Administration of morphine into the knee joint is the best-studied clinical procedure documenting the use of topically-applied opioids. When 1-5 mg morphine were injected into the knee joint, patients experienced pain relief for up to 24 hours, whereas similar doses given systemically (i.e. intravenously) were effective for 2-4 hours. Furthermore, the analgesic effect was reversed when the opioid antagonist naloxone was injected into the knee joint. Both these findings indicate that the effect is mediated by local opioid receptors in the knee joint.