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

Abstract

Rationale: 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.

Objectives: This clinical study tested whether yohimbine increases opioid-seeking behavior.

Methods: 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).

Results: 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.

Conclusions: 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.

Trial registration: ClinicalTrials.gov NCT00684840.

Conflict of interest statement

Disclosures/Conflict of Interest

The authors declare no conflict of interest with respect to the conduct or content of this work. Dr. Greenwald has received compensation as a consultant to Reckitt-Benckiser Pharmaceuticals, Inc., the company that markets buprenorphine products. Both Dr. Greenwald and Dr. Steinmiller have received compensation from Titan Pharmaceuticals, Inc., which manufactures a buprenorphine product. Dr. Lundahl has received compensation from Gateway Community Health (Michigan), and the National Football League.

Figures

Figure 1

Statistically significant effects of oral yohimbine dose (0, 16.2 and 32.4 mg) across time on subjective and physiological responses during choice sessions. Gray squares indicate the 3-h period when the drug vs. money choice task occurred. For each measure illustrated, post-yohimbine area under the curve (0.3 – 3.7 h time point) scores showed a dose-related effect (see Table 2). Asterisks indicate the time points at which an active yohimbine dose significantly (p < .05) differed from the placebo condition. Upper left: Yohimbine increased opioid withdrawal symptom scores. Upper right: Yohimbine decreased opioid agonist symptom scores. Lower left: Yohimbine decreased Profile of Mood States (POMS) Elation scale scores. Lower right: Yohimbine increased systolic blood pressure (as well as diastolic blood pressure; not shown).

Figure 2

Upper panels Effects of oral yohimbine pretreatment dose (0, 16.2 and 32.4 mg) on demand for hydromorphone (HYD) 1-mg unit dose (upper left) and 2-mg unit dose (upper right). Each panel shows the relationship between HYD unit prices (response requirements of the progressive ratio schedule [125, 225, 365, 590, 950, 1500, 2300, 3415, 4915, 6875, 9375 and 12500] divided by the HYD unit dose) and log10 group-percent HYD choice (left ordinate) and corresponding absolute group-percent choice (right ordinate). Yohimbine 16.2 and 32.4 mg doses vs placebo significantly increased demand inelasticity with the HYD 1-mg unit dose (3.5 to 4-fold rightward curve shifts in left panel) whereas yohimbine produced a non-significant increase in demand inelasticity with the 2-mg unit dose (hence, a single curve fit is used in the right panel, reflecting the null hypothesis). The horizontal dashed line in each panel represents peak choice at the lowest unit price (parameter L = 70 for the 1-mg unit dose, and L = 100 for the 2-mg unit dose); this regression parameter was incorporated in the separate non-linear curve fits. See Table 3 for elasticity (A parameter), Pmax and curve fit (R2) values. Lower panels: Effects of oral yohimbine dose on total group responding for (HYD) 1-mg unit dose (lower left) and 2-mg unit dose (lower right). Curves reflect overall drug seeking, and were fit by the second order polynomial equation: Y=A+BX+CX2, where A = intercept (fixed at 500 here), B and C are slope parameters, X = unit price and Y = total group responding. Actual group responding data are the points fitted by the curves. Omax is located at the peak of each bitonic response curve. See Table 3 for Omax and curve fit values.