Pharmacologic management of relapse prevention in addictive disorders.

Substance use disorders are an important public health problem associated with significant mortality and morbidity. Effective maintenance pharmacotherapies are available for tobacco, alcohol, and opioid use disorders. For optimum treatment response, these medications should be used in conjunction with behavioral interventions. For other drugs of abuse, especially for cocaine, medication development is an active area of research. Further research is needed to develop new pharmacotherapies for substance use disorders and establish clinical guidelines on how to use these medications most effectively.     

Recent advances in the psychotherapy of addictive disorders

Rigorous research has recently identified a range of behavioral therapies that have been shown to be effective across the most prevalent types of substance dependence. This review summarizes the roles of behavioral therapies as contrasted with those of pharmacotherapies for substance use disorders and then provides an overview of the major classes of behavioral therapies (clinical management, coping skills approaches, motivational interviewing, and family and interpersonal approaches), highlighting their effectiveness across cocaine, opioid, alcohol, and cannabis use disorders. Lastly, important areas of current research emphasis including combined treatments, strategies for effectively transporting empirically validated treatments into clinical practice, and increasing the efficiency of treatment are described.     

Psychostimulant treatment of cocaine dependence

The use of stimulant medications for the treatment of cocaine dependence is an evolving scientific line of research. To date, the most promising results are with the higher-potency medications, the amphetamine analogues, or a combination of a dopaminergic medication with a contingency management behavioral intervention. The development of effective pharmacotherapies for opioid and nicotine dependence using an agonist replacement approach suggests that these promising findings needs to continue to be vigorously investigated. In clinical trial reports, there are very few instances of cardiovascular adverse events, which suggests that for well-selected patients with cocaine dependence, stimulant replacement therapy can be safe. However, clinical trial eligibility criteria excludes most high-risk patients from participating, and introducing stimulant substitution to the wider treatment community would likely expose more vulnerable patients to the medical risks associated with stimulant treatment while using cocaine. As treatment development research moves forward, attention must be paid to helping clinicians select patients who are most likely to benefit from stimulant substitution treatment and how to identify those at risk. An additional concern with the use of stimulant medication treatment of cocaine dependence is prescribing controlled substances for patients with active substance use disorders. Again, within a clinical trial, medication supplies are monitored and distributed carefully in small quantities. In a community setting, misuse or diversion will be risks associated with prescribing controlled substances to patients with addictive disorders, but therapeutic strategies for monitoring and limiting that risk can be implemented. Psychostimulant pharmacotherapy is a promising line of research for the treatment of cocaine dependence, a condition for which no effective pharmacotherapy has been identified. Further research is required to confirm positive results from single-site trials, in particular the study of amphetamines as a treatment for cocaine dependence. As this literature evolves, strategies to manage the risk of prescribing controlled substances to patients with addictive disorders need to be tested and refined. Biases against using controlled substances as a treatment for cocaine dependence should be challenged, much in the way the use of agonist treatment transformed the treatment of opioid dependence despite initial resistance from the field.     

Targeting behavioral therapies to enhance naltrexone treatment of opioid dependence: efficacy of contingency management and significant other involvement

BACKGROUND: Contingency management (CM) and significant other involvement (SO) were evaluated as strategies to enhance treatment retention, medication compliance, and outcome for naltrexone treatment of opioid dependence. METHODS: One hundred twenty-seven recently detoxified opioid-dependent individuals were randomly assigned to 1 of 3 conditions delivered for 12 weeks: (1) standard naltrexone treatment, given 3 times a week; (2) naltrexone treatment plus contingency management (CM), with delivery of vouchers contingent on naltrexone compliance and drug-free urine specimens; or (3) naltrexone treatment, CM, plus significant other involvement (SO), where a family member was invited to participate in up to 6 family counseling sessions. Principal outcomes were retention in treatment, compliance with naltrexone therapy, and number of drug-free urine specimens. RESULTS: First, CM was associated with significant improvements in treatment retention (7.4 vs 5.6 weeks; P =.05) and in reduction in opioid use (19 vs 14 opioid-free urine specimens; P =.04) compared with standard naltrexone treatment. Second, assignment to SO did not significantly improve retention, compliance, or substance abuse outcomes compared with CM. Significant effects for the SO condition over CM on retention, compliance, and drug use outcomes were seen only for the subgroup who attended at least 1 family counseling session. The SO condition was associated with significant (P =.02) improvements in family functioning. CONCLUSION: Behavioral therapies, such as CM, can be targeted to address weaknesses of specific pharmacotherapies, such as noncompliance, and thus can play a substantial role in broadening the utility of available pharmacotherapies.     

