol as a teenager or young adult did you experience the following?
o Vomiting o Severe Headache o Seizure o Passing Out

10. When you had alcoholic drinks before you became a pain patient, compare your intake to your friends.
o Had to Drink More to Get High o Even a Little Alcohol Made Me Sick
o Could Drink Same Amount as Friends

11. Do you have a genetic or inheritable disease that is the cause of your pain? o Yes o No
If yes, what is the name of your inherited disease?______________________________________________

12. Have you ever had a severe reaction to any of the following:
o Antidepressant o Antihistamine o Antibiotic o Anti-hypertensive

Three Key CYP450 Enzymes

Out of over 50 CYP450 enzymes, only three account for over 90% of opioid metabolism: CYP-3A4, CYP-2D6 and CYP-2C9.9-12 Pain practitioners who prescribe opioids must understand some basics of these three enzymes. CYP-3A4 is the major hepatic enzyme for opioid metabolism accounting for 40 to 60% of all opioid metabolism.7,8 Unfortunately, there is not yet a widely available commercial test for CYP-3A4 but the other two, CYP-2C9 and CYP-2D6, can be tested for genetic defects which are technically referred to as “polymorphism” since the alleles on the gene may be altered or absent. Fortunately, unique characteristics and new knowledge regarding these three enzymes provide some simple screening questions that allow the opioid prescriber to have a high index of suspicion that a GOMD of the enzyme exists in a patient.

How Common Are GOMDs?

GOMDs are much more common than is realized (see Table 2). To date there are no wide-scale testing surveys involving the three CYP enzymes most critical to opioid metabolism. A number of investigators including the major genetic testing laboratories, however, provide estimates of prevalence. Quest Laboratories, which is a national leader in genetic testing publishes, with each CYP450 test result, some estimates of genetic defect prevalence. For example, if you order a CYP-2C9, one of the two major enzymes for opioid metabolism that can be tested, you will receive a report that states “Approximately one-third of Caucasians, 2.8% of Asians, and 3-13% of Africans carry one or both of the variant alleles.” The prevalence statement written on a CYP-2D6 report states that abnormal metabolism of this enzyme is “5-10% of Caucasian individuals, approximately 2% of Asians, and 2-17% of Africans carry loss of function that result in the poor metabolizer phenotype.” If you consider these statements in light of the fact that the CYP-3A4 gene is far more involved in opioid metabolism and that there are likely some genetic defects in the non-CYP opioid metabolism system, it is reasonable to assume that 20-30% of pain patients have a GOMD.

Table 2. Opioid dosage and CYP enzyme deficiences
Enzyme Variation Opioid Dosage Laboratory
Normal Normal Extensive metabolizer
Overactive High or ultra high because the enzyme continuously deactivates the opioid and thus lowers serum levels Rapid metabolizer
Underactive CYP enzymes are slow or “lazy" thus needing extra opioid dosage to “force” metabolism Intermediate
Inactive or Absent Won’t process opioid thus causing serum levels to rise and produce toxicity Poor metabolizer
Table 3. Quick Reference Metabolism of Opioids by Class and System

Pro-opioids that require conversion to an active metabolite
Codeine ---------------------->Morphine
Hydrocodone----------------------> Hydromorphone
Dihydrocodeine ---------------------->Morphine
Tramadol ---------------------->O-desmethytramadol

These opioids primarily rely on the enzyme CYP-2D6 to make the conversion.

Opioids that act directly on opioid receptors without the necessity of metabolic conversion



Morphine Levorphanol Oxycodone
Hydromorphone Oxymorphone Propoxyphene  
Methadone Meperidine Tapentadol  
These opioids primarily rely on CYP-3A4, CYP-2C9, or glucoronidation (non-CYP) for metabolism to an excretable, non-active metabolite.
Common opioids that primarily rely on the CYP450 enzyme system for metabolism
Codeine Methadone Fentanyl Oxycodone Hydrocodone Morphine
Common opioids that bypass the CYP450 enzyme system and use glucoronidation for metabolism
Oxymorphone Tapentadol Hydromorphone
Note: Some opioids are converted to active metabolites and/or metabolized by a combination of CYP450 enzymes and non-CYP metabolism.

What Does The CYP System Do?

The CYP450 system, depending on the opioid being administered, performs one or two actions:

Table 4. Opioid Toxicity Symptoms with a Genetic Opioid
Metabolic Defect
Allergic Manifestation
Respiratory Impairment
Stands and walks
Sudden weakness
Cardio-pulmonary shut down
Note: the above symptoms may present if a GOMD or drug inhibits a CYP450 enzyme system. Emergency treatment may necessitate naloxone, epinephrine, corticosteroids, and respiratory support.

