Implementing Genomics in Practice (IGNITE): CYP2D6 Genotype-Guided Pain Management in Patients Undergoing Arthroplasty Surgery

This will be a randomized, open-labeled pilot pragmatic clinical trial. Patients undergoing arthroplasty surgery will be recruited from the University of Florida (UF) Health Gainesville and the Villages Orthopedic clinics for CYP2D6 pharmacogenetic testing to manage post-surgical pain. Patients will be randomized 2:1 to either usual care or genotype-guided care. The aims of the study were to: 1) test the feasibility of a genotype-guided opioid prescribing approach for patients undergoing an outpatient surgical procedure, a group at high risk for persistent opioid use; and 2) evaluate the effect of genotype-guided post-surgical pain management on pain control and opioid prescribing.

Study Overview

• Status: Completed
• Conditions: Pain, Postoperative
• Intervention / Treatment: Genetic: CYP2D6-guided opioid therapy

Detailed Description

This study was a randomized, open-label, type 2 hybrid implementation effectiveness trial conducted to test the hypothesis that CYP2D6 genotype-guided management of post-surgical pain 1) was feasible, and 2) reduced the use of codeine, tramadol, hydrocodone, and oxycodone in Poor Metabolizers (PMs), Intermediate Metabolizers (IMs), and Ultrarapid metabolizers (UMs). In addition to the reduced use of opioids listed above, we aimed to see if participants had improved post-operative pain control in PMs/IMs and reduced Drug Enforcement Administration (DEA) Schedule II (C-II) opioids in Normal Metabolizers (NMs). Patients scheduled to undergo arthroplasty surgery were recruited from the UF Health Gainesville and the Villages Orthopedic clinics. Patients were randomized 2:1 to a genotype-guided versus usual care approach. For patients with CYP2D6 PM, IM or UM phenotype based on genotype or drug interactions, a recommendation to avoid hydrocodone, tramadol, codeine, and oxycodone were made. In NMs, tramadol was recommended, given evidence of its lower potential addiction risk than C-II opioids. Patient-Reported Outcomes Measurement Information System (PROMIS) measures were administered at baseline (within 30 days of surgery) and 2 weeks ± 4 days post-surgery for patients in each arm. Pain scores and assessments of physical functioning, emotional functioning, and mobility from the PROMIS measures and utilization of pain medications during the 2-week period following surgery were also compared between groups.

• Study Type: Interventional
• Enrollment (Actual): 260
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • UF Health at the University of Florida
    • Gainesville, Florida, United States, 32611
      • Unversity of Florida
    • Summerfield, Florida, United States, 34491
      • UF Health Orthopaedic--Villages

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Scheduled to undergo total joint arthroplasty at area hospital
• Primary unilateral total hip or knee arthroplasty scheduled within approximately 6 months of the initial evaluation clinic visit

Exclusion Criteria:

• Patients scheduled to undergo a revision or bilateral procedure
• Receiving chronic opioid therapy, defined as the use of opioids on most days for > 3 month
• Allergy to opioids

