Oral morphine/naltrexone extended release capsules comprise the selective mu-opioid receptor agonist morphine in a sustained-release formulation combined with a sequestered core of the mu-opioid receptor antagonist naltrexone for use in the management of moderate to severe pain. When morphine/naltrexone is taken as intended, naltrexone exerts no clinically significant effect. However, when the capsule contents are taken after being tampered with by crushing, chewing or dissolution, naltrexone is rapidly released and absorbed, thereby mitigating the effects of morphine. Morphine/naltrexone was effective in the treatment and management of moderate to severe chronic pain in patients with pain due to osteoarthritis of the hip or knee participating in a randomized, double-blind, placebo-controlled, phase III study (n = 344). Changes in mean Brief Pain Inventory (BPI) average scores from baseline of the double-blind maintenance phase to 12 weeks were significantly better with morphine/naltrexone (20 mg/0.8 mg to 80 mg/3.2 mg twice daily) than with placebo. In a 12-month, open-label safety study, morphine/naltrexone also provided effective pain relief and sustained pain control in patients with chronic, moderate to severe, nonmalignant pain (n = 465 at baseline; 162 at study end). Furthermore, significant mean changes from baseline in BPI worst, least, average and current pain scores were seen from week 1 onwards. Morphine/naltrexone treatment was generally well tolerated in adult patients with chronic moderate to severe nonmalignant pain in clinical trials of up to 1-year duration.