Barriers to Use of Pharmacotherapy for Addiction Disorders and How to Overcome Them

Substance use disorders are highly prevalent, debilitating conditions for which effective pharmacotherapies exist with a broad evidence base, yet pharmacotherapy for the treatment of addiction disorders is underutilized. The goals of this review are to describe the barriers that may contribute to poor adoption and utilization of pharmacotherapy for alcohol and opioid dependence at the system, provider, and patient level and to discuss ways to overcome those barriers. Multifaceted efforts directed at all three levels may be needed to speed pharmacotherapy adoption. More research is needed to help us better understand barriers from patients’ perspectives. Strategies to promote adoption of pharmacotherapy for addiction disorders should be modified to fit the needs of the practice, system, and individual patients. Pharmacotherapy is a valuable tool in the clinical armamentarium of addiction treatment; thus, overcoming barriers to implementation may improve clinical and social outcomes.     

Evidenced-based treatment of opioid-dependent patients.

OBJECTIVE: To provide an overview of treatment options for opioid-dependent patients. METHOD: We screened all published studies on the treatment of opioid dependence, with a special focus on systematic literature reviews, formal metaanalyses, and recent trials. RESULTS: Both clinical experience and neurobiological evidence indicate that opioid dependence is a chronic relapsing disorder. Treatment objectives depend on the pursued goals: crisis intervention, abstinence-oriented treatment (detoxification and relapse prevention), or agonist maintenance treatment. The high quality of solid evidence in the literature demonstrates that there are numerous effective interventions available for the treatment of opioid dependence. Crisis intervention, frequently necessary owing to the high overdose rate, can be effectively handled with naloxone. Abstinence-oriented interventions are effective for only a few motivated patients with stable living conditions and adequate social support. Agonist maintenance treatment is considered the first line of treatment for opioid dependence. Numerous studies have shown efficacy for methadone and buprenorphine treatment, while maintenance with other agonists is also becoming available to a greater extent. Maintenance treatment with diamorphine should be made available for the small group of treatment-resistant, severely dependent addicts. Other harm-reduction measures can serve to engage individuals with opioid addiction who are not in treatment. CONCLUSION: Opioid dependence is a chronic relapsing disease that is difficult to cure, but effective treatments are available to stabilize patients and reduce harm, thereby increasing life expectancy and quality of life.     

The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Substance Use and Related Disorders. Part 2: Opioid dependence

Abstract

Objectives. To develop evidence-based practice guidelines for the pharmacological treatment of opioid abuse and dependence. Methods. An international task force of the World Federation of Societies of Biological Psychiatry (WFSBP) developed these practice guidelines after a systematic review of the available evidence pertaining to the treatment of opioid dependence. On the basis of the evidence, the Task Force reached a consensus on practice recommendations, which are intended to be clinically and scientifically meaningful for physicians who treat adults with opioid dependence. The data used to develop these guidelines were extracted primarily from national treatment guidelines for opioid use disorders, as well as from meta-analyses, reviews, and publications of randomized clinical trials on the efficacy of pharmacological and other biological treatments for these disorders. Publications were identified by searching the MEDLINE database and the Cochrane Library. The literature was evaluated with respect to the strength of evidence for efficacy, which was categorized into one of six levels (A–F). Results. There is an excellent evidence base supporting the efficacy of methadone and buprenorphine or the combination of buprenorphine and naloxone for the treatment of opioid withdrawal, with clonidine and lofexidine as secondary or adjunctive medications. Opioid maintenance with methadone and buprenorphine is the best-studied and most effective treatment for opioid dependence, with heroin and naltrexone as second-line medications. Conclusions. There is enough high quality data to formulate evidence-based guidelines for the treatment of opioid abuse and dependence. This task force report provides evidence for the efficacy of a number of medications to treat opioid abuse and dependence, particularly the opioid agonists methadone or buprenorphine. These medications have great relevance for clinical practice.     

Desipramine in opioid-dependent cocaine abusers maintained on buprenorphine vs methadone

