Since the 1990s, high-income countries have seen an exponential increase in opioid use, misuse, and overdose. This “opioid crisis”, or “opioid epidemic”, began in the USA, spread to Europe, and is now extending to Asia. Today, opioids are still rarely available in many low and middle-income countries. In Pakistan, for instance, the only available opioids are morphine, fentanyl, nalbuphine, and tramadol, and these too are available only in tertiary hospitals. Is there a relationship between opioid exposure during anesthesia and opioid-induced hyperalgesia, hospital readmission, opioid addiction, cancer recurrence, immune system impairment, higher risk of postoperative delirium, and cognitive dysfunction? Signs in the recent literature confirm some of these hypotheses, and reducing opioid use in anesthesia is becoming a necessity. The concept of “opioid-free anesthesia” has emerged over the years in the literature. Is opioid-free anesthesia the solution? Is it a real paradigm shift? Nevertheless, it is important to keep in mind that stress-induced postoperative pain negatively influences outcome. The use of opioids in the postoperative phase could be necessary, but they have to be titrated and reduced to the minimum needed. Opioid-free postoperative analgesia is a new debate in the literature.