Amid the ever-growing toll of the opioid epidemic, chronic pain remains both discouragingly common and difficult to treat, experts said at ASHP Pharmacy Futures 2024, in Portland, Ore. The presenters noted that more than 100 million Americans suffer from pain, analgesics often provide insufficient relief and poorly controlled pain is itself the most common motivation for opioid misuse (J Pain 2015;16[8]:769-780; AHRQ 2020; Bookshelf ID: NBK556253; Ann Intern Med 2017;167[5]:293-301). However, pharmacogenomics (PGx)—the field concerned with understanding how genes affect drug response—offers promising avenues to improve pain treatment.
Genetic tests can flag whether a patient is vulnerable to adverse events or ineffective pain control for certain analgesics. This information could enable pharmacists to identify patients who may respond well to lower potency opioids and nonopioid analgesics. (Other pain treatment strategies such as nerve blockers can also be considered as alternatives, noted speaker Henry M. Dunnenberger IV, PharmD, BCPS, the assistant vice president of personalized medicine and pharmacogenomics at Endeavor Health, in Illinois.) A PGx-guided approach could provide safer and more effective pain management while decreasing the risk for opioid misuse (J Am Coll Clin Pharm 2022;5[2]:239-250).
“I’m very committed to viewing pharmacogenomics as a patient safety strategy that we should use more,” said James M. Hoffman, PharmD, MS, FASHP, the senior vice president of quality and safety at St. Jude Children’s Research Hospital, in Memphis, Tenn.
Dr. Hoffman and his fellow presenters discussed current evidence and strategies for using PGx to guide prescribing of pain medications.
PGx Genes of Interest
The Clinical Pharmacogenetics Implementation Consortium (CPIC) offers guidelines on how to use PGx results for the drug classes most widely deployed against pain: opioids and nonsteroidal anti-inflammatory drugs (NSAIDs). “These are the guidelines I use on a daily basis in my clinical practice,” said D. Max Smith III, PharmD, BCPS, a clinical pharmacogenomics specialist at MedStar Health and an assistant professor at Georgetown University Medical Center, in Washington, D.C.
Based on current CPIC guidelines, Dr. Dunnenberger said, two genes have enough clinical evidence to support broad implementation in pain care: CYP2D6 and CYP2C9. “But the story for how genetics helps optimize pain management isn’t finished; CYP2B6, OPMR1 and COMT should be viewed as potential future candidates with more research,” he told Pharmacy Practice News.
Resource Box: A How-to Guide for PGx
Dr. Smith and his colleagues developed a how-to guide to implement PGx-guided pain management based on CPIC recommendations (J Am Coll Clin Pharm 2022;5[2]:239-250).
“Optimizing pain management through genotype-guided approaches may provide more effective pain control including promoting nonopioid options for some patients, thus representing one additional important tool in combatting the opioid epidemic,” the authors wrote.
They proposed key considerations for incorporating PGx data into prescribing decisions, which involve:
- assessing clinical factors;
- determining whether a patient’s PGx panel includes the appropriate genetic variants;
- synthesizing genetic test results and the patient’s medication list to determine how they will metabolize the relevant opioid or NSAID; and
- using CPIC guidelines to guide therapeutic recommendations.
CYP2D6 encodes an enzyme crucial for metabolizing opioids, such as tramadol, into more potent forms. Tramadol’s active metabolite, O-desmethyltramadol, “has a 200-fold higher affinity for the opioid receptor compared with the parent drug,” Dr. Smith said. “CYP2D6 is the gateway to get to that analgesic effect. So, if there’s variability in CYP2D6, then there could be variability in that effect.”
Depending on which CYP2D6 alleles a person carries, they may be an ultrarapid, normal, intermediate or poor metabolizer of tramadol or codeine (Clin Transl Sci 2020;13[1]:116-124; Clin Pharmacol Ther 2021;110[4]:888-896). “As you have less enzyme function, you get less active metabolite. So those poor and intermediate metabolizers are associated with less of the active metabolite,” Dr. Smith said. “On the flip side, as you add more enzyme function—as in ultrarapid metabolizers—you get more active metabolite.”
He noted that although evidence for this gene’s influence on hydrocodone, oxycodone and methadone remains weak, CPIC offers relevant clinical recommendations for tramadol and codeine (which is converted to morphine by the CYP2D6 enzyme). The drugs should be avoided in ultrarapid and poor metabolizers due to the risks for, respectively, toxicity and ineffectiveness. “The risk for hypoxia and respiratory depression, including fatal toxicity, in CYP2D6 ultrarapid metabolizers may be elevated in pediatric patients or those with other risk factors for respiratory depression,” Dr. Smith noted. Normal and intermediate metabolizers can receive the label-recommended dose, he added, but the latter should be monitored more closely and switched to a different drug if needed.
“What the genetics tells us is the instruction manual of what is supposed to happen with the enzyme function,” Dr. Smith said. However, he emphasized that a patient’s other medications constitute another important variable for pharmacists to consider because certain drugs, such as the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and paroxetine, can interfere with CYP2D6 activity. “They would shut off that enzyme function even though your genetics say you should have CYP2D6 function,” he said.
In contrast to the aforementioned opioids, Dr. Smith continued, NSAIDs are metabolized into inactive metabolites. The enzyme encoded by the CYP2C9 gene plays a major role in this process. Patients with CYP2C9 variants that decrease their ability to break down NSAIDs will carry higher concentrations of the drugs in their bodies. “As you have higher exposure to NSAIDs, there’s also a higher risk for toxicity,” Dr. Smith said. This can take the form of serious gastrointestinal, renal or cardiovascular adverse events. Depending on the rate at which a patient metabolizes an NSAID—for example, meloxicam, ibuprofen or piroxicam—CPIC offers clinical recommendations that range from standard therapy to dose reductions or alternative drugs such as naproxen and aspirin (Clin Pharmacol Ther 2020;108[2]:191-200).