BACKGROUND: Cocaine abuse occurs in 40% to 60% of patients entering opioid maintenance treatment, and effective pharmacotherapies are needed for this combined dependence. METHODS: This 13-week, randomized, double-blind, placebo-controlled trial evaluated the efficacy of desipramine hydrochloride (0 or 150 mg/d) plus buprenorphine hydrochloride (12 mg/d) or methadone hydrochloride (65 mg/d) in 180 opioid-dependent cocaine abusers (124 men, 56 women). Supervised urine samples were obtained thrice weekly, and self-reported cocaine and heroin use was reported once weekly. Desipramine plasma levels were determined at weeks 4 and 10. RESULTS: In men, opioid abstinence was increased more rapidly over time when treated with methadone than with buprenorphine, whereas cocaine abstinence was increased more with buprenorphine than with methadone. In women, opioid abstinence was increased the least rapidly when treated with buprenorphine plus placebo, while cocaine abstinence was increased more rapidly over time when treated with methadone than with buprenorphine. Regardless of sex or opioid medication, desipramine increased opioid and cocaine abstinence more rapidly over time than placebo. Self-reported opioid use confirmed these findings. Desipramine plasma levels were higher in women than in men, particularly those on buprenorphine maintenance. Higher desipramine plasma levels were associated with greater opioid, but not cocaine, abstinence. CONCLUSIONS: Desipramine may be a useful adjunctive medication in facilitating opioid and cocaine abstinence in opioid-maintained patients. The efficacy of opioid medications to treat opioid or cocaine dependence may differ by sex. These findings highlight the importance of including sex as a factor when examining treatment outcome in these types of trials.     

Naltrexone depot formulations for opioid and alcohol dependence: a systematic review

Naltrexone is an opioid receptor antagonist that blocks the reinforcing effects of opioids and reduces alcohol consumption and craving. It has no abuse potential, mild and transient side effects, and thus appears an ideal pharmacotherapy for opioid dependence. Its effectiveness in alcohol dependence is less evident, but compliance with naltrexone combined with psychosocial support has been repeatedly shown to improve drinking outcomes. Limited compliance with oral naltrexone treatment is a known drawback. Several naltrexone implant and injectable depot formulations are being investigated and provide naltrexone release for at least 1 month. Studies among opioid-dependent patients indicate significant reductions in heroin use, but sample sizes are usually small. In alcohol dependence, two large multicenter trials report alcohol and craving reductions for naltrexone and placebo groups, indicating a significant but moderate effect. The pharmacokinetic profile of the injectable formulation indicates reliable naltrexone release over 1 month at therapeutic levels. Implant formulations releasing naltrexone up to 7 months are reported. Findings on safety and tolerability confirm the generally mild adverse effects described for naltrexone tablets. However, further research on therapeutic levels (i.e., opioid blocking) is warranted. The majority of naltrexone implants lacks approval for regular clinical use and larger longitudinal studies are needed. The available naltrexone depot formulations have the potential to significantly improve medication compliance in opioid and alcohol dependence. In certain circumstances, they may constitute a promising new treatment option.     

Acamprosate in the treatment of alcohol dependence: clinical and economic considerations

Acamprosate has been commercially available in the USA since 2004 to treat alcohol dependence. Its safety and efficacy have been demonstrated in a number of clinical trials worldwide, which overall have shown significant improvements in abstinence compared with placebo. As with all alcoholism pharmacotherapies, acamprosate is used in conjunction with psychosocial interventions. One frequently described mechanism stipulates that acamprosate supports abstinence by normalizing the often protracted dysregulation of NMDA-mediated glutamatergic neurotransmission that follows chronic heavy alcohol use and withdrawal. This article reviews the clinical safety and efficacy of acamprosate, as well as results from recent pharmacoeconomic and human laboratory studies. These data elucidate the economic benefits of acamprosate, as well as its effects on cognition and alcohol-related sleep disturbances.     

Compulsion and impulsion of substance dependence: frontline of pharmacotherapy for craving

Substance-seeking behavior appears to be compulsive because of unclear motivation, and also appears to be impulsive because of difficulty to be predicted. Compulsivity and impulsivity of substance-dependent individuals are common in unaccountability. This unaccountability is the result form craving for psychoactive substance. If a therapist does not understand it, a treatment session is likely to be punished, not psychotherapeutic. This paper reviews the pharmacotherapies conducted in foreign countries, and suggests the pharmacotherapies which are expected to be introduced into Japan. One of the reasons why psychiatrists tend to be reluctant to treat substance-dependent patients is that there have been no available pharmacotherapies in Japan. Accordingly, pharmacotherapies for substance dependence are required to be developed and established.     

