Opioids are the most potent centrally acting analgesic drugs for the treatment of pain. For the past years, since the discovery of spinal opioid receptors, the use of spinal opioids has been adopted in clinical practice in the hope of producing intense segmental analgesia that was devoid of the dose-limiting side effects associated with systemic opioid administration. Experimental studies have demonstrated that after their perispinal administration, liposolubility is inversely proportional to their spinal selectivity, which is higher for the most water-soluble drug, morphine, than for other more lipophilic drugs, such as fentanyl and sufentanil. Clinical trials have shown that epidural morphine in the form of extended-release liposome injections gives good analgesia for a period of 48 hours, with no need for epidural catheterization. Conversely, fentanyl is the most appropriate opioid in ambulatory surgery and seems to have the strongest effect at the spinal cord administered epidurally as a bolus and supraspinally using continuous epidural infusion. Epidural methadone and hydromorphone are suitable alternatives for analgesia in the postoperative period, given that they have intermediate pharmacokinetic characteristics with respect to the two aforementioned groups of opioids. All opioids administered intrathecally will produce some degree of spinally mediated analgesia. The main differences are related to their duration of action, rate of clearance, and the pathways by which the drugs reach their receptors in the brain. In general, lipophilic opioids produce short-term analgesia (1-4 hours), which is very useful for immediate postoperative pain. However, morphine produces intense analgesia for up to 24 hours with doses as low as 100 μg.