Chronic pain treatment represents one of the most complex clinical challenges and even though opioids exhibit particular efficacy on nociceptive pain, their use must be controlled to avoid the risk of adverse reactions. A useful approach, aimed at maintaining analgesia and mitigating side effects, is represented by the use of a new class of analgesics endowed of µ-opioid (MOR) receptor agonism and noradrenaline reuptake inhibition (NRI) mechanisms. Tapentadol is the progenitor of this new class of drugs called MOP-NRI. A literature review has been conducted to gain information about the efficacy and the tolerability profile of tapentadol shifting from MOR agonism (acute pain) to NRI activity (chronic pain). The tolerability and therapeutic safety of tapentadol in neuropathic pain models, as well as in clinical settings, has been analyzed showing a good gastrointestinal tolerability profile, a moderate effect on hormone levels (in healthy volunteers and in patients) and on cognitive performance, a lack of significant alteration of the electrocardiogram recording and no changes of the QT/QTc interval, a minimal effect on serotonin reuptake in vivo with a low risk of serotonin syndrome, a longer time for the onset of analgesic tolerance and a less occurrence of abuse liability compared to formulations containing other comparator compounds. Tapentadol represents a great innovation in chronic pain therapy with a unique analgesic profile different form classical opioids, therefore, thanks to its synergistic MOR-NRI action, it may be a good option for the treatment of chronic, neuropathic and mixed pain.