Cholinergic receptor system as a target for treating alcohol abuse and dependence

Alcohol dependence and other alcohol use disorders are major public health problems. Due to the limitations in efficacy with current medications for the management of alcohol abuse and dependence, there is a need for alterantive pharmacotherapies. Emerging preclinical and clinical data indicate that brain nicotinic acetylcholine receptors (nAChRs), a heterogeneous family of ion channels expressed in the mammalian brain, are critical targets for the development of pharmacotherapies for alcohol abuse and dependence. Evidence suggests that the effects of nAChR partial agonists and antagonists have promise for the management of alcohol dependence and other alcohol use disorders. The present review summarizes information on the most recent pharmacotherapies targeting nAChRs, including cytisine, sazetidine A, varenicline, lobeline mecamylamine, PF-4575180 and CP-601932, that are able to treat alcohol dependence. The role of α4β2*, α3β4* and/or other subtypes associated effects in reducing voluntary alcohol consumption or modulate alcohol drinking behavior in animal models and humans are reviewed. Patents discussed include those targeting α4β2* and α7 subtypes as well as cholinesterase inhibitors. Future research indicating the ability of nAChR based compounds to reduce alcohol consumption or modulate alcohol drinking behavior in preclinical and clinical studies, are also discussed.     

Single nucleotide polymorphism near CREB1, rs7591784, is associated with pretreatment methamphetamine use frequency and outcome of outpatient treatment for methamphetamine use disorder

Although stimulant dependence is highly heritable, few studies have examined genetic influences on methamphetamine dependence. We performed a candidate gene study of 52 SNPs and pretreatment methamphetamine use frequency among 263 methamphetamine dependent Hispanic and Non-Hispanic White participants of several methamphetamine outpatient clinical trials in Los Angeles. One SNP, rs7591784 was significantly associated with pretreatment methamphetamine use frequency following Bonferroni correction (p < 0.001) in males but not females. We then examined rs7591784 and methamphetamine urine drug screen results during 12 weeks of outpatient treatment among males with treatment outcome data available (N = 94) and found rs7591784 was significantly associated with methamphetamine use during treatment controlling for pretreatment methamphetamine use. rs7591784 is near CREB1 and in a linkage disequilibrium block with rs2952768, previously shown to influence CREB1 expression. The CREB signaling pathway is involved in gene expression changes related to chronic use of multiple drugs of abuse including methamphetamine and these results suggest that variability in CREB signaling may influence pretreatment frequency of methamphetamine use as well as outcomes of outpatient treatment. Medications targeting the CREB pathway, including phosphodiesterase inhibitors, warrant investigation as pharmacotherapies for methamphetamine use disorders.     

Opioid antagonists in the treatment of alcohol dependence

This article reviews the use of opioid antagonists in the pharmacologic treatment of alcohol dependence. The rationale for using the opioid antagonists naltrexone and nalmefene to prevent relapse in alcohol-dependent subjects is discussed by reviewing past and current clinical trials. The role of psychotherapies, particularly coping skills therapy, in combination with opioid antagonists is highlighted in the presentations of the clinical data. Finally, future research directions for opioid antagonists are discussed.     

Brazilian guideline for the treatment of patients with opioids dependence syndrome

There is a relatively low prevalence of opioid use in Brazil, particularly involving the non-medical use of codeine and opiate-containing syrups. However, opioid dependence syndrome shows a significant total impact on mortality and morbidity. Over the past 20 years, scientific progress has changed our understanding of the nature of opioid addiction and its various possible treatments. Addiction is a chronic illness treatable if the treatment is well-delivered and tailored to the needs of the particular patient. There is indeed an array of treatments that can effectively reduce drug use, help manage drug cravings, prevent relapses and restore people to productive social functioning. The treatment of drug addiction will be part of long-term, medical, psychological, and social perspectives. This guideline aims at providing guidance to psychiatrists and other mental health professionals who care for patients with opioid dependence syndrome. It comments on the somatic and psychosocial treatment that is used for such patients, and reviews scientific evidences and their strength. Also, the essential historical, epidemiological and neurobiological aspects of opioid dependence are reviewed.     

Choosing the right medication for the treatment of alcoholism

In the past decade, scientists have made important progress toward understanding the neurobiology underlying an alcohol disorder. This knowledge has led to the development of promising pharmacotherapies that target the neural pathways involved in the brain’s reward center in such a way that the usual treatment response (via counseling) is substantially improved upon. There are now four US Food and Drug Administration (FDA)-approved pharmacotherapies for the treatment of alcohol dependence: disulfiram (Antabuse; Odyssey Pharmaceuticals, East Hanover, NJ), oral naltrexone (ReVia; Barr Pharmaceuticals, Inc., Pomona, NY), acamprosate (Campral; Forest Laboratories, Inc., New York, NY), and, as of April 2006, an extended-release (30-day) injectable suspension formulation of naltrexone (Vivitrol; Alkermes, Inc., Cambridge, MA). Other types of medications (eg, topiramate and quetiapine) are currently under investigation for the treatment of alcohol dependence. Research also has provided insights into best practices for prescribing the available medications. This report reviews the latest innovations in pharmacotherapy for the treatment of alcohol dependence, focusing on FDA-approved medications presently available to the treatment community.