Non-responsive Pain Patients with CYP-2D6 Defect

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

The article continues with Case Examples

18 thoughts on “Non-responsive Pain Patients with CYP-2D6 Defect

    1. Colleen Pisaneschi

      This could be a first step in interpreting why pain patients react so differently to all of the available medications. Thanks so much for posting this!

      Liked by 2 people

  1. an_angel_with_wings

    I’m actually one of those quirky ones with the duplication that causes ultra RAPID metabolism. I have always had problems with pain medication lasting as long as it was supposed to. With the cytochrome p450 testing done, I can now prove it’s not all in my head. I just wish I had these papers sooner, and that I understood them better than I do. I want to be sure to use the ‘defect’ to my advantage when it comes to acute pain control.

    As you can imagine, when I tell doctors that I can’t use any NSAIDs or muscle relaxers, and that many of the pain medicines I’ve taken last only half as long as they should, the red flags go right up all over my chart. The next thing I know, they’re discreetly (but not very discreetly) checking me for track marks. It makes it hard to seek care when I know there’s a chance I’ll deal with that again. My mantra these days is: unless I think I’m dying, I’m waiting. If i’m ready to die, I’m waiting. :)

    Oh how I wish I could open up an EDS care center / community in Southern California. We don’t have very many doctors here, but maybe we can recruit some from those cold places, like Chicago and Maryland if the herd grew large enough here? *smile*

    Liked by 2 people

      1. Zyp Czyk Post author

        I agree: Oxycontin is supposed to work for 12 hours, and that’s just baloney. I’ve heard countless people say it doesn’t last that long and for me it’s only 6-8 hours. Then you have to subtract an hour or two for the time it takes to work in the first place, leaving you with only 5-7 hours effective pain control.

        Yet, if you tell that to your doctor hoping for more frequent dosing, who are they going to believe? The pharma company that says it lasts 12 hours, or the “drug seeking” patient in front of them saying it lasts only 6?

        At $4 per pill, I sure wish it worked as advertised.

        Liked by 1 person

          1. an_angel_with_wings

            The first doctor that tried to treat my pain (who called it fibromyalgia, and I no longer see) used to give me percocet sometimes. When I reported that they were moderately effective, but not extremely, and that they only seemed to last for 3-4 hours, he told me that I had a pain processing problem and that they’d probably never work for me. It was almost impossible to ever get any pain medication other than tramadol from him after that.

            I’d love to go shove these genetic results right up in his… medical chart.

            Liked by 2 people

        1. frustratedcaregiver

          Hopefully you were prescribed pain meds for “breakthrough pain”, right? Well, take one of those, which start to work immediately, along with the “long-lasting” one. It helps because the fast-acting starts to kick in immediately, then the long-lasting (what a joke) one will eventually kick in. Then take breakthrough pain med(s) until it’s time to take another long-lasting one (which you will take along with the fast-acting one. The plastic coatings on the Extended Release pain meds were supposed to prevent abuse (crushing) but addicts figured out that they could heat and melt the plastic coating. Then they could access the core, where strongest ingredient is, and get high.

          Liked by 1 person

  2. Pingback: Screening for Defects in Opioid Metabolism | EDS Info (Ehlers-Danlos Syndrome)

  3. Pingback: Cytochrome P450 Testing In High-dose Opioid Patients | EDS Info (Ehlers-Danlos Syndrome)

  4. Michael Wagner

    I am very lucky I run into your web site, As I live in Tacoma, Wa. and a pain patient for 25 years, and last year I went to CA to a pain specialist and he did the 4 swabs and come to find out he sent it to Seattle 35 miles from my house, They charged a big price for the test and my billing from medicare showed where medicare paid Genelex $2250.00 They sent me a card with the results a year ago, I couldn’t make senmce out of it, I ended up calling them 20 time or more giving them a list of about 8 prescriptions drugs I was taking and they never could give me any kind of a answer of any kind, I talked to sebveral drug stores and many DR’s and none of them knew anything. in just a few minutes reading your web site I am amazed at what I have read.

    My question can I ask questions here and get help””???? If so that would be o great, as I do have some problem’s with medications.
    my email is:

    Liked by 1 person

    1. Zyp Czyk Post author

      This isn’t a forum, but I can try to help with what I’ve learned.

      Much of what I first learned came from the support forums – those groups are intended for questions.

      But you can ask here, and I’ll check it out and help you find the answers you need.


    1. Zyp Czyk Post author

      Thanks a bunch for this link, Ingrid. I’ll be blogging it soon.

      It’s hard to believe that the CDC guidelines with arbitrary dose limits were pushed through despite the fact that individual differences in drug metabolism are so well known by now.

      So much for “evidence based medicine” – this is a direct affront to the Precision Medicine Initiative that Obama recently kicked off to much fanfare. (unlike the CDC guidelines, which were released almost silently with as little fuss as they could get away with)

      From the website:
      So what is Precision Medicine? It’s health care tailored to you.

      But not pain meds!! For those we have precise standards that apply to everyone equally, no matter what percentage of the drug a patient is actually metabolizing and getting benefit from.


      1. Ingrid

        Yes, it is so frustrating!! I think I’m still in shock over the CDC guidelines. I did see HHS launched the NPS for pain care yesterday.
        When the Precision Medicine Initiative it came out I did write to them about genetic differences and metabolism esp. regarding pain medications.. too important to ignore, but they are!!

        Liked by 1 person

  5. Pingback: Cytochrome P450 Testing In High-dose Opioid Patients | EDS and Chronic Pain News & Info

  6. Pingback: Defective Opioid Metabolism in Pain Patients | EDS and Chronic Pain News & Info

  7. Pingback: Justification of MME Dosage Above 90mg | EDS and Chronic Pain News & Info

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