Pharmacogenetics: Using science to reduce racial bias in pain management?

The medical community stands at an important crossroads and must move towards a more biologically based approach to health care if it hopes to dismantle systemic racism and ensure equitable care to all patients. Currently, systemic racism in health care harms patients of color, as evidenced by healthcare disparities for people of color during the COVID pandemic. The pandemic and other recent movements in medicine, such as eliminating race from equations used to estimate kidney function, have raised greater awareness in the medical community about the illegitimacy of race as a biologic construct and its use for directing medical care.^1,2 These events also provide an opportunity to address the racial bias inherent to certain aspects of health care. Opiate prescribing is a classic example of where race issues introduce inequity. This article will discuss race and opiate prescribing and how a pharmacogenetic-based approach may help address some of the healthcare disparities resulting from raced-based medicine and the systemic racism present in our current healthcare system.

Opiate prescribing is demonstrably complicated by racial bias, and this leads to health care disparities.³ In the United States (US), patients are provided differing pain management strategies depending on whether they are Black or White. These practice patterns are evident across many distinct types of pain including acute pain, chronic back pain, peri-surgical pain, and cancer-related pain.⁴ The disparities related to cancer-related pain assessment and treatment are particularly striking. Minority patients with cancer frequently report higher pain severity relative to nonminority patients.^5,6 Despite these differences in pain severity, Black patients are routinely under-prescribed opiates compared with White patients.^3,4 Minority patients with cancer-related pain have twice the odds of having their pain undertreated relative to White patients.⁷ These differences persist across the age spectrum as older Black patients with cancer-related pain are also less likely to receive opiates for their pain compared to their White counterparts.⁸

There are multiple reasons why these discrepancies exist, but provider beliefs and biases in regard to race play a role. Prior work by Hoffman, et al. demonstrated that many medical providers hold false beliefs about biological differences in pain responses amongst different races.³ These beliefs, in turn, lead to differences in pain management strategies. For example, White physicians wrongly label Black patients as possessing a higher pain tolerance relative to White patients.³ This misconception, which leads to Black patients being undertreated for pain, does have not a basis in biology but instead reflects ongoing racial bias. Racial bias inherent in the medical system affects assessment of interindividual pain thresholds and opiate dosing resulting in under-treatment of pain in Black patients. This flawed model of approaching pain assessment and opiate dosing necessitates a novel, superior, biologically based approach instead of one based on biased societal constructs.

Our group recently began investigating the impact of pharmacogenetic variations on opiate metabolism and clinical response. Considerable variation exists in many single-nucleotide polymorphisms (SNP’S) involved in opiate response and pain threshold. For example, SNPs rs7439366 in UGT2B7 and rs776746 in CYP3A5 are associated with inter-individual variability in fentanyl serum concentrations.⁹ Loss of function mutations such as ones observed at rs776746 likely lead to an exposure-response relationship in that reduced metabolism of fentanyl leads to increased serum concentrations and more adverse effects from opiates (e.g., over sedation).¹⁰ Individuals with two T copies at this location experience decreased fentanyl serum concentrations per a given fentanyl dose compared with those with two C copies. The clinical effect of this is that the individuals with two T copies may experience less pain control and those with two C copies are at risk for over sedation or other adverse effects. There is substantial heterogeneity along social constructed racial and ethnic demographics at this SNP (Figure 1). Six percent of Whites have the T variation at this allele, compared with 82% of Blacks and 20% of Hispanics. Taken in isolation, this would suggest that Blacks are more likely to have decreased fentanyl concentrations and resultant pain control per given dose compared to Whites.

FIGURE 1.

Minor Allele prevalence by ancestry for single nucleotide polymorphisms involved in opiate pharmacogenetics.

Functional SNPs in genes are also likely important predictive biomarkers of clinical opiate response. Two examples of such SNP’s are rs1799971 in the μ-opioid receptor gene (OPRM1) and the rs4680 in the catechol-O-methyl transferase gene (COMT). Individuals with two copies of the mutant G allele at OPRM1 rs1799971 experience significantly more somnolence, per given fentanyl dose, compared with those with at least one copy of the wild-type A allele.¹⁰ Postoperative patients with two copies of the mutant A allele at rs4680 have increased pain sensitivities compared with those with the wild-type G allele.¹¹ Individuals with two copies of the G allele have lower pain scores after a given opioid dose compared with those with two copies of the A allele. 72% of Blacks have the G variation at this allele, compared with 50% of Whites and 62% of Hispanics. Taken in isolation, this would suggest that Blacks and Hispanics have a greater response to a given opioid dose compared to Whites.

There is heterogeneity in the prevalence of all these SNP’s that varies, to a degree, along socially constructed racial and ethnic demographics (Figure 1). As our examples illustrate, not all members in the socially constructed racial categories possess the at-risk SNP changes. For example, only half of White participants had the COMT variation, and a third of Black participants possessed it. This demonstrates ancestral admixtures that conflict with societally constructed racial categories. Further, the pharmacogenetic approach can differ from preexisting biases in the medical field. For example, the finding that the Black population has a higher prevalence of an allele at rs776746 that leads to decreased fentanyl concentrations is contrary to the belief that Black patients require less opiates for pain control.

SNP analysis and pharmacogenetic-based opiate prescribing offers a much more precise and biologically driven approach which could reduce the racial and ethnic bias in opiate prescribing practices.^12–16 Evidence of the impact of different SNP’s in opiate drug response is growing. We suggest that it will soon be time to incorporate a pharmacogenetic-based opiate prescribing approach into clinical practice and is past time to abandon societal constructs of race. This approach could potentially reduce health care disparities in under-prescribing of pain medications of Black patients. It could additionally ensure that Hispanic populations are provided with medications that are most likely to effectively treat their symptoms while minimizing adverse effects.

Further research into pharmacogenetics and a biologically driven approach to pain management, and other areas, is imperative. Further defining the pharmacogenetics of opiates will provide a biologically sound approach to clinical decision making regarding opiate prescribing. We posit that this will lead to more targeted opiate selection and dosing. This should lead to improved, equitable care delivery to minority patients. Although this approach will not remove the barriers to accessing high-quality health care for people of color in the United States, it will hopefully reduce some of the current impact of systemic racism by improving the diagnosis and management of pain and reduce health disparities.