The neurobiology of opioid dependence: implications for treatment

Opioid tolerance, dependence, and addiction are all manifestations of brain changes resulting from chronic opioid abuse. The opioid abuser's struggle for recovery is in great part a struggle to overcome the effects of these changes. Medications such as methadone, LAAM, buprenorphine, and naltrexone act on the same brain structures and processes as addictive opioids, but with protective or normalizing effects. Despite the effectiveness of medications, they must be used in conjunction with appropriate psychosocial treatments.     

Agonist-like, replacement pharmacotherapy for stimulant abuse and dependence

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.     

Pharmacotherapy of dual substance abuse and dependence

The US FDA has approved a limited number of treatments for alcohol, nicotine and opioid dependence; however, no treatments for other abused drugs such as marijuana, cocaine or methamphetamine are approved. This review focuses on research into drug pharmacotherapies, particularly single-drug therapies, for substance abuse and dependence contributing to the most important dual substance use disorders (SUDs). Given the implications of poly-substance abuse, it is essential that clinicians and researchers be aware of potential pharmacotherapies for the treatment of dual SUDs.A substantial number of patients abuse more than one drug concurrently, complicating the treatment of SUD and leaving clinicians with few FDA-approved drug options for their patients. In this era of evidence-based medicine, such patients are typically treated with therapeutically proven medications, but in ways that are outside the scope of a drug's original indication by the FDA. Such 'off-label' prescribing has become an important therapeutic strategy for practitioners seeking treatments for other diseases in subpopulations such as paediatrics and gerontology or for medical conditions such as oncology or mental illness. Similarly, the information that most clinicians use to make their decisions for treating patients abusing multiple drugs stems from trials treating a single SUD, anecdotal experiences from their own practice or that of their colleagues, or single-case studies reported in the literature.The existing evidence suggests there are few treatments for SUDs that confer significant reductions in substance use across a broad patient population. Moreover, even fewer clinical efficacy trials have been conducted that provide evidence of therapeutic benefit for these drugs. Recognising the difficulty in making the proper drug choice for facilitating maximum treatment success, this review highlights the single drugs or drug combinations that show some potential for treating dual SUDs. This review finds strongest support for the use of disulfiram for treatment of alcohol and cocaine dependence (with or without concomitant methadone maintenance), baclofen for alcohol and cocaine dependence (but not opioid-dependent cocaine users), tiagabine for cocaine dependence in methadone-maintained patients, and topiramate for alcohol, nicotine and cocaine dependence. While ondansetron and olanzapine show some efficacy in treating alcohol and cocaine dependence, more research is needed to better delineate the subpopulation in which these drugs may provide their maximum effect.     

The role of human drug self-administration procedures in the development of medications

The purpose of this review is to illustrate the utility and value of employing human self-administration procedures in medication development, including abuse liability assessments of novel medications and evaluation of potential pharmacotherapies for substance use disorders. Traditionally, human abuse liability testing has relied primarily on subjective reports describing drug action by use of questionnaires; similarly, drug interactions between putative treatment agents and the drugs of abuse have relied on these measures. Subjective reports are highly valued because they provide qualitative and quantitative information about the characteristics of central and peripheral pharmacodynamic effects as well as safety and tolerability. However, self-administration procedures directly examine the behavior of interest-that is, drug taking. The present paper (1) reviews the most commonly used human self-administration procedures, (2) discusses the concordance of subjective reports and self-administration within the context of medications development for substance use disorders, focusing primarily on illustrative examples from development efforts with opioid and cocaine dependence, and (3) explores the utility of applying self-administration procedures to assess the abuse liability of novel compounds, including "abuse-deterrent" formulations (ADFs). The review will focus on opioid and cocaine dependence because a rich database from both clinical laboratory and clinical trial research exists for these two drug classes. The data reviewed suggest that drug-induced changes in self-administration and subjective effects are not always concordant. Therefore, assessment of self-administration in combination with subjective effects provides a more comprehensive picture that may have improved predictive validity for translating to the clinical setting.     

