Changes in fentanyl demand following naltrexone, morphine, and buprenorphine in male rats

Abstract

Background: Individuals with opioid use disorder (OUD) exhibit high levels of economic demand for opioids, with high levels of consumption and relative insensitivity to changes in price. Because the medications used to treat OUD in medication-assisted therapy (MAT) act as antagonists or agonists at μ opioid receptors, they may alter the relationship between price and opioid intake.

Methods: This study examined demand for a commonly abused synthetic prescription opioid, fentanyl, in male rats following s.c. pre-treatment with naltrexone (0.1-1.0 mg/kg), morphine (0.3-3.0 mg/kg) or buprenorphine (0.3-3.0 mg/kg). We normalized demand curves to intake at the lowest price and estimated effects on elasticity (sensitivity to changes in price). Rats were first trained to earn fentanyl (5 μg/kg/infusion) on a fixed ratio schedule, then they underwent daily training under a threshold procedure designed to produce within-session demand curve estimates. Rats received 14 threshold sessions before undergoing a series of tests encompassing each drug, at each dose.

Results: Elasticity was increased by pretreatment with naltrexone, morphine or buprenorphine. Morphine also decreased initial intake, when the price for fentanyl was lowest. In contrast, initial intake was increased by naltrexone (according to an inverted-U shaped curve). The effects of naltrexone did not persist after the test session, but morphine and buprenorphine continued affecting demand elasticity 24 h or 48 h after the test, respectively.

Conclusions: These results indicate that fentanyl demand is sensitive to blockade or activation of opioid receptors by the drug classes used for MAT in humans.

Keywords: Behavioral economics; Buprenorphine; Demand; Fentanyl; MAT; Morphine; Naltrexone.

Figure 1.

(A) Responding for fentanyl during pre-training and acquisition of the threshold procedure (n = 9). Rats responded more on the active lever during daily FR1 training sessions. Sessions occurring during the autoshaping phase (A, left) were analyzed separately from the remaining FR1 training sessions (A, right). (B) During the threshold task, initial intake was similar during sessions 1–7 and 8–14. (C) Fentanyl demand (normalized to initial intake) and (D) estimates of elasticity were also similar during the first and second half of threshold training sessions. * p < 0.05 positive slope for relationship between day and lever presses; #p < 0.05 slope of line differs in active vs inactive; +p < 0.05 effect of lever.

Figure 2.

Effects of naltrexone pretreatment on (A) initial fentanyl intake, (B) normalized fentanyl demand, and (C) the estimate of elasticity during the test session (n = 9). Naltrexone had dose-dependent effects on initial intake (quadratic) and the elasticity of normalized demand (linear). Note that the scale for elasticity (C) is 20-fold higher than elasticity at baseline (Fig 1D) or elasticity 24 h later (F), while the scale for initial intake (A) is 2-fold higher than in any other graph presented here. During the subsequent maintenance session, 24 h later, there was no effect of previous naltrexone on (D) initial intake, (E) normalized demand or (F) the estimate of elasticity, although there may have been a trend for an effect on elasticity (p = 0.08). Initial intake was used to normalize demand. *p < 0.05 linear dose-dependent effect; ^p < 0.05 quadratic dose-dependent effect.

Figure 3.

Effects of morphine pretreatment on (A) initial fentanyl intake, (B) normalized fentanyl demand, and (C) the estimate of elasticity during the test session (n = 9). Morphine had dose-dependent effects on initial intake (quadratic) and the elasticity of normalized demand (quadratic); although these curves were fit with a quadratic model, the dose response appears to be monophasic. Morphine continued to affect (D) initial intake, (E) normalized fentanyl demand, and (F) the estimate of elasticity 24 h after the test session. There was increased elasticity at the highest dose and an inverted U-shaped effect on initial intake 24 h after. Initial intake was used to normalize demand. ^p < 0.05 quadratic dose-dependent effect.

Figure 4.

Effects of buprenorphine pretreatment on (A) initial intake, (B) normalized fentanyl demand and (C) the estimate of elasticity during the test session (n = 8). Although buprenorphine did not affect initial intake, the mixed agonist increased elasticity in a linear dose-dependent fashion, leading to lower fentanyl demand. Buprenorphine continued to exert these effects 24 h after the test session (D-F) and 48 h after the test session (G-I). Note that the scale for elasticity during the maintenance session 24 h after buprenorphine treatment (F) is 5-fold higher than at baseline (Fig 1D). Initial intake was used to normalize demand. *p < 0.05 linear dose-dependent effect.