Opioids are the oldest and most potent drugs for the treatment of severe pain. Their clinical application is undisputed in acute pain (e.g. associated with trauma or surgery) but their long-term use in chronic pain has met increasing scrutiny. Therefore, this article will review sensory mechanisms related to opioid analgesia and side effects with a special emphasis on chronic pain. Central and peripheral sites of analgesic actions and side effects, as well as conventional and novel opioid compounds will be discussed. Since pain is a complex bio-psycho-social phenomenon, non-pharmacological considerations important for the understanding of opioid analgesic efficacy are also included. Finally, examples of challenging clinical situations such as the perioperative management of patients receiving long-term opioid treatment are illustrated.