We tested whether aerobic exercise training altered morphine analgesic responses or reduced morphine dosages necessary for adequate analgesia. Chronic back pain patients were randomized to an 18-session aerobic exercise intervention (n = 38) or usual activity control (n = 45). Before and after the intervention, participants underwent three laboratory sessions (double-blinded, crossover) to assess effects of saline placebo, i.v. morphine (0.09 mg/kg), and i.v. naloxone (12 mg) on low back pain and evoked heat pain responses. Differences in evoked and back pain measures between the placebo and morphine conditions indexed morphine analgesia, with pre-post intervention changes the primary outcome. Endogenous opioid (EO) analgesia was indexed by differences in evoked and low back pain measures between the naloxone and placebo conditions. A Sex X Intervention interaction on the analgesic effects of morphine on VAS back pain intensity was observed (p = .046), with a similar trend for evoked pain threshold (p = .093). Male exercisers showed reduced morphine analgesia pre-post intervention whereas male controls showed increased analgesia (with no differences in females). Of clinical significance were findings that relative to the control group, aerobic exercise produced analgesia more similar to that observed after receiving ≈7 mg morphine pre-intervention (p’s < .045). Greater pre-post intervention increases in EO function (from any source) were significantly associated with larger pre-post intervention decreases in morphine analgesia (p's < .046). The overall pattern of findings suggest that regular aerobic exercise has limited direct effects on morphine responsiveness, reducing morphine analgesia in males only.Copyright © 2020 International Association for the Study of Pain.