Desmetramadol is an investigational analgesic consisting of (+) and (-) enantiomers of the tramadol metabolite O-desmethyltramadol (M1). Tramadol is racemic and exerts analgesia by monoaminergic effects of (-)-tramadol and (-)-M1, and by the opioid (+)-M1. Tramadol labeling indicates CYP2D6 ultra-metabolizers can produce dangerous (+)-M1 levels, and CYP2D6 poor metabolizers insufficient (+)-M1 for analgesia. We hypothesized desmetramadol could provide the safety and analgesia of tramadol without its metabolic liabilities. We conducted consecutive double-blind, randomized, placebo-controlled, three segment cross-over trials 'A' and 'B' to investigate the steady-state pharmacokinetics and analgesia of 20 mg desmetramadol and 50 mg tramadol in 103 healthy subjects without (N=43) and with (N=60) cotreatment with the cytochrome P450 (CYP) inhibitor paroxetine. In the absence of CYP inhibition (trial A), 20 mg desmetramadol and 50 mg tramadol dosed every 6 hours gave equivalent steady-state (+)-M1, similar adverse events, and analgesia significantly greater than placebo, but equal to each other. In trial B, CYP inhibition significantly depressed tramadol steady-state (+)-M1, reduced its adverse events, and led to insignificant analgesia comparable to placebo. In contrast, CYP inhibition in trial B had no deleterious effect on desmetramadol (+)-M1 or (-)-M1, which gave significant analgesia as in trial A and superior to tramadol (P = 0.003). Desmetramadol has the safety and efficacy of tramadol without its metabolic liabilities. CLINICALTRIALS.GOV REGISTRATIONS: NCT02205554, NCT03312777 PERSPECTIVE: To our knowledge, this is the first study of desmetramadol in humans and the first to show it provides the same safety and analgesia as tramadol, but without tramadol's metabolic liabilities and related drug-drug interactions. Desmetramadol could potentially offer expanded safety and utility to clinicians seeking an alternative to schedule II opioids.