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 registrationsNCT02205554, NCT03312777 PerspectiveTo 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.
Highlights
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
It is thought to have a limited role in analgesia,[1,58,73] but increases the potential for adverse effects and the serotonin syndrome when taken with serotonergic antidepressants that are CYP2D6 inhibitors.[53]
In the trial A cohort, 4 participants discontinued; 1 discontinued owing to Adverse events (AEs) and 3 were lost to followup
Summary
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. Tramadol is approved in the United States for moderate to moderately severe pain and, as a schedule IV analgesic, is less prone to abuse than schedule II opioids, as well as being safer.[10,86,87] Tramadol is extensively metabolized by CYP enzymes,[88] and its analgesic activity in humans is thought to be due to a mixed mechanism of 1) norepinephrine reuptake inhibition by the negative enantiomers of tramadol and the O-desmethyltramadol metabolite ((-)-M1), and 2) agonism at the m-opioid receptor by the positive M1 enantiomer (+)-M1 (Fig 1).[29,58] The (+)-tramadol enantiomer inhibits uptake by the serotonin transporter.[16,58] It is thought to have a limited role in analgesia,[1,58,73] but increases the potential for adverse effects and the serotonin syndrome when taken with serotonergic antidepressants that are CYP2D6 inhibitors.[53]
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