An open-label study of a functional opioid kappa antagonist in the treatment of opioid dependence

Several lines of evidence, including the well-established observation that kappa opiate agonists produce dysphoria and psychotomimetic effects in huma ns, suggest that dysfunction of the endogenous kappa opioid system may cont ribute to opioid and cocaine addiction. The objective of this open-label st udy was to determine the effectiveness of a functional K antagonist as a tr eatment for opioid dependence. This was accomplished by combining a partial mu agonist/kappa antagonist (buprenorphine. 4 mg, sublingual) with a mu an tagonist (naltrexone, 50 mg by mouth), theoretically leaving kappa antagoni sm as the major medication effect. Subjects were treatment-seeking heroin-d ependent las per Diagnostic and Statistical Manual of Mental Disorders, 4th ed.) men (41 +/- 7 years old; 19 +/- 8 years heroin use) eligible for meth adone maintenance. After inpatient detoxification and a naloxone-challenge test to verify that they were not physically dependent on opioids, subjects received naltrexone. Starting on the fourth day, patients also received li quid buprenorphine. All patients received medication at the clinic 6 days p er week and a full program of psychosocial treatment. The major endpoints o f the study were: pupil diameter to determine if the mu agonist effects of buprenorphine were blocked by naltrexone, urine toxicology, and retention i n treatment. Five patients (33%) completed the 3-month study. Four were abs tinent from opioids and cocaine for the entire study, and one was abstinent from opioids and cocaine for the last 9 weeks. Six subjects dropped out du e to either minor side effects or disliking the sensation of sublingual bup renorphine. There were no significant changes in pupillary diameter. The po sitive response to treatment exceeds that expected from naltrexone alone (9 0% dropout). These promising results suggest that controlled studies of thi s medication combination should be conducted. (C) 2000 Elsevier Science Inc . All rights reserved.