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TIP 49 Incorporating Alcohol Pharmacotherapies Into Medical

TIP 49 Incorporating Alcohol Pharmacotherapies Into Medical

Incorporating Pharmacotherapies Into Medical Practice

A Treatment Improvement Protocol TIP 49

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Substance Abuse and Mental Health Services Administration Center for Substance Abuse Treatment www.samhsa.gov PHARMACO­ THERAPIES Incorporating Alcohol Pharmacotherapies Into Medical Practice

Treatment Improvement Protocol (TIP) Series 49

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Substance Abuse and Mental Health Services Administration Center for Substance Abuse Treatment

1 Choke Cherry Road Rockville, MD 20857 Acknowledgments specific, written authorization of the Office of Communications, SAMHSA, This publication was produced under HHS. the Knowledge Application Program, contract number 270-04-7049, a Joint Venture of The CDM Group, Inc., and Electronic Access and Copies JBS International, Inc., for the Center of Publication for Substance Abuse Treatment (CSAT), Substance Abuse and Mental Health This publication may be downloaded Services Administration (SAMHSA), or ordered at http://www.samhsa.gov/ U.S. Department of Health and Human shin. Or, please call SAMHSA’s Health Services (HHS). Christina Currier served Information Network at 1-877-SAMHSA-7 as the CSAT Government Project Officer. (1-877-726-4727) (English and Español).

Disclaimer Recommended Citation The views, opinions, and content Center for Substance Abuse Treatment. expressed herein are those of the expert Incorporating Alcohol Pharmacotherapies panel and do not necessarily reflect the Into Medical Practice. Treatment views, opinions, or policies of CSAT, Improvement Protocol (TIP) Series 49. SAMHSA, or HHS. No official support of HHS Publication No. (SMA) 09-4380. or endorsement by CSAT, SAMHSA, or Rockville, MD: Substance Abuse and HHS for these opinions or for particular Mental Health Services Administration, instruments, software, or resources is 2009. intended or should be inferred. Originating Office Public Domain Notice Quality Improvement and Workforce All materials appearing in this Development Branch, Division of Services volume except those taken directly Improvement, Center for Substance from copyrighted sources are in the Abuse Treatment, Substance Abuse and public domain and may be reproduced Mental Health Services Administration, or copied without permission from 1 Choke Cherry Road, Rockville, MD SAMHSA/CSAT or the authors. Citation 20857. of the source is appreciated. However, this publication may not be reproduced HHS Publication No. (SMA) 09-4380 or distributed for a fee without the Printed 2009 Contents

Consensus Panel ...... vii

Expert Advisory Board ...... ix

What Is a TIP? ...... xi

Foreword ...... xiii

Chapter 1—Introduction ...... 1 Alcohol Use Disorders in Medical Settings ...... 1 Audience for TIP 49 ...... 2 Recognition of as a Chronic Illness ...... 3 Purpose of TIP 49 ...... 3 What TIP 49 Does Not Cover ...... 4 Specialty Treatment Versus Screening and ...... 5 Why Use To Treat Alcohol Dependence? ...... 5 Format, Approach, and Organization of TIP 49 ...... 7

Chapter 2—Acamprosate ...... 9 What Is Acamprosate? ...... 9 Why Use Acamprosate? ...... 10 How Is Acamprosate Used? ...... 11 Who Is Appropriate for Treatment With Acamprosate? ...... 13 Treatment Duration and Discontinuing Acamprosate ...... 14 Final Clinical Thoughts ...... 14

Chapter 3— ...... 15 What Is Disulfiram?...... 15 Why Use Disulfiram? ...... 18 How Is Disulfiram Used? ...... 19 Who Is Appropriate for Treatment With Disulfiram? ...... 25 Treatment Duration and Discontinuing Disulfiram ...... 25 Final Clinical Thoughts ...... 26

iii Chapter 4—Oral ...... 27 What Is Oral Naltrexone? ...... 27 Why Use Oral Naltrexone? ...... 28 How Is Oral Naltrexone Used? ...... 29 Who Is Appropriate for Treatment With Oral Naltrexone? ...... 34 Treatment Duration and Discontinuing Oral Naltrexone ...... 35 Final Clinical Thoughts ...... 35

Chapter 5—Extended-Release Injectable Naltrexone ...... 37 What Is Extended-Release Injectable Naltrexone? ...... 37 Why Use Extended-Release Injectable Naltrexone? ...... 38 How Is Extended-Release Injectable Naltrexone Used? ...... 39 Who Is Appropriate for Treatment With Extended-Release Injectable Naltrexone? ...... 42 Treatment Duration and Discontinuing Extended-Release Injectable Naltrexone...... 43 Final Clinical Thoughts ...... 43

Chapter 6—Patient Management ...... 45 Integrating for Alcohol Dependence Into Clinical Practice Settings ...... 45 Initial Assessment ...... 46 Choosing a Medication ...... 51 Combination Therapy ...... 51 Choosing a Psychosocial Intervention ...... 54 Developing a Treatment Plan ...... 56 Patient Awareness ...... 57 Monitoring Patient Progress ...... 57 Modifying the Treatment Strategy ...... 60 Discontinuing Pharmacotherapy ...... 61 Final Clinical Thoughts ...... 61

Appendix A—Bibliography ...... 63

Appendix B—NIAAA’s A Pocket Guide for Alcohol Screening and Brief Intervention ...... 71

Appendix C—Excerpts From Quick Guide for Clinicians Based on TIP 45 ...... 77

Appendix D—Excerpts From Quick Guide for Clinicians Based on TIP 24 ...... 87

Appendix E—Resource Panel ...... 97

Appendix F—Field Reviewers ...... 99

Appendix G—Acknowledgments ...... 101 iv Contents Index ...... 103

Exhibits 2-1 Acamprosate Side Effects ...... 12 2-2 Acamprosate Contraindications ...... 12 2-3 Acamprosate Cautions ...... 13 2-4 Adverse Reactions to Acamprosate and Their Management ...... 13 3-1 Brief History of Disulfiram Development ...... 16 3-2 Possible Effects of the Disulfiram–Alcohol Reaction ...... 17 3-3 Disulfiram Dosages ...... 20 3-4 Disulfiram Side Effects...... 20 3-5 Symptoms of Disulfiram-Induced Hepatic Impairment ...... 21 3-6 Disulfiram Contraindications ...... 21 3-7 Disulfiram Cautions ...... 22 3-8 Adverse Reactions to Disulfiram and Their Management ...... 23 3-9 Drug Interactions With Disulfiram ...... 24 3-10 Laboratory Testing in Disulfiram Therapy ...... 25 4-1 Oral Naltrexone Dosages...... 30 4-2 Oral Naltrexone Side Effects ...... 30 4-3 Naltrexone Contraindications ...... 31 4-4 Naltrexone Cautions ...... 31 4-5 Adverse Reactions to Naltrexone and Their Management ...... 32 4-6 Signs and Symptoms of Disease ...... 32 4-7 Drug Interactions With Oral Naltrexone ...... 33 5-1 Extended-Release Injectable Naltrexone Side Effects ...... 40 5-2 Extended-Release Injectable Naltrexone Contraindications ...... 40 5-3 Extended-Release Injectable Naltrexone Cautions ...... 41 6-1 Useful Laboratory Tests ...... 47 6-2 Questions To Assess Quantity and Frequency of Consumption ...... 50 6-3 Questions To Assess Patients’ Readiness for Change ...... 51 6-4 AUD Medication Decision Grid ...... 52 6-5 Comparison of Approved Medications for Maintenance of Abstinence From Alcohol ...... 53 6-6 Resources for Office-Based Psychosocial Approaches ...... 55 6-7 Elements of Patient Education ...... 57 6-8 Information Resources for Patients ...... 58

Contents v

Consensus Panel

Chair Mary Elizabeth McCaul, Ph.D. Professor Eric C. Strain, M.D. Department of Psychiatry and Professor Behavioral Sciences Department of Psychiatry and Johns Hopkins School of Medicine Behavioral Sciences Baltimore, Maryland Johns Hopkins University School of Medicine Andrew Saxon, M.D. Baltimore, Maryland Professor of Psychiatry Department of Psychiatry and Behavioral Sciences Consensus Panelists University of Washington Seattle, Washington Adam J. Gordon, M.D., M.P.H. Assistant Professor Robert Swift, M.D., Ph.D. Division of General Internal Medicine Professor of Psychiatry and Human Department of Medicine Behavior University of Pittsburgh Brown University Medical School Pittsburgh, Pennsylvania Center for Alcohol and Studies Bankole A. Johnson, M.D., Ph.D., Providence, Rhode Island D.Sc. Chairman Allen Zweben, D.S.W. Department of Psychiatric Medicine Professor and Associate Dean University of Virginia Health System for Research and Sponsored Projects Charlottesville, Virginia School of Social Work Columbia University New York, New York

vii

Expert Advisory Board

Randall T. Brown, M.D. Henry Kranzler, M.D. Assistant Professor Associate Scientific Director Department of Family Medicine Alcohol Research Center University of Wisconsin School University of Connecticut Health of Medicine and Public Health Center Madison, Wisconsin Farmington, Connecticut

Dominic Ciraulo, M.D. Robert J. Malcolm, Jr., M.D. Professor and Chairman Associate Dean and Attending Division of Psychiatry Psychiatrist Boston University School of Medicine Institute of Psychiatry Boston, Massachusetts Medical University of South Carolina Charleston, South Carolina Scott M. Davis, M.D. Physician Barbara J. Mason, Ph.D. Inpatient Medical Services Professor Betty Ford Center Molecular and Integrative Rancho Mirage, California Neurosciences Department Scripps Research Institute George Kolodner, M.D. La Jolla, California CEO and Medical Director Kolmac Clinic Richard N. Rosenthal, M.D. Silver Spring, Maryland Chairman Department of Psychiatry St. Luke’s Roosevelt Hospital Center New York, New York

ix

What Is a TIP?

Treatment Improvement Protocols (TIPs), developed by the Center for Substance Abuse Treatment (CSAT), part of the Substance Abuse and Mental Health Services Administration (SAMHSA) within the U.S. Department of Health and Human Services (HHS), are best-practice guidelines for the treatment of substance use disorders. CSAT draws on the experience and knowledge of clinical, research, and administrative experts to produce TIPs, which are distributed to facilities and individu­ als across the country. As alcohol and drug use disorders are increasingly recognized as a major problem, the audience for TIPs is expanding beyond public and private treatment facilities to include practitioners in mental health, criminal justice, primary care, and other healthcare and social service settings.

TIP Development Process TIP topics are based on the current needs of substance abuse treatment professionals and other healthcare practitioners for information and guidance. After selecting a topic, CSAT invites staff from Federal agencies and national organizations to be members of a resource panel that reviews an initial draft pro­ spectus and outline and recommends specific areas of focus as well as resources that should be considered in developing the content for the TIP. These recommendations are communicated to a consensus panel composed of experts on the topic who have been nominated by their peers. In partnership with Knowledge Application Program writers, consensus panel members par­ ticipate in creating a draft document and then meet to review and discuss the draft. The information and recommendations on which they reach consensus form the foundation of the TIP. A panel chair ensures that the guidelines mirror the results of the group’s collaboration. A diverse group of experts closely reviews the draft document. Once the changes recommended by these field reviewers have been incorporated, the TIP is prepared for publication, in print

xi and online. TIPs can be accessed via the • TIPs increasingly use quick-reference tools Internet at http://www.kap.samhsa.gov. such as tables and lists in lieu of extensive text discussion, making the information Although each TIP strives to include an evi­ more readily accessible and useful for treat­ dence base for the practices it recommends, ment providers. CSAT recognizes that the field of substance abuse treatment is evolving, and research frequently lags behind the innovations pio­ How TIP 49 Is Organized neered in the field. A major goal of each TIP is to convey “front-line” information quickly This TIP, Incorporating Alcohol but responsibly. For this reason, recommen­ Pharmacotherapies Into Medical Practice, dations proffered in the TIP are based on revises and expands on TIP 28, Naltrexone either panelists’ clinical experience or the and Treatment, and includes dis­ literature. cussion of the other medications currently approved for treating alcohol use disorders (AUDs). It provides the basic information, TIP Format evidence- and consensus-based guidelines, tools, and resources necessary to help health- CSAT is embarking on a new approach to care practitioners treat patients with AUDs. and format for TIPs: Chapter 1 provides an overview of the use • Most of the fundamental research that of medications to treat AUDs. Chapters 2 forms the evidence basis for a particu­ through 5 present detailed information about lar TIP is not provided in the TIP itself. each medication: Rather, those who wish to review the sup­ porting research can access an annotated • Chapter 2—Acamprosate bibliography and literature review via the Internet at http://www.kap.samhsa.gov. • Chapter 3—Disulfiram These online resources include abstracts • Chapter 4—Oral Naltrexone along with references; the online bibliog­ raphy and literature review are updated • Chapter 5—Extended-Release Injectable every 6 months for 5 years after publication Naltrexone. of the TIP.