Types of CYP450 Opioid Metabolic Defects

There are three types of GOMDs that may exist in any one of the three major opioid CYP450 enzymes (see Table 2). They are inactive or absent, underactive, or over-active.7,8

The first type of defect is an inactive or absent enzyme that simply won’t metabolize the opioid thus leaving the opioid to be excreted in an unchanged form. The danger here is that an opioid that can’t be metabolized in a timely manner builds up in the serum. If opioid dosages are repeated, particularly in a non-tolerant person, there is the danger of opioid toxicity which are, primarily, allergic manifestations or respiratory depression (see Table 4). This mechanism is undoubtedly responsible for some if not most, of the numerous overdose deaths that have occurred since opioid prescribing for pain became so popular in the last decade.

The second type of defect is an enzyme that is over-active.4,10 Laboratories refer to this GOMD as a “rapid metabolizer." Fundamentally, the enzyme clears opioids from the serum too fast thus lowering the serum opioid concentration. This leaves the patient in pain and constantly needing additional opioids for relief. Also, each opioid dosage lasts only a short time. For example, a long-acting opioid that is supposed to last 12 hours may only last 4 hours.

The third type of defect is an underactive enzyme and is the most common CYP-2C9 defect found by the author in high dose opioid-maintained pain patients.5 Laboratories refer to this GOMD as an “intermediate metabolizer" (see Table 2). Think of this situation as a slow or “lazy" enzyme. When this GOMD is present, opioids clear the serum slowly leaving a high serum concentration which can be toxic. Apparently a high serum opioid concentration is necessary when this GOMD is present, however, to “force" the “lazy" enzyme to work.

High Opioid Dosages and Odd Regimens

If a GOMD of the CYP450 enzyme system is present, a higher-than-usual dosage of opioid will almost always be required.4,5,13,14 It is the author’s opinion that the most common GOMD in pain patients is an overactive CYP-3A4.4,5,9,11 These patients state that opioids provide a very short time period of pain relief and a requirement for high dosages of anesthesia or alcohol to achieve an effect (see Table 1). The author believes the second most common GOMD is a underactive CYP-2C9 known as a “intermediate metabolizer." These patients clinically tend to require a high dose of those opioids that rely on the CYP450 system as well as one or more opioids that bypass the CYP450 system15 (see Table 3). It is clear that a search and investigation for a GOMD in an opioid-dependent patient is in order before any label and claim of addiction, abuse, or “over-prescribing" can be made. Forced or arbitrary reductions of opioids in an existing opioid-dependent pain patient may be hazardous if a GOMD exists because the opioid serum concentrations may drop too fast to a low or zero level producing severe opioid withdrawal, pain flares, and cardiovascular hyperactivity with cardiac arrest or stroke being a potential danger.

How to Make a Clinical Diagnosis of GOMD

Although routine genetic laboratory testing for CYP and other enzyme systems is not yet available, we know enough about the clinical history of GOMDs to recommend some simple historical questions on GOMD (see Table 1). What follows here is, to a great extent, the author’s surveys of pain patients on opioids who have documented CYP-2C9 and CYP-2D6 defects. A short rationale for each of the historical questions in Table 1 is given.

First, the opioids hydrocodone, codeine, dihydrocodeine, tramadol and, to a lesser extent, oxycodone, require CYP-2D6 and/or CYP-2C9 to convert these opioids to one or more active metabolites.1-3 If a patient has a GOMD of CYP-2D6 or CYP-2C9, they will report that they get little or no pain relief with these opioids. The common escalation or run-up of hydrocodone-acetaminophen dosage by patients may be due to a GOMD.

The most common GOMD in ultra high dose opioid patients is probably a hyperactive or rapid metabolizing CYP-3A4.4,9,10,12 Unfortunately, a commercial assay for CYP-3A4 isn’t yet commercially available. Patients with a GOMD will historically tell you that throughout their life they have had to routinely take a higher dose of opioids, anesthetics, or alcohol to get an effect. The problem is that the excess or hyperactive enzyme removes opioids so rapidly from the serum and deactivates them that a frequent, high dose opioid dosage schedule is required to maintain an adequate serum concentration and achieve pain relief. These patients are frequently mislabeled as drug seekers or addicts.

