We found that residents who initiated CYP2D6-metabolized opioids while receiving CYP2D6-inhibiting (versus residents receiving CYP2D6-neutral) antidepressants had a higher risk of worsening pain and higher incidence rates of pain-related hospitalizations and pain-related ED visits, with no difference in physical function, depression, OUD, and OD. Here, CYP2D6 is linked to major depressive disorder.