Non-responsive Pain Patients with CYP-2D6 Defect | By Alan Edwards, PAC, BS-PHARM
The clinical report presented here contains the only collection of pain patients with CYP-2D6 deficiencies that have been systematically studied. There is a practical salient point in this article for pain practitioners. Any patient who doesn’t respond to hydrocodone or low dosages of oxycodone may have this genetic defect.
Since 2005, I have been testing patients for cytochrome P450-2D6 (CYP-2D6) genetic abnormalities. This was when the blood test was first available for use by us clinicians in private practice
An abnormality of the CYP-2D6 enzyme may be referred to elsewhere in this paper as a deficiency or defect. All told, I’ve tested 15 patients who I have suspected—on a clinical basis—of having a CYP-2D6 genetic defect and, indeed, all have shown an abnormality
Included in this cohort is a single patient who has CYP-2D6 gene duplicity and is termed a rapid- or ultra-metabolizer.
The clinical history of these persons is quite typical
These patients may require high dosages of opioids or may be falsely accused of drug-seeking behavior.
There are more than 50 enzymes within the human intestinal tract and liver that are involved in digestion of food and other substances. The cytochrome-P450 super-family of liver/intestinal enzymes makes up a large portion of the enzyme system that is responsible for the disposal of potentially harmful substances
In terms of CYP-related drug metabolism, there are nine CYP-enzymes of known clinical importance and they are referred to as CYP-1A2, CYP-2B6, CYP-2C9, CYP-2C18, CYP-2C19, CYP-2D6, CYP-2E1, and CYP-3A4.3
Of those drugs that un-dergo liver metabolism, a specific CYP enzyme or a specific combination of CYP enzymes is responsible for each drug’s metabolism.
For instance, CYP-2D6 is completely responsible for some drugs’ metabolism. It appears completely re-sponsible for the metabolism of the antihypertensive/B-blocker, metoprolol (Lopressor®/Toprol®), while the antihypertensive/B blocker, propranolol (In-deral®) is metabolized by CYP-2D6 (42%), CYP-1A2 (41%), and 17% by non-CYP metabolism.
CYP-3A4 is involved in the metabolism of the largest percentage (>50%) of presently-available drugs followed by CYP-2D6 (>25%).
While there doesn’t appear to be any polymorphism of any frequency with the CYP-3A4 enzyme that results in a significant clinic impact, the CYP-2C9, CYP-2C19, and CYP-2D6 enzymes have shown polymorphism.
A single gene is responsible for the production of an enzyme. With the technology used to map the genetic code of the human, we can now identify each person’s individual gene makeup for some enzymes
for these genes, there can be allelic differences or polymorphism that can result in significant differences in the actual functionality of the enzyme for which the gene is responsible.
This potential for genetic variation of the same gene is called ‘polymorphism’
These differences can have significant clinical consequences, espe-cially when extrapolating the effects of a drug from one patient to another or to another race.
The CYP-2D6 Enzyme
There are more than 20 possible allelic variations in the code of the CYP-2D6 enzyme.
Since autosomal chromosomes are paired, everybody has two alleles. People with the usual or “normal/wild” type have the phenotypic allelic designation of CYP-2D6*1/*1 and they are referred to as extensive drug metabolizers
Those individuals with other “non-normal” alleles (e.g., CYP-2D6*4) will not be able to metabolize drugs to the same degree as those people with the normal/wild genotype and are referred to as “2D6-Deficient.”
They are referred to as non-metabolizers and poor metabolizers, respectively.
Those individuals who express poor or a complete lack of enzyme function (non-metabolizers) are predisposed to the accumulation of the parent drug and will achieve excessive serum levels and prolonged half-lives of the drugs.
Cytochrome P450 Genotype Testing
A blood test for some cytochrome P450 genotypes has been available since 2005 so that we can now identify some people who will clear liver metabolized drugs from their body differently than the norm. People with two abnormal alleles will exhibit the least enzymatic activity and are referred to as poor drug metabolizers. Those individuals who have one normal (*1) allele and one abnormal (i.e., *10), are referred to as heterozygote’s and will exhibit intermediate drug metabolism. It is also possible for about 2% of whites and >25% of Saudi Arabians to have duplication of the functional *1 gene and results in ultra drug metabolism. Up to 13 copies of CYP-2D6 in the same person have been reported.
For over the last eight years, the FDA has mandated that drug companies identify which CYP enzyme are responsible for the metabolism of their drug. They must also report whether the drug has any activating or inhibiting effects on the function of these CYP enzymes. This has been an immense aid in being able to identify specific drug-drug interactions
CYP-2D6 Polymorphism and Its Clinical Significance With Opioids
CYP-2D6 polymorphism is of particular importance as to whether patients are able to receive the expected analgesic effect from all of the most commonly prescribed oral opioids (e.g., codeine, hydrocodone (Vicodin®), oxycodone (Per-cocet®), tramadol (Ultram®)
This is because all of these agents are pro-drugs that need to be metabolized to be effective and are relatively inactive as the parent drug. Codeine is converted by liver enzymes—particularly by CYP-2D6—to morphine; hence, it is the morphine, not the codeine, that results in the patient’s analgesia.
If the patient is “CYP-2D6 deficient,” they will not be able to convert the codeine to the active morphine component and will not receive any analgesic effect—especially if they are homozygous for an abnormal allele no matter the dose
The same is true for hydrocodone, which is converted to its active component hydromorphone (Dilaudid®), and for oxycodone, which is converted to its active component oxymorphone.
Tramadol is somewhat active as the parent drug but its 2D6-mediated metabolite, M-1, is six times more potent than the parent drug. Therefore, while 2D6-deficient patients may receive some analgesic effect from tramadol, it is no where close to the effect/potency that “normal/wild” type patients receive
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