The absent, slow, or “lazy” enzyme, gives rise to a different set of issues. In this situation, the enzyme doesn’t remove the opioid from the serum in a timely manner so that the serum opioid concentration rises too fast, too high and thus causes toxicity (see Table 4). The most common response is an allergic manifestation. The rising, high blood level of opioid may attach to opioid receptors on mast and other immune-reactive cells and release histamine and other “allergic” compounds. The common historical recall by the patient is “I’m allergic to codeine or hydrocodone.” In most cases, the reaction is merely itching that is of short duration. The allergic manifestation can be much more severe and include edema, urticaria, angio-edema, and wheezing. Anaphylaxis can occur in rare cases as illustrated by the following case report: A 50-year-old woman had two documented episodes of anaphylaxis following a single, low dose of oxycodone. Intensive care treatment with adrenalin and corticosteroids were necessary to save her life on both occasions. The author patch-tested her with solutions of oxycodone, morphine, fentanyl, and meperidine. Only meperidine failed to cause an inflammatory reaction, so it was recommended as an emergency opioid treatment should it be needed. This case illustrates that a GOMD that doesn’t clear opioids from the serum can be hazardous.

A serum opioid concentration or level that keeps rising due to a GOMD may not cause an allergic-type reaction but, instead, a respiratory suppression reaction. This is the dreaded, unexpected reaction that may lead to death. The early symptoms of opioid toxicity prior to death may include, breathlessness, hyperventilation, dizziness, sudden weakness, and a desire to stand or sit (effort to “catch breath” or obtain oxygen). Interestingly, opioid toxicity due to a rising serum level apparently gives a perception of constipation or need to defecate. Many opioid overdose deaths occur on the toilet, and families of overdose victims frequently relate a history that the decedent got out of bed, walked or even crawled to the toilet and later died.

Some points about GOMDs are un-known or unclear. Are GOMDs inherited like some other genetic diseases? Indeed, some families report that first degree relatives have a similar GOMD. The author has found that practically every opioid-maintained pain patient with a CYP-2C9 defect has a relative that doesn’t respond to normal opioid or anesthetic dosages or were “allergic” to some opioids. Consequently, practitioners may find it useful to ask a screening question about relatives who have had symptoms compatible with a GOMD. Does one genetic disease beget another? Pain practitioners who prescribe opioids are quite familiar with severe, high dose, pain patients who have a genetic disease as the cause of their severe, chronic pain. Included here are Ehler-Danlos Syndrome, acromegaly, porphyria, Bechetts Disease, and rheumatoid spondylitis among others. Although not scientifically documented, patients with genetic diseases appear to have a very high prevalence of GOMDs and often require an ultra-high dose opioid regimen.

Drug Interaction (We Really Mean Opioid Toxicity)

One of today’s practical issues facing the opioid–prescribing practitioners are the pharmaceutical companies whose representatives are taught—and their promotional materials proclaim—that their new opioid avoids drug interactions. Part of this claim is taking advantage of all the publicity that drug interactions in the United States each year cost millions of dollars and result in countless hospital admissions. The not-so-subtle message here is that physicians are ignorant and the cause of this “unacceptable situation” can be resolved if the doctor just prescribes the new opioid. Interestingly, I’ve yet to have a pharmaceutical representative explain precisely what they mean by “drug interaction.” The simple fact is that pain practitioners really fear only one “drug interaction” and that is opioid toxicity (see Table 4). A constant fear is that a common drug like a benzodiazepine, anti-depressant, or antibiotic is being taken by the patient and silently inhibiting or shutting down a CYP450 enzyme. If this happens, the enzyme won’t clear the serum of opioid in a timely manner so opioid blood levels rise causing opioid toxicity of either the allergic or respiratory depression type.

Table 5. Classes of Drugs of Which a Member Has Been Reported to Inhibit a P450 Enzyme
  • Benzodiazepines
  • Antidepressants
  • Anti-seizure
  • Anti-infective
  • Anti-hypertensive
  • Anti-histamine
  • Bronchodilators
Note: these drug classes are so ubiquitous that opioid prescribers must seek safety in initially prescribing low opioid dosages or use opioids that primarily avoid the CYP450 enzyme system.

