Our experience during almost 20 years with various epidural analgesia regimes and a review of published studies attempting to assess the role of epidural drug combinations and spinal-segmental site of injection, indicate the following. The hydrophilic morphine is insensitive to the segmental site of injection and may be given in the lumbar epidural area for thoracic pain. Morphine causes a high incidence of nausea, pruritus and urinary retention. With an epidural infusion of less than 200 μg/hour the risk of respiratory depression is probably not higher than with other epidural opioids. The lipophilic opioids (fentanyl, sufentanil, diamorphine) are absorbed rapidly into the epidural vasculature. When given epidurally in doses that are high enough for systemic analgesic effect, fentanyl and sufentanil are no more effective than when administered intravenously. Such high lumbar epidural doses will also affect thoracic pain through the systemic effects. Dilute concentrations and addition of adrenaline impede systemic absorption and improve selective spinal analgesic effects of epidural fentanyl and sufentanil. When applied at a segmental level appropriate for the surgery, low-dose fentanyl and sufentanil are more effective than when given intravenously. Low doses of local anaesthetics have a selective spinal cord analgesic effect that synergizes with the spinal analgesic effect of opioids. Adrenergic agonists cause a selective spinal cord analgesia that synergizes with the analgesic effects of opioids and local anaesthetics. The systemic effects of epidural clonidine cause hypotension and sedation. Adrenaline has beneficial effects on the pharmacokinetics of epidural lipophilic opioids and local anaesthetics, reducing their absorption into the epidural vasculature. This reduces systemic side effects and enhances the spinal analgesic effects of opioids and local anaesthetics. Thus, epidural analgesia is best obtained, with the lowest dose and least side effects, by infusing a low-dose combination of each of these three classes of drugs at a spinal cord segment level appropriate for the site of surgery. We have obtained optimal post-operative analgesia with epidural fentanyl (mean: 14–16 μg/hour) in combination with bupivacaine (mean: 7–8 mg/hour and adrenaline (mean: 14–16 μg/hour) in 90% of more than 3000 patients when the infusion was given at an appropriate, site-specific segmental level (epidural catheter tip above L2). This gave satisfactory analgesia without motorneurone blockade and leg weakness. The total amount of fentanyl needed was so low that nausea and pruritus were insignificant problems. Respiratory depression and hypotension did not occur. However, one patient had an erroneous prescription for fentanyl 100 μg bolus-injections and developed respiratory depression. Epidural catheter problems continue to be obstacles to perfect epidural analgesia. Too low epidural catheter placement or lateral catheter-tip position caused failure in 5–8% with insufficient analgesia and/or leg weakness. In another 5–9%, later displacement of the epidural catheter, disconnections, or entry-site skin infection caused discontinuation of epidural analgesia one or more days earlier than planned. A high degree of vigilance and routine monitoring by well educated nurses on surgical wards of possible epidural catheter complications such as epidural infection, haematoma or catheter migration is mandatory for safe epidural analgesia practice on surgical wards. In 3000 patients receiving epidural post-operative analgesia on surgical wards for about 15 000 patient-days, we have observed only three potentially dangerous complications (one patient had erroneous fentanyl bolus-injection with consequent respiratory depression and two patients had epidural infections), detected early and treated successfully without permanent patient damage. These results testify to the efficacy and safety of our triple-component, low-dose, and site-specific epidural infusion analgesia regimen for post-operative pain relief after major surgery.