Agonist-like, replacement pharmacotherapy for stimulant abuse and dependence
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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