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: CYP2D6-guided opioid therapy; Participants randomized to the CYP2D6-guided arm will have their CYP2D6 genotyping completed prior to surgery (in the absence of any genotyping error) with results reported in the electronic health record (EHR). Patients will be categorized as CYP2D6 PM, IM, NM, or UM based on CYP2D6 genotype/activity score and FDA guidance on drug interactions. Strong inhibitors (e.g. bupropion, fluoxetine, paroxetine) phenoconvert patients to PMs, with moderate inhibitors (e.g. duloxetine, fluvoxamine) reducing CYP2D6 activity scores by 50%.	Genetic: CYP2D6-guided opioid therapy; Using a standardized consult note, recommendations were made to avoid tramadol, hydrocodone, codeine, and oxycodone in PMs, IMs, and UMs and to use an alternative opioid (e.g. morphine, hydromorphone) or non-opioid (e.g. NSAID). Consideration of tramadol as the first-line opioid will be recommended for NMs.
No Intervention: Usual Care; Participants randomized to the usual care arm will have their DNA collected at the start of the study and stored at the lab until after they have completed their surgery and the 2-week follow-up, at which time, their sample was genotyped with the results reported in the EHR.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients Who Agreed to Participate	The feasibility of clinical implementation was measured by the percentage of approached patients who agreed to be the study. This was measured by the number of patients approached and the number of patients who enrolled in the study.	12 months
Percentage of Participants With a Clinical Phenotype Warranting Alternative Therapy	The feasibility of implementing a genotype-guided opioid prescribing approach for participants undergoing an elective surgical procedure was analyzed by the percentage of participants in the genotype-guided arm and usual care arm with a high-risk CYP2D6 phenotype. CYP2D6 phenotypes were based on CYP2D6 genotype and phenoconversion. High-risk CYP2D6 phenotypes were poor metabolizers (PM), intermediate metabolizers (IM), ultrarapid metabolizers (UM), and ranged phenotypes such as normal to ultrarapid metabolizers and intermediate to ultrarapid metabolizers.	An average of 2 weeks after genotype sample collection
Percentage of Participants in the Genotype-guided Arm for Whom a Clinical Phenotype-guided Recommendation Was Accepted by the Clinician	The feasibility of clinical implementation was measured by the percentage of participants in the genotype-guided arm for whom a clinical phenotype-guided recommendation was accepted by the clinician. Study recommendations were considered accepted for participants with a high-risk phenotype if an alternative opioid (e.g., hydromorphone, morphine) was prescribed. For CYP2D6 normal metabolizers (NM), consult recommendations were accepted if tramadol was prescribed. Participants were typically prescribed a tramadol-based regimen where in most cases hydrocodone, or another opioid, was prescribed concomitantly with tramadol as is usual practice at the clinics where participants were enrolled. Participants whose genotype resulted after the preoperative appointment were excluded from the analysis of acceptance of consult recommendations. Data for this outcome were only collected from participants in the genotyped-guided arm with CYP2D6 results returned prior to the preoperative appointment.	An average of 2 months after genotype results returned
Opioid Utilization	Opioid consumption was calculated as the difference between participant-reported opioid pills prescribed at the preoperative appointment and opioid pills remaining at the 2-week time point. This difference was calculated for each opioid and then expressed as morphine milligram equivalents (MME) using standard conversion factors and the medication strength of the prescribed opioid analgesic. If a participant was prescribed multiple opioids, MMEs were calculated for each opioid and then summed to give a total MME value.	2 weeks after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite Pain Intensity	Composite pain intensity was compared between the genotype-guided arm and usual care arm 2 weeks after surgery. The first two scales in the PROMIS Pain Intensity item bank assess pain intensity utilizing a 7-day recall period (items include the phrase "the past 7 days") while the third scale asks the patient to rate their pain intensity "right now." Each of the 3 scales (worst pain, average pain, and current pain) used to calculate the composite pain intensity score has a range of 1 to 5, with the following text assigned to the numeric scale, 1 -"had no pain", 2 -"mild", 3 -"moderate", 4 -"severe", and 5 -"very severe." The mean composite pain intensity ranges from 1-5. The higher the composite pain score, the more pain and thus worse outcomes.	2 weeks after surgery

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: University of Florida Health
• Investigators: Principal Investigator: Larisa Cavallari, PharmD, University of Florida

Publications and helpful links

General Publications

• Thomas CD, Parvataneni HK, Gray CF, Deen JT, Prieto HA, Pulido LF, Elsey AR, Elwood EN, Starostik P, Gong Y, Fillingim RB, Johnson JA, Cavallari LH. A hybrid implementation-effectiveness randomized trial of CYP2D6-guided postoperative pain management. Genet Med. 2021 Apr;23(4):621-628. doi: 10.1038/s41436-020-01050-4. Epub 2021 Jan 8.

Study record dates

Study Major Dates

• Study Start (Actual): June 7, 2018
• Primary Completion (Actual): April 29, 2020
• Study Completion (Actual): April 29, 2020

Study Registration Dates

• First Submitted: May 10, 2018
• First Submitted That Met QC Criteria: May 10, 2018
• First Posted (Actual): May 23, 2018

Study Record Updates

• Last Update Posted (Actual): July 17, 2023
• Last Update Submitted That Met QC Criteria: July 11, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Arthroplasty Surgery; Genotype-Guided Pain Management
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Narcotics; Analgesics, Opioid
• Other Study ID Numbers: IRB201800445; UL1TR001427-04 (U.S. NIH Grant/Contract); OCR17562 (Other Identifier: Universiy of Florida)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No