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Robert Nerenz and Gregory Tsongalis. Pharmacogenetics of Opioid Use and Implications for Pain Management.
J Appl Lab Med 2017;2:622-32.
Dr. Robert Nerenz is Assistant Professor of Pathology and Laboratory Medicine and the Assistant Director of Clinical Chemistry at Dartmouth-Hitchcock Medical Center.
Hello, and welcome to this edition of “JALM Talk” from The Journal of Applied Laboratory Medicine, a publication of the American Association for Clinical Chemistry. I’m your host, Randye Kaye.
Opioids are frequently prescribed for pain management but there is large inter-individual variation in opioid-induced pain relief. These compounds are metabolized by enzymes leading to active and inactive metabolites, and there are differences in the quantity or presence of these metabolites between individuals. This complicates the interpretation by clinicians of urine drug tests that are often administered to patients prescribed opioids. Further, although opioid addiction is a worldwide problem, only some of the individuals exposed to these drugs become addicted to them.
A mini-review titled “The Pharmacogenetics of Opioid Use and Implications for Pain Management” published in the January 2018 special issue of JALM on Laboratory Support of Pain Management discusses these complex topics. The first author of this article is Dr. Robert Nerenz, Assistant Professor of Pathology and Laboratory Medicine and the Assistant Director of Clinical Chemistry at Dartmouth-Hitchcock Medical Center, and he’s our guest for today’s podcast.
Welcome Dr. Nerenz. First question, in your review, you indicate that an estimated 30% of the U.S. population suffers from chronic pain and that in 2012, enough opioid prescriptions were written for each American to have his or her own bottle. Yet, expert guidelines discourage such widespread prescription of opioid painkillers. Why is this?
I think there’s a general understanding that opioids for acute pain, a short term thing immediate response following a medical procedure like a wisdom tooth extraction, you can do Tylenol-3 with codeine for two to three days to deal with the worst of the pain, and opioids for acute pain are not a big problem.
It’s really more the chronic pain that I think is drawing people’s attention for a number of reasons. One is there’s really limited evidence that opioids for the treatment of chronic pain really have long-term benefit in terms of improved function or improved quality of life. And then, there’s also the potential for serious immediate adverse events like nausea, vomiting, dysregulation of the hypothalamic-pituitary-adrenal axis, and then in the most extreme, potentially fatal respiratory depression. In 2015, 33,000 Americans died from an opioid overdose and that number has quadrupled since 1999 and continues to climb every year.
So in addition to the acute adverse events, like we talked about, we also need to consider the risk for the long-term adverse events like opioid dependence. And we know that approximately 80% of heroin users started out by misusing prescription painkillers. So either their own that were prescribed for them legally or somebody else’s that they obtained somehow. And so, there’s an understanding that as medical professionals, we need to limit the potential for abuse by being careful about the amount of drug that we distribute.
Wow, that’s quite an amazing statistic, 80% of heroin users started out by misusing prescription painkillers. Wow, that is of note. Now, you also note that not all people react to opioids the same way. Can you explain why?
Yes, it’s is true. And we know that some people experience adequate pain relief using a standard dose while other people require much higher dose or a much lower dose. We also know that opioids make some people nauseous, while other people can take opioids just fine. Some people become addicted to opioid treatment while others don’t. Some people adhere to opioid addiction treatment programs while others relapse.
So there is lots of variability in a number of different opioid treatment-related outcomes. And we also know there are lots of variables that go into determining an individual’s opioid response, both in terms of immediate pain relief and then also long-term risk for addiction. And some of those things are psychosocial factors, like who you interact with, who are in your social circle, how you feel about yourself, what your employment status is. And then there are also things like age and sex and general state of health. And then lastly, genetics are now being shown to play a pretty important role in determining opioid response.
Clearly, the genetics is a very interesting piece and it’s clearly an area of interest to you, so let’s talk more about that. How do genetics help determine an individual’s response to opioids?