• TIPs focus on how-to information. Coverage Finally, Chapter 6 discusses factors to con­ of topics is limited to what the audience sider when treating patients with medica­ needs to understand and use to improve tions for AUDs. The appendices in the TIP treatment outcomes. provide handy resources for practitioners.

xii What Is a TIP? Foreword

The Treatment Improvement Protocol (TIP) series supports SAMHSA’s mission of building resilience and facilitating recovery for people with or at risk for mental or substance use disorders by providing best-practices guidance to clinicians, program administrators, and payers to improve the quality and effectiveness of service delivery and, thereby, promote recovery. TIPs are the result of careful consideration of all relevant clinical and health services research findings, demonstration experience, and implementation requirements. Clinical researchers, clinicians, and program administrators debate and discuss their particular areas of expertise until they reach a consensus on best practices. This panel’s work is then reviewed and critiqued by field reviewers. The talent, dedication, and hard work that TIP panelists and reviewers bring to this highly participatory process have helped bridge the gap between the promise of research and the needs of practicing clinicians and administrators to serve, in the most scientifically sound and effective ways, people who abuse substances. We are grateful to all who have joined with us to contribute to advances in the substance abuse treatment field.

Eric B. Broderick, D.D.S., M.P.H. Acting Administrator Substance Abuse and Mental Health Services Administration

H. Westley Clark, M.D., J.D., M.P.H., CAS, FASAM Director Center for Substance Abuse Treatment Substance Abuse and Mental Health Services Administration

xiii

1 Introduction

Alcohol Use Disorders in Medical In This Settings Chapter . . . Many health problems or mental disorders that healthcare prac­ Alcohol Use Disorders titioners (particularly those in primary care) encounter in their in Medical Settings everyday practices derive from or are complicated by alcohol use disorders (AUDs). Consequently, healthcare practitioners are in Audience for TIP 49 key positions to manage the care of large numbers of individuals Recognition with AUDs. However, only a small percentage of these patients of Alcohol Dependence are actually treated for AUDs in these settings. as a Chronic Illness The U.S. Food and Drug Administration (FDA) has approved Purpose of TIP 49 four medications to treat AUDs. These medications make What TIP 49 treatment in primary care and other general medical settings Does Not Cover a viable adjunct or alternative to specialty care, with many potential advantages. The consensus panel for this Treatment Specialty Treatment Improvement Protocol (TIP) believes that direct intervention Versus Screening and by healthcare practitioners to treat AUDs is both possible and Brief Intervention practical. Why Use Medications To Treat Alcohol Screening for and providing brief interventions to treat AUDs Dependence? in general medical settings promote healthy life choices and increase the likelihood of recovery, especially for patients who Format, Approach, and have not yet progressed to chronic alcohol dependence, those Organization of TIP 49 with comorbid medical disorders being treated in these settings, and those who otherwise would not seek or receive treatment for their AUDs. Interventions in primary care provide an opportu­ nity to educate and motivate patients who are alcohol dependent and need long-term care to consider a specialty substance abuse treatment program. From the patient’s viewpoint, initiating treatment in a health- care practitioner’s office may be more acceptable than entering a specialty substance abuse treatment program. Perceived or actu­ al barriers to these programs, such as stigma, cost, employment concerns, lack of family or social support, misunderstandings

1 about the nature of treatment, and lack Initiating treatment in a physician’s office of program availability, discourage many offers advantages for these patients: patients from seeking specialty treatment for AUDs. In fact, the number of persons • Screening, diagnosis, and treatment with alcohol or substance use disorders of AUDs can increase patient motiva­ who received treatment at a private doc­ tion and cooperation (versus the effect tor’s office increased from 254,000 in of delays between screening, diagno­ 2005 to 422,000 in 2006 (Office of Applied sis, and treatment when patients are Studies, 2007). referred to specialty programs). • Integration of treatment for AUDs with that for comorbid medical disorders may Terms Used in TIP 49 increase the likelihood of adherence to Abstinence. The point at which a person has treatment and overall patient recovery. refrained from any use of alcohol or illicit • drugs. Familiarity with the primary care set­ ting and “mainstream” methods (e.g., Alcohol use disorders. As used in the medical management) to treat AUDs Diagnostic and Statistical Manual of Mental reduces the stigma surrounding AUDs. Disorders IV-TR (American Psychiatric Association, 2000), encompasses • The ongoing relationship a patient has and dependence. This TIP uses the term broadly with a healthcare practitioner may to encompass the range of alcohol use prob­ make referral to specialty substance lems, from intermittent to haz­ abuse care more acceptable to a patient. ardous drinking to chronic alcohol abuse and dependence. Helping patients with AUDs can be grati­ Brief intervention. A treatment modality in fying; few interventions in medicine can which treatment approaches ranging from lead to such substantial improvement in simple suggestions and unstructured counseling individual and public health. This TIP and feedback to more formal structured meth­ provides a resource to assist the health- ods (e.g., motivational enhancement) are used, care provider in this effort. usually in short one-on-one sessions between the practitioner and patient. Healthcare practitioners. Individuals Audience for TIP 49 with prescribing privileges, including The intended audience for this TIP physicians, physician assistants, and nurse includes physicians and other health- practitioners. care practitioners who can prescribe and Medical management. The components of brief administer medications for AUDs, in intervention such as patient education, feed­ either specialty substance abuse treat­ back, motivational enhancement, and medi­ ment programs or healthcare settings cation monitoring that facilitate medication such as primary care physicians’ offices. adherence. Other addiction professionals (e.g., coun­ selors) who want to understand how Specialty substance abuse treatment or spe­ cialty substance abuse care. The integrated these medications work and to review the group of counseling and complementary ser­ recommended guidelines for medication- vices offered in substance abuse treatment assisted treatment of AUDs also will find programs. Services focus on achieving and the book useful. maintaining long-term recovery from AUDs and other substance use disorders.

2 Chapter 1 Recognition of Alcohol Costs and Prevalence of AUDs Dependence as a Annual economic costs of AUDs in the have been estimated at Chronic Illness approximately $185 billion (Harwood, Research has clarified the strong simi­ 2000) and include the following: larity between • Direct treatment costs and other chronic illnesses (e.g., asth­ ma, diabetes, ) for which • Lost earnings primary care physician-administered pharmacotherapy and medical manage­ • Costs of other medical consequences, ment are routine practices (reviewed by including premature death McLellan, Lewis, O’Brien, & Kleber, 2000, • Costs of accidents and emergencies p. 1693). Genetics, personal choice, and environmental factors contribute to both • Criminal justice costs. substance dependence and other illnesses. Research into the pathophysiologic effects Approximately 7.9 percent of Americans of alcohol and drugs—including enduring ages 12 and older (about 19.5 million and possibly permanent neurophysiologic people) met standard diagnostic crite­ changes—provides further evidence that ria for alcohol abuse or dependence in substance dependence is a chronic illness. 2006 (Office of Applied Studies, 2007). By addressing AUDs in their practices, However, only 1.6 million people with an healthcare practitioners also address the AUD received treatment at a specialty source of substantial risk for many other facility (Office of Applied Studies, 2007). health problems in their patients (see Of those who did not receive treatment, Why Use Medications To Treat Alcohol just 3.0 percent thought they needed Dependence? on page 5). treatment and 40.6 percent tried to get treatment but were unable to (Office of Applied Studies, 2007). Purpose of TIP 49 This TIP provides clinical guidelines for Findings on Medication-Assisted the proper use of medications in the treat­ ment of AUDs. The underlying objective Treatment for AUDs is to expand access to information about Researchers continue to evaluate the the effective use of these medications, not efficacy of numerous compounds to treat only in specialty substance abuse treat­ AUDs. To date, FDA has approved four ment programs but also in physicians’ medications for treatment of AUDs: offices and other general medical care set­ • ® tings. Members of the Clinical Research Acamprosate (Campral ) Roundtable of the Institute of Medicine • Disulfiram (Antabuse®) have identified failure to disseminate information about and implement new • Oral naltrexone (ReVia®, Depade®) therapies proven effective in clinical trials as a principal roadblock to health- • Extended-release injectable naltrexone ® care improvement in the United States (Vivitrol ). (Crowley et al., 2004). TIP 49 addresses This TIP provides recommended guide­ this problem for the pharmacotherapy of lines for using the four FDA-approved AUDs. medications in clinical practice.

Introduction 3 Although the mechanisms of action Advances in medication development and of these medications in treating AUDs behavioral treatment methods are provid­ are not fully understood, knowledge about ing the tools needed to improve long-term them is growing. recovery for patients in specialty treat­ ment settings. These advances increase Researchers are evaluating the efficacy access to and effective use of AUD treat­ of combinations of medications and the ment services in general medical settings. use of individual medications along with behavioral approaches to treat AUDs The medications discussed in this TIP (e.g., Mason, 2005b). In 2006, an ambi­ help people maintain abstinence or tious —the Combining decrease drinking and avoid serious Medications and Behavioral Interventions setbacks after the initial withdrawal (COMBINE) study, sponsored by the period. None of the four FDA-approved National Institute on Alcohol Abuse medications is considered a “magic bul­ and Alcoholism (NIAAA)—compared let.” Developing new and more effective the relative efficacy of two medications medications remains a high priority for (acamprosate and naltrexone) admin­ researchers in this field. istered individually, together, or in combination with specialty substance abuse treatment or medical manage­ Information Updates in This TIP ment to improve treatment for alcohol TIP 49 updates the information in TIP dependence (Anton et al., 2006). The 28, Naltrexone and Alcoholism Treatment results of this study are noted in this TIP (Center for Substance Abuse Treatment when applicable for treatment planning [CSAT], 1998). It also builds on TIP 24, and decisionmaking, and a review of the A Guide to Substance Abuse Services for research can be accessed in the online Primary Care Physicians (CSAT, 1997). literature review for this TIP (http://www. When TIP 28 was published, FDA had kap.samhsa.gov). approved only two medications for the treatment of AUDs: disulfiram and oral naltrexone. FDA has since approved Access to Medication-Assisted two more medications: acamprosate and Treatment for AUDs extended-release injectable naltrexone. Although precise numbers are unknown, These four medications have unique phar­ it seems that a small percentage of macological actions and profiles of effects, Americans being treated for AUDs and they produce different types of out­ receive any of the four FDA-approved comes in individual patients, hence, the medications for their disorder. Most need for separate guidelines on their use. specialty substance abuse care is provided As more information about these medica­ outside medical settings by nonmedical tions becomes available, it will be added personnel (e.g., counselors) and is based to the online bibliography and literature on psychosocial approaches, such as review that supplement this TIP. (See cognitive-behavioral therapy and Format, Approach, and Organization of motivational enhancement, reinforced TIP 49, page 7.) by participation in community 12-Step or mutual-help groups. These programs increase rates of abstinence and prevent What TIP 49 Does Not serious relapse for many patients. Cover Unfortunately, many people needing This TIP assumes that a patient’s health- treatment for AUDs do not get it (Office care practitioner is acquainted with of Applied Studies, 2007).

