Opioids are a commonly administered analgesic medication in the intensive care unit, primarily to facilitate invasive mechanical ventilation. Consensus guidelines advocate for an opioid-first strategy for the management of acute pain in ventilated patients. As a result, these patients are potentially exposed to high opioid doses for prolonged periods, increasing the risk of adverse effects. Adverse effects relevant to these critically ill patients include delirium, intensive care unit–acquired infections, acute opioid tolerance, iatrogenic withdrawal syndrome, opioid-induced hyperalgesia, persistent opioid use, and chronic post–intensive care unit pain. Consequently, there is a challenge of optimising analgesia while minimising these adverse effects. This narrative review will discuss the characteristics of opioid use in the intensive care unit, outline the potential short-term and long-term adverse effects of opioid therapy in critically ill patients, and outline a multifaceted strategy for opioid minimisation.