Long-term opioid therapy may be associated with analgesic efficacy and also predictable adverse events, including cardiovascular and pulmonary events, gastrointestinal disorders, endocrinological harms, psychological problems, impairment of driving ability, and risk of abuse. These effects of opioids are mostly due to the wide expression of the mu receptor. Tapentadol, a centrally acting analgesic, is the first agent of a new class of drugs (MOR-NRI), since it combines two mechanisms of action, namely µ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition. Noteworthy, MOR activation with tapentadol is markedly lower compared with that exerted by classical opioids, thus likely resulting in fewer opioid-related adverse effects. In this review, we discuss current safety data on tapentadol, with a focus on some specific events, risk of abuse, and driving ability, a well-accepted proxy of the ability of taking critical decisions.