Desmetramadol (INN) is an investigational analgesic consisting of the (+) and (-) enantiomers of the tramadol active M1 metabolite. Tramadol is schedule IV with better safety than schedule II opioids. Tramadol is racemic and exerts analgesia by a monoaminergic effect mediated by (-)-tramadol and (-)-M1, and an opioid effect mediated by (+)-M1. CYP2D6 metabolizes (+)-tramadol to (+)-M1. CYP2D6 ultra-metabolizers can produce dangerous (+)-M1 levels and respiratory depression, whereas poor metabolizers produce insufficient (+)-M1 for analgesia. The objectives of this study were to test the hypotheses that (i) desmetramadol and tramadol doses giving equal plasma (+)-M1 yield equal hypoalgesia in metabolically normal subjects, but that (ii) the same doses in metabolically deficient subjects result in desmetramadol having greater plasma (+)-M1 and greater hypoalgesia than tramadol. Consecutive double-blind, randomized, placebo-controlled, three segment cross-over trials ‘A’ and ‘B’ investigated steady-state pharmacokinetics and hypoalgesia of 20 mg desmetramadol and 50 mg tramadol in healthy subjects without (N=43) and with (N=60) cotreatment with the potent CYP2D6 inhibitor paroxetine (20 mg daily). In the absence of CYP2D6 inhibition (trial A), 20 mg desmetramadol and 50 mg tramadol dosed q6 hours gave bioequivalent plasma (+)-M1: Cssmin, 26 + 6 vs. 28 + 7 ng/mL (90% CI, 0.85-1.08); Cssmax, 36 + 10 vs. 37 + 10 ng/mL (90 CI, 0.88-1.13). Hypoalgesia (cold pressor) of desmetramadol and tramadol were significantly greater than placebo, but equal to each other. In trial B, CYP2D6 inhibition significantly depressed tramadol (+)-M1 Cssmin (-58%) and Cssmax (-60%), but increased desmetramadol (+)-M1 Cssmin (46%) and Cssmax (41%). In trial B desmetramadol produced significant hypoalgesia as it did in trial A, whereas in trial B tramadol hypoalgesia was insignificant and comparable to placebo. Desmetramadol offers tramadol analgesia without metabolic liabilities. Supported by grant R44 DA027304 from the National Institute on Drug Abuse (NIDA) of NIH.