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Genetic Testing in High-Dose Opioid Patients

Editor's Memo from July/August 2016

The new Centers for Disease Control and Prevention (CDC) opioid prescribing guidelines for primary care physicians have clearly set a national standard for opioid selection and dosing, cautioning prescribers to carefully assess and reassess the risks versus benefits of opioid therapy for each patients. Specifically, the guidelines note that primary care clinicians should avoid increasing a dosage beyond a threshold of 90 morphine milligram equivalents (MME) a day.1 Indeed, this level need seldom be exceeded in primary care.  

My personal gripe about the CDC guidelines is that I can’t find a single, public statement from any CDC official or member of its panel of consultants indicating that a pain patient may legitimately require and benefit from a daily opioid dosage over 90 MME, or who should treat these high-dose patients. The guidelines note that physicians “should justify a decision to titrate dosage to 90 MME or more per day,” which may be in reference to new chronic pain patients. The guidelines also legitimately urge clinicians to evaluate “benefits and harms” of continued opioid therapy at least every 3 months—and when there are signs that the opioid is no longer beneficial, “have a plan to taper opioids to lower dosages or to taper and discontinue opioids.”1

Interestingly, Nora Volkow, MD, the director of the National Institute on Drug Abuse, along with Thomas McLellan, PhD, a highly noted and respected addiction researcher, just published a thoughtful and objective article, “Opioid Abuse in Chronic Pain—Misconception and Mitigation Strategies,” in which they wrote: “We acknowledge that such higher dosages may be warranted in some circumstances.”2 It’s nice to see that some government officials see the side of the legitimate, suffering pain patient who doesn’t abuse opioids but yet requires over 90 MME.

For the record, there are thousands of severe, chronic pain patients who have been rescued by and maintained on an opioid dosage over 90 MME. There are also thousands of severe, chronic pain patients currently maintained on opioid dosages over 90 MME who are in good health, function well, and have a good quality of life. Their entire well-being will be endangered if they can’t remain on an opioid dosage over 90 MME. Attempts to strip patients of their lifesaving medication through barriers imposed by insurance coverage, governmental guidelines, or supply restrictions are disgraceful and inhumane.

Screening Tool: Genetic Testing

The new CDC guidelines and some state guidelines now force us to answer this pertinent question: “Which chronic pain patients legitimately require over 90 MME a day?” How do we identify these individuals? Very little scientific information is known about patients who find pain relief only at high opioid dosages.

Genetic variability (that is, the inability to metabolize opioids normally) is one obvious answer. Fortunately, genetic testing has recently taken a step forward to help explain the necessity for high-dose opioids in some patients, as well as provide the ability to identify severe chronic pain patients who will require over 90 MME.

Practical Pain Management published the first article introducing cytochrome P (CYP) 450 defects in pain patients in 2010.3 This was followed by my first article on genetic testing in 2011, which focused on the newly developed CYP450 enzyme tests.4 At that time, only 3 enzymes (2D6, 2C9, and 2C19) were available for clinical testing. Preliminary studies with these 3 enzymes indicated that there was a high prevalence of enzymatic defects in patients who required over 100 MME. In recent months, 2 additional CYP 450 enzymes (2B6, 3A4,5) have become universally available in genetic profiles. The CYP 450 enzymes are known as “pharmacokinetic” in that they metabolize or process an ingested drug, including opioids.

Now we also have 2 new genetic tests, which are known as “pharmacodynamic tests” in that they describe a drug’s physiologic action after it is ingested and metabolized. They are now widely available in genetic profile testing and are very helpful in explaining why some patients require high-dose opioids. One measures opioid receptor binding capacity (opioid mu receptor 1, OPMR1), and the other measures catechol-o-methyltransferase activity (COMT). This enzyme deactivates catecholamines, such as norepinephrine and dopamine, that are known to be critical neurotransmitters in the central nervous system (CNS) for pain relief. If a patient has low or intermediate opioid receptor binding capacity, the patient will need a higher than normal opioid dosage. If a patient has too much COMT activity, the CNS won’t have enough catecholamines for maximal pain control, so the patient who has a high or intermediate genetic rating will need a higher than usual dose of opioids.

I have found the new genetic profiles to be most critical and helpful in identifying patients who need over 90 MME.5,6 In a recent survey I conducted in my clinic, 101 severe intractable pain patients on opioid dosages over 90 MME were tested for CYP 450 defects.7 Of the 101, 91 (90%) tested positive for 1 or more CYP450 defects. A total of 132 defects were found in the 91 patients. Twenty-eight (30%) of these patients had a defect in 2 CYP450 enzymes, and 8 (8.7%) had defects in 3 enzymes. Forty-five patients were also tested for OPRM1 and COMT. Thirteen of 45 (28.9%) had intermediate or low OPRM 1 activity, and 28 (62.2%) had intermediate or high COMT activity levels. These activity levels indicate that higher opioid doses will be necessary for pain control.  

Justifying Higher Doses

Every pain practitioner has to make it abundantly clear to all parties that some severe chronic pain patients require over 90 MME. In addition, new genetic profile testing helps identify and explain why this is the case. Table 1 lists the genetic tests that I recommend. This same profile should be performed on a severe chronic pain patient who may require an unusual, nonopioid pain regimen. Even in my early experience in pain management, I have found patients with such bizarre genetic profiles that the patient will need to bypass systemic metabolism and use intrathecal pump administration. One patient with such a profile receives more pain relief with zolpidem than oxycodone.

It is now common knowledge that some bona fide, severe chronic pain patients are being denied opioids via insurance company restrictions, supply limitations, and governmental guidelines. Genetic testing and the presence of metabolic abnormalities give us a critical tool that we can use to advocate against some misguided and harmful threats to patients.

Last updated on: August 5, 2016
First published on: August 1, 2016
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