BACKGROUND: Oral naltrexone's effectiveness as an opioid antagonist has been limited due to poor patient adherence. A long-acting naltrexone formulation may be beneficial. This study evaluated the effects of extended-release injectable naltrexone (XR-NTX), targeted for a one-month duration of action, in blocking opioid agonist challenge effects in humans. METHODS:Outpatient non-dependent opioid abusers (N=27) were randomly assigned to a single double-blind IM administration of 75, 150, or 300 mg XR-NTX. To assess the extent of opioid blockade, hydromorphone challenges (0, 3, 4.5, 6 mg IM in ascending order at 1-h intervals [up to 13.5 mg total]) were given at pretreatment baseline and on days 7, 14, 21, 28, 42, and 56. Opioid blockade was assessed via (1) tolerability of the ascending hydromorphone doses; (2) visual analog scale (VAS) ratings of subjective opioid effects and (3) pupil diameter. Effects on the VAS and pupils were assessed via the slope of the time-action function over ascending hydromorphone doses, with zero slope indicating complete blockade. RESULTS: Blockade of the VAS "any drug effect" response to 3 mg hydromorphone was complete for 14, 21, and 28 days, respectively, for the XR-NTX doses of 75, 150, and 300 mg. Subjective effects were more readily blocked than was pupil constriction. Higher hydromorphone doses produced only modest increases in agonist effects. With the 300 mg XR-NTX dose the slope of VAS responses remained at or near zero for one month even with maximal cumulative hydromorphone dosing. CONCLUSIONS: These data quantify the month-long opioid blockade underlying XR-NTX's efficacy in opioid dependence treatment.
RCT Entities:
BACKGROUND: Oral naltrexone's effectiveness as an opioid antagonist has been limited due to poor patient adherence. A long-acting naltrexone formulation may be beneficial. This study evaluated the effects of extended-release injectable naltrexone (XR-NTX), targeted for a one-month duration of action, in blocking opioid agonist challenge effects in humans. METHODS:Outpatient non-dependent opioid abusers (N=27) were randomly assigned to a single double-blind IM administration of 75, 150, or 300 mg XR-NTX. To assess the extent of opioid blockade, hydromorphone challenges (0, 3, 4.5, 6 mg IM in ascending order at 1-h intervals [up to 13.5 mg total]) were given at pretreatment baseline and on days 7, 14, 21, 28, 42, and 56. Opioid blockade was assessed via (1) tolerability of the ascending hydromorphone doses; (2) visual analog scale (VAS) ratings of subjective opioid effects and (3) pupil diameter. Effects on the VAS and pupils were assessed via the slope of the time-action function over ascending hydromorphone doses, with zero slope indicating complete blockade. RESULTS: Blockade of the VAS "any drug effect" response to 3 mg hydromorphone was complete for 14, 21, and 28 days, respectively, for the XR-NTX doses of 75, 150, and 300 mg. Subjective effects were more readily blocked than was pupil constriction. Higher hydromorphone doses produced only modest increases in agonist effects. With the 300 mg XR-NTX dose the slope of VAS responses remained at or near zero for one month even with maximal cumulative hydromorphone dosing. CONCLUSIONS: These data quantify the month-long opioid blockade underlying XR-NTX's efficacy in opioid dependence treatment.
Authors: Stephanie S O'Malley; James C Garbutt; David R Gastfriend; Qunming Dong; Henry R Kranzler Journal: J Clin Psychopharmacol Date: 2007-10 Impact factor: 3.153
Authors: Ryan Z Turncliff; Joi L Dunbar; Qunming Dong; Bernard L Silverman; Elliot W Ehrich; Stacy C Dilzer; Kenneth C Lasseter Journal: J Clin Pharmacol Date: 2005-11 Impact factor: 3.126
Authors: Evgeny Krupitsky; Edward V Nunes; Walter Ling; Ari Illeperuma; David R Gastfriend; Bernard L Silverman Journal: Lancet Date: 2011-04-30 Impact factor: 79.321
Authors: Bankole A Johnson; Nassima Ait-Daoud; Henri-Jean Aubin; Wim Van Den Brink; Richard Guzzetta; John Loewy; Bernard Silverman; Elliot Ehrich Journal: Alcohol Clin Exp Res Date: 2004-09 Impact factor: 3.455
Authors: Rebekah D Tenney; Steven Blake; Paul T Bremer; Bin Zhou; Candy S Hwang; Justin L Poklis; Kim D Janda; Matthew L Banks Journal: Neuropharmacology Date: 2019-07-29 Impact factor: 5.250
Authors: Brantley P Jarvis; August F Holtyn; Meredith S Berry; Shrinidhi Subramaniam; Annie Umbricht; Michael Fingerhood; George E Bigelow; Kenneth Silverman Journal: J Subst Abuse Treat Date: 2017-04-20
Authors: E Andrew Townsend; Paul T Bremer; Kaycee E Faunce; S Stevens Negus; Alaina M Jaster; Hannah L Robinson; Kim D Janda; Matthew L Banks Journal: ACS Chem Neurosci Date: 2020-04-22 Impact factor: 4.418
Authors: Kathryn L Schwienteck; Steven Blake; Paul T Bremer; Justin L Poklis; E Andrew Townsend; S Stevens Negus; Matthew L Banks Journal: Drug Alcohol Depend Date: 2019-08-24 Impact factor: 4.492
Authors: Brantley P Jarvis; August F Holtyn; Anthony DeFulio; Mikhail N Koffarnus; Jeannie-Marie S Leoutsakos; Annie Umbricht; Michael Fingerhood; George E Bigelow; Kenneth Silverman Journal: Drug Alcohol Depend Date: 2019-02-14 Impact factor: 4.492
Authors: Maria A Sullivan; Adam Bisaga; Andrew Glass; Kaitlyn Mishlen; Martina Pavlicova; Kenneth M Carpenter; John J Mariani; Frances R Levin; Edward V Nunes Journal: Drug Alcohol Depend Date: 2014-12-09 Impact factor: 4.492
Authors: Brantley P Jarvis; Anthony DeFulio; Lauren Long; August F Holtyn; Annie Umbricht; Michael Fingerhood; George E Bigelow; Kenneth Silverman Journal: J Subst Abuse Treat Date: 2016-12-24
Authors: Brantley P Jarvis; August F Holtyn; Shrinidhi Subramaniam; D Andrew Tompkins; Emmanuel A Oga; George E Bigelow; Kenneth Silverman Journal: Addiction Date: 2018-03-24 Impact factor: 6.526
Authors: Joshua D Lee; Peter D Friedmann; Timothy W Kinlock; Edward V Nunes; Tamara Y Boney; Randall A Hoskinson; Donna Wilson; Ryan McDonald; John Rotrosen; Marc N Gourevitch; Michael Gordon; Marc Fishman; Donna T Chen; Richard J Bonnie; James W Cornish; Sean M Murphy; Charles P O'Brien Journal: N Engl J Med Date: 2016-03-31 Impact factor: 91.245