You may need a higher dose of opiates to manage your pain because …

Cytochrome P450 Testing In High-dose Opioid Patients

Severe, chronic pain patients who seek opioid dosages above normal standards should now be tested for genetic cytochrome P450 deficiencies.

While it is common knowledge that the cytochrome P450 (CYP450) enzyme system is critical for the metabolism of some opioids, genotype testing of pain patients for CYP450 polymorphism has not been generally recommended.1,2 This situation, however, may change as pain specialists begin to recognize that patients who require high doses of opioids may have a genetic defect that may affect their ability to metabolize these agents.

In the past, genotyping for CYP450 polymorphisms was not cost effective or convenient. However, testing technology, commercial availability, third-party reimbursement, and most of all, clinical understanding, have recently coalesced to make CYP450 genetic testing an essential component of high-dose opioid therapy. It is my recommendation, therefore, that patients who require more than 150 mg per day of morphine equivalents be tested for three specific CYP defects—2D6, 2C9, and 2C19.

To study the validity of genotype testing, I prospectively studied 66 patients on high-dose opioids in my pain clinic. The study found that the vast majority of these patients had CYP450 defects.

What Is CYP450?
Although the name cytochrome P450 is somewhat unfortunate—perhaps a better name would have been “drug metabolizing enzyme system”—the enzyme derives its name from the heme pigment (deep red color), which absorbs light at a characteristic wavelength of 450 nanometers. CYP450 enzymes are primarily found in the liver, but can exist in the intestine, lungs, brain, and kidney. The CYP450 system consists of 481 separate genes that code for 74 unique families. A family name is denoted by an Arabic number, the subfamily by a Roman uppercase letter, and the individual enzymes by another Arabic number following the letter indicating the subfamily (ie, CYP-2D6).3-5

Table: Metabolism of opiods

Why Is CYP450 Important?
There are a number of opioids that are affected by CYP450 (Table 1).6-20 Those that are metabolized via CYP enzymes include codeine, hydrocodone, oxycodone, tramadol (Ultram), fentanyl, and methadone. Some of these opioids are metabolized to metabolites for analgesic effectiveness and for elimination from the body to prevent a toxic build-up of opioids. Those opioids that are unaffected or mildly affected by CYP450 include morphine, hydromorphone, oxymorphone (Opana), and tapentadol (Nucynta).6-19 Three opioids—hydromorphone, oxymorphone, and tapentadol—primarily use the alternate system, glucuronidation, for metabolism, so they may be used as therapeutic alternatives for clinical trials in patients who have defective CYP450 metabolism.1,20

Patients vary in their CYP enzyme expression and function, which leads to distinct phenotypes. Genetic CYP testing has a terminology that may be unfamiliar to some medical practitioners.4 Laboratory results will list patient results as extensive metabolizer (EM; normal enzyme), rapid or ultrarapid metabolizer (UM; overactive enzyme), intermediate metabolizer (IM; underactive), or poor metabolizer (PM; inactive or minimally active). The latter two, IM and PM, mean the enzyme has decreased function (Table 2).21

Table: Opioid dosage and CYP enzyme deficiencies

It is also important to point out that most opioids will act without biotransformation at the opioid receptor, and provide pain relief without being metabolized by the CYP or glucuronidation system. However, some opioids are robustly metabolized in first-pass effect. This explains the increasing utilization of sublingual, buccal, patch, subcutaneous and intravenous injection, and intrathecal routes for opioid administration, since these non-oral routes allow either greater opioid effect or reach the central nervous system (CNS) prior to entering the liver.

Who Should Be Screened?
No published guidelines yet exist for generalized testing of the CYP system outside of certain populations (specific cancers, patients requiring anticoagulation, and human immunodeficiency virus patients). A major reason to perform CYP450 genetic testing is to identify pain patients who legitimately require a high-dose, or unusual, opioid regimen.2,22 This includes patients who continually complain of inadequate pain relief despite standard opioid dosages, identify drugs that are more effective, or describe medicines that do not work well. Patients with a daily morphine equivalent dosage requirement of more than 150 mg per day should be tested to help validate that a high opioid dosage is needed. Caution must be exercised, however. All too often, these patients may be erroneously labeled as drug seekers or addicts. Before these labels are applied to a patient in pain, CYP450 testing should be considered.

Another reason to consider testing is the risk of drug–drug interactions (DDIs). A significant number of drugs may inhibit or enhance (induce) the activity of certain agents, thereby increasing or reducing clinical effects of drugs. Most DDIs involving opioid medications involve CYP450 inhibitors, which cause an increased level of opioids in the system—thus, placing a patient at risk of sedation, respiratory depression, and possible toxic effect.1,10,13

CYP450 testing also may guide the practitioner in the selection of opioids that are compatible with a patient’s genetic status. For example, a patient with a CYP-2D6 defect may not respond well to codeine, which is considered a prodrug with the active metabolite morphine. Therefore, the efficacy and safety of codeine as an analgesic are governed by CYP-2D6 polymorphisms. Codeine has little therapeutic effect in patients who are CYP-2D6 PMs, whereas the risk of morphine toxicity following codeine administration is higher in UMs.23

Since the CYP450 system is primarily liver-based, routes that avoid oral administration and first-pass liver metabolism may be an option in certain populations. This is particularly true in patients who demonstrate multiple CYP defects. Non-oral routes include sublingual, buccal, suppository, injection, topical (patches), and intrathecal.