There are many proteins involved in a number of different biological processes that collectively determine an individual’s opioid response, and several different sequence variants had been identified in the genes that encode these proteins. And these sequence variants are typically single-nucleotide polymorphism or SNPs for short, they can also be deletion or duplication events wherein an individual will have more than the standard two copies or fewer. And all of these things can affect the function and expression of the proteins that these genes encode.
You mentioned about different biological processes, can you say more about that? What do these proteins do exactly?
Well, some of these proteins are involved in opioid metabolism and when we think about pharmacogenetics, this is really the group of proteins that first comes to most people’s minds. These are the hepatic cytochrome P450 enzymes that mediate phase one reactions, where you modify apparent opioid in some way, you either add a chemical group or you remove a chemical group. It’s important to keep in mind that the metabolite which the parent compound gets turned into can either be more or less potent than the parent drug.
So a good example here is CYP2D6 that’s responsible for converting codeine to the more active morphine, and hydrocodone is a parent to the more active hydromorphone. And we know that CYP2D6 is a very polymorphic gene, there are lots of different sequence variants that have been characterized. And importantly, we know that about 1-2% of the general population are ultrarapid metabolizers with a very high degree of enzyme activity. And so these people actually convert more of the parent codeine to the active morphine than your typical patient. And so, they need a lower dose to avoid respiratory depression. On the other hand, approximately 5% to 10% of people are poor metabolizers, and conversely, they need a higher dose to experience pain relief because they convert relatively little of that codeine to morphine.
Interesting. Are the efforts to predict the opioid response, are they solely focused on drug metabolizing enzymes?
Not really. As we talked about, there are a number of different biological processes that are relevant here. We know that opioids exert their effects by binding to opioid receptors in the central nervous system which then translate that opioid signal into the analgesic effect that we feel. And just like SNPs in the metabolizing enzymes, we know that there are SNPs in the genes that encode these opioid receptors. The SNPs can generate non-functional receptors, receptors with variant amino acid sequence that then may bind drug with a different affinity or exhibit different signal tranduction properties.
And so even if two patients metabolized drug the same way, they may feel its effects in very different ways because the differences in their receptor activity.
A good example here is OPRM1, that’s the gene that encodes the mu opioid receptor which is one of the main opioid receptors. There are number of well-characterized SNPs that generate receptors with altered opioid binding affinity. And some of these SNPs have been shown to occur more frequently in opioid-addicted patients relative to non-addicted controls which implies that this altered binding affinity somehow influences the drug’s effect in a way that makes these individuals that harbors this SNP, or this altered receptor, more drug-dependent or more susceptible to becoming drug-dependent.
In addition to those two general classes, an opioid response is also dependent on rates of drug transfer into and out of the central nervous system by specific transporters.
One example here is ABCB1 and it has been shown that particular variants in this gene are associated with different morphine dose requirements in patients with chronic pain or different methadone dose requirements in patients who are undergoing addiction treatment.
There’s so much to this, isn’t there? What are the tools that are available now that would help clinicians determine what opioid dose the patient should receive or might signal that the patient should be steered away from opioids all together because of that high risk for addiction?
Well, there a couple of different ways to answer this question. For immediate dosing decisions about pain management, will somebody get a full analgesic effect? CYP2D6 is really the best we have to identify poor metabolizers and ultrarapid metabolizers. For the other side of that question, for risk of addiction, the current standard is to use a risk questionnaire. So kind of move away from genetic testing entirely. And so, we ask patients, “Do they have a family history of substance abuse? Do they have a personal history of substance abuse? What’s their age? Have they experienced sexual abuse? Do they have history of mental illness?” And we acknowledge that it’s a largely imperfect system, it relies on accurate self-reporting by the patient and it includes largely psychosocial factors without incorporating other determinants of opioid response like genetics.