It is presumed that a patient with a GOMD is more likely to have an enzyme shut down or be inhibited by a non-opioid drug. This belief, while probably true, is unproven since persons with an apparent normal CYP system may be subject to inhibition or shut down by these commonly used drugs. Consequently, every new pain patient who must be started on opioids needs to be screened for a GOMD. If a GOMD is suspected, it is most appropriate to start treatment with one of the new opioids—particularly oxymorphone or tapentadol—since the compounds at least partially avoid the CYP450 system and are less subject to “drug interaction” or opioid toxicity.15

Opioids That Bypass the CYP450 System

Most helpful—and a great safety valve for the pain practitioner—is the fact that some opioids primarily use glucoronidation for metabolism and bypass the CYP450 system.7,15 For safety purposes, these opioids are far safer in a patient who may be practicing polypharmacy as most severe pain patients must. The safest appears to be oxymorphone as it apparently is essentially devoid of CYP450 and neurosynaptic activity. Hydromorphone and tapentadol are other opioids relatively free of CYP450 metabolism.

Drugs That Inhibit the CYP450 Enzyme System

The key point for the pain practitioner is to know that one or more drugs in the benzodiazepine, anti-depressant, sedative, anti-hypertensive, anti-seizure, and anti-infective classes have been known to produce CYP enzyme inhibition (see Table 5). Rather than try to isolate a specific drug, pain practitioners need to prescribe opioids in such a manner that even if a GOMD and inhibition of a CYP450 enzyme is silently present, the patient won’t develop opioid toxicity. If a patient is taking a drug that may inhibit an enzyme in the CYP450 system, use opioids that bypass the CYP450 system until you are sure that the patient can appropriately metabolize all opioids. The following is a case example: A 35-year-old female with fibromyalgia syndrome—including gen-eralized muscle pain, arthritis, degenerating spine, hypothyroidism, and irritable bowel—was referred to our office. Her daily medications were levothyroxin, gabapentin, amphetamine sulfates, baco-fen, propanolol, clonazepam, temazepam, and citalopram. She gave a history of requiring extra anesthesia for dental extractions and dysphoria and vomiting with alcohol. For safety reasons, her initial starting opioid was short-acting oxymorphone, 5mg every four to six hours.

There is also the concept of CYP450 induction but this phenomenon is essentially a thing of the past. Some years ago tuberculosis was common and the first generation of anti-seizure drugs were widely used. Some of the anti-tuberculosis drugs and anti-seizure medications (particularly phenytoin; Dilantin®) would cause a CYP450 enzyme to speed up or become over-active. The author recalls a heroin addict with tuberculosis main-tained on methadone. Fifteen minutes after a dose of rifampin, he went into severe opioid withdrawal and severe hypotension. He may have perished had not intravenous opioids been administered. These situations are now essentially non-existent with the disappearance of cavitary tuberculosis and newer anti-seizure drugs. Sudden, severe opioid withdrawal symptoms and a severe pain flare in a formerly stable, comfortable, opioid-maintained pain patient should recall to pain practitioners, however, that CYP450 induction is, albeit rare, a possibility.

Table 6. Answers to Some Key Questions.

1. Should you do cytochrome P450 testing on your pain patients? Not routinely. You may wish to consider testing those patients who give a history which suggests the presence of a genetic opioid metabolic defect and who require an ultra-high or unusual opioid regimen.

2. Can I make a diagnosis of genetic cytochrome P450 deficiency by clinical history? Not definitely, but you can have a high index of suspicion if you ask a few of the screening questions given here such as “Do you get pain relief with hydrocodone?” or “Are you allergic to an opioid?” Only a laboratory test for cytochrome P450 deficiencies can make a definitive diagnosis.

3. What is the key clinical point for prescribing opioids related to genetic opioid metabolic defects? In a NEW pain patient who is participating in polypharmacy—including antidepressants or benzodiazepines—it is wise to start with a low dose of an opioid, such as tapentadol or oxymorphone that doesn’t rely heavily on cytochrome P450 metabolism. If you unknowingly give hydrocodone or methadone, for example, to a patient with a genetic defect, you may get opioid toxicity and even on overdose death.

4. How common are GOMD’s? No one knows for sure. Current indications suggest 20 to 30% of pain patients.

Table 7. Some guidelines to prevent opioid toxicity and overdoses

1. Start all opioids at a low dose and increase the dosage slowly over time.

2. Screen every patient who may need opioids with questions that may suggest the presence of a genetic opioid metabolic defect (GOMD).

3. Use opioids that primarily by-pass the CYP450 enzyme system if a genetic opioid defect is suspected or the patient is taking a number of non-opioid drugs.

4. Use a low dose, short-acting opioid to initiate opioid treatment—particularly in a patient not well known to the practitioner.

5. Closely monitor and educate opioid-treated patients about the dangers of benzodiazepines, antidepressants, and other substances that may inhibit the CYP450 enzyme system.

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
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