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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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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.

Last updated on: August 5, 2016