Although instances of CYP2D6 ultrarapid metabolizers experiencing overdoses with codeine have been reported, Dr. Dunnenberger said, there is not enough clinical evidence to support using PGx to predict opioid use disorder. “How best to use PGx to optimize treatment plans and better control pain is an area of continued research,” he said.
Pragmatic Trials of Guided Prescribing
Dr. Smith and his colleagues have explored the effects of PGx-guided prescribing on pain control.
“Prior studies have shown that ineffective pain control is the most commonly reported motivation for opioid misuse,” he told PPN. “My colleagues and I have found CYP2D6-guided pain management can [yield] more effective treatment. … Therefore, we’ve suggested CYP2D6-guided opioid prescribing may be able to reduce the risk for opioid misuse by selecting more effective treatment plans upfront” (see box).
In one study, the researchers enrolled 370 chronic pain patients from seven clinics in CYP2D6-guided opioid prescribing or typical care groups. In the former group, Dr. Smith or another pharmacist reviewed PGx test results and a patient’s other medications to determine whether their genotype or drug interactions rendered them a poor or intermediate metabolizer of tramadol or codeine. For these patients, the pharmacist then sent consult notes to the patient’s provider with recommendations to prescribe alternative therapies.
The researchers reported that, over three months, 24% of the PGx-guided group experienced a 30% or greater reduction in pain intensity, compared with none of the usual-care participants (Genet Med 2019;21[8]:1842-1850). This percentage “is still not great,” Dr. Smith acknowledged. “Chronic pain is difficult to treat … [but 24%] is significantly better than zero.” He described the work as a “pragmatic trial” to evaluate the clinical significance of PGx test results and whether their approach could offer a model for integrating PGx into routine care.
Dr. Smith and his team recently concluded a larger trial that took a similar approach and included 20 primary care practice sites (ClinicalTrials.gov Identifier: NCT04685304). Patients were tested with an eight-gene panel (CPIC recommendations were available for seven of the genes). “We scanned the patient’s chart and really took a whole-patient approach to this where we said, ‘I know that this patient has chronic pain, but let’s … see what else they have going on,’” Dr. Smith said. “Do they have depression? If so, there are CPIC guidelines for antidepressants like SSRIs. We would then integrate those guideline recommendations into our consultation.”
The primary analysis did not identify a difference between PGx-guided and standard care, Dr. Smith said. “These results were not surprising once we saw the proportion of patients with PGx-aligned care was similar between groups,” he explained. “In other words, our recommendations didn’t change prescribing decisions and so it was not surprising to see pain symptoms were similar [in the study].” However, Dr. Smith added, a pre-planned secondary analysis found that patients with an analgesic medication change that aligned with PGx results had improved pain intensity, improved physical function and less opioids prescribed to them compared with care unaligned with PGx.
The results raise questions about “how do we actually get more PGx-aligned care to happen?” Dr. Smith said. During the trial, about a month on average elapsed between the pharmacists uploading their recommendations to a patient’s chart and that patient seeing their primary care provider. “The provider needed to remember … ‘Max sent me a message with pharmacogenomic results,’” Dr. Smith said. “For this trial, we did not have pharmacists embedded in the clinics; having pharmacists in [such settings]might be one way to overcome that.”
Applying PGx to Clinical Practice
When deciding whether to order PGx testing to guide prescribing for a patient’s pain, there are several considerations to keep in mind, said Dr. Dunnenberger, who is a member of the PPN editorial advisory board.
He noted that PGx tests are relatively inexpensive, although payor reimbursement varies. “This [test] is only a couple of hundred dollars … but [it] will have lifetime value for that patient. You can keep going back to the well if it’s stored correctly,” Dr. Dunnenberger said. “And insurance coverage is growing; Medicare in most areas … will cover pharmacogenomics for some indication.”
Another challenge in applying PGx testing to pain management is that “the pain phenotype is so heterogeneous,” Dr. Dunnenberger said. “There are so many different types of pain that you can experience.” He called for more detailed investigation into the classification of pain and its causes. He envisions a future when different types of pain are linked to specific genetic variants. Understanding the genetic underpinnings of pain could make PGx implementation more effective.
Furthermore, he said, a person’s genes represent just one piece of the puzzle when it comes to their experience of pain. Dr. Dunnenberger and his colleagues evaluated 305 patients who underwent knee replacement surgery for activity on three genes involved in the opioid pathway and pain modulation. However, in this study, PGx testing was less predictive of pain and opioid use following the procedure than psychosocial variables (pain interference and anxiety scores in the Patient-Reported Outcomes Measurement Information System-43 assessment) (J Arthroplasty 2024;39[5]:1214-1219). “Pharmacogenomics is not a crystal ball,” Dr. Dunnenberger said. “It doesn’t tell you everything; you really have to contextualize it in the patient.”
“Think about your audience; not only are you going to have to be involved in talking to the patient, but also clinicians,” he said. Pharmacists can “provide clinicians with recommendations on not only just the interpretation of the results, but also therapeutic recommendations on what to do with certain drug therapies.”
Drs. Dunnenberger and Hoffman reported no relevant financial disclosures. Dr. Smith reported a financial relationship with Kailos Genetics.
This article is from the September 2024 print issue.