Desmetramadol Has the Safety and Analgesic Profile of Tramadol Without Its Metabolic Liabilities: Consecutive Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Trials

Abstract

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 cytochrome P450 (CYP) isozyme 2D6 ultrarapid metabolizer can produce dangerous (+)-M1 levels, and CYP2D6 poor metabolizers insufficient (+)-M1 for analgesia. We hypothesized that desmetramadol could provide the safety and analgesia of tramadol without its metabolic liabilities. We conducted consecutive double-blind, randomized, placebo-controlled, 3 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 participants without (n = 43) and with (n = 60) cotreatment with the 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 with 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 = .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 usefulness to clinicians seeking an alternative to schedule II opioids.

Keywords: Desmetramadol; metabolism; poor metabolizer; tramadol; ultrarapid metabolizer.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.

Chemical structure and dominant pharmacology of each enantiomer of tramadol and the M1 metabolite. An enantiomer is each of a pair of molecules that are mirror images of each other.

Figure 2.

Study design. Participants were randomized in trials A and B to all 6 possible treatment sequences with each segment separated by 1 week (trial A) or 2 weeks (trial B). Nine doses of each study drug were given every 6 hours in each segment to reach steady-state levels and then cold-induced pain was assessed after the ninth dose. All participants in trial B additionally received daily paroxetine beginning 1 day before each treatment segment. S, participants randomized.

Figure 3.

Participant flow and disposition.

Figure 4.

Mean steady-state plasma levels of (+)-M1 (A, E), (−)-M1 (B, F), (+)-tramadol (C, G), and (−)-tramadol (D, H) in trials A (n = 43) and B (n = 60). Bars are for SD and shown in 1 direction. Baseline points all below the quantitation limit.

Figure 5.

Cold-induced pain at 30 seconds in trial A and trial B. Bars are SE of the mean. Abbreviation: NS, not statistically significant. *P < .05; **P < .01; ***P < .001.

Figure 6.

Mean respiratory rate before and after each study drug administration in trial A. Bars are for SD for desmetramadol (up bars) and placebo (down bars). The horizontal separation of data points at each dose (ie, before and after dosing) are exaggerated to allow adequate visualization of the respiration rate before and after each dose.

Figure 7.

Tramadol and desmetramadol metabolism catalyzed by CYPs in vitro.