Tapentadol HCl [(−)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] is a novel dual mode μ-opioid receptor (MOR) agonist and norepinephrine (NE) reuptake inhibitor. The compound exhibited analgesic effects in a wide range of animal models of acute pain (hot-plate; tail-flick; writhing; chemically and mechanically induced visceral pain) and chronic neuropathic and inflammatory pain (formalin; yeast; chronic constriction injury [CCI] and spinal nerve ligation [SNL]; vincristine-induced and diabetic neuropathy) in rats and mice, using various routes of administration (IV, IP, and PO). In most models, the potency of tapentadol HCl was between that of the reference compounds morphine and tramadol. After IV administration, the ED50 values of tapentadol HCl, morphine and tramadol ranged from 0.7, 0.4, and 3.6 mg/kg, respectively (phenylquinone writhing, mouse) to 5.5, 3.5, and 18 mg/kg, respectively (colorectal distension-induced visceral pain, rat), and after IP administration from 3.8, 0.8, and 5.9 mg/kg, respectively (formalin test, rat) to 13, 14, and 7.1 mg/kg, respectively (CCI model of neuropathic pain, rat). Tolerance development to the analgesic effects of equianalgesic doses of tapentadol HCl and morphine was investigated in an acute (tail-flick) and a chronic (CCI) pain model in rats. In both models, morphine tolerance developed at least twice as fast (complete tolerance on day 22 and 10 for morphine, and on day 51 and 23 for tapentadol HCl, in the tail-flick and CCI model, respectively). The main metabolite, the glucuronide of tapentadol, which does not bind to the MOR and does not inhibit NE uptake, was devoid of any analgesic activity. It is concluded that tapentadol HCl is a novel analgesic drug with a dual mode of action, resulting in a broad analgesic profile that might to be more resistant to the development of tolerance than classical opiates such as morphine. Tapentadol HCl [(−)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] is a novel dual mode μ-opioid receptor (MOR) agonist and norepinephrine (NE) reuptake inhibitor. The compound exhibited analgesic effects in a wide range of animal models of acute pain (hot-plate; tail-flick; writhing; chemically and mechanically induced visceral pain) and chronic neuropathic and inflammatory pain (formalin; yeast; chronic constriction injury [CCI] and spinal nerve ligation [SNL]; vincristine-induced and diabetic neuropathy) in rats and mice, using various routes of administration (IV, IP, and PO). In most models, the potency of tapentadol HCl was between that of the reference compounds morphine and tramadol. After IV administration, the ED50 values of tapentadol HCl, morphine and tramadol ranged from 0.7, 0.4, and 3.6 mg/kg, respectively (phenylquinone writhing, mouse) to 5.5, 3.5, and 18 mg/kg, respectively (colorectal distension-induced visceral pain, rat), and after IP administration from 3.8, 0.8, and 5.9 mg/kg, respectively (formalin test, rat) to 13, 14, and 7.1 mg/kg, respectively (CCI model of neuropathic pain, rat). Tolerance development to the analgesic effects of equianalgesic doses of tapentadol HCl and morphine was investigated in an acute (tail-flick) and a chronic (CCI) pain model in rats. In both models, morphine tolerance developed at least twice as fast (complete tolerance on day 22 and 10 for morphine, and on day 51 and 23 for tapentadol HCl, in the tail-flick and CCI model, respectively). The main metabolite, the glucuronide of tapentadol, which does not bind to the MOR and does not inhibit NE uptake, was devoid of any analgesic activity. It is concluded that tapentadol HCl is a novel analgesic drug with a dual mode of action, resulting in a broad analgesic profile that might to be more resistant to the development of tolerance than classical opiates such as morphine.