Elsevier

Addictive Behaviors

Volume 29, Issue 7, September 2004, Pages 1439-1464
Addictive Behaviors

Agonist-like, replacement pharmacotherapy for stimulant abuse and dependence

https://doi.org/10.1016/j.addbeh.2004.06.018Get rights and content

Abstract

Stimulant abuse and dependence are disproportionately problematic due to the combination of legal and social issues added to the serious behavioural and biological features of the disorders. These problems are compounded by adverse consequences for families and society. Illegality and stigma multiply the consequences of use and difficulties in providing treatment. Specific behavioural interventions have been demonstrated as useful in treatment of substance use disorders (SUDs). Medications also have an important role in treatment. Effective agonist and antagonist pharmacotherapies as well as symptomatic treatments exist for opioid and nicotine dependence. Neither agonists nor antagonists have been approved as uniquely effective for treatment of stimulant abuse or dependence. Still, promising results are emerging for an agonist-like or ‘replacement’ strategy paralleling that for nicotine and opioid dependence. Supporting data have emerged from both preclinical and clinical research environments. There are scientific, clinical, social, and legal impediments to application of an agonist-like approach to stimulant abuse and dependence. Some resemble past and current concerns about opioid replacement. Others are unique to the stimulant agents, effects, and clinical features. Here, the authors consider (1) agonist and antagonist pharmacotherapy strategies; (2) preclinical research, including methodological approaches, opioid and nicotine replacement, and agonists for stimulant dependence; (3) clinical reports with stimulant medications in cocaine dependence, and the amphetamine replacement strategy for amphetamine dependence; (4) application of agonist-like/replacement strategies, including clinical requirements and risks; and (5) directions for research.

Introduction

The cyclic nature of stimulant abuse and dependence over the last century has been well described (Musto, 1990, Musto, 1991, Musto, 1992, Pickering & Stimson, 1994). Cocaine use was prevalent in the early 1900s and again in the last third of the 20th century. Limited therapeutic amphetamine use exists, but illicit abuse and dependence flourished in the 1940s to 1971 (Comprehensive Drug Abuse Prevention and Control Act of 1970), then reemerged dominantly as illegal use in the 1990s. Other stimulant drugs also have had periods of favor. Stimulant use in varied forms permeates many cultures, and abuse and dependence cross socioeconomic boundaries.

Potent stimulants are used for narcolepsy, activity disorders, and in limited circumstances, for obesity. There is no evidence that therapeutic regimens are problematic (e.g., Kolins, 2003, Wilens et al., 2003). ‘Quasi-therapeutic,’ or functional use such as reversing performance impairment due to fatigue or to facilitate ‘shift work’ adaptation is not uncommon (Laties & Weiss, 1967, Laties & Weiss, 1981, Weiss & Laties, 1962). Likelihood of abuse is related to origins or use (e.g., therapeutic vs. achieving euphoria), and also to route and patterns of administration (Seigel, 1984). Individuals seeking treatment for stimulant dependence typically smoke or inject the drug. They often have other problems resulting from or predating abuse and dependence. Psychiatric conditions are known to frequently coexist with substance use disorders (SUDs; e.g., Narrow et al. 2002).

Extensive preclinical research has delineated stimulants' behavioural–biological actions and mechanisms. This facilitates conceptualization and development of pharmacotherapeutic strategies (Howell & Wilcox, 2000; Mello & Negus, 1996, Platt et al., 2002). An extensive clinical literature (e.g., Levin et al., 2000) describes candidate medications but no medication has been approved for treatment of stimulant use disorders. Research devoted to pain management produced agents for opioid use treatment, including the agonists methadone and l-alpha-acetylmethadol (LAAM), the partial agonist buprenorphine, and the antagonist naltrexone. Several nicotine preparations are useful for treatment of nicotine dependence resulting from tobacco use (Fiore, 2000, Silagy et al., 2004). Development of pharmacotherapy for stimulant dependence has been problematic, slowed in part by focus on potential antagonists combined with reticence about ‘replacement’ or agonist-like conceptualization for the disorders. Here, we examine basic and clinical science, translation of findings to clinical settings, medication development, and plausible strategies for application or an agonist approach for these recurrent substance use problems.

Section snippets

Agonists and antagonists

Pharmacotherapeutic options for treatment of stimulant dependence include the following: agonists partially replacing effects of the abused drug, thereby stabilizing the patient; antagonists blocking the abused drugs effects thus precluding use (with vaccines being a variant of the concept); symptomatic treatment attenuating symptoms of use or withdrawal, or a combination of these approaches (see Table 1).

Cocaine and amphetamine analogs have diverse effects. The complex interplay of multiple

Preclinical research with stimulant medications

Preclinical studies are critical for SUD medication development and evaluation because genetic, pharmacological, and environmental variables can be precisely controlled, and medications or regimens not approved for use in humans can be rigorously examined. Preclinical studies have used a wide array of techniques to examine candidate medications for the treatment of dependence. Previous reviews have addressed this research effort in depth (Carroll et al., 1999, Howell & Wilcox, 2001, Mello &

Clinical reports with stimulant medications

An increasing literature indicates potent agonists may have utility for treatment of stimulant dependence, and these reports are considered below. The types of reports include cases, open trials, randomized trials, and a few double-blind, placebo-controlled trials. They have been conducted in several countries, and in diverse settings ranging from academic medical center research clinics to community-based SUD programmes. Nevertheless, despite these considerable differences in research

Early observational trials

The earliest report of treating amphetamine dependence with an amphetamine was that of Mitcheson, Edwards, Hawks, and Ogbourne (1976) during a wave of misuse in London during the late 1960s. The 23 young participants had typically used amphetamine for less than 1 year, and most were treated with injectable methylamphetamine. Only three stayed in treatment beyond 3 months, but 2 of these became abstinent from all drugs. The authors' conclusion that amphetamine substitution was a therapeutic

Application of replacement/agonist-like strategy for stimulant dependence

Comment here should be prefaced with a clear statement that substantial further research is required. There are insufficient data to specify when a potent agonist might be optimal for treatment and we must be cautious in attributing improvement to dextroamphetamine alone in the reports described. However, data for current approaches for methadone treatment (van Beusekom & Iguchi, 2001) are still being clarified after 35 years of clinical use. U.S. regulations for opioid maintenance are unduly

Directions

There is agreement that an armamentarium of pharmacological adjuncts would facilitate stimulant dependence treatment. Similarly, as for other agonist-like approaches, agreement exists that efficacy is dependent on regimen, use pattern, and severity. Opinion is divergent concerning directions for pharmacotherapy research to enhance treatment of this difficult-to-treat disorder. Most studies for most categories of agents for stimulant dependence do not show benefits and some indicate increased

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