Implementing a pragmatic clinical trial to tailor opioids for acute pain on behalf of the IGNITE ADOPT PGx investigators

Abstract

Opioid prescribing for postoperative pain management is challenging because of inter‐patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6‐guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype‐guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient‐reported pain‐related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype‐guided opioid selection for improving postoperative pain control and reducing opioid‐related risks.

Rationale and design for a pragmatic randomized trial to assess gene‐based prescribing for SSRIs in the treatment of depression

“…The design of the ADOPT‐PGx acute pain trial was described previously. 24 In the depression trial, participants were randomly assigned to two groups: one that receives recommendations for SSRI therapy guided by genotyping CYP2C19 and CYP2D6 (immediate genotyped arm), and the other that follows the conventional approach for SSRI prescription and dosing to manage depression symptoms, with genotyping delayed until after completing trial procedures. The study assessed patient‐reported outcomes at several time points: baseline, 1 month, 3 months, and 6 months.…”

“… 27 This process has been described in detail elsewhere, and a parallel process for determining activity scores and assigning clinical CYP2D6 phenotype was utilized for this study. 16 , 24 Two commonly used antidepressants (fluoxetine and paroxetine) are also potent CYP2D6 inhibitors. For the trial, patients on one of these antidepressants which inhibit CYP2D6 were not considered to be phenoconverted to an intermediate or poor metabolizer phenotype, as it was assumed the CYP2D6‐inhibitor antidepressant would be stopped for the new therapy.…”

“… 21 , 22 , 23 The ADOPT‐PGx Trial (A Depression and Opioid Pragmatic Trial of Pharmacogenetics) represents a series of three pragmatic randomized trials, assessing the clinical utility of genotype‐guided prescribing for patients diagnosed with (A) acute pain, (B) chronic pain, or (C) depression. 24 , 25 In this article, we report the design of the depression clinical trial. Within the depression trial, we are testing the hypothesis that genotype‐guided selection or dosing of SSRI antidepressants leads to improved control of depressive symptoms at 3 months compared with usual care.…”

“…At present, there is tremendous interest in determining whether SSRI therapy guided by these key drug metabolizing genes affect depression outcomes 21–23 . The ADOPT‐PGx Trial (A Depression and Opioid Pragmatic Trial of Pharmacogenetics) represents a series of three pragmatic randomized trials, assessing the clinical utility of genotype‐guided prescribing for patients diagnosed with (A) acute pain, (B) chronic pain, or (C) depression 24,25 . In this article, we report the design of the depression clinical trial.…”

Precision Medicine in Oral Health and Diseases: A Systematic Review

“…Thomas et al evaluated the management of postsurgical pain based on CYP2D6 phenotype [79]. Good results were also achieved by Cavallari et al: this trial encouraged the use of CYP2D6 genotyping in clinical practice, to be taken into account in conjunction with the use of CYP2D6 inhibitors, to guide customized opioid dosing to enhance postoperative pain control [78]. In the orofacial pain and Temporomandibular disorders (TMD), the use of PM needs great effort.…”