Yeah. So self-determination, it’s always a little bit risky. Can genetic testing predict whether someone will experience the desired therapeutic response?
Yes, for some things. We’ve talked a lot about CYP2D6 and codeine. And for the purposes of pain management that gene drug pair has been fairly well-characterized but it’s really the only one that’s available to us. So yes, for some things, but no for others, like, if you want to determine likelihood of success in the methadone maintenance program for individual seeking opioid addiction treatment. We know that there’s variability in treatment program adherence. But these firm associations like we have for codeine and CYP2D6 between a genetic variant and methadone treatment outcome really have yet to be made.
Well then, can genetic testing predict whether someone is at risk for addiction?
Yes. That’s also a tricky question to answer. At present, no, not really. But there is a lot of preliminary evidence that associates certain SNPs, like the OPRM1 variant that we talked about earlier, with increased risk of addiction. And so far, these are really compelling studies but we need to take the next step to translate these basic research findings into clinical practice and show conclusive benefit. We really need to show that patients who undergo this type of testing can have their treatment modified in a predictable and meaningful way and that this actually improves outcomes.
I can certainly envision a future state in which opioid treatment decisions are informed by the presence of a certain SNP or the absence of a certain SNP. But we really have a long way to go before that becomes common practice.
Tell me about that challenges that might be facing the routine use of pharmacogenetic testing for pain management in clinical practice.
So there are at least three big challenges that come to mind and there are probably more that I haven’t quite thought of. But the first one is if you review the literature, there’s a fair amount of conflicting evidence in these basic research manuscripts that talk about association of a certain SNP with some kind of outcome or some kind of observation.
And so, an individual SNP may be associated with opioid dose or addiction risk, for example, in one study, but another study may come along and find no association. We understand that the genetic background in which this SNP is found could explain some of these discrepancies. So in one ethnic group with one genetic background, the SNP may be relevant and in a different ethnic group with a very different genetic background, the SNP may show no association or no clinical value.
And so moving forward, we have to look very closely at these genetic background ethnicity type questions. And then, also taking into account multiple different SNPs rather than looking at single SNPs in isolation. Let’s look at the effect a single SNP of interest may have in kind of co-inheritance situation with other different SNPs.
A second big problem is there’s really a lack of clinician experience in the whole realm of pharmacogenetic testing. Many clinicians went to school in an era where pharmacogenetics didn’t exist. In their current practice, they really don’t use them on a routine basis. And so, they’re not comfortable ordering pharmacogenetic testing. If they do, they’re not comfortable interpreting the results when they come back. And they’re certainly not comfortable changing their patient management based on those test results. This is certainly an area where we, as laboratorians, can take the lead by providing some active utilization guidance and getting clinicians into this whole new realm of testing.
And then another big one is reimbursement. And so, tests with clear objective improvements and outcome, and that are being performed for patients who meet to certain predetermined criteria, are reimbursable. CYP2C19 for example, in patients with acute coronary syndrome who are undergoing percutaneous intervention and initiating Plavix therapy, so there are lot of conditions there. There are a lot of “ands.” So, testing is covered in these patients but it’s not covered or determined to be medically necessary for other indications.
So it’s really up to the lab medicine community to demonstrate improved outcomes in the patients for whom pharmacogenetic testing is performed to either increase coverage from a payer perspective or convince hospital administration to make the institutional commitment to pay for testing, understanding that it won’t be reimbursed, but knowing that downstream cost savings will offset the cost of this non-reimbursed testing.
Wow, such interesting information and a very important topic. Dr. Nerenz, thank you so much for joining us today.
Absolutely. Thank you for having me.
That was Dr. Robert Nerenz from Dartmouth-Hitchcock Medical Center, talking about the JALM mini-review, Pharmacogenetics of Opioid Use and Implications for Pain Management (PMSI) for this podcast. Thanks for tuning in for “JALM Talk.” See you next time and don’t forget to submit something for us to talk about.