4 Chapter 1 screening and diagnostic procedures, Decisions about care level, setting, and the patient has a diagnosed AUD, and type of treatment should be based on the patient has gone through (or has not patient assessment and commitment to needed) detoxification. Therefore, the change, as well as treatment availabil­ following information about treating ity. For example, the most appropriate AUDs is not covered in this TIP: patients for brief interventions in a physi­ cian’s office—and the least appropriate • Screening and diagnostic assessment for long-term treatment in a substance for AUDs. The reader can refer to abuse treatment program—are those Helping Patients Who Drink Too Much: whose drinking exceeds what is recom­ A Clinician’s Guide (NIAAA, 2006), mended, but who are not dependent available at http://www.niaaa.nih.gov. (NIAAA, 2006). NIAAA’s A Pocket Guide for Alcohol Screening and Brief Intervention is in Appendix B of this TIP. Why Use Medications • Detoxification and methods to deal To Treat Alcohol with initial withdrawal symptoms. This information is covered in TIP 45, Dependence? Detoxification and Substance Abuse When implemented according to recom­ Treatment (CSAT, 2006a). Excerpts mended guidelines, medication-assisted from the Quick Guide based on TIP 45 treatment combined with brief inter­ are in Appendix C of this TIP. vention or more intensive levels of nonpharmacologic treatment can do the • Medical conditions associated with following: excessive alcohol use such as cirrho­ sis. Treatment for these disorders • Reduce postacute withdrawal symptoms is covered in resources from NIAAA that can lead to a return to drinking (http://www.niaaa.nih.gov/Publications/ (e.g., acamprosate’s hypothesized mech­ AlcoholResearch). anisms of action) • Lessen craving and urges to drink or Specialty Treatment use drugs (e.g., naltrexone) Versus Screening and • Decrease impulsive or situational use of Brief Intervention alcohol (e.g., disulfiram). Treatment of AUDs can be viewed as In addition, maintaining a therapeutic continuum-of-care options that include alliance with a healthcare practitioner choices of treatment settings, types and can achieve the following: levels of treatment services, and medica­ • Improve patients’ attitudes toward tions. Services may range from screening change and brief intervention to specialty treat­ ment, with numerous levels of care in • Enhance motivation between. Primary care practitioners can provide screening, brief interventions, • Facilitate treatment adherence, includ­ and medical management for many ing participation in specialty substance patients who have AUDs or are at risk abuse care and support groups. for alcohol-related disorders but are not The Collaborative Study on the Genetics receiving care. of Alcoholism indicates a genetic link between how an individual experiences

Introduction 5 alcohol and his or her susceptibility to an reasonable. Medication for AUDs may be AUD (reviewed by Edenberg, 2002). Risk employed indefinitely or intermittently of chronic AUDs appears higher for peo­ along with interventions aimed at chang­ ple with certain genetic variants. Further ing lifestyle practices to sustain recovery. identification of these genes may lead to new medications for treating AUDs that Research into alcohol dependence and can help repair, alter, or disrupt alcohol’s treatment has shown that integrating negative effects. brief intervention and counseling and an appropriate medication can have a syn­ According to a recent review, chronic ergistic or additive effect and improve heavy drinking can cause long-lasting treatment outcome. Medication can changes in brain cell receptors and other reduce the cravings that disrupt recovery. types of neuroadaptations (Oscar-Berman When cravings are decreased, counsel­ & Marinkovic, 2003). These neuroad­ ing is more likely to strengthen the aptations are linked with cognitive and individual’s coping resources, which are behavioral changes, resulting in the necessary to promote medication adher­ need to drink more to ward off craving ence and behavioral change. Summaries and symptoms of withdrawal. Studies of research findings have highlighted the reviewed by Hoffman and colleagues following beneficial effects of medication- (2000) found that neuroadaptations assisted treatment for AUDs (Garbutt, related to symptoms of withdrawal and West, Carey, Lohr, & Crews, 1999; persistent craving may trigger relapse Kranzler & Van Kirk, 2001; O’Malley & even after prolonged abstinence. Kosten, 2006): Pharmacotherapy has revolutionized • Lengthens periods of abstinence, which the treatments of brain-based disor­ in turn can increase individual cop­ ders, including mental disorders such ing capacities necessary for long-term as depression, and treatments for these recovery disorders are increasingly provided by healthcare practitioners. Making such • Prevents a lapse from becoming a full- treatments available in general medi­ blown relapse cal settings can improve continuity and • Allows brain cells to readapt to a accessibility of care. Expansion in treat­ normal nonalcoholic state, helping ment settings is underway in patients stabilize, think more clearly, addiction treatment. Although most have more positive emotional responses, opioid addiction treatment is provided strengthen coping mechanisms, enhance in specialty programs (i.e., self-esteem, and increase motivational treatment clinics), the growing use of readiness for change by physicians in office- based settings is increasing access to • Relieves symptoms of protracted with­ treatments. The widespread use of drawal (a hypothesized mechanism of buproprion in primary care settings for action of acamprosate) smoking cessation is another example of how the boundaries of addiction treat­ • Supports the effects of psychosocial ment have expanded. treatment and sustains the gains of intervention. Medication-assisted treatment of AUDs is consistent with treatment of other chronic The consensus panel for this TIP believes disorders such as diabetes or hyperten­ that providing brief interventions (includ­ sion. Long-term, perhaps indefinite, use ing pharmacotherapy) for AUDs in of medication for patient stabilization is physicians’ offices and general medical

6 Chapter 1 settings is a reasonable, practical, and 5, respectively. Each chapter follows a desirable trend that should be greatly template: general description of the medi­ expanded. The panel also recommends cation, rationale for its use, how to use it, that screening and periodic reassessment which patients are most appropriate for of all patients for AUDs should become the medication, and clinical advice. regular parts of patient management in primary care and general medical prac­ Chapter 6 covers practical informa­ tices because the problem has been shown tion about patient management during to be more widespread than many prima­ pharmacotherapy that applies to all four ry care practitioners have realized. At a FDA-approved medications for AUDs, minimum, patients diagnosed with health including how to do the following: problems often associated with AUDs • Integrate pharmacotherapy for AUDs should receive alcohol disorder screening. into clinical settings

• Assess appropriateness of medications Format, Approach, and for patients with AUDs

Organization of TIP 49 • Choose AUD medications The format and approach used in this TIP differ substantially from those used in • Choose psychosocial interventions other TIPs: • Develop and adjust treatment plans

• Most of the evidence base for • Educate patients about pharmaco­ medication-assisted treatment for therapy for AUDs AUDs is not included in this TIP. Those who wish to review the research • Monitor patient progress in medication base can access the annotated bibli­ treatment ography and literature review via the Internet at http://www.kap.samhsa.gov. • Discontinue AUD medications. The online bibliography and literature Appendices include the following: review will be updated every 6 months for 5 years after publication of TIP 49. • Bibliography (Appendix A) • TIP 49 focuses on how-to information • NIAAA’s A Pocket Guide for Alcohol about medication-assisted treatment for Screening and Brief Intervention AUDs. Coverage is limited to what the (Appendix B) audience needs to understand to use these medications to improve treatment • Excerpts from the Quick Guide outcomes. for Clinicians Based on TIP 45, Detoxification and Substance Abuse • Increased use of quick-reference tools Treatment (Appendix C) such as tables and lists in lieu of exten­ sive text discussion makes the informa­ • Excerpts from the Quick Guide for tion readily accessible and useful for Clinicians Based on TIP 24, A Guide to physicians and other practitioners. Substance Abuse Services for Primary Care Clinicians (Appendix D) Practical information and guidelines for treating patients with acampro­ • Lists of the TIP’s resource panelists and sate, disulfiram, oral naltrexone, or field reviewers (Appendices E and F, extended-release injectable naltrexone respectively). are presented in Chapters 2 through

Introduction 7

2 Acamprosate

Acamprosate At a Glance Chemical name: Calcium acetyl homotaurinate. Trade name: Campral® Delayed-Release Tablets. U.S. distributor: Forest Pharmaceuticals (subsidiary of Forest Laboratories, Inc.), St. Louis, MO. U.S. Food and Drug Administration approval to treat alcohol dependence: July 2004. Dosage/How taken: Two 333 mg delayed-release tablets by mouth three times per day, with or without food (a lower dose may be effective with some patients and must be used with those with impaired renal function). Pills are swallowed whole, not crushed or broken. How supplied: Opaque bottles or Dose Paks of 180 enteric-coated 333 mg tablets. Storage: Keep out of reach of children; keep tightly closed in original container; store at room temperature, away from excess heat and moisture (not in the bathroom or near a sink); discard when outdated or no longer needed.

What Is Acamprosate? Acamprosate was the third medication, after disulfiram and naltrexone, to receive U.S. Food and Drug Administration (FDA) approval for postwithdrawal maintenance of alcohol abstinence. Acamprosate’s has not been clearly estab­ lished, but it is thought that acamprosate helps modulate and normalize alcohol-related changes in brain activity, thereby reducing symptoms of postacute (protracted) withdrawal, such as disturbances in sleep and mood, that may trigger a relapse to drinking.

Brief History of Development The French pharmaceutical company Laboratoires Meram began clinical development and testing of acamprosate in 1982. From 1982 to 1988, acamprosate was tested for safety and for efficacy as a treatment for alcohol dependence. Based on these studies, in 1989 Laboratories Meram was granted marketing authorization for acamprosate in France under the trade name

9 Aotal®. Since then, acamprosate has been Why Use Acamprosate? extensively used and studied throughout Europe and, subsequently, in the United States. Efficacy Considerable evidence supports the Although acamprosate has been used in efficacy of acamprosate in the treat­ Europe for more than 20 years, it was ment of alcohol use disorders (AUDs). not approved by FDA until July 2004. Numerous European trials have found Acamprosate became available for use acamprosate significantly more effec­ in the United States in January 2005, ® tive than in reducing drinking under the trade name Campral days, increasing complete abstinence, and Delayed-Release Tablets (Merck Santé, lengthening time to relapse. Evidence a subsidiary of Merck KGaA, Darmstadt, from U.S. studies has been mixed. The Germany). Campral is currently mar­ Combining Medications and Behavioral keted in the United States by Forest Interventions (COMBINE) study did Pharmaceuticals. not find acamprosate to be more effec­ tive than placebo (Anton et al., 2006). Pharmacology However, some analyses and reviews have concluded otherwise (although these Acamprosate’s action in maintenance analyses did not include data from the of alcohol abstinence is not completely COMBINE study). A meta-analysis (an understood, but evidence indicates that analysis of the outcome data of multiple acamprosate interacts with the glutamate individual studies) of European studies system, reducing and concluded that acamprosate is moderate­ normalizing the pathologic glutamater­ ly effective in achieving and maintaining gic hyperactivity that occurs during abstinence (Bouza, Magro, Muñoz, & protracted withdrawal from alcohol. It Amate, 2004). This analysis of 12 stud­ is hypothesized that this normalization ies found that acamprosate increased the leads to a reduction of common symptoms continuous abstinence rate and doubled of protracted, or postacute, withdrawal continuous abstinence duration compared such as , anxiety, and restless- with placebo. Similarly, a review of clini­ ness—symptoms that may contribute to a cal trials by Mann (2004) concluded that patient’s return to alcohol use (reviewed acamprosate is more effective than place­ by Litten, Fertig, Mattson, & Egli, bo in the short and long term. Mason and 2005; Myrick & Anton, 2004; Thomson colleagues (2006) found acamprosate to Healthcare, Inc., 2006). Chick, Lehert, be superior to placebo only when control­ and Landron (2003) have proposed that ling for patient characteristics associated patients who returned to drinking while with treatment efficacy. They also found taking acamprosate drank less, and less acamprosate superior to placebo for a frequently, than those taking placebo. subgroup of patients motivated to achieve The of acamprosate after total abstinence. is approximately Methodological differences between U.S. 11 percent, and stable plasma concentra­ and European studies may account for tions are reached within 5 days of taking differing results. These differences have the medication. Acamprosate is not included the following: metabolized and is excreted primarily by the kidneys as acamprosate. • Duration of pretreatment abstinence required

10 Chapter 2 • Duration of treatment (European • Because acamprosate is not metabolized studies tended to be longer than U.S. by the liver, it can be used safely even studies) by patients with severe , unlike oral or injectable naltrexone or • Concomitant medications allowed disulfiram. (European studies tended to be more flexible in allowing medications than • Because it does not affect endogenous or U.S. studies) exogenous , it can be used with patients receiving opioid maintenance • Nature and intensity of psychosocial therapy (reviewed by Myrick & Anton, treatment (U.S. studies tended to have 2004) or undergoing treatment with more standardized and intensive psy­ opioids for acute or chronic , unlike chosocial treatments) oral or injectable naltrexone. • Outcome measures used • Because acamprosate does not interact • Severity of participants’ AUDs. with or other medica­ tions used in medical detoxification, A thorough discussion of acamprosate it can be continued safely if a patient efficacy studies is in this TIP’s online lit­ returns to drinking and subsequently erature review. requires detoxification.

