Progress in agonist therapy for substance use disorders: Lessons learned from methadone and buprenorphine

Abstract

Substance use disorders (SUD) are serious public health problems worldwide. Although significant progress has been made in understanding the neurobiology of drug reward and the transition to addiction, effective pharmacotherapies for SUD remain limited and a majority of drug users relapse even after a period of treatment. The United States Food and Drug Administration (FDA) has approved several medications for opioid, nicotine, and alcohol use disorders, whereas none are approved for the treatment of cocaine or other psychostimulant use disorders. The medications approved by the FDA for the treatment of SUD can be divided into two major classes - agonist replacement therapies, such as methadone and buprenorphine for opioid use disorders (OUD), nicotine replacement therapy (NRT) and varenicline for nicotine use disorders (NUD), and antagonist therapies, such as naloxone for opioid overdose and naltrexone for promoting abstinence. In the present review, we primarily focus on the pharmacological rationale of agonist replacement strategies in treatment of opioid dependence, and the potential translation of this rationale to new therapies for cocaine use disorders. We begin by describing the neural mechanisms underlying opioid reward, followed by preclinical and clinical findings supporting the utility of agonist therapies in the treatment of OUD. We then discuss recent progress of agonist therapies for cocaine use disorders based on lessons learned from methadone and buprenorphine. We contend that future studies should identify agonist pharmacotherapies that can facilitate abstinence in patients who are motivated to quit their illicit drug use. Focusing on those that are able to achieve abstinence from cocaine will provide a platform to broaden the effectiveness of medication and psychosocial treatment strategies for this underserved population. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'.

Keywords: Addiction; Agonist replacement therapy; Atypical dopamine uptake inhibitor; Cocaine; Dopamine transporter; Methadone; Opioids; Substance use disorders.

Figure 1:

A summary diagram illustrating the mesolimbic DA reward system, and targets of heroin, nicotine, cocaine, and compounds used as agonist therapies for the treatment of substance use disorder.

Figure 2.

Characterization of the neurochemical and behavioral effects of heroin and methadone in vivo in rats. A, B: Systemic administration of heroin or methadone produced significant and dose-dependent increases in extracellular NAc DA, with methadone displaying a longer-duration of action than heroin. C, D: Systemic administration of heroin or methadone dose-dependently increased open-field locomotor activity. Again, methadone displays a long-acting profile. E, F: Systemic administration of heroin produced a dose-dependent increase in intracranial brain-stimulation reward (BSR) maintained by electrical stimulation of the medial forebrain bundle of the hypothalamus, while methadone produced a modest increase in BSR only at 3 mg/kg. G, H: Heroin priming induced robust reinstatement of heroin-seeking behavior in rats extinguished from previous heroin self-administration, while methadone did not induce reinstatement at either dose tested. *p<0.05, **p<0.01, ***p<0.001, compared to baseline before heroin or methadone injection or compared to vehicle control group. (Some data are replotted from Peng et al., 2010).

Figure 3:

Methadone pretreatment attenuates heroin action in animal models of addiction. A: Effects of methadone pretreatment on heroin-induced increase extracellular NAc DA; B: Heroin-induced increases in extracellular DA are blocked by methadone pretreatment (data highlighted in gray were normalized over the baseline before heroin injection); C: Methadone dose-dependently attenuated heroin-enhanced BSR; D: Methadone, at 5 mg/kg, attenuated heroin-enhanced BSR produced by multiple heroin doses; E: Methadone inhibited intravenous heroin self-administration in rats in a dose-dependent manner; F: Methadone, administered 30 min prior to heroin, dose-dependently attenuated 0.25 mg/kg heroin-induced reinstatement of drug-seeking behavior. *p<0.05, ***p<0.001, compared to vehicle control group. (Some data are replotted from Peng et al., 2010).