Non-responsive Pain Patients with CYP-2D6 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 (see Table 1). This includes myself and my brother. 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 and I share this information to help practitioners identify pain patients who may have a genetic defect of CYP-2D6. They will likely not respond to some opioids. 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.1-4 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. These enzymes are referred to as ‘CYP450’ enzymes. They are heme-related enzymes that use iron to oxidize substances to usually—but not always—less harmful and water-soluble metabolites that are then excreted into the urine and eliminated from the body. To enhance the water-solubility of the substances even further, the liver often also attaches a group such as a glucuronide or sulfate moiety to the metabolite. This is referred to as conjugation. The CYP450–mediated oxidation is referred to as ‘Phase 1’ metabolism and the conjugation step is referred to as ‘Phase 2’ metabolism.
CYP450 enzymes are responsible for:
- 1) synthesis of cholesterol and cholesterol-based substances (e.g., sex hormones, cortisol, vitamin D3, bile acids);
- 2) catabolism of ingested food substances (xenobiotic metabolism with implied protection against plant alkaloids/poisons);
- 3) conversion of arachidonic acid to certain prostaglandins (e.g., thromboxane-A synthetase (CYPS), Prostacyclin synthetase (CYPS); and
- 4) ‘Phase 1’ metabolism of drugs—either activation of pro-drugs or inactivation of active-parent drugs.
All of the P450 enzymes have been identified and have been classified into various CYP families and subfamilies. These enzymes appear in the greatest concentration within the liver, but some of them (e.g., CYP-3A4) can also be found within the walls of the small intestine.2
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. We now know what the usual or “wild” genetic makeup of CYP450 enzymes is for the vast majority of individuals. As a result of mutations in the actual sequence of the nucleotide bases (e.g., adenine could be switched for guanine) 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. If a person’s gene contains nucleotide alterations, the resultant en-zyme may have either reduced, enhanced, or normal oxidase activity compared to what is considered to be the normal or “wild” gene/enzyme type. This potential for genetic variation of the same gene is called ‘polymorphism.’ In different races and even between individuals of the same race there can be significant allelic differences in the overall activity/potency of a CYP enzyme. 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.1-4 The frequency of these poly-morphisms varies within the major ethnic groups. It has been shown that up to 10% of whites, 2% of blacks, and 1% of Asians exhibit CYP-2D6 polymorphism.4 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.” These individuals can be either completely devoid of enzymatic function or have intermediate enzymatic activity, depending upon the allele combination they possess. 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. These individuals have a tendency to become toxic on the “usual” doses of medications. An example of a potentially very harmful polymorphism can be seen in those individuals who are CYP-2C9 non-metabolizers and are put on warfarin (Coumadin®). Up to 35% of whites have CYP-2C9 allele variants that result in 50% less-than-normal 2C9 enzyme activity.6 These individuals are not able to effectively clear warfarin, which relies heavily on 2C9 for its normal metabolism and thus may be significantly over-anticoagulated on doses above 1mg qday. Phenytoin (Dilantin®), fluvastatin (Lescol®), glyburide (Diabeta®, Micronase®), glimepiride (Amaryl®), and glipizide (Glucotrol®) are other medications that rely heavily on 2C9 for their metabolism and could lead to significant adverse clinical outcomes in patients who have genetic CYP-2C9 defects.