Safety How Is Acamprosate Acamprosate has a good safety profile: Used? • Patients maintained on acamprosate have not developed tolerance for or Initiating Treatment With dependence on it, and it appears to have Acamprosate no potential for abuse. Acamprosate is typically initiated 5 days • It carries virtually no overdose risk; following drinking cessation. However, even at overdoses up to 56 grams (a acamprosate can be used safely with normal daily dose is 2 grams), acamp­ alcohol (and with benzodiazepines), and rosate was generally well tolerated by it can be started during medically super­ patients (Thomson Healthcare, Inc., vised withdrawal. Acamprosate therapy 2006). should be maintained if a patient relapses to alcohol use. Acamprosate reaches full • Most side effects are mild and transient, effectiveness in 5 to 8 days. lessening or disappearing within the first few weeks of treatment (diarrhea Before initiating treatment, healthcare tends to persist). practitioners should do the following: • Although there is a pharmacokinetic • Conduct or refer patients for a thor­ interaction by which acamprosate can ough medical exam and assessment increase naltrexone blood levels, there (as described in Chapter 6—Patient are no other clinically significant inter­ Management). actions between acamprosate and other medications (Johnson et al., 2003). • Perform renal function tests (a standard panel for urea, electrolytes, and serum Acamprosate also has advantages over creatinine) to rule out severe renal other medications for treating AUDs in impairment. some patients:

Acamprosate 11 Side Effects, Contraindications, Chapter 6, healthcare providers should and Cautions ensure that patients taking acamprosate know the following: Exhibit 2-1 lists acamprosate’s side effects. The most common side effect of • The benefits and limitations of acamprosate is diarrhea. This and other acamprosate side effects are usually mild and resolve • What to expect— quickly. In some patients, diarrhea is severe and persistent. Patients should – Possible side effects be instructed not to discontinue acampro­ – Full effectiveness in 5–8 days sate if they experience side effects and to inform their prescribing professional. • For women of childbearing age, the importance of using an effective birth Exhibit 2-2 lists acamprosate contraindi­ control method cations, and Exhibit 2-3 lists cautions. • To continue taking acamprosate if a slip or relapse occurs and to inform their Patient Management prescribing professional immediately Ways for managing adverse reactions to • acamprosate are listed in Exhibit 2-4. To notify the prescribing professional immediately if they begin to have There is no evidence that acampro­ suicidal thoughts, if they begin to feel sate impairs renal function. Followup depressed, or if an existing depression laboratory work is not necessary unless worsens evidence of renal impairment exists at • treatment initiation. That tablets should not be crushed • Not to take extra medication if a dose Patient Education is missed and it is time to take the next In addition to giving patients the general dose. patient education guidelines discussed in

Exhibit 2-1 Acamprosate Side Effects

Most Common Side Effect Less Common Side Effects Diarrhea Suicidal ideation Insomnia (less common, but serious) Anxiety Intestinal Muscle weakness Headache Nausea Flatulence Itchiness Increased or decreased libido Dizziness

Exhibit 2-2 Acamprosate Contraindications

Patient Condition or Circumstance Treatment Recommendation Previous hypersensitivity to acamprosate or its components Do not prescribe acamprosate Severe renal impairment (creatinine clearance Do not prescribe acamprosate ≤30 mL/min)

12 Chapter 2 Exhibit 2-3 Acamprosate Cautions

Patient Condition or Circumstance Treatment Recommendation Moderate renal impairment (creatinine Reduce dosage to one 333 mg tablet daily clearance 30–50 mL/min) Pregnant or nursing women Avoid using acamprosate unless potential benefits out­ weigh risks (Acamprosate is FDA category C; it is unknown whether acamprosate is excreted in human milk.) Age 65 or older Because of a higher risk of diminished renal function in persons 65 or older, perform baseline and frequent renal function tests; acamprosate has not been evaluated for safety or efficacy in geriatric populations Children or adolescents Prescribe with caution; acamprosate has not been evaluated for safety or efficacy in pediatric or adolescent populations

Exhibit 2-4 Adverse Reactions to Acamprosate and Their Management

Adverse Reaction Management Suicidal ideation, attempts Inform patients to contact the prescribing professional immediately (very uncommon, but serious)* Monitor patients for onset or worsening of depression

Obtain a psychiatric consult and/or prescribe antidepressant medication as necessary

Discontinue acamprosate Severe and/or persistent diarrhea Treat with Imodium® or Pepto-Bismol®

Recommend appropriate dietary changes

Reduce acamprosate dosage or discontinue use if diarrhea remains intolerable after treatment *Suicidal ideation is closely linked with substance use disorders, with or without acamprosate use. More informa­ tion about managing the risk can be found at the National Suicide Prevention Center’s Web site (http://www.sprc. org) and at the Suicide Prevention for Physicians Web site (http://suicideandmentalhealthassociationinternational. org/preventionphy.html).

Who Is Appropriate Koeter, & Van Den Brink, 2005). However, evidence exists that acampro­ for Treatment With sate is most effective for patients who, at Acamprosate? treatment onset, are motivated for com­ plete abstinence rather than decreased Research on patient-specific characteris­ drinking (Mason et al., 2006). tics as predictors of acamprosate efficacy has not identified any particular char­ As noted earlier, acamprosate does not acteristics (e.g., level of physiological affect endogenous or exogenous opioids, dependence on alcohol, age of onset, gen­ so it may be particularly appropriate for der) that predict acamprosate treatment patients who are receiving opioid main­ outcomes (Verheul, Lehert, Geerlings, tenance therapy (reviewed by Myrick &

Acamprosate 13 Anton, 2004), at risk of relapsing to opioid There is no withdrawal syndrome associ­ use, or undergoing treatment with opioids ated with discontinuing acamprosate, and for pain. Because there are no clinically it is not necessary to taper the dose. significant drug interactions with acam­ prosate, it can be a safe medication for patients who are coping with multiple Final Clinical Thoughts medical issues and are taking many other Evidence from European studies and medications. clinical experience suggest acamprosate Acamprosate must be taken three times can be an effective medication for the per day. Extra support will be needed for treatment of AUDs. Acamprosate has patients with cognitive deficits or who several attractive features, including its otherwise might have trouble remember­ minimal side effects, lack of negative liver ing and adhering to a schedule. Seven-day effects, and drug interaction profiles. For dosing pillboxes or blistercard packages many patients, these features make it a that indicate the time of day for each dose worthwhile agent to try despite its small may be useful. therapeutic effect. Hence, the clinician using medications to treat patients with alcohol dependence should be familiar with Treatment Duration acamprosate and its use and may find it a useful medication for certain patients and Discontinuing (e.g., those treated with opioid ) Acamprosate or under certain circumstances (e.g., for a patient who is taking several other medi­ The effectiveness and safety of acampro­ cations). The healthcare provider may also sate have been evaluated for up to 1 year. find it useful when combined with other The length of time a particular patient alcohol treatment medications and with takes acamprosate will be determined, psychosocial support. ideally, with input from the prescribing professional, the specialty treatment Because acamprosate must be taken three provider, and the patient. Discontinuation times per day, providers must pay par­ of acamprosate may be considered once ticular attention to patient adherence. a patient has achieved stable abstinence Providers can help patients adhere to the from alcohol, reports diminished craving, regimen by helping them develop ways to and has established a sound plan and sup­ remember, such as wearing a “reminder” port for ongoing recovery. Acamprosate bracelet, setting a watch alarm, imple­ therapy also may be discontinued if a menting a recovery-oriented ritual around patient is not adhering to the medication taking the medication, or providing them regimen. Acamprosate should not be dis­ with a special pillbox or blistercard pack. continued just because a patient returns to alcohol use.

14 Chapter 2 3 Disulfiram

Disulfiram At a Glance Chemical name: Bis(diethylthiocarbamoyl) disulfide. Trade name: Antabuse®. U.S. distributor: Odyssey Pharmaceuticals, Inc., East Hanover, NJ. U.S. Food and Drug Administration approval to treat alcohol dependence: 1951. Dosage/How taken: Tablet by mouth once daily (also may be crushed and mixed with water, coffee, tea, milk, soft drink, or fruit juice). How supplied: Bottles of 100 or 1,000 250 mg tablets or bottles of 50, 100, or 500 500 mg tablets. Storage: Keep out of reach of children; keep tightly closed in original container; store at room temperature, away from excess heat and moisture (not in the bathroom or near a sink); discard when outdated or no longer needed.

What Is Disulfiram? Disulfiram was the first medication approved by the U.S. Food and Drug Administration (FDA) to treat chronic alcohol depen- dence. In its pure state, disulfiram is a white to off-white, odorless, almost tasteless powder, which is soluble in water and alcohol. Disulfiram, an alcohol-aversive or alcohol-sensitizing agent, causes an acutely toxic physical reaction when mixed with alcohol. Continuing research and clinical findings have clarified disulfiram’s mode of action and established its safe and effective use in the treatment of alcohol use disorders (AUDs) in some patient groups.

Brief History of Development Exhibit 3-1 summarizes disulfiram’s development history.

15 Exhibit 3-1 Brief History of Disulfiram Development

Dates Events 1930s Disulfiram’s alcohol-aversive effects are first observed when workers in the vulcanized rubber industry, exposed to tetraethylthiuram disulfide, become ill after drinking alcohol. 1947 In Copenhagen, researchers studying compounds to treat parasitic stomach take a small dose of disulfiram to check its side effects. Later they become ill after an . They conclude that an interaction of disulfiram and alcohol is respon­ sible and conduct a study to confirm their findings (Hald & Jacobsen, 1948). Late 1940s, The Danish group performs additional studies of disulfiram treatment for alcohol early 1950s dependence. Basing its initial paradigm on aversion conditioning, it administers high disulfiram doses (e.g., 1,000 to 3,000 mg daily) to maximize patient reactions.

FDA approves disulfiram to treat alcohol dependence in the United States.

Wyeth-Ayerst Laboratories begins manufacturing Antabuse® tablets (now manufac­ tured by PLIVA and distributed in the United States by Odyssey Pharmaceuticals).

Ruth Fox, M.D., the founding president of the American Society of Addiction Medicine, is the first American to use disulfiram to treat alcohol dependence, starting in 1949. When her patients report serious side effects, Fox reduces the dosage and counsels them on the severe reactions that could result from drinking alcohol. She concludes that disulfiram is effective in deterring drinking in patients with alcohol dependence and treats about 2,500 patients with disulfiram. Late 1950s to After reports of severe reactions, including some deaths, therapeutic emphasis shifts the present from using disulfiram for aversion conditioning to using it to support abstinence. This entails using lower dosages to control disulfiram toxicity, excluding patients with or of the liver, and combining the medication with other types of support.

