Effects of buprenorphine/naloxone in opioid-dependent humans

Rationale: Buprenorphine is a partial mu opiold agonist under development a s a sublingual (SL) medication for opioid dependence treatment in the Unite d States. Because buprenorphine may be abused, tablets combining buprenorph ine with naloxone in a 4:1 ratio have been developed to reduce that risk. L ow doses of injected buprenorphine/naloxone have been tested in opiold-depe ndent subjects, but higher doses (more than 3 mg of either medication) and direct comparisons to SL buprenorphine/naloxone have not been examined. Obj ec tives: To assess and compare the effects of intramuscular (IM) versus SL buprenorphine/naloxone in opioid-dependent volunteers. Methods: Opioid-dep endent volun teers were maintained on 40 mg per day of oral hydro- morphone while on a residential research ward. After safety testing in two pilot su bjects, participants (n=8) were tested with both IM and SL buprenorphine/na loxone (1/0.25, 2/0.5, 4/1, 8/2, 16/4 mg); IM hydromorphone (10 mg) and nal oxone (0.25 mg); both IM and SL buprenorphine alone (8 mg); and placebo. Te st sessions were twice per week, dosing was double blind. Results: Intramus cular buprenorphine/naloxone produced dose-related increases on indices of opioid antagonist effects. Effects were consistent with naloxone-precipitat ed withdrawal, and were short-lived. As withdrawal effects dissipated, euph oric opioid agonist effects from buprenorphine did not appear. Sublingual b upre- norphine/naloxone produced neither opioid agonist nor antagonist effe cts. Conclusions: Intramuscular injection of buprenorphine/naloxone precipi tates withdrawal in opioid dependent persons; therefore, the combination ha s a low abuse potential by the injection route in this population. Sublingu al buprenorphine/naloxone by tablet is well tolerated in opioid dependent s ubjects, and shows neither adverse effects (i.e., precipitated withdrawal) nor a high abuse potential (i.e., opioid agonist effects).