Sustained-release naltrexone: novel treatment for opioid dependence

The devastating costs of opioid abuse and dependence underscore theneed for effective treatments for these disorders. At present, several different maintenance medications exist for treating opioid dependence, including methadone, buprenorphine and naltrexone. Of these, naltrexone is theonly one that possesses no opioid agonist effects. Instead, naltrexoneoccupies opioid receptors and prevents or reverses the effects produced by opioid agonists. Despite its clear pharmacologic effectiveness, its clinical effectiveness in treating opioid dependence has been disappointing, primarily due to non-compliance with taking the medication. However, the recent availability of sustained-release formulations of naltrexone has renewed interest in this medication. The present paper describes the development of sustained-release naltrexone formulations and discusses the clinical issues associated with their use in treating opioid dependence.     

Sustained-release naltrexone: novel treatment for opioid dependence

The devastating costs of opioid abuse and dependence underscore the need for effective treatments for these disorders. At present, several different maintenance medications exist for treating opioid dependence, including methadone, buprenorphine and naltrexone. Of these, naltrexone is the only one that possesses no opioid agonist effects. Instead, naltrexone occupies opioid receptors and prevents or reverses the effects produced by opioid agonists. Despite its clear pharmacologic effectiveness, its clinical effectiveness in treating opioid dependence has been disappointing, primarily due to non-compliance with taking the medication. However, the recent availability of sustained-release formulations of naltrexone has renewed interest in this medication. The present paper describes the development of sustained-release naltrexone formulations and discusses the clinical issues associated with their use in treating opioid dependence.     

Medications in the treatment of addictive disease.

Medication has become an increasingly accepted adjunct to other forms of drug abuse treatment. Its acceptance is due in part to clinicians' frustration in treating crack cocaine abusers and to increasing integration of drug abuse treatment into mainstream medicine. A rapidly growing body of literature attests to clinical researchers' interest in pharmacotherapy of substance abuse. Medications can be a useful adjunct to drug abuse treatment in many different ways. The clinical challenge is to decide who should be treated with what medication and at what stage of recovery medications are helpful. This article discusses medications currently in use for treatment of addictive disease, describes some aspects of medication development, and suggests more cost-effective methods of exploring the efficacy of medications for treatment of drug abuse.     

Naltrexone decreases D-amphetamine and ethanol self-administration in rhesus monkeys

Amphetamines are the second most highly abused illicit drugs worldwide, yet there is no pharmacological treatment for amphetamine abuse and dependence. Preclinical studies and, more recently, human studies, suggest that the opioid receptor antagonist, naltrexone, might be useful in the treatment of amphetamine abuse. Naltrexone, an opioid receptor antagonist, is currently used for the treatment of alcohol dependence. The aim of this study was to explore the ability of naltrexone to modify self-administration of amphetamine or ethanol in rhesus monkeys. Monkeys were trained to respond to intravenous injections of either D-amphetamine (0.003 mg/kg/injection) or ethanol (0.05 g/kg/injection) on a fixed ratio 30 schedule. Naltrexone (0.01-1 mg/kg) was administered intramuscularly 30 min before the start of treatment test sessions. Naltrexone dose-dependently decreased both amphetamine and ethanol self-administration. These findings support the potential use of naltrexone as therapy for amphetamine and polydrug abuse.     

Research on naltrexone in the criminal justice system

Many parolees and probationers are opioid abusers, and substance abuse is a leading factor for the revocation of probation, parole, and other alternatives to incarceration. The opioid antagonist naltrexone would appear to be an excellent treatment for opioid abuse and dependence in this population and the authors sought to systematically review this literature. Using the PubMed database, the authors identified large bodies of criminal justice (CJS) and naltrexone literature. The search terms used in both searches were crosschecked to identify all articles that involved research on naltrexone in the CJS. Only two articles were identified. The lack of research on naltrexone in the criminal justice system highlights the need for more research on naltrexone in our overburdened CJS.     

Current pharmacotherapies for opioid dependence

Pharmacotherapy of intravenous opioid abusers has taken on increased urgency with the acquired immunodeficiency syndrome (AIDS) epidemic, because in major cities intravenous drug abuse now accounts for half of new AIDS cases. The pharmacotherapy of acute dependence and withdrawal has benefited from the use of clonidine, particularly in combination with antagonist-precipitated withdrawal. However, protracted abstinence and its associated risk of relapse to drug abuse has underscored the need for maintenance pharmacotherapies. Maintenance pharmacotherapies such as methadone and naltrexone are frequently needed to sustain outpatient retention and abstinence from heroin. Methadone is more widely used than is naltrexone, an oral, long acting heroin blocker that can maintain drug abstinence after detoxification. Because of limitations in both of these maintenance agents, two investigational maintenance treatments have been tested: levo-alpha-acetylmethadol (LAAM), a long-acting form of methadone, and buprenorphine, a long-acting mixed opioid agonist-antagonist with properties similar to either methadone or naltrexone, depending on dose. Clinical use, limitations, and outcome with each medication are reviewed.     

