The analgesic and adverse effects of intrathecal methadone 5 mg, 10 mg and 20 mg were assessed and compared with intrathecal morphine 0.5 mg. The study was conducted on 38 patients who underwent total knee or hip replacement surgery. The intrathecal opioid was administered at the end of surgery and assessments began 1 h thereafter and continued for 24 h. Pain measurements, supplementary analgesia requirements, and adverse effects were recorded. Intrathecal morphine 0.5 mg provided effective and prolonged analgesia. Intrathecal methadone 5 mg, 10 mg, and 20 mg produced good analgesia of 4 h duration. Thereafter the median pain scores with intrathecal methadone were consistently higher (worse) than those with intrathecal morphine (P less than 0.05). The time to the onset of discomfort severe enough to require supplemental morphine was longer after intrathecal morphine than following methadone (15 h with morphine 0.5 mg; 6.25 h, 6.5 h and 6 h with methadone 5 mg, 10 mg, and 20 mg respectively: P less than 0.05). Central nervous system depression manifesting as respiratory depression, hypotension, and excessive drowsiness occurred in 3 of 8 patients injected with methadone 20 mg intrathecally. Generalized pruritus, nausea, vomiting, and urinary retention were common and equally distributed among the treatment groups. We conclude that both intrathecal morphine 0.5 mg and methadone 5, 10, and 20 mg provide excellent analgesia but that morphine has a more prolonged effect. Methadone 20 mg produced unacceptable side effects. Clinical evidence for rostral spread of methadone within the CSF, as indicated by facial itching and excessive drowsiness, was less apparent with 5 mg than with 10 and 20 mg. Various explanations for the observed differences between the drugs are discussed.