Potential iatrogenic mood and cognitive declines associated with long-acting opioid therapy were examined in 19 patients receiving long-acting oral opioid medications and compared to ten patients receiving usual care. Pain, mood, and cognitive function were measured before and after achieving stable doses. In addition to reducing pain, long-acting opioid medication reduced anxiety and hostility. No declines in cognitive function were associated with the long-acting opioid medications, and the group receiving long-acting opioid medications showed significant improvement on a measure of psychomotor speed and sustained attention. Both patient groups reported significant reductions in perceived impairment in daily activities due to pain. Treatment responders taking long-acting opioid medications (63%) were taking a significantly lower dose at follow-up than the treatment non-responder group. These findings suggest that long-acting opioid medications can improve mood and do not impair cognitive functioning in patients with chronic non-cancer pain.