The variation in response to pharmacological agents between individuals has been recognized for decades. However, the underlying genetic basis that provides a rational explanation for the observation that different individuals can display widely different responses to the same pharmacological agent came to light with the sequencing of the human genome, which allowed the identification of thousands of gene polymorphisms, most often single nucleotide polymorphisms (SNPs).1,2
Polymorphism at the level of drug receptors, transporters, or other proteins involved in drug metabolism or action may have an impact on the effect of a drug, eg, by dampening its efficacy, or by increasing its toxicity. Genetic polymorphisms for many drug targets and enzymes involved in drug metabolism have been identified, particularly for anti-cancer drugs.3 Experts estimate that genetic factors account for 20% to 95% of patient variability in response to individual drugs.4 As a result, despite significant advances in pharmacotherapy, challenges related to patient subpopulations experiencing serious to fatal adverse events or not responding to standard therapy remain.
The impact of genetic polymorphism is evident in many clinical areas, including pain management. Evidence is accumulating that supports the notion that an individual’s specific response to pain or pain treatments may be affected by particular gene polymorphisms.
Cytochrome P450 2D6 (CYP2D6) genotype has been implicated in the response to opioid analgesics that depend on its metabolism for bio-activation. Variations in the CYP2D6 genotype may determine how well an individual responds to opioid analgesics.5,6 For example, “poor CYP2D6 metabolizers” (PMs) have lower concentrations of active metabolites of codeine (morphine), tramadol (O-desmethyltramadol), oxycodone (oxymorphone), and hydrocodone (hydromorphone), compared with “extensive metabolizers” of CYP2D6 (EMs), for similar treatment doses. PMs may therefore fail to achieve pain relief with these opioids compared with EMs.
The role of genetic polymorphism on postoperative pain and its response to treatment was highlighted in a study investigating the impact of several genetic variants on pain, opioid consumption, and opioid side effects. Results from this study indicated that the A118G allele variant of OPRM1 has the greatest impact on inter-individual differences in response to opioids in the postoperative patients studied.8,9
Morphine and other µ-opioid agonists are among the most commonly prescribed narcotic analgesics in the management of moderate-to-severe pain. While effective, these analgesics have highly addictive properties. The well-documented challenges resulting from opioid use and abuse10 prompted the Centers for Disease Control and Prevention to publish a guideline and checklist for prescribing opioids in the management of chronic pain.11,12
Methadone – because it reduces opioid-associated craving, withdrawal symptoms, and risk of relapse – is the treatment of choice to wean individuals off opioids.13 Titrating methadone to determine the effective maintenance dose in each patient is critical and can prove challenging. Underdosing methadone increases the risk of relapse in patients, while overdosing may lead to respiratory depression.
Opioid dependency treatment programs indicate that African-American patients are more likely to report methadone under-dosing than European-American patients, but it is unclear whether this observation reflects differences in responses to medication.14,15 Evidence is accumulating that points to genetic variants in African-Americans that influence opioid sensitivity.
Mu-opioids receptors are encoded by the OPRM1 gene, and a common missense SNP, rs1799971, has attracted attention as it plays a significant role in determining the response to opiate analgesics.
A genome-wide association study found a significant association between the therapeutic dose of methadone and another SNP, rs73568641 in African-Americans (n = 383, P =2.8 x10-8).16 A similar association was not observed in the cohort of European-Americans studied (n = 1027). In addition, a correlation between rs1799971 and the requirement of higher doses of morphine was also reported in opioid-naïve African-American children being treated for postsurgical pain.16
Commenting on the study, Joel Gelernter, MD, professor of genetics and neuroscience at Yale University School of Medicine, and lead author of this study, told Clinical Pain Advisor: “in African-American subjects, this [rs73568641] variant could identify subjects who will need a higher dose of methadone (or morphine)… We suppose that from time to time people on methadone say they are not getting enough of an effect. If a person with 1, or especially 2, effect alleles made such a complaint, one might reasonably be less skeptical about their complaint.”
While acknowledging the limitations of the current study, Dr Gelernter added: “We do think the paper suggests a role for genotyping to predict dose requirements [for example, of methadone] in the relatively near term.”
Summary and Clinical Applicability
Polymorphism of enzymes involved in drug metabolism may underlie inter-individual differences in response to medication and adverse drug reactions. Although still in its infancy, the field of pharmacogenetics already provides useful clinical information to improve patient care.
According to Professor Gelernter, the main limitation of the study is its limited sample size. In addition, the replication sample included in the study was for morphine, not methadone. This is due to the fact that there are few individuals of African ancestry diagnosed with opioid dependence.
- Tomalik-Scharte D, Lazar A, Fuhr U, Kirchheiner J. The clinical role of genetic polymorphisms in drug-metabolizing enzymes. Pharmacogenomics J. 2008;8(1):4-15.
- Robert J, Morvan VL, Smith D, Pourquier P, Bonnet J. Predicting drug response and toxicity based on gene polymorphisms. Crit Rev Oncol Hematol. 2005;54(3):171-196.
- Lee NH. Pharmacogenetics of drug [HAS1] metabolizing enzymes and transporters: effects on pharmacokinetics and pharmacodynamics of anticancer agents. Anticancer Agents Med Chem. 2010;10(8):583-592.
- Kalow W, Tang BK, Endrenyi L. Hypothesis: comparisons of inter- and intra-individual variations can substitute for twin studies in drug research. Pharmacogenetics. 1998;8(4):283-289.
- Dean L. Codeine Therapy and CYP2D6 Genotype. www.ncbi.nlm.nih.gov/books/NBK100662/. Last update: March 8, 2016. Accessed January 31, 2017.
- Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II. Clin Pharmacokinet. 2009;48(12):761-804.
- ClinicalTrials.gov. Precision medicine guided treatment for cancer pain [NCT02664350]. https://clinicaltrials.gov/ct2/show/NCT02664350. Accessed January 31, 2017.
- Ren ZY, Xu XQ, Bao YP, et al. The impact of genetic variation on sensitivity to opioid analgesics in patients with postoperative pain: a systematic review and meta-analysis. Pain Physician. 2015;18(2):131-152.
- Hwang IC, Park JY, Myung SK, Ahn HY, Fukuda K, Liao Q. OPRM1 A118G gene variant and postoperative opioid requirement: a systematic review and meta-analysis. Anesthesiology. 2014;121(4):825-834.
- Volkow ND, McLellan AT. Opioid abuse in chronic pain–misconceptions and mitigation strategies. N Engl J Med. 2016;374(13):1253-1263.
- Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain – United States, 2016. MMWR Recomm Rep. 2016;65(1):1-49.
- Centers for Disease Control and Prevention. Checklist for prescribing opioids for chronic pain. https://stacks.cdc.gov/view/cdc/38025. Publish date: March 2016. Accessed January 31, 2017.
- Kreek MJ, LaForge KS, Butelman E. Pharmacotherapy of addictions. Nat Rev Drug Discov. 2002;1:710 –726.
- D’Aunno T, Pollack HA, Frimpong JA, Wuchiett D. Evidence-based treatment for opioid disorders: a 23-year national study of methadone dose levels. J Subst Abuse Treat. 2014;47(4):245-250.
- Zhou HH, Sheller JR, Nu H, Wood M, Wood AJ. Ethnic differences in response to morphine. Clin Pharmacol Ther. 1993;54(5):507-513.
- Smith AH, Jensen KP, Li J, et al. Genome-wide association study of therapeutic opioid dosing identifies a novel locus upstream of OPRM1 [published online January 24, 2017]. Mol Psychiatry. doi: 10.1038/mp.2016.257