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Background: Tapentadol is a combined opioid agonist and norepinephrine reuptake inhibitor with fewer gastrointestinal side effects at equianalgesic doses compared with classical strong opioids. Previous studies on tapentadol have included multi‐morbid patients in whom confounders exclude detailed assessment of the mechanistic effects and strict comparison with other opioids or placebo. This study aimed at investigating the effects of tapentadol and oxycodone on gastrointestinal motility and gastrointestinal side effects. Methods: 21 healthy males participated in a randomized, double‐blind, placebo‐controlled, crossover study. Tapentadol (50 mg twice daily), oxycodone (10 mg twice daily), or placebo tablets were administered for 14 days. Segmental gastrointestinal transit times and colonic motility parameters were measured with electromagnetic capsules. Gastrointestinal side effects were assessed using questionnaires. Key Results: During dosing with tapentadol, gastrointestinal side effects and motility parameters were on placebo level. Compared with tapentadol, oxycodone increased whole gut transit time by 17.9 hours (p =.015) and rectosigmoid transit time by 6.5 hours (p =.005). Compared with tapentadol, oxycodone also reduced long, fast antegrade colonic movements (p =.001). In comparison with placebo, oxycodone prolonged whole gut transit time by 31.6 hours, (p <.001). Moreover, less long, fast antegrade colonic movements (p =.002) were observed during oxycodone. For oxycodone only, slow colonic movements were associated with gastrointestinal side effects. Conclusions & Inferences: In this mechanistic study, tapentadol caused significantly less colonic dysmotility and gastrointestinal side effects as compared with oxycodone in equianalgesic doses. [ABSTRACT FROM AUTHOR]

• In a population of healthy male men, oxycodone and tapentadol reduced pain perception. • Spectral analysis and source localization showed differences in the central processing of tonic pain between oxycodone and tapentadol. • Different mechanisms of action were involved, but oxycodone affected cortical structures more than tapentadol. The present study investigated differences between opioids to experimental tonic pain in healthy men. Twenty-one males participated in this cross-over-trial. Interventions twice daily were oxycodone (10 mg), tapentadol (50 mg) and placebo for 14 days. Tonic pain was induced on day 1, 4 and 14 by immersing the hand in 2 °C water for 120 s. Electroencephalography was recorded during test pain at baseline and after 14 days. Spectral analysis and source localization were investigated in predefined frequency bands. A decreased perception of pain on day 4 persisted throughout the 14 days compared to baseline (p < 0.006). Oxycodone decreased the electroencephalography spectral power in the delta and theta bands and increased power in the alpha1, alpha2 and beta1 bands (p < 0.03). Tapentadol increased spectral power in the alpha1 band (p < 0.001). Source localization revealed that oxycodone decreased activity of the temporal and limbic region in the delta band, and frontal lobe in the alpha2 and beta1 bands, whereas tapentadol decreased alpha1 band activity in the temporal lobe compared to placebo. Oxycodone and tapentadol reduced pain perception and changed the central processing of tonic pain. Different mechanisms of action were involved, where oxycodone affected cortical structures more than tapentadol. [ABSTRACT FROM AUTHOR]