Background: Serotonin–norepinephrine reuptake inhibitors inhibit the reuptake of serotonin and noradrenalin and are used in the treatment of neuropathic pain. Animal studies suggest that milnacipran co-administered with opioids may potentiate the analgesic effect of μ-opioid receptor agonists. This study hypothesized that co-administration of milnacipran and buprenorphine would have a synergistic effect in evoked pain models in healthy subjects. Methods: This was a randomized double-blinded, placebo-controlled, four-way cross-over, multiple dose clinical trial to investigate the analgesic effects of buprenorphine (placebo, 0.5, 1 and 3 μg/kg) in combination with milnacipran (placebo, 25 and 50 mg) in healthy subjects. Results: 11 healthy men were enrolled in the study. Buprenorphine alone showed a dose–response relationship indicative of anti-nociception in the pain tests. Following milnacipran administration, no changes were seen in the pharmacodynamic measurements for pain, psychomotor function, body stability or eye movements. For the electrical tests, cold pressor test and pressure pain test, buprenorphine alone was superior when compared with buprenorphine plus milnacipran. No differences in pharmacodynamic variables, besides an increase in pupil/iris ratio, were observed after repeated administration of milnacipran 50 mg. Single and multiple doses of 25 or 50 mg milnacipran did not further potentiate the anti-nociceptive effects of buprenorphine. Conclusions: Buprenorphine showed dose-dependent effects consistent with its pharmacological profile. Milnacipran alone did not affect any of the pain variables. The combination of both buprenorphine and milnacipran did not potentiate or show a synergistic effect on the pain models used in this study. Significance: Buprenorphine is known to be a potent opioid agonist. Animal studies suggest that milnacipran co-administered with opioids may potentiate the analgesic effect of μ-opioid receptor agonists. Here, we found that buprenorphine showed a dose-dependent analgesic effect, but that no potentiation or synergy on a battery of evoked pain tasks could be observed after co-administration of both milnacipran and buprenorphine.