Acute administration of buprenorphine in humans: Partial agonist and blockade effects

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 08/1995; 274(1):361-72.
Source: PubMed


Buprenorphine, a mixed opioid agonist-antagonist, is being investigated as a treatment for opioid dependence. This study compared the acute subjective and physiological effects of sublingual buprenorphine to those of p.o. methadone over a wide range of doses and compared the ability of both drugs to alter the effects of an opioid challenge. Male inpatient volunteers (n = 9) with histories of opioid abuse participated in this double-blind, double-dummy study. Sublingual buprenorphine (0, 0.5, 2, 8, 16 and 32 mg) and p.o. methadone (3.75, 15 and 60 mg) were administered once weekly according to a Latin-square design, and subjects were monitored on a variety of physiological and subjective measures. Twenty-four hours later, subjects were tested with ascending doses of i.m. hydromorphone (0, 1 and 4 mg) given 45 min apart. Buprenorphine and methadone produced typical opioid agonist effects of long duration, including pupillary constriction, respiratory depression and elevations on subject-rated and observer-rated indices of euphoria, sedation and opioid-like symptoms. The buprenorphine dose-effect curves were nonlinear and maximal effects for most physiological and subjective measures were observed between 4 and 8 mg, with no greater effects observed at higher doses. The methadone dose-effect curves were linear across the range of doses tested. High doses of buprenorphine and methadone both attenuated the response to hydromorphone challenge 24 hr later. These data indicate that there is a ceiling on the effects of buprenorphine in humans that may reduce its abuse liability and increase its safety, and indicate that opioid blockade occurs after acute administration of buprenorphine or methadone.