Table 3: CYP450 enzymes to be tested

Three CYPs to Test
Of all the enzymes in the CYP family, researchers have identified three that account for a significant amount of opioid metabolism and may currently be tested—2D6, 2C9, and 2C19 (Table 3).1,3,12 These three enzymes have been intensively studied and there are now data detailing their interactions with numerous drugs.1,4 Laboratory testing technology is reliable for these three enzymes, and third-party carriers, including Medicare, are now paying for these tests. Biologic samples for analysis can be taken from saliva, blood, or a buccal swab.

3 Responses

  1. This is so true…need to be tested again.

  2. OMG, I suffer from to much nerve damage from spinal trauma to list so I will say multilevel, from my head to sacral. 2cm cyst at the S2/S3 level and 1.5cm cyst at the T1/T2 level. Right knee is in need of total replacement an right shoulder severe impingement syndrome with severe neuropathy in my legs from the trauma to my spine, with a good dose of PTSD. In other words lots of chronic pain. I was started on pain management in 2006, loritab 10/650, 3 times daily among a host of other medication’s. In less than three years my liver shut down. After two hospitals had given up I ended up in University of Ky hospital under the care of there top surgical transplant team. I tell this from people telling me because I was swelled and extremely jaundice an have no memory of it other than initial hospital. Ended up with Chemical hepatitis, from Tylenol and infiltrated fatty liver, NAFLD. I was taken off the high Tylenol doseage an given oxycodone 15mg twice daily for what I was previously going thru and liver pain.Finally got recoverd doing pretty good. 2 years later I was upped to oxycodone 15mg 3 times daily. Then in 2012 the HB-1 pill mill bill was to save everybody from the devil opiates and all of a sudden you cant find a Dr that will prescribe I was cut off cold turkey. Untill that time I had never had any issues with my medicines other than not enough but allways tried to take less, when I understood what they were talking about when they said withdrawal. I almost died. Since 2012 when I try to see a new Dr, because I hand my records and say I cant take Tylenol I’m automatically a drug seeker and told that its bad for me and I don’t need it learn to cope. I am at my wits end can’t sleep, can’t walk hands are drawing up, constant sickening pain with no relief since the oxycodone was taken in 2012. Finally gave up and didn’t say anything about my liver condition and was given 7.5/325 hydrocodone 3 times daily just to keep my sanity. But god bless you for this info because I’ve always felt like it has taken more for me to get relief since my liver failed maybe this is it . I will be printing this page and attempting to discuss with my DR to at least run tests as my liver enzymes are messed up anyway, but about afraid to, my experience has been if you say anything you are kicked out. Set down shut up be stupid and just let them do what they want just to get a little relief. Thanks again so much for this info it just might be a Godsend

    • You are absolutely right!! The Dr.s almost ALWAYS just see you as a drug-seeker & or junkie. It made me feel like shit when they treated me like that. I wanted to die!! Thank the Lord, he guided me to my new Dr. of now almost 3 yrs. He is a GOD send!! He actually sits there for as long as you or he needs to talk about everything, so you understand why hes putting you on certain meds. I was diagnosed with 2 bulged discs in my lower back, horrible pain!! And even tho i knew it since i was 11 when i got my first period, that my cramps where worse than everyone elses, finally my family dr.(bitch) got tired of me complaining & sent me to a female parts dr./surgeon. Finally after 16 yrs, he did minor surgery and diagnosed me with level 2 endometriosis (tiny blood clots on my uterus, that swell during my monthly & cause me terrible, debilitating cramps & HEAVY bleeding.) And bad thing about it, is the dr. can burn some of the timy blood clots with a laser but they come back & spread throughout your body. When he did the first surgery & diagnosed me, he also had to remove my appendix cuz it was infected wih the tiny blood clots. Also, i broke my left tibia & ankle in 2013, so there is still pain from that. Plus, fibromyalgia & sciatica. But i am gonna show my dr. this cuz ive been on a low dose of oxycontin for almost 1 1/2 yrs now & it doesnt last as long as it used to. My worst experience before i met my current God sent dr. I had to drive 2 hours to another city to see this pain management dr that actually made me cry!! He called me a junkie to my face! And said because i used to be a cutter, he saw the scars, that he thought i was just a junkie & he would prescribe me something, but only cuz he had to treat my bulged discs, but not oxy or hydrocodone, instead he put me on 2 low dose patches of fentyl a day. They left horrible marks on my body & didnt work!!

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