A hybrid implementation-effectiveness randomized trial of CYP2D6-guided postoperative pain management

Cameron D Thomas, Hari K Parvataneni, Chancellor F Gray, Justin T Deen, Hernan A Prieto, Luis F Pulido, Amanda R Elsey, Erica N Elwood, Petr Starostik, Yan Gong, Roger B Fillingim, Julie A Johnson, Larisa H Cavallari, Cameron D Thomas, Hari K Parvataneni, Chancellor F Gray, Justin T Deen, Hernan A Prieto, Luis F Pulido, Amanda R Elsey, Erica N Elwood, Petr Starostik, Yan Gong, Roger B Fillingim, Julie A Johnson, Larisa H Cavallari

Abstract

Purpose: Cytochrome P450 2D6 (CYP2D6) genotype-guided opioid prescribing is limited. The purpose of this type 2 hybrid implementation-effectiveness trial was to evaluate the feasibility of clinically implementing CYP2D6-guided postsurgical pain management and determine that such an approach did not worsen pain control.

Methods: Adults undergoing total joint arthroplasty were randomized 2:1 to genotype-guided or usual pain management. For participants in the genotype-guided arm with a CYP2D6 poor (PM), intermediate (IM), or ultrarapid (UM) metabolizer phenotype, recommendations were to avoid hydrocodone, tramadol, codeine, and oxycodone. The primary endpoints were feasibility metrics and opioid use; pain intensity was a secondary endpoint. Effectiveness outcomes were collected 2 weeks postsurgery.

Results: Of 282 patients approached, 260 (92%) agreed to participate. In the genotype-guided arm, 20% had a high-risk (IM/PM/UM) phenotype, of whom 72% received an alternative opioid versus 0% of usual care participants (p < 0.001). In an exploratory analysis, there was less opioid consumption (200 [104-280] vs. 230 [133-350] morphine milligram equivalents; p = 0.047) and similar pain intensity (2.6 ± 0.8 vs. 2.5 ± 0.7; p = 0.638) in the genotype-guided vs. usual care arm, respectively.

Conclusion: Implementing CYP2D6 to guide postoperative pain management is feasible and may lead to lower opioid use without compromising pain control.

Figures

Figure 1.
Figure 1.
CONSORT Flow Diagram
Figure 2.
Figure 2.
Implementation Outcomes: Opioid Use Among Study Participants Stratified by Treatment Assignment and CYP2D6 Phenotype High-risk phenotype defined as CYP2D6 IM (intermediate metabolizer), PM (poor metabolizer), UM (ultrarapid metabolizer), or NM-UM (range from NM to UM).
Figure 3.
Figure 3.
Effectiveness Outcomes: Opioid Consumption and Composite Pain Intensity at 2-weeks Post-op by Study Arm (a) Opioid consumption and (b) composite pain intensity. Boxes represent the median values and upper and lower quartiles. Whiskers extend to show the rest of the distribution, except for outliers which are represented by diamonds.

