Background: A significant amount of evidence suggests that Opioid-Free Anaesthesia (OFA) may provide better outcomes for patients undergoing surgery, sparing patients who are particularly vulnerable to adverse side effects of opioids. However, to what extent personalizing OFA is feasible and beneficial has not been adequately described. Methods: We conducted a narrative literature review aiming to provide a comprehensive understanding of nociception and pain and its context within the field of OFA. Physiological (including monitoring), pharmacological, procedural (type of surgery), genetical and phenotypical (including patients’ conditions) were considered. Results: We did not find any monitoring robustly associated with improved outcomes. However, we found evidence supporting particular OFA indications, such as bariatric and cancer surgery. We found that vulnerable patients may benefit more from OFA, with an interesting field of research in patients suffering from vascular disease. We found a variety of techniques and medications making it impossible to consider OFA as a single technique. Our findings suggest that a vast field of research remains unexplored. In particular, a deeper understanding of nociception with an interest in its genetic and acquired contributors would be an excellent starting point paving the way for personalised OFA. Conclusion: Recent developments in OFA may present a more holistic approach, challenging the use of opioids. Understanding better nociception, given the variety of OFA techniques, may help to maximize their potential in different contexts and potential indications.