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The use of the thin catheter technique for exogenous surfactant delivery, as per the less invasive surfactant administration (LISA) method, not only reduces the need for mechanical ventilation (within seventy-two hours of life or during hospitalization), but also decreases the incidence of bronchopulmonary dysplasia, pneumothorax, and hemodynamically significant patent ductus arteriosus when compared with a standard endotracheal intubation procedure with sedation. Recent studies show that LISA might also lead to fewer other complications of preterm birth, such as severe intraventicular hemorrhage. LISA should always be performed with the use of sedative premedication. LISA is increasingly used in spontaneously breathing premature infants supported with continuous positive airway pressure, but little data is available to guide adequate premedication for this procedure. Propofol and ketamine seem to be effective for reducing pain scores, with acceptable tolerance for the LISA procedure, although propofol seems to be easier to titrate in this population. The administration of 2 μg/kg remifentanil as premedication in premature infants can provide stable hemodynamics and good analgesic effects. More research is obviously needed to determine the best premedication strategy.