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    • "Our intervention consists of four components, each selected to support delivery of an efficacious pharmacotherapy to waitlisted opioid-dependent adults while reducing the risk of medication nonadherence and diversion. First, we chose buprenorphine as the interim dosing medication because its pharmacological profile is associated with reduced abuse liability and overdose risk (Bickel & Amass, 1995; Johnson, Strain, & Amass, 2003; Walsh, Preston, Stitzer, Cone, & Bigelow, 1994; Walsh, Preston, Bigelow, & Stitzer, 1995). Buprenorphine is also available without the rigid regulatory regulations, daily observation of dosing and 120-day limit required for interim methadone. "
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    ABSTRACT: Despite the effectiveness of agonist maintenance for opioid dependence, individuals can remain on waitlists for months, during which they are at significant risk for morbidity and mortality. Interim dosing, consisting of daily medication without counseling, can reduce these risks. In this pilot study, we examined the initial feasibility of a novel technology-assisted interim buprenorphine treatment for waitlisted opioid-dependent adults. Following buprenorphine induction during Week 1, participants (n=10) visited the clinic at Weeks 2, 4, 6, 8, 10 and 12 to ingest their medication under staff observation, provide a urine specimen and receive their remaining doses via a computerized Med-O-Wheel Secure device. They also received daily monitoring via an Interactive Voice Response (IVR) platform, as well as random call-backs for urinalysis and medication adherence checks. The primary outcome was percent of participants negative for illicit opioids at each 2-week visit, with secondary outcomes of past-month drug use, adherence and acceptability. Participants achieved high levels of illicit opioid abstinence, with 90% abstinent at the Week 2 and 4 visits and 60% at Week 12. Significant reductions were observed in self-reported past-month illicit opioid use (p<.001), opioid withdrawal (p<.001), opioid craving (p<.001) and ASI Drug composite score (p=.008). Finally, adherence with buprenorphine administration (99%), daily IVR calls (97%) and random call-backs (82%) was high. Interim buprenorphine treatment shows promise for reducing patient and societal risks during delays to conventional treatment. A larger-scale, randomized clinical trial is underway to more rigorously examine the efficacy of this treatment approach. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Addictive behaviors 07/2015; 51:136-142. DOI:10.1016/j.addbeh.2015.07.030 · 2.76 Impact Factor
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    • "is considered an effective and realistic option for treating patients for a variety of pain conditions (Walsh et al., 1995; Johnson et al., 2005; Pergolizzi et al., 2010). "
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    ABSTRACT: Buprenorphine is known as a μ-opioid peptide (MOP) receptor agonist, but its antinociception is compromised by the activation of nociceptin/orphanin FQ peptide (NOP) receptors in rodents. The aim of this study was to investigate the roles of MOP and NOP receptors in regulating buprenorphine-induced physiological responses in primates (rhesus monkeys). The effects of MOP antagonist (naltrexone), NOP antagonist [(±)-1-[(3R*,4R*)-1-(cyclooctylmethyl)-3-(hydroxymethyl)-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397)], and NOP agonists [(1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5] decan-4-one (Ro 64-6198) and 3-endo-8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510)] on buprenorphine were studied in three functional assays for measuring analgesia, respiratory depression, and itch in primates. Over the dose range of 0.01 to 0.1 mg/kg, buprenorphine dose-dependently produced antinociception, respiratory depression, and itch/scratching responses, and there was a ceiling effect at higher doses (0.1-1 mg/kg). Naltrexone (0.03 mg/kg) produced similar degrees of rightward shifts of buprenorphine's dose-response curves for all three endpoints. Mean pK(B) values of naltrexone (8.1-8.3) confirmed that MOP receptors mediated mainly buprenorphine-induced antinociception, respiratory depression, and itch/scratching. In contrast, J-113397 (0.1 mg/kg) did not change buprenorphine-induced physiological responses, indicating that there were no functional NOP receptors in buprenorphine-induced effects. More importantly, both NOP agonists, Ro 64-6198 and SCH 221510, enhanced buprenorphine-induced antinociception without respiratory depression and itch/ scratching. The dose-addition analysis revealed that buprenorphine in combination with the NOP agonist synergistically produced antinociceptive effects. These findings provided functional evidence that the activation of NOP receptors did not attenuate buprenorphine-induced antinociception in primates; instead, the coactivation of MOP and NOP receptors produced synergistic antinociception without other side effects. This study strongly supports the therapeutic potential of mixed MOP/NOP agonists as innovative analgesics.
    Journal of Pharmacology and Experimental Therapeutics 06/2012; 343(1):72-81. DOI:10.1124/jpet.112.194308 · 3.97 Impact Factor
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    • "Buprenorphine, a partial mu-opioid receptor agonist, has been generally accepted for treatment of opioid dependence in adults and is effective for both detoxification (Gowing, Ali, & White, 2009) and maintenance (Amato et al., 2005). It has minimal overdose risk, a good safety profile, and less intense withdrawal than full agonists (Amato, Davoli, Ferri, Gowing, & Perucci, 2004; Breen et al., 2003; Garfein, Vlahov, Galai, Doherty, & Nelson, 1996; Gowing et al., 2009; Hser, Hoffman, Grella, & Anglin, 2001; Levy, Vaughan, Angulo, & Knight, 2007; Walsh, Preston, Bigelow, & Stitzer, 1995). "
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    ABSTRACT: In opioid dependent youth there is substantial attrition from medication-assisted treatment. If youth at risk for attrition can be identified at treatment entry or early in treatment, they can be targeted for interventions to help retain them in treatment. Opioid dependent adolescents and young adults (n=152), aged 15-21, were randomized to 12 weeks (BUP, n=74) or 2 weeks of detoxification (DETOX, n=78) with buprenorphine/naloxone (Bup/Nal), both in combination with 12 weeks of psychosocial treatment. Baseline and early treatment related predictors of treatment attrition were identified in each group using bivariate and multivariate logistic regression. In the DETOX group 36% left between weeks 2 and 4, at the end of the dose taper, while in the BUP group only 8% left by week 4. In the BUP group, early adherence to Bup/Nal, early opioid negative urines, use of any medications in the month prior to treatment entry, and lifetime non-heroin opioid use were associated with retention while prior 30-day hallucinogen use was associated with attrition. In the DETOX group, only use of sleep medications was associated with retention although not an independent predictor. A broad range of other pre-treatment characteristics was unrelated to attrition. Prompt attention to those with early non-adherence to medication or an early opioid positive urine, markers available in the first 2 weeks of treatment, may improve treatment retention. Extended Bup/Nal treatment appeared effective in improving treatment retention for youth with opioid dependence across a wide range of demographics, and pre-treatment clinical characteristics.
    Addictive behaviors 05/2012; 37(9):1046-53. DOI:10.1016/j.addbeh.2012.04.011 · 2.76 Impact Factor
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