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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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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.

Last updated on: September 27, 2017