Substance abuse and schizophrenia: pharmacotherapeutic intervention

Substance use disorder is common in patients with schizophrenia and dramatically worsens their outcome. The typical antipsychotic medications, introduced more than 50 years ago, are effective for the treatment of psychosis but may have only limited efficacy in patients with these co-occurring disorders because patients continue to use substances while taking them. In preliminary studies, however, several of the atypical antipsychotic medications have shown promise for reducing alcohol and drug use in patients with schizophrenia. A neurobiological formulation is discussed, suggesting that the use of substances in patients with schizophrenia may be based on a dysfunction within the dopamine-mediated brain reward circuitry and that clozapine, in particular, may potentially ameliorate this dysfunction and lessen the desire for substance use. Medications for the treatment of alcohol use disorders, such as disulfiram, naltrexone, and acamprosate, as well as other adjunctive medications, may also be useful. Further studies are required to establish a solid evidence base of best practices for the use of medications in these patients.     

Clinical uses of naltrexone: a review of the evidence

The implication of the opioidergic system in the pathogenesis of various substance use disorders has led to renewed interest in expanding the clinical uses of naltrexone, an opioid antagonist. This article examines the evidence for the efficacy of naltrexone in a variety of substance use and psychiatric disorders. Naltrexone can be an effective treatment for alcohol and opioid dependence if issues of compliance are adequately addressed. Thus far, no definitive role has been found for naltrexone in the treatment of other psychiatric disorders. Further research needs to be done in self-injurious behavior, gambling, cocaine, and nicotine dependence.     

Novel pharmacological approaches for treating tobacco dependence and withdrawal: current status

Increasing the diversity and availability of medications for the treatment of tobacco dependence and/or withdrawal, to aid in the achievement of smoking cessation, is crucial to meet the diverse needs of tobacco users. Despite a general awareness that smoking is harmful and widespread interest in smoking cessation, nearly 50 million adults in the US and 1.3 billion worldwide continue to smoke. Nicotine replacement therapies are effective in the treatment of tobacco dependence and withdrawal, but do not meet the needs of all tobacco users. Improvement of tobacco dependence and/or withdrawal treatments is likely to rely on novel pharmacological approaches that include new chemical entities and new formulations of current drugs. In addition, new indications for treating tobacco dependence and withdrawal show promise for reducing tobacco use and associated disease. This article focuses on a range of novel pharmacological approaches for the treatment of tobacco dependence and/or withdrawal, including oral and pulmonary nicotine delivery and the following non-nicotinic medications: antidepressants, an alpha4beta2 nicotine partial agonist, an alpha2-noradrenergic agonist, cytochrome P450 (CYP) 2A6 inhibitors, opioid antagonists and GABAergic medications. In addition to existing medications, this article addresses novel medications in the clinical development stage and those that have been evaluated previously. Novel medications in the clinical development stage include at least three nicotine vaccines and the cannabinoid receptor acting drug rimonabant. Medications evaluated previously include lobeline, mecamylamine and an anticholinergic drug regimen comprising atropine, scopolamine and chlorpromazine. Having not been approved by major drug regulatory authorities for the treatment of tobacco dependence and/or withdrawal, these medications have been evaluated in an experimental capacity.     

Addiction Diagnostic Update: DSM-III-R Psychoactive Substance Use Disorders

Abstract

This article reviews the Community Reinforcement Approach (CRA) in the treatment of opioid dependence. It covers the use of CRA with both methadone maintenance patients and patients withdrawing from opioids. The data reviewed in the use of CRA in combination with methadone maintenance shows improvement in a number of areas. These include the reduction of opioid use, as well as other drugs of abuse, improved legal status, less psychiatric symptoms, and improved vocational and social functioning. CRA coupled with vouchers can assist in retaining patients in treatment long enough to improve opioid detoxification rates from buprenorphine and coupled with naltrexone may sustain abstinence. Further, the use of a standardized computerized format may extend the utility of CRA.