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



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.


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.


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.


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

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Fig. 1: CONSORT flow diagram.
Fig. 2: Implementation outcomes: opioid use among study participants stratified by treatment assignment and CYP2D6 phenotype.
Fig. 3: Effectiveness outcomes at the 2 week postoperative timepoint by study arm.

Data availability

Data set and code available upon request.


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This work was supported by the University of Florida Clinical and Translational Science Institute, which is supported in part by the NIH National Center for Advancing Translational Sciences under award number UL1TR001427 and University of Florida Health Shands. Work by C.D.T. was supported by T32 HG008958. Research reported in this publication was also supported by NIH/NHGRI (U01 HG 007269). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information




Conceptualization: L.H.C., J.A.J., R.B.F., H.K.P., C.F.G., C.D.T. Data curation: C.D.T. Formal analysis: C.D.T., Y.G. Funding acquisition: J.A.J., L.H.C. Investigation: H.K.P., C.F.G., J.T.D., H.A.P., L.F.P., E.N.E., C.D.T. Methodology: L.H.C., J.A.J., R.B.F., H.K.P., C.F.G., P.S., Y.G. Project administration: A.R.E., E.N.E. Resources: J.T.D., C.F.G., H.A.P., H.K.P., L.F.P., P.S. Supervision: L.H.C., R.B.F., J.A.J., H.K.P. Validation: L.H.C., R.B.F., Y.G., J.A.J., H.K.P., C.D.T. Visualization: C.D.T. Writing—original draft: C.D.T., L.H.C., Y.G., J.A.J. Writing—review & editing: L.H.C., J.T.D., R.B.F., C.F.G., Y.G., J.A.J., H.A.P., H.K.P., L.F.P., P.S., C.D.T.

Corresponding author

Correspondence to Larisa H. Cavallari PharmD.

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Competing interests

Y.G., R.B.F., J.A.J., and L.H.C. have received research funding from the National Institutes of Health. P.S. receives support from University of Florida Health Pathology Laboratories. C.F.G. is a stockholder for ROMTech. The other authors declare no competing interests.

Ethics declaration

All study participants provided written, informed consent. The study was approved by the University of Florida Institutional Review Board, and all procedures were in accordance with the ethical standards of the Declaration of Helsinki and registered in ClinicalTrials.gov (NCT03534063).

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Thomas, C.D., Parvataneni, H.K., Gray, C.F. et al. A hybrid implementation-effectiveness randomized trial of CYP2D6-guided postoperative pain management. Genet Med (2021). https://doi.org/10.1038/s41436-020-01050-4

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