Opioid dependent patients require higher than normal doses of opioid analgesics. However, this regimen has not been formally tested. This study utilised a double-blind placebo-controlled design to examine antinociceptive responses to saline and pseudo-steady-state plasma morphine concentrations (173+/-11 (mean+/-SEM), range 106-305 ng/ml) in 18 methadone participants in three stable, once daily methadone dose ranges 11-45 mg (n=6), 46-80 mg (n=6), 81-115 mg (n=6) and 10 controls. Testing commenced approximately 20 h after the maintenance dose with the next dose given 1h after morphine cessation. Nociceptive stimuli (cold pressor (seconds) and electrical stimulation (volts)) were used to measure pain detection threshold and pain tolerance. Blood samples were analysed by HPLC for plasma morphine and R-(-)-methadone concentrations. Methadone participants were hyperalgesic to cold pressor pain. High plasma morphine concentrations failed to significantly change cold pressor and electrical stimulation pain tolerance for methadone patients, but in controls, morphine significantly (P<0.05) increased mean pain tolerance to cold pressor by 59+/-29% (range -17% to 311%) and electrical stimulation by 19+/-6% (range 0% to 58%). Morphine significantly (P<0.05) decreased respiration rates by 12+/-3% (range -29% to 8%) in methadone subjects. On saline days, rising methadone concentrations significantly (P<0.01) increased cold pressor pain detection threshold by 32+/-6% (range 1-81%) and cold pressor pain tolerance by 23+/-6% (range -32% to 56%). Methadone maintained patients are hyperalgesic and cross-tolerant to the antinociceptive effects of very high plasma morphine concentrations. While even higher morphine doses may achieve some pain relief, this may be at the cost of unacceptable respiratory depression.