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Yohimbine increases opioid-seeking behavior in heroin-dependent, buprenorphine-maintained individuals.

ABSTRACT: In laboratory animals, the biological stressor yohimbine (?(2)-noradrenergic autoreceptor antagonist) promotes drug seeking. Human laboratory studies have demonstrated that psychological stressors can increase drug craving but not that stressors alter drug seeking.This clinical study tested whether yohimbine increases opioid-seeking behavior.Ten heroin-dependent, buprenorphine-stabilized (8 mg/day) volunteers sampled two doses of hydromorphone [12 and 24 mg IM in counterbalanced order, labeled drug A (session 1) and drug B (session 2)]. During each of six later sessions (within-subject, double-blind, randomized crossover design), volunteers could respond on a 12-trial choice progressive ratio task to earn units (1 or 2 mg) of the sampled hydromorphone dose (drug A or B) vs money ($2) following different oral yohimbine pretreatment doses (0, 16.2, and 32.4 mg).Behavioral economic demand intensity and peak responding (O (max)) were significantly higher for hydromorphone 2 than 1 mg. Relative to placebo, yohimbine significantly increased hydromorphone demand inelasticity, more so for hydromorphone 1-mg units (P (max)?=?909, 3,647, and 3,225 for placebo, 16.2, and 32.4 mg yohimbine doses, respectively) than hydromorphone 2-mg units (P (max)?=?2,656, 3,193, and 3,615, respectively). Yohimbine produced significant but clinically modest dose-dependent increases in blood pressure (systolic???15 and diastolic???10 mmHg) and opioid withdrawal symptoms, and decreased opioid agonist symptoms and elated mood.These findings concur with preclinical data by demonstrating that yohimbine increases drug seeking; in this study, these effects occurred without clinically significant subjective distress or elevated craving, and partly depended on opioid unit dose.

SUBMITTER: Greenwald MK

PROVIDER: S-EPMC3558534 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Yohimbine increases opioid-seeking behavior in heroin-dependent, buprenorphine-maintained individuals.

Greenwald Mark K MK Lundahl Leslie H LH Steinmiller Caren L CL

Psychopharmacology 20121117 4

<h4>Rationale</h4>In laboratory animals, the biological stressor yohimbine (α(2)-noradrenergic autoreceptor antagonist) promotes drug seeking. Human laboratory studies have demonstrated that psychological stressors can increase drug craving but not that stressors alter drug seeking.<h4>Objectives</h4>This clinical study tested whether yohimbine increases opioid-seeking behavior.<h4>Methods</h4>Ten heroin-dependent, buprenorphine-stabilized (8 mg/day) volunteers sampled two doses of hydromorphone ...[more]

PMID: 23161001

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Project description:BACKGROUND:Sublingual buprenorphine is an effective maintenance treatment for opioid dependence, yet intravenous buprenorphine misuse occurs. A buprenorphine/naloxone formulation was developed to mitigate this misuse risk. This randomized, double-blind, cross-over study was conducted to assess the intravenous abuse potential of buprenorphine/naloxone compared with buprenorphine in buprenorphine-maintained injection drug users (IDUs). METHODS:Intravenous heroin users (n = 12) lived in the hospital for 8-9 weeks and were maintained on each of three different sublingual buprenorphine doses (2 mg, 8 mg, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intravenous placebo, naloxone, heroin and low and high doses of buprenorphine and buprenorphine/naloxone were examined. Every participant received each test dose under the three buprenorphine maintenance dose conditions. RESULTS:Intravenous buprenorphine/naloxone was self-administered less frequently than buprenorphine or heroin (P < 0.0005). Participants were most likely to self-administer drug intravenously when maintained on the lowest sublingual buprenorphine dose. Subjective ratings of 'drug liking' and 'desire to take the drug again' were lower for buprenorphine/naloxone than for buprenorphine or heroin (P = 0.0001). Participants reported that they would pay significantly less money for buprenorphine/naloxone than for buprenorphine or heroin (P < 0.05). Seven adverse events were reported; most were mild and transient. CONCLUSIONS:These data suggest that although the buprenorphine/naloxone combination has intravenous abuse potential, that potential is lower than it is for buprenorphine alone, particularly when participants received higher maintenance doses and lower buprenorphine/naloxone challenge doses. Buprenorphine/naloxone may be a reasonable option for managing the risk for buprenorphine misuse during opioid dependence treatment.

Project description:BACKGROUND:Managing acute pain in buprenorphine-maintained individuals in emergency or perioperative settings is a significant challenge. This study compared analgesic and abuse liability effects of adjunct hydromorphone and buprenorphine using quantitative sensory testing, a model of acute clinical pain, in persons maintained on 12 to 16?mg sublingual buprenorphine/naloxone. METHODS:Participants (N = 13) were enrolled in a randomized within-subject, double-blind, placebo-controlled three-session experiment. Each session used a cumulative dosing design with four IV injections (4, 4, 8, and 16?mg of hydromorphone or 4, 4, 8, and 16?mg of buprenorphine); quantitative sensory testing and abuse liability assessments were measured at baseline and after each injection. The primary analgesia outcome was change from baseline cold pressor testing; secondary outcomes included thermal and pressure pain testing, as well as subjective drug effects and adverse events. RESULTS:A significant two-way interaction between study drug condition and dose was exhibited in cold pressor threshold (F10,110 = 2.14, P = 0.027) and tolerance (F10,110 = 2.69, P = 0.006). Compared to after placebo, participants displayed increased cold pressor threshold from baseline after cumulative doses of 32?mg of IV hydromorphone (means ± SD) (10?±?14?s, P = 0.035) and 32?mg of buprenorphine (3?±?5 s, P = 0.0.39) and in cold pressor tolerance after cumulative doses of 16?mg (18?±?24?s, P = 0.018) and 32?mg (48?±?73?s, P = 0.041) IV hydromorphone; cold pressor tolerance scores were not significant for 16?mg (1?±?15?s, P = 0.619) or 32?mg (7?±?16 s, P = 0.066) buprenorphine. Hydromorphone and buprenorphine compared with placebo showed greater ratings on subjective measures of high, any drug effects, good effects, and drug liking. Adverse events were more frequent during the hydromorphone compared with buprenorphine and placebo conditions for nausea, pruritus, sedation, and vomiting. CONCLUSIONS:In this acute clinical pain model, high doses of IV hydromorphone (16 to 32?mg) were most effective in achieving analgesia but also displayed higher abuse liability and more frequent adverse events. Cold pressor testing was the most consistent measure of opioid-related analgesia.

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Yohimbine increases opioid-seeking behavior in heroin-dependent, buprenorphine-maintained individuals.

Publications

Yohimbine increases opioid-seeking behavior in heroin-dependent, buprenorphine-maintained individuals.

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