Pharmacology is thought to increase the patient’s motivation to remain abstinent. Some Aversive treatment experts (e.g., Schuckit, 2006) question Unlike other medications approved to disulfiram’s effectiveness because the treat alcohol dependence, disulfiram does time between alcohol ingestion and the not affect brain , g-aminobutyric reaction can be as long as 30 minutes acid, or glutamate receptors directly. and the intensity of the reaction is However, it does have some central unpredictable. effects, inhibiting enzyme dopamine β-hydroxylase and affecting Effect on oxidation of alcohol serotonergic function. Whether disulfiram Normally, the enzyme alcohol dehydro- directly decreases the urge to drink genase in the liver and brain transforms remains uncertain. However, disulfiram alcohol into acetaldehyde. The enzyme definitely disrupts the metabolism aldehyde dehydrogenase (ALDH), also of alcohol, causing a severe reaction in the liver and brain, oxidizes the acet- when patients mix disulfiram and aldehyde byproduct into . alcohol. Patient knowledge of a possible Disulfiram blocks this oxidation by severe reaction to alcohol consumption inhibiting ALDH, causing a rapid rise

16 Chapter 3 of acetaldehyde in the blood when alco- alcohol is ingested. Its adverse effects hol is consumed. The result is called a range from moderate to severe (Exhibit disulfiram–alcohol reaction, and it may 3-2). Intensity varies with individual increase the acetaldehyde concentration patient characteristics. The reaction is in blood to 5 to 10 times that occurring generally proportional to the amounts without disulfiram. Disulfiram does not of disulfiram and alcohol ingested. appear to affect the rate of alcohol elimi- Mild effects may occur at blood alcohol nation from the body. concentrations of 5 to 10 mg/100 mL. At 50 mg/100 mL, effects usually are The disulfiram–alcohol reaction fully developed. When the concentration reaches 125 to 150 mg/100 mL, uncon- The disulfiram–alcohol reaction usually sciousness may occur. Although begins about 10 to 30 minutes after

Exhibit 3-2 Possible Effects of the Disulfiram–Alcohol Reaction

Body Part Affected Moderate Severe Body skin Sweating None

Warmth and flushing, particularly on upper chest and face Respiratory system Hyperventilation Respiratory depression

Respiratory difficulty/dyspnea Head, neck, Acetaldehyde breath odor None

Blurred vision

Head and neck throbbing

Thirst Stomach, Nausea/vomiting None digestive system Chest, heart, circulatory Chest pain/palpitations Cardiovascular collapse system

Tachycardia Myocardial infarction (in individuals with preexisting coronary artery disease)

Acute congestive (in individuals with preexisting myocardial dysfunction) Brain/nervous system Vertigo

Syncope

Marked uneasiness

Confusion Other Weakness Death

Disulfiram 17 disulfiram–alcohol reactions can be life Positive findings threatening, as indicated in Exhibit 3-2, Studies concluding that disulfiram is the reduced dosages and careful patient effective in treating AUDs frequently medical screening now in practice have emphasize the circumstances in which it made this outcome extremely rare. is administered to patients. In particu- Early researchers believed that patients lar, the level and quality of supervision a needed to experience at least one super- patient receives while taking disulfiram vised disulfiram–alcohol reaction to are believed to be important elements understand its effects. The practice of in its success (e.g., Brewer, Meyers, & deliberately inducing a reaction by giving Johnsen, 2000; Kristenson, 1995). Some large doses of disulfiram in conjunction studies have found that court-ordered with “alcohol challenges” has been aban- disulfiram therapy promotes efficacy doned. A clear, convincing description of by increasing adherence to the disul- the reaction is considered sufficient for firam regimen (Martin, Clapp, Alfers, most patients. & Beresford, 2004; Martin, Mangum, & Beresford, 2005). Use of incentives, con- Disulfiram absorption and elimination tracting with the patient and a significant other to ensure adherence, providing reg- About 80 to 95 percent of ingested ular reminders to the patient, and patient disulfiram is absorbed from the gastroin- behavioral training and social support testinal tract and rapidly distributed to also may enhance disulfiram efficacy by tissues and organs. It is then metabolized increasing treatment adherence. to various mixed disulfides. The unab- sorbed fraction is excreted. Disulfiram is Most experts (e.g., Schuckit, 2006) agree irreversibly bound to ALDH. It can take that an optimum disulfiram response up to 2 weeks for the body to synthesize requires its use in a specialty substance sufficient unbound enzyme to metabolize abuse treatment program. One study alcohol adequately. This is why alcohol suggests that disulfiram might be more ingestion may produce unpleasant symp- effective in promoting short-term absti- toms for up to 2 weeks after a patient has nence and treatment retention after taken the last dose of disulfiram. detoxification than in preventing long- term relapse (e.g., Chandrasekaran, Sivaprakash, & Chitraleka, 2001). Why Use Disulfiram? Nevertheless, the most rigorous study of Disulfiram may work as an adjunct to disulfiram therapy (Fuller et al., 1986) psychosocial treatment to eliminate alco- showed unequivocally that disulfiram hol consumption for patients who can (250 mg/day), compared with placebo (1 achieve initial abstinence of at least 12 mg/day) or a vitamin, reduced the pro- hours, are committed to maintaining portion of days of alcohol consumption abstinence, agree to take the medica- for the duration of the study (1 year) in tion, and do not have contraindications to male veterans who reported some drink- disulfiram. ing. However, there were no differences between treatment groups in the percent- age of veterans sustaining abstinence Efficacy throughout the study period. Findings on the efficacy of disulfiram treatment are mixed. (To review some Negative findings reports, see the online annotated bibli- Some experts dismiss disulfiram as a ography and literature review at http:// viable treatment option, particularly in www.kap.samhsa.gov.) primary care settings. This conclusion

18 Chapter 3 is based on mixed results with disul- Laboratory Work, page 21). Disulfiram firam in clinical trials and the severe may cause hepatitis, but the risk is low. adverse effects that may result from the Estimates of disulfiram-induced hepatitis disulfiram–alcohol reaction, as well as are between 1 in 25,000 (Wright, Vafier, concerns about other potentially serious & Lake, 1988) and 1 in 30,000 (Chick, side effects and “problems with compli- 1999, p. 427) patients treated per year. A ance” (Williams, 2005, pp. 1776–1777). disproportionate number of these cases The capacity to arrange ongoing super- may be associated with use of disulfiram vision of disulfiram ingestion may be lim- to treat nickel (an unusual but ited in a primary care setting. known indication for use of disulfiram).

Appropriate patients A black-box warning about treatment with disulfiram is included in the The consensus panel concludes that Antabuse package insert. Before admin- disulfiram is most effective for patients istering disulfiram, the clinician should who have undergone detoxification or inform patients and their families about are in the initiation stage of abstinence, the disulfiram–alcohol reaction, includ- especially when they are committed to ing that this reaction may occur for up to abstinence and receive adequate, ongoing 14 days between the last ingested dose of supervision. Disulfiram may not reduce disulfiram and alcohol consumption. the urge to drink alcohol. However, it may assist in motivating the patient not to drink. As with other medications, Disulfiram Black-Box Warning general efficacy also increases when dis- Disulfiram should never be administered to a ulfiram is administered in conjunction patient who is in a state of with intensive behavioral interventions. or without the patient’s full knowledge. The physician should instruct relatives accordingly. Patients with severely impaired judg- ment or who are highly impulsive from a severe mental illness or cognitive impair- ment may be inappropriate candidates for How Is Disulfiram Used? treatment with disulfiram. Before Initiating Treatment With Safety Disulfiram Disulfiram has been used to treat AUDs Physicians should not administer disul- for almost 60 years. Deaths from the firam until the following steps have been disulfiram–alcohol reaction have become taken: rare because lower dosages are used • Educate the patient about disulfiram and patients with severe cardiac disease and obtain informed consent. are excluded from disulfiram treatment (Chick, 1999). Its hepatotoxicity in some • Wait until the patient has abstained patients remains a concern (see Side from alcohol at least 12 hours and/or Effects, Contraindications, and Cautions breath or blood alcohol level is zero. on page 20). • Perform a physical exam, baseline Side effects of disulfiram are usually liver and function tests, and a minor (see Exhibit 3-4, page 20). Severe pregnancy test for women. Perform an adverse reactions are uncommon (see electrocardiogram if clinically indicated Exhibit 3-8, page 23). However, patients (e.g., history of heart disease). receiving disulfiram should be monitored for hepatotoxicity (see Timing of

Disulfiram 19 • Complete a medical and psychiatric his- routine starting dose (which is rare), tory. Determine to disulfiram increase the dosage (dosage may be or other drugs; prescription and non- increased up to 500 mg/day with careful prescription medications taken, includ- monitoring). Never exceed 500 mg/day. ing vitamins; history of cardiovascular disease, diabetes, thyroid disease, sei- • Instruct patients who miss a dose to zure disorder, central nervous system take it as soon as they remember. impairment, or kidney or liver disease; However, if it is almost time for the and for women, reproductive status, next dose, they should skip the missed including current pregnancy or plans to dose. become pregnant or to breast-feed. • Tell patients never to take a double dose of disulfiram. Supervised Ingestion There is strong evidence that supervised Side Effects, Contraindications, ingestion is necessary for disulfiram ther- and Cautions apy compliance (e.g., Brewer et al., 2000; Kristenson, 1995; reviewed by Fuller & Disulfiram can cause minor side effects Gordis, 2004). Although not absolutely (Exhibit 3-4). The common side effects essential, supervised administration by typically occur during the first 2 weeks of a pharmacist, healthcare provider, or therapy and wane either spontaneously or family member is preferred as a key com- after a decrease in the disulfiram dosage. ponent of the treatment plan. Exhibit 3-4 Dosage Disulfiram Side Effects Exhibit 3-3 summarizes standard dosage Skin/acneiform eruptions* Headache information for disulfiram. Allergic dermatitis* Impotence Additional dosage information includes Mild drowsiness Metallic or garlic- like aftertaste the following: Fatigue *Dermatologic side effects often can be managed • Instruct patients who experience with concomitant . sedation with disulfiram to take it at bedtime. If daytime sedation persists, adjust the dosage downward. Hepatic toxicity including hepatic failure resulting in transplantation or death has • If a patient can drink alcohol without been reported. Severe and sometimes problems when compliant with the fatal hepatitis associated with disulfiram therapy may develop even after many Exhibit 3-3 months of therapy. Hepatic toxicity has Disulfiram Dosages occurred in patients with or without a history of abnormal liver function. Initial dosage 250 mg/day in 1 morning or evening dose for 1–2 Patients should be instructed to call their weeks physician immediately if they develop Average mainte­ 250 mg/day symptoms of possible hepatic impairment nance dosage (Exhibit 3-5). Dosage range 125–500 mg/day Exhibit 3-6 summarizes contraindications Maximum dosage 500 mg/day for disulfiram therapy, and Exhibit 3-7 summarizes cautions.

20 Chapter 3 Timing of laboratory work Exhibit 3-5 Symptoms of Disulfiram-Induced Exhibit 3-10 summarizes the recom- Hepatic Impairment mended laboratory testing regimen for disulfiram therapy. In general, liver Excessive tiredness Vomiting function requires ongoing monitoring because of disulfiram’s occasional Weakness Yellowness of the skin/eyes association with hepatic injury. In Lack of energy Dark urine contrast to liver injury caused by Loss of appetite Fever alcohol, which typically shows a high Upset stomach Light-colored stools aspartate aminotransferase-to-alanine aminotransferase ratio, disulfiram liver injury usually shows equivalent and very high elevations of both enzymes Patient Management (Bjornsson, Nordlinder, & Olsson, 2006). Exhibit 3-8 lists severe adverse reactions Pregnant women should discontinue that may occur with disulfiram and ways taking disulfiram immediately. Urine to manage them. These reactions are toxicology screening is not an ideal uncommon. method of detecting alcohol use, although it sometimes can detect use that occurred Drug interactions with disulfiram and within a few hours of test administration. their management Disulfiram overdose and its Exhibit 3-9 describes the most common management drug interactions with disulfiram and their clinical management. Severe cases of disulfiram poisoning have been reported, mainly in children who

Exhibit 3-6 Disulfiram Contraindications

Patient Condition or Circumstance Treatment Recommendation Known hypersensitivity to disulfiram Do not administer disulfiram. or other thiuram derivatives used in pesticides and rubber vulcanization; sulfur or nickel allergy Psychosis Disulfiram is relatively contraindicated in patients with decompensated psychoses but can be used with caution in treated, stable patients with schizophrenia or other psychotic disorders. Severe myocardial disease and/or Disulfiram is relatively contraindicated in patients with severe coronary occlusion myocardial disease or coronary occlusion, with clinical risk of disulfiram therapy balanced against clinical risk of ongoing alcohol abuse. Perform an electrocardiogram before and during disulfiram therapy and follow closely. Pregnant or nursing women Although disulfiram is not absolutely contraindicated, it should be avoided because risk to the fetus is unknown. (Pregnant patients should receive behavioral treatment, on an inpatient basis if necessary.) Do not give disulfiram to nursing mothers. Patients should discontinue nursing before taking disulfiram.