References

    1. Gereau RWt, Sluka KA, Maixner W, et al. A pain research agenda for the 21st century. The journal of pain : official journal of the American Pain Society. 2014;15(12):1203–1214.
    1. Hoots BE, Xu L, Kariisa M, et al. 2018. Annual surveillance report of drug-related risks and outcomes--United States. In: Services USDoHaH, ed2018.
    1. Levy B, Paulozzi L, Mack KA, Jones CM. Trends in Opioid Analgesic-Prescribing Rates by Specialty, U.S., 2007–2012. American journal of preventive medicine. 2015;49(3):409–413.
    1. Aubrun F, Langeron O, Quesnel C, Coriat P, Riou B. Relationships between measurement of pain using visual analog score and morphine requirements during postoperative intravenous morphine titration. Anesthesiology. 2003;98(6):1415–1421.
    1. Abdel Shaheed C, Maher CG, Williams KA, Day R, McLachlan AJ. Efficacy, Tolerability, and Dose-Dependent Effects of Opioid Analgesics for Low Back Pain: A Systematic Review and Meta-analysis. JAMA Intern Med. 2016;176(7):958–968.
    1. Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain. 2004;112(3):372–380.
    1. Lopes GS, Bielinski SJ, Moyer AM, et al. Sex Differences in Associations Between CYP2D6 Phenotypes and Response to Opioid Analgesics. Pharmacogenomics and personalized medicine. 2020;13:71–79.
    1. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clinical pharmacology and therapeutics. 2014;95(4):376–382.
    1. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther. 2014;95(4):376–382.
    1. Volpe DA, McMahon Tobin GA, Mellon RD, et al. Uniform assessment and ranking of opioid mu receptor binding constants for selected opioid drugs. Regulatory toxicology and pharmacology : RTP. 2011;59(3):385–390.
    1. Ultram (tramadol) [package insert]. Titusville, NJ: Janssen Pharmaceutical Companies; 2019.
    1. Davis MP, Varga J, Dickerson D, Walsh D, LeGrand SB, Lagman R. Normal-release and controlled-release oxycodone: pharmacokinetics, pharmacodynamics, and controversy. Support Care Cancer. 2003;11(2):84–92.
    1. Smith DM, Weitzel KW, Elsey AR, et al. CYP2D6-guided opioid therapy improves pain control in CYP2D6 intermediate and poor metabolizers: a pragmatic clinical trial. Genetics in Medicine. 2019.
    1. Ciszkowski C, Madadi P, Phillips MS, Lauwers AE, Koren G. Codeine, ultrarapid-metabolism genotype, and postoperative death. N Engl J Med. 2009;361(8):827–828.
    1. Gasche Y, Daali Y, Fathi M, et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004;351(27):2827–2831.
    1. Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet. 2006;368(9536):704.
    1. Kapil RP, Friedman K, Cipriano A, et al. Effects of paroxetine, a CYP2D6 inhibitor, on the pharmacokinetic properties of hydrocodone after coadministration with a single-entity, once-daily, extended-release hydrocodone tablet. Clinical therapeutics. 2015;37(10):2286–2296.
    1. Monte AA, Heard KJ, Campbell J, Hamamura D, Weinshilboum RM, Vasiliou V. The effect of CYP2D6 drug-drug interactions on hydrocodone effectiveness. Acad Emerg Med. 2014;21(8):879–885.
    1. Curran GM, Bauer M, Mittman B, Pyne JM, Stetler C. Effectiveness-implementation hybrid designs: combining elements of clinical effectiveness and implementation research to enhance public health impact. Medical care. 2012;50(3):217–226.
    1. Loudon K, Treweek S, Sullivan F, Donnan P, Thorpe KE, Zwarenstein M. The PRECIS-2 tool: designing trials that are fit for purpose. Bmj. 2015;350:h2147.
    1. Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clinical pharmacology and therapeutics. 2008;83(2):234–242.
    1. Hicks JK, Swen JJ, Gaedigk A. Challenges in CYP2D6 phenotype assignment from genotype data: a critical assessment and call for standardization. Current drug metabolism. 2014;15(2):218–232.
    1. Borges S, Desta Z, Jin Y, et al. Composite functional genetic and comedication CYP2D6 activity score in predicting tamoxifen drug exposure among breast cancer patients. Journal of clinical pharmacology. 2010;50(4):450–458.
    1. Kim KM, Murray MD, Tu W, et al. Pharmacogenetics and healthcare outcomes in patients with chronic heart failure. Eur J Clin Pharmacol. 2012;68(11):1483–1491.
    1. Mosley SA, Hicks JK, Portman DG, et al. Design and rational for the precision medicine guided treatment for cancer pain pragmatic clinical trial. Contemp Clin Trials. 2018;68:7–13.
    1. Adams EH, Breiner S, Cicero TJ, et al. A comparison of the abuse liability of tramadol, NSAIDs, and hydrocodone in patients with chronic pain. J Pain Symptom Manage. 2006;31(5):465–476.
    1. Preston KL, Jasinski DR, Testa M. Abuse potential and pharmacological comparison of tramadol and morphine. Drug Alcohol Depend. 1991;27(1):7–17.
    1. Cella D, Yount S, Rothrock N, et al. The Patient-Reported Outcomes Measurement Information System (PROMIS): progress of an NIH Roadmap cooperative group during its first two years. Medical care. 2007;45(5 Suppl 1):S3–s11.
    1. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain--United States, 2016. Jama. 2016;315(15):1624–1645.
    1. Virtanen P, Gommers R, Oliphant TE, et al. SciPy 1.0: fundamental algorithms for scientific computing in Python. Nature Methods. 2020.
    1. Han B, Compton WM, Blanco C, Crane E, Lee J, Jones CM. Prescription Opioid Use, Misuse, and Use Disorders in U.S. Adults: 2015 National Survey on Drug Use and Health. Annals of internal medicine. 2017;167(5):293–301.
    1. Dai F, Silverman DG, Chelly JE, Li J, Belfer I, Qin L. Integration of pain score and morphine consumption in analgesic clinical studies. The journal of pain : official journal of the American Pain Society. 2013;14(8):767–777.e768.
    1. Brummett CM, Waljee JF, Goesling J, et al. New Persistent Opioid Use After Minor and Major Surgical Procedures in US Adults. JAMA surgery. 2017;152(6):e170504.
    1. Ringwalt C, Gugelmann H, Garrettson M, et al. Differential prescribing of opioid analgesics according to physician specialty for Medicaid patients with chronic noncancer pain diagnoses. Pain Res Manag. 2014;19(4):179–185.
    1. Wick EC, Grant MC, Wu CL. Postoperative Multimodal Analgesia Pain Management With Nonopioid Analgesics and Techniques: A Review. JAMA surgery. 2017;152(7):691–697.
    1. Sjoveian AKH, Leegaard M. Hip and knee arthroplasty - patienťs experiences of pain and rehabilitation after discharge from hospital. International journal of orthopaedic and trauma nursing. 2017;27:28–35.
    1. Jhun EH, Apfelbaum JL, Dickerson DM, et al. Pharmacogenomic considerations for medications in the perioperative setting. Pharmacogenomics. 2019;20(11):813–827.
    1. Truong TM, Apfelbaum J, Shahul S, et al. The ImPreSS Trial: Implementation of Point-of-Care Pharmacogenomic Decision Support in Perioperative Care. Clinical pharmacology and therapeutics. 2019;106(6):1179–1183.
    1. Seripa D, Latina P, Fontana A, et al. Role of CYP2D6 Polymorphisms in the Outcome of Postoperative Pain Treatment. Pain medicine (Malden, Mass). 2015;16(10):2012–2023.
    1. Dong H, Lu SJ, Zhang R, Liu DD, Zhang YZ, Song CY. Effect of the CYP2D6 gene polymorphism on postoperative analgesia of tramadol in Han nationality nephrectomy patients. European journal of clinical pharmacology. 2015;71(6):681–686.
    1. Stamer UM, Lehnen K, Höthker F, et al. Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain. 2003;105(1–2):231–238.
    1. Slanar O, Dupal P, Matouskova O, Vondrackova H, Pafko P, Perlik F. Tramadol efficacy in patients with postoperative pain in relation to CYP2D6 and MDR1 polymorphisms. Bratisl Lek Listy. 2012;113(3):152–155.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner