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

Neuropharmacology. 2019 Nov 1;158:107609. doi: 10.1016/j.neuropharm.2019.04.015. Epub 2019 Apr 19.


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.

Publication types

  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Analgesics, Opioid / therapeutic use*
  • Buprenorphine / therapeutic use
  • Central Nervous System Stimulants / therapeutic use
  • Cocaine-Related Disorders / drug therapy*
  • Dextroamphetamine / therapeutic use
  • Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors
  • Dopamine Uptake Inhibitors / therapeutic use*
  • Drug Development
  • Humans
  • Methadone / therapeutic use
  • Methylphenidate / therapeutic use
  • Modafinil / therapeutic use
  • Nicotinic Agonists / therapeutic use
  • Opiate Substitution Treatment*
  • Opioid-Related Disorders / drug therapy*
  • Opioid-Related Disorders / metabolism
  • Oxalates
  • Piperazines
  • Receptors, Opioid, mu / agonists
  • Tobacco Use Disorder / drug therapy
  • Tropanes / therapeutic use
  • Varenicline / therapeutic use


  • 3beta-(4-chlorophenyl) tropane-2beta-(3-(4'-methylphenyl) isoxazol-5-yl) hydrochloride
  • Analgesics, Opioid
  • Central Nervous System Stimulants
  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors
  • JJC8-091
  • Nicotinic Agonists
  • Oxalates
  • Piperazines
  • Receptors, Opioid, mu
  • Tropanes
  • Methylphenidate
  • Buprenorphine
  • Modafinil
  • Dextroamphetamine
  • Methadone
  • Varenicline