Disulfiram 21 Exhibit 3-7 Disulfiram Cautions

Patient Condition or Circumstance Treatment Recommendation History of cardiac disease, diabetes mellitus, Use with caution. No evidence exists that patients with , epilepsy, cerebral damage, preexisting liver disease are more likely to suffer severe chronic or acute nephritis, hepatic cirrhosis, hepatotoxicity from disulfiram therapy. or hepatic insufficiency Patients with hepatitis C According to current available evidence, if baseline transaminase levels are normal or only moderately elevated (less than five times the upper limit of normal), use with careful monitoring of liver function. Children and adolescents Safety and efficacy for children has not been determined. One study indicates that disulfiram can be safe and effective with adolescents (Niederhofer & Staffen, 2003). Administer with caution. Patients receiving or who have recently Do not use disulfiram until substances are out of the received metronidazole, paraldehyde, patient’s system. alcohol, or alcohol-containing preparations (e.g., cough syrups, tonics); also patients exposed to ethylene dibromide or its vapors (e.g., in paint, paint thinner, varnish, shellac) Patients using products that contain alcohol Instruct patients to test any alcohol-containing product in disguised forms (e.g., vinegars, sauces, before using it by applying some to a small area of the aftershave lotions, liniments) skin for 1 to 2 hours. If there is no redness, itching, or unwanted effects, the product may be used safely. Age 61 or older Dosages may need to be decreased.

have ingested large amounts because of conclude that disulfiram is ineffective patients’ negligent handling or storage of until patients are proved to have been their medication. Symptoms of overdose taking their daily tablets. Once patient include drowsiness followed by or adherence is confirmed, the physician persistent nausea, vomiting, aggressive should consider increasing the disul- or psychotic behavior, and ascending flac- firam dosage (see Exhibit 3-3, page cid paralysis that can reach the cranial 20) or changing the patient to another nerves. Treatment consists of administra- medication. tion of oxygen therapy, glucose (5 percent intravenously), and sodium ascorbate (1 Genetic factors may influence sensitivity gram intravenously). The patient should to disulfiram in some patients (reviewed be kept in bed and as quiet as possible by Kenna, McGeary, & Swift, 2004a, with appropriate symptomatic treatment. 2004b). Wide individual differences exist in the activity of the target enzyme Addressing reported drinking ALDH. Individuals with low intrinsic ALDH activity are more likely to exhibit Patients seemingly on an adequate main- high sensitivity to disulfiram, and those tenance dosage of disulfiram who report with high intrinsic ALDH are more that they can drink with impunity could likely to show little or no sensitivity to be disposing of their tablets without tak- disulfiram. ing them. Physicians should not

22 Chapter 3 Managing a disulfiram–alcohol motivation, and supportive intervention, reaction disulfiram is unlikely to have more than a brief effect on drinking patterns, par- The duration of the disulfiram–alcohol ticularly in patients with poor medication reaction varies from 30 to 60 minutes in compliance, more severe forms of alcohol mild cases to several hours or until the dependence, or both. alcohol is metabolized in more severe cases. When effects are severe, supportive In addition to giving patients the general measures may be needed to restore blood patient education discussed in Chapter pressure and treat shock. Administration 6, healthcare providers should educate of oxygen or carbogen (95 percent oxygen, patients about the following key points 5 percent carbon dioxide), large intrave- regarding disulfiram therapy: nous doses of vitamin C (1 g), ephedrine sulfate, or intravenous antihistamines • Benefits and limitations of disulfiram may be indicated. Potassium levels should • be monitored particularly in patients on What to expect from disulfiram and because hypokalemia has been normal time to full effect reported. • Complete information about the disulfiram–alcohol reaction Patient Education • Strong cautions about surreptitious Patients should receive thorough educa- drinking while on disulfiram tion about disulfiram. Use of disulfiram • should include ongoing monitoring, Warnings about using alcohol in medical management, and counseling. disguised forms, such as in sauces, Used without proper patient education, vinegars, cough mixtures, aftershave lotions, or liniments

Exhibit 3-8 Adverse Reactions to Disulfiram and Their Management

Adverse Reaction Management Optic Usually diagnosed after patient complains of visual disturbance. Discontinue disulfiram and conduct an ophthalmologic examination. Peripheral neuritis, polyneu­ Usually diagnosed after patient complains of (numbness or ritis, tingling). Discontinue disulfiram and observe patient or arrange for neu­ rological evaluation. Hepatitis, including chole­ When symptoms of hepatic dysfunction are reported or observed (see static and fulminant Exhibit 3-5), perform a medical history and physical examination and hepatitis, as well as hepatic obtain followup liver function tests. When clinical or laboratory evidence failure* of hepatic dysfunction is found, discontinue disulfiram immediately. Maintain clinical monitoring of symptoms and liver function. Follow findings to resolution. Psychosis Psychotic reactions to disulfiram have been noted, usually attributable to high disulfiram dosage associated with toxicity to other drugs (e.g., metronidazole, isoniazid) or the unmasking of underlying psychoses in patients stressed by alcohol withdrawal. When psychosis is diagnosed and other interacting drugs are present, reduce or discontinue disulfiram and treat underlying psychoses as indicated. *Serious disulfiram-induced hepatic injury occurs rarely, and the precise etiology is unknown.

Disulfiram 23 • Importance of continued counseling and • Importance of carrying a safety identi- 12-Step or mutual-help group participa- fication card indicating that the patient tion during disulfiram therapy is taking disulfiram, symptoms of pos- sible disulfiram–alcohol reactions, and • Importance of informing the counselor the physician or institution to contact in and prescribing professional if a slip or an emergency relapse occurs • Symptoms of potential neurologic injury • Importance of telling physicians or to report immediately to the physician dentists that the patient is taking dis- ulfiram when he or she is scheduled for • Symptoms of potential liver injury to surgery, including dental surgery report immediately to the physician.

Exhibit 3-9 Drug Interactions With Disulfiram

Drug Effect With Disulfiram Recommended Action Benzodiazepines Decreases plasma clearance of Substitute (Serax®) or chlordiazepoxide or (Ativan®) (Librium®) Diazepam (Valium®) Isoniazid May cause unsteady gait, changes Discontinue disulfiram if either effect in mental state is noted Rifampin (Rifidin®, If used with isoniazid to treat Adjust dosages as needed Rimactane®) tuberculosis, see isoniazid effects above Metronidazole (Flagyl®) Leads to a greater likelihood of Do not prescribe disulfiram and confusion or psychosis metronidazole concomitantly Oral anticoagulant (e.g., Inhibits warfarin metabolism Adjust dosages as needed warfarin [Coumadin®]) Oral hypoglycemic Produces disulfiram-like reactions Monitor carefully if prescribing with alcohol oral hypoglycemics and disulfiram concomitantly (Dilantin®) Increases serum levels through Obtain baseline phenytoin serum CYP 450 2C9 inhibition level before disulfiram therapy; reevaluate level during therapy; adjust dosage if phenytoin level increases Theophylline Increases serum levels through Obtain baseline theophylline serum CYP 450 1A2 inhibition level before disulfiram therapy; reevaluate level during therapy; adjust dosage if theophylline serum level increases Tricyclic antidepressants, May cause delirium with Adjust dosages, discontinue (Elavil®) concurrent administration disulfiram, or switch to another class of antidepressant medication Decreases total body clearance and Monitor closely; adjust dosages if (Norpramin®), increases elimination half-life and needed (Tofranil®) peak plasma levels of desipramine or imipramine

24 Chapter 3 Exhibit 3-10 Laboratory Testing in Disulfiram Therapy

Interval/Period Type of Test Before starting disulfiram therapy to Breath or blood alcohol tests (if clinically indicated to confirm confirm abstinence and determine abstinence) baselines after stabilization Liver function tests: Alanine aminotransferase, aspartate aminotransferase, gamma glutamyltransferase, alkaline phosphatase, lactate dehydrogenase, bilirubin, total protein, albumin, prothrombin time , routine chemistries (if clinically indicated) Kidney function tests: Routine blood urea nitrogen (BUN), creatinine Pregnancy test (women of childbearing age) 10–14 days after initiation of therapy Liver function tests: Alanine aminotransferase, aspartate and then monthly (or more frequently) aminotransferase, gamma glutamyltransferase, bilirubin for first 6 months of therapy; every 3 months thereafter Monthly during therapy Pregnancy test (women of childbearing age) As clinically indicated during therapy Kidney function tests: BUN, creatinine Urine toxicology screen: Perform only when concern exists about unreported alcohol or drug use

Clinicians are advised to document that a • Patients who maintain abstinence dur- patient has received and understands the ing treatment information described above and to obtain the patient’s informed written consent to • Patients who are codependent on or also treatment before prescribing disulfiram. abuse .

Who Is Appropriate Treatment Duration and for Treatment With Discontinuing Disulfiram Prolonged disulfiram administration does Disulfiram? not produce tolerance. Daily, uninter- • Patients motivated for treatment and rupted dosing may be continued until the committed to total abstinence patient has established stable, long-term alcohol abstinence. Depending on the • Patients capable of understanding the patient, disulfiram therapy may continue consequences of drinking alcohol while for months or years. A 9-year study of 180 taking disulfiram patients with chronic alcohol dependence • Medically appropriate patients (Krampe et al., 2006) concluded that the beneficial action of long-term (12- to • Patients who can receive supervised 20-month) supervised disulfiram therapy dosing was psychological, not pharmacological, because placebo worked as well as disul- • Patients who are abstinent from alcohol firam. Nevertheless, the study found

Disulfiram 25 that the likelihood that a patient would have supervised dose administration, remain continuously abstinent years after and understand and participate in their termination of medication therapy was treatment appear to derive the great- directly related to the length of time the est benefits from disulfiram therapy. patient continued supervised therapy However, disulfiram does not appear to with either disulfiram or placebo. produce overall higher abstinence rates than placebo. Disulfiram therapy also has For some patients who have completed rare but serious risks of neurologic and successful treatment with disulfiram hepatic toxicity. Patients require careful and who are facing anticipated high- clinical and laboratory monitoring dur- risk relapse situations such as social ing disulfiram therapy. Disulfiram can be events or travel, it may be appropriate to considered for any patient who is alcohol restart disulfiram along with behavioral dependent, does not display contraindica- interventions to help them cope with the tions, has a goal of total abstinence, and high-risk situation and avoid relapse. can comply with appropriate monitoring. No withdrawal syndrome is associ- Clinical visits in which the practitioner ated with discontinuing disulfiram, but and patient discuss the risks and benefits patients must be warned that disulfiram– of disulfiram therapy can motivate the alcohol reactions may occur within 2 patient to commit to alcohol abstinence. weeks of discontinuing the medication. In addition to the pharmacologic actions of the medication, the patient’s simply deciding to take the medication can Final Clinical Thoughts enhance motivation for abstinence. The Disulfiram appears to have modest risks associated with disulfiram are well clinical efficacy in maintaining alco- known and serious. However, patients hol abstinence in patients with AUDs, can benefit from disulfiram as long as particularly when administered under they receive careful clinical and labora- supervision. Patients who are motivated tory monitoring to manage the risks for treatment, commit to abstinence, associated with this therapy.

26 Chapter 3 4 Oral Naltrexone

Oral Naltrexone At a Glance Chemical name: Naltrexone hydrochloride (morphinan-6-one, 17-[cyclopropylmethyl]-4,5-epoxy-3, 14-dihydroxy-[5α]). Trade names: ReVia®; Depade®.

U.S. distributor: Barr Pharmaceuticals, Inc., Pomona, NY; Mallinckrodt, Inc., St. Louis, MO. U.S. Food and Drug Administration approval to treat alcohol dependence: 1994. Dosage/How taken: Tablet by mouth once daily. How supplied: Bottles of 30 or 100 50 mg tablets (ReVia); bottles of 30 or 100 25, 50, and 100 mg tablets (Depade). Storage: Keep out of reach of children; keep tightly closed in original container; store in a cool, dry place, away from excess heat and moisture (not in the bathroom or near a sink); discard when outdated or no longer needed.

What Is Oral Naltrexone? Naltrexone hydrochloride is a relatively pure and long-lasting . Oral naltrexone has been used to treat opioid dependence for many years and has been approved to treat alco­ hol use disorders (AUDs) since 1994. Naltrexone reduces both the rewarding effects of alcohol and craving for it.

Brief History of Development Naltrexone was first synthesized in 1963 by Endo Laboratories, which was acquired by DuPont in 1969. Naltrexone was initially developed to treat addiction to opioids and was approved by the U.S. Food and Drug Administration (FDA) for the treatment of addiction to drugs such as , , and in 1984. DuPont branded naltrexone as Trexan® and promoted it for the treatment of opioid addiction.

27 Animal studies conducted in the 1980s to Spanagel and colleagues (as cited in established that naltrexone decreased Spanagel & Zieglgansberger, 1997), the alcohol consumption through its action mesolimbic dopamine reward system is at the opiate receptors. Human clini­ important in initiating and maintain­ cal trials followed that confirmed that ing the use of many substances of abuse, naltrexone, when used in combination including alcohol, and may mediate both with psychosocial therapy, could reduce the positive effects of alcohol and the cravings for alcohol and decrease relapse development of craving. rates to alcohol use (O’Malley et al., 1992; Volpicelli, Alterman, Hayashida, & Oral naltrexone is rapidly and nearly O’Brien, 1992; Volpicelli, Watson, King, totally absorbed in the gastrointestinal Sherman, & O’Brien, 1995). tract and is metabolized almost exclu­ sively by the liver to the primary active With FDA approval of naltrexone to treat metabolite, 6-β-naltrexol. Peak naltrexone AUDs in 1994, DuPont renamed the drug plasma concentrations are reached within ReVia®. ReVia and a generic version of 1 hour of dosing. The long-acting proper­ naltrexone are now manufactured by ties of naltrexone are due primarily to Barr Pharmaceuticals. Mallinckrodt also 6-β-naltrexol, which has an elimination manufactures naltrexone under the brand half-life of 13 hours. Naltrexone achieves name Depade®. therapeutic effectiveness rapidly follow­ ing the initiation of oral dosing. Pharmacology Drinking alcohol enhances endogenous Why Use Oral opioid activity. Several researchers who Naltrexone? conducted animal studies observed that, under certain conditions, administration Naltrexone appears to be effective for of small doses of morphine (an opioid attenuating craving in people who are ) increased consumption of alcohol alcohol dependent (Monti et al., 1999, in rats (Czirr, Hubbell, Milano, Frank, 2001). By blocking craving, naltrexone & Reid, 1987; Reid, Czirr, Bensinger, may enhance the ability of patients to Hubbel, & Volanth, 1987; Reid, Delconte, abstain from drinking. By blocking the Nichols, Bilsky, & Hubbell, 1991). Some pleasure from alcohol, naltrexone also researchers also reported that adminis­ may reduce the amount of heavy drinking tration of opioid antagonists, including in those who do drink. naloxone (which is similar to naltrex­ one), decreased alcohol consumption Efficacy (Hubbell et al., 1986; Reid et al., 1991). It can be concluded that the reward­ A meta-analysis (Bouza, Magro, Muñoz, ing effects of alcohol are mediated at & Amate, 2004) of 19 controlled clinical least partly through the opiate system. trials of naltrexone for treatment of Two teams of researchers, Woodson and AUDs (most of which were randomized Holman and Benjamin and colleagues and single or double blind) found that, (as cited in Spanagel & Zieglgansberger, compared with using placebo, short- 1997), reported that these rewarding term treatment (less than or equal to effects are reduced when opioid antago­ 12 weeks) with naltrexone significantly nists block opiate occupancy, improved relapse rates during active thereby decreasing the amount of the treatment and a medication-free followup neurotransmitter dopamine released period. Short-term naltrexone treatment from the nucleus accumbens. According was also linked with a lower percentage

28 Chapter 4 of drinking days, fewer drinks per withdrawal. Healthcare providers must drinking day, longer times to relapse, ensure that patients have been fully more days of abstinence, and lower total withdrawn from all opioids before consid­ alcohol consumption during treatment. ering therapy with naltrexone. Naltrexone may afford people with AUDs a measure of control that can prevent a slip from becoming a full-blown relapse. How Is Oral Naltrexone A European meta-analysis (Roozen et al., Used? 2006) corroborated the positive findings of the Bouza and other studies. Initiating Treatment With Oral A more thorough discussion of oral nal­ Naltrexone trexone efficacy studies is in the TIP’s online literature review (http://www.kap. FDA labeling recommends that treatment samhsa.gov). with naltrexone not begin until signs and symptoms of acute alcohol withdrawal have subsided. At least 3 days of absti­ Safety nence are usually recommended, with as Naltrexone has a low incidence of com­ many as 7 days if possible. Patients may mon adverse events. Naltrexone’s experience fewer medication side effects FDA-approved label includes a black- (particularly nausea) if they are abstinent box warning regarding hepatotoxicity, from alcohol when they begin treatment although these reversible effects tend to with naltrexone. However, it is safe for be associated with much higher doses patients to begin taking naltrexone dur­ than those used in routine clinical prac­ ing medically supervised withdrawal or if tice (e.g., 300 mg/day or more) and tend to they are actively drinking. occur only after a patient is on these high Before initiating treatment with naltrex­ doses for extended periods. one, healthcare practitioners should do As an opioid antagonist, naltrexone com­ the following: petitively displaces opioid medications • Conduct a medical evaluation that from their binding sites, precipitating includes a physical exam, psychosocial assessment, and laboratory testing, Oral Naltrexone Black-Box Warning including toxicological screening and Naltrexone has the capacity to cause hepatocel­ liver function testing to establish suit­ lular injury when given in excessive doses. ability for medication and to establish a Naltrexone is contraindicated in acute hepatitis baseline for comparison or liver failure, and its use in patients with active • Discuss the risks of naltrexone use dur­ liver disease must be carefully considered in light ing pregnancy and advise women of of its hepatotoxic effects. childbearing age to use birth control The margin of separation between the apparent­ while taking naltrexone ly safe dose of naltrexone and the dose causing hepatic injury appears to be only fivefold or less. • Ensure that patients are not regular Naltrexone does not appear to be a hepatotoxin users of opioids (illicit drugs, opioid at the recommended doses. maintenance medications, or opioid Patients should be warned of the risk of hepatic pain medications) to avoid precipitating injury and advised to stop the use of naltrexone withdrawal and seek medical attention if they experience • Strongly caution patients of the symptoms of acute hepatitis. unpleasant physical effects of opioid

Oral Naltrexone 29 withdrawal that will result if patients Side Effects, Contraindications, are not completely detoxified from and Cautions opioids. An attractive feature of naltrexone for treating patients who are alcohol Dosage dependent is that, like disulfiram and Exhibit 4-1 summarizes dosage informa­ acamprosate, the medication has tion for oral naltrexone. Naltrexone’s virtually no abuse potential and patients duration of action (which is greater do not develop tolerance for its effi­ than 24 hours) allows a variety of cacy. Side effects are generally mild and flexible dosing schedules. Although 50 often diminish over time (Exhibit 4-2), mg of naltrexone is currently the FDA although less common reactions and some recommended daily dose for treating potentially serious reactions have been AUDs, evidence from an open-label, reported (Exhibit 4-3). Nausea is one of small-scale trial suggested that higher the most frequently reported side effects. doses (up to 150 mg/day) may be effective One study (O’Malley, Krishnan-Sarin, in reducing alcohol consumption in Farren, & O’Connor, 2000) suggests that patients with complicated conditions women may be particularly susceptible to (Oslin et al., 1999). Recent results this side effect, which the authors argue from the large, multisite Combining supports the use of risk-minimizing strat­ Medications and Behavioral Interventions egies, such as gradual dosing starting (COMBINE) study suggest that 100 mg with a lower dose, requiring abstinence naltrexone in combination with a brief for a specific amount of time before start­ medical management intervention is ing naltrexone, and providing support and efficacious and well tolerated in patients supervision to help patients cope with dependent on alcohol (Anton et al., 2006). nausea until it subsides. However, in clin­ Mean adherence (the ratio of pills taken ical studies side effects were rarely cited from returned blistercard pack counts to by patients as reasons for discontinuing those prescribed throughout 16 weeks treatment with naltrexone. of treatment) for this higher naltrexone Data on safety and effectiveness with dose was more than 85 percent, and only adolescents are limited. The results of a 12 percent of patients required a dose recent small, open-label pilot study reduction.

Exhibit 4-2 Exhibit 4-1 Oral Naltrexone Side Effects Oral Naltrexone Dosages Most Less Initial dosage for 50 mg/day in a single Common Common most patients tablet Nausea Diarrhea, constipation, stomach Initial dosage for 12.5 mg/day (quar­ Vomiting , cramps patients at risk of ter tablet) or 25 mg/ Headache Chest pain, joint/muscle pain adverse events (e.g., day (half tablet) for 1 Dizziness Rash women, younger week, taken with food Fatigue Difficulty sleeping patients, those with (2 weeks, if necessary); Nervousness Excessive thirst, loss of appetite shorter abstinence) gradually increase to Anxiety Sweating 50 mg/day Somnolence Increased tears Average mainte­ 50 mg/day Mild depression nance dosage Delayed ejaculation

30 Chapter 4 suggest that naltrexone is well tolerated C, meaning its effects on the fetus are in adolescents seeking treatment and unknown. Women of childbearing age may reduce alcohol consumption and should be informed of this and counseled craving (Deas, May, Randall, Johnson, & to use effective birth control when sexu­ Anton, 2005). However, additional work is ally active. Some clinicians may choose needed before widespread naltrexone use to obtain a pregnancy test before starting in this population can be recommended. naltrexone and whenever pregnancy is suspected. If a patient becomes pregnant Exhibit 4-4 lists situations in which use while using naltrexone, the clinician and of naltrexone may require careful con­ patient should decide whether to continue sideration or monitoring. Naltrexone the medication, given the potential risks is considered FDA pregnancy category and benefits.

Exhibit 4-3 Naltrexone Contraindications

Patient Condition or Circumstance Treatment Recommendation Current illicit opioid use (as indicated by self-report or Do not prescribe oral naltrexone; consider an a positive urine screen) or buprenorphine (Suboxone® alternative medication or Subutex®) or methadone maintenance therapy for the treatment of opioid dependence; currently under­ going Acute hepatitis or liver failure Do not prescribe oral naltrexone Anticipated need for opioid analgesics within the next Do not prescribe oral naltrexone 7 days History of sensitivity to naltrexone, to structurally Do not prescribe oral naltrexone similar compounds (e.g., naloxone or ), or to any inactive ingredients in the tablet

Exhibit 4-4 Naltrexone Cautions

Patient Condition or Circumstance Treatment Recommendation Active liver disease Monitor liver function frequently Moderate to severe renal impairment Use with careful monitoring (naltrexone is eliminated through the kidneys) Pregnant and nursing women Do not prescribe during pregnancy and nursing unless potential benefits outweigh risks (oral naltrexone is FDA pregnancy category C; it is unknown whether oral naltrexone is excreted in human milk) Women of childbearing age Caution patients that effects on fetus are unknown and encourage use of an effective birth control method Serum aminotransferase levels greater Generally avoid, unless potential benefits outweigh risks than 5 times the upper limit of normal syndromes; acute or Have patients abstain from naltrexone for at least 3 days recurring need for opioid analgesics (conservatively, 7 days) before initiating opioid analgesics

Oral Naltrexone 31 Exhibit 4-5 Adverse Reactions to Naltrexone and Their Management

Adverse Reaction Management Nausea Suggest that the patient take naltrexone with complex carbohydrates (e.g., bread) rather than on an empty stomach Suggest that the patient take naltrexone with a tablespoon of simethicone (e.g., Gas-X® and Mylicon®) or bismuth subsalicylate (e.g., Pepto-Bismol®) Reduce dose or cease for 3 or 4 days and reinitiate at lower dose Liver toxicity Discontinue naltrexone Precipitated opioid Discontinue further doses of naltrexone withdrawal Provide supportive treatments (i.e., hydration and antispasmodic and antidiarrheal medications) until opioid withdrawal symptoms resolve Provide α-2- such as to mitigate some withdrawal symptoms; watch for enhanced side effects of clonidine, including dizziness, hypotension, fatigue, and headache Naltrexone overdose Treat symptomatically under close supervision Contact poison control for most recent information

Patient Management aminotransferase results are greater than five times the upper limit of normal. Exhibit 4-5 lists adverse reactions and their management. Patients should A careful drug use history and urine call their physician if they experience toxicological screening should be used to any signs or symptoms of liver disease. confirm abstinence from opioids, includ­ Exhibit 4-6 lists symptoms of liver ing prescribed pain medications, and a disease. lack of opioid dependence before initiating treatment. A comprehensive urine test Exhibit 4-7 lists interactions between nal­ should be used to measure methadone trexone and other drugs. and other opioids. However, urine test­ The consensus panel recommends that ing can be subject to error because typical liver function tests (i.e., ALT, AST, urine screening tests may not cover all gamma glutamyltransferase, bilirubin) opioids and samples can be tampered be performed before naltrexone treat­ with to affect the results. ment begins and at intervals thereafter. In healthy patients without liver dis­ ease, typical intervals can be 1, 3, and Exhibit 4-6 6 months, then yearly thereafter. Liver Signs and Symptoms function tests should be performed more of Liver Disease frequently if baseline liver function test results are high, there is a history of Abdominal pains that last more Fatigue than a few days hepatic disease, a potential hepatotoxic Fever medication is also prescribed, or the Light-colored bowel movements patient is taking doses higher than Nausea Dark, tea-colored urine 50 mg/day. Naltrexone should be used Weakness cautiously in patients whose serum Yellowing of the eyes or skin

32 Chapter 4 Exhibit 4-7 Drug Interactions With Oral Naltrexone

Drug Effect With Oral Naltrexone Cough/cold medications May decrease benefit if medication contains an opioid Antidiarrheal medications May block benefit if medication contains an opioid Opioid analgesics May require greater amount of than usual and may result in deeper and more prolonged respiratory depression than if the patient were not taking naltrexone May result in lethargy and somnolence Yohimbine May result in anxiety and increased pulse and Nonsteroidal anti- May result in liver enzyme elevations (i.e., aspartate aminotransferase inflammatory drugs [AST] and alanine aminotransferase [ALT]) in combination with regular use (NSAIDs) of very high doses of naltrexone (200–250 mg/day) (Kim, Grant, Adson, & Remmel, 2001); this effect has not been observed in the recommended therapeutic dose range of naltrexone (50–100 mg)

Patient Education • Administering opioids to overcome naltrexone’s blockade of the opiate In addition to the general patient educa­ receptors increases the risk of overdose, tion guidelines discussed in Chapter 6, , coma, and death. education about naltrexone should pre­ cede its use. Patients should be informed • After taking naltrexone for some time of the following: and then stopping it, patients may be more sensitive to lower doses of opioids • The effects of naltrexone on the fetus and thus risk overdose if they take are unknown, so women who are opioids. pregnant or think they may be preg­ nant should inform their physician. • Patients should continue to take naltrexone if they slip and return to • The symptoms of protracted alcohol drinking because it may help limit the withdrawal (e.g., sleep disturbance) severity of relapse. may overlap with side effects of naltrexone; patients should be • Participation in psychosocial interven­ reassured that symptoms typically tions (e.g., cognitive-behavioral or other improve with time. specialized treatment) and 12-Step or other mutual-help groups can increase • Naltrexone blocks the effects of the effectiveness of therapy with opioids in prescription drugs such as naltrexone. pain relievers (e.g., morphine, oxy­ codone) and antidiarrheal and antitus­ • Patients should carry a medical alert sive medications. Physicians should card that indicates they are taking inform patients about other options for naltrexone and lists the physician or pain relief. institution to contact in an emergency.

Oral Naltrexone 33 Who Is Appropriate for Pain Management Treatment With Oral As an opioid antagonist, naltrexone blocks the effect of opioid analgesics. Typical doses of Naltrexone? narcotic analgesics (e.g., , morphine, oxycodone, ) may not be effective. Patients Who Are Motivated Fortunately, many nonopioid analgesic medica­ or Monitored tions (e.g., , NSAIDs) and procedures (e.g., regional nerve block) can still be used for A study by Volpicelli and colleagues analgesia. (1997) concluded that patient compli­ ance with naltrexone dosing is associated When opioids must be used, it is possible to reverse the naltrexone blockade using higher with treatment retention and positive than usual doses of opioids. However, because treatment outcomes. As a result, it is of the potential for opioid-induced respiratory important that either the patient be depression, reversal of naltrexone blockade highly motivated for treatment or a should be done only in medical settings with medication monitoring plan be used to the provision for respiratory support. encourage naltrexone use if the patient is not highly motivated. To maximize Naltrexone does not block aspirin, acetamino­ phen, or NSAIDs, including and compliance, physicians should observe sodium. It does not block the effects dosing or encourage a family member or of local such as lidocaine or general significant other to monitor medication (nonopioid) anesthetics. (If patients taking nal­ use, especially at the beginning of treat­ trexone require opioid pain medication, a rap­ ment with naltrexone. Strategies such as idly acting opioid analgesic is recommended to incentives and feedback on medication minimize the duration of respiratory depression. compliance have been incorporated into Patients should be monitored closely.) treatment planning to enhance compli­ ance. After the patient’s motivation has increased and he or she feels better and Patients With Intense Alcohol stronger, medication monitoring may no Craving longer be needed. Patients with intense alcohol cravings during treatment may experience greater Patients Who Are Abstinent medication benefit than patients with From Opioids low levels of alcohol craving (Monterosso et al., 2001). Also, patients with more Naltrexone is an opioid antagonist; somatic complaints may have better patients who are using opioids, being outcomes when treated with naltrexone maintained on opioid replacement compared with patients with less physical therapy, or anticipating surgery or dental distress. Both human laboratory studies work that will require opioid analgesics and clinical trials have suggested that are not good candidates for treatment patients with a family history of alcohol with naltrexone. Naltrexone’s opioid dependence may benefit more from nal­ antagonist properties may make it a trexone treatment than patients without particularly good treatment option for a family history of alcohol dependence individuals with a history of opioid abuse/ (Monterosso et al., 2001; Rubio et al., dependence who are seeking treatment 2005). for AUDs because naltrexone will reduce the reinforcing effects of and curb cravings for both opioids and alcohol.

34 Chapter 4 Treatment Duration anecdotal reports provide intriguing sug­ gestions that particular patient types or and Discontinuing Oral subgroups may be more likely than other Naltrexone groups to respond to naltrexone. A recent finding has suggested that a variant in The FDA label states that naltrexone a gene encoding for the m opiate receptor should be taken for up to 3 months to (OPRM1) in the opiate neurotransmitter treat AUDs. Healthcare providers should system may predict response to nal­ tailor the length of treatment to indi­ trexone treatment in people dependent vidual patients. Naltrexone has been on alcohol (Anton et al., 2008). When administered to patients who are alcohol treated with naltrexone and a medical dependent for 6 months to 1 year with no management intervention, 87.1 percent additional safety concerns (Balldin et al., of persons carrying the less prevalent 2003; O’Malley et al., 2003). Asp40 variant had a good clinical out­ come, compared with only 54.8 percent One controlled study (Hernandez-Avila et of individuals with the more common al., 2006; Kranzler et al., 2003) addressed Asn40/Asn40 genotype (odds ratio, 5.75; targeted use of naltrexone during periods confidence interval, 1.88–17.54); no dif­ of risk for problem alcohol use. The ference between groups was observed in findings and clinical experience support placebo treatment outcomes. This finding periodic or targeted dosing. Because suggests that OPRM1 genotyping may of naltrexone’s efficacy in reducing the be a useful procedure for improving iden­ rewarding effects of alcohol consumption tification of those patients most likely (McCaul, Wand, Eissenberg, Rohde, & to benefit from naltrexone treatment for Cheskin, 2000) and reducing cravings for alcohol dependence. It also suggests that alcohol (O’Malley et al., 1992), patients clinicians should not become discour­ who achieve abstinence may benefit aged if the first patients they prescribe from taking naltrexone at times when naltrexone for do not find it beneficial. they are at higher risk of relapse, such Naltrexone’s efficacy is modest, but it is as on vacations, on holidays, or during a significantly better than placebo in most personal tragedy. studies, and some patients benefit from Discontinuation of oral naltrexone is not naltrexone therapy. associated with a withdrawal syndrome, Although attention is frequently drawn and it is not necessary to taper the dose. to the risks of hepatotoxicity with nal­ Providers should remind patients that trexone, this rarely occurs, is typically they should not take opioid medications reversible, and is more likely with very for at least 3 days and that they may high doses used over a sustained period. be more sensitive to the effects of opioid It is unfortunate that such effects have drugs (see Patient Education, page 33). become so closely associated with naltrex­ one, but the clinician would be prudent to Final Clinical Thoughts monitor liver function. Controlled clinical trials have dem­ Naltrexone—and all the medications onstrated that naltrexone can be an described in this TIP—does not “cure” effective medication for the treatment AUDs the way an cures of patients who are alcohol dependent. bacterial pneumonia. However, as a Clinicians indicate that some patients part of comprehensive treatment, it report that naltrexone helps, and some may increase the likelihood of sustained report no difference with its use. These remission from problem alcohol use.

Oral Naltrexone 35

5 Extended-Release Injectable Naltrexone

Extended-Release Injectable Naltrexone At a Glance Chemical name: Naltrexone for extended-release injectable suspension. Trade name: Vivitrol®. U.S. distributor: Alkermes, Inc., Cambridge, MA (manufacturer); Cephalon, Inc., Frazer, PA (distributor). U.S. Food and Drug Administration approval to treat alcohol dependence: 2006. Dosage/How taken: 380 mg intramuscular injection once every 4 weeks. How supplied: Single-use cartons, containing one 380 mg vial of Vivitrol microspheres, one vial containing 4 mL (to deliver 3.4 mL) diluent for the suspension of Vivitrol, one 5 mL prepackaged , one 20-gauge ½-inch needle, and two 20-gauge 1½-inch needles. Storage: Store entire dose pack in refrigerator (2–8° C, 36–46° F); store unrefrigerated Vivitrol at temperatures not exceeding 25° C (77° F) for no more than 7 days before administration; do not freeze.

What Is Extended-Release Injectable Naltrexone? Extended-release injectable naltrexone is a microsphere formu­ lation of the opioid antagonist (blocker) medication naltrexone. It is administered by intramuscular (IM) gluteal injection once a month. The extended-release injectable form helps address patient noncompliance, which can limit the effectiveness of oral naltrexone (Volpicelli et al., 1997).

Brief History of Development Interest existed in developing an injectable, long-acting naltrex­ one formulation for many years. Various long-acting naltrexone formulations were studied, but there was particular interest in the polylactide (Nuwayser, DeRoo, Balskovich, & Tsuk, 1990) and polylactide glycolide (PLG) polymer (Sharon & Wise, 1981). These polymers are prepared from naturally occurring sugar 37 acids (lactic acid and glycolic acid), are the two medications has not yet been known to be safe, and are used widely performed. in human and veterinary medicine (e.g., in absorbable sutures and biodegradable orthopedic screws). The U.S. Food and Why Use Extended- Drug Administration (FDA) approved Release Injectable Alkermes’ PLG polymer formulation of extended-release injectable naltrexone for Naltrexone? treating alcohol dependence in April 2006. Efficacy Pharmacology Findings on the efficacy of naltrexone Some behavioral effects of alcohol are in general to treat alcohol use disorders caused by alcohol acting to release endog­ (AUDs) are briefly discussed in Chapter enous opioid (e.g., 4, page 28. More detailed information is endorphins, enkephalins, dynorphins) included in the TIP’s online annotated that bind to opiate receptors in the brain. bibliography and literature review at Opioid antagonists, such as naltrexone, http://www.kap.samhsa.gov. Garbutt and bind to opiate receptors and block the colleagues (2005) conducted a 6-month, action of both opioid medications and opi­ randomized clinical trial of injectable ate neurