If the use of natural opiates, such as opium, is more than millennial, the history of synthetic opioids begins after 1950, with the development of the so-called ‘modern’ anaesthetic techniques. In 1962, in Belgium, the use of fentanyl, the first synthetic opioid for use in anaesthesia, is described. Subsequently, the use of opioids at high doses during surgery became common. However, over the last twenty years, many studies have questioned this practice, highlighting the many unknowns as the side effects of these molecules. The so-called opioid-free anaesthesia (OFA) techniques were developed in parallel with a better understanding of perioperative pain. In this work, the following questions are addressed: Why is the human body producing endogenous opioids? Is the concept of pain valid during general anaesthesia? What are the effects of intraoperative opioids on postoperative pain? Is anaesthesia without opioids actually possible? With these questions, the reader can question the use of intraoperative opioids within an historical and evolutionary perspective. In the same time, if OFA is feasible, the research agenda still includes a formal testing of its added value over classical opioid-sparing techniques.