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

Abstract

Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment.

FIGURE 1

Overall trial scheme. Time 0 for the intervention arm is when the results are returned to the electronic health records and 1 week after the sample collection for the control arm. AS, CYP2D6 activity score; IM, intermediate metabolizer; NM, normal metabolizer; PM, poor metabolizer; UM, ultra‐rapid metabolizer. *Intermediate metabolizer was defined as CYP2D6 activity score >0 and ≤0.75. Parts of this figure are similar or the same as those in the following manuscript with permission from the publisher and authors.

FIGURE 2

Clinical recommendations for pain medication use in participants with each CYP2D6 metabolizer status based on genetics and with the CYP2D6 inhibitor adjustments. Parts of this figure are similar or the same as those in the following manuscript with permission from the publisher and authors.

FIGURE 3

Example of a clinical decision support alert triggered by a tramadol prescription in a participant whose genotyping result revealed a CYP2D6 poor metabolizer.