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

Highlights

• Behavioral economic analysis can be used with fentanyl self-administration.

• Elasticity of fentanyl demand is sensitive to activation or blockade of opioid receptors.

• Demand for fentanyl decreases following naltrexone, morphine or buprenorphine.

• Buprenorphine continued affecting fentanyl demand at least 48 h after treatment.

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.

Introduction

The recent rise in deaths related to opioid misuse has increased focus on the need for effective treatment of opioid use disorder (OUD). The most effective approach for treating OUD is medication-assisted therapy (MAT) using drugs that target primarily μ opioid receptors (Kraus et al., 2011; McCarty et al., 2018). The two classes of medication used in MAT, opioid antagonists and agonists, are used separately or together. Antagonists such as naltrexone and naloxone decrease the reinforcing effect of opioids by blocking opioid receptors (Nunes et al., 2018). However, antagonists alone are not ideal for MAT because of patient noncompliance (Ling et al., 2012) and because they can exacerbate the symptoms of withdrawal. In contrast, full agonists such as methadone and partial agonists such as buprenorphine reduce illicit opioid use by providing steady, moderate activation of opioid receptors (Clark et al., 2015). Although these medications are more effective than psychotherapy alone, at least 20–40 % of patients continue misusing illicit opioids while undergoing MAT (Nunes et al., 2018; Weiss et al., 2011). While there are numerous factors that lead to failure to sustain abstinence, one factor is the magnitude of an individual’s economic demand for illicit opioids, with higher demand predicting greater failures to abstain with MAT (Worley et al., 2015).

Economic demand curve analyses can be used to generate estimates of elasticity (price sensitivity) and demand intensity (consumption at low prices) for drugs of abuse (Hursh and Silberberg, 2008; Hursh and Winger, 1995). Individuals with OUD characteristically exhibit exaggerated demand, with relative insensitivity to changes in price (Hursh and Roma, 2013). This may be associated with addiction severity in humans (Murphy et al., 2011, 2009) and has been identified as a potential target for evaluating therapeutic efficacy (Hursh and Roma, 2013). While individuals that spend a greater percentage of their income on obtaining opioids prior to entering MAT are less likely to achieve abstinence during treatment (Worley et al., 2015), it is unclear if individuals using illicit opioids during MAT continue to exhibit the same degree of economic demand. Because medications act on the same receptors as abused opioids, they may alter demand by serving as substitutes or by changing the effective price of a drug (Hursh and Roma, 2013). Although MAT reduces the frequency of drug use in humans (Kakko et al., 2003), it is not known from human or non-human animal studies if MAT directly alters the metrics of demand, such as elasticity.

In the current study, we used male rats to determine if economic demand for fentanyl is altered following treatment with drugs that target primarily μ opioid receptors. Rats were trained to self-administer fentanyl (5 μg/kg/infusion), then they transitioned to a threshold procedure in which unit doses were decreased across 10-min components in order to derive a within-session demand curve estimation (Oleson et al., 2011). After responding stabilized, we obtained normalized demand curves following pretreatment with varying doses of naltrexone (opioid antagonist), morphine (classic full μ-opioid agonist), and buprenorphine (mixed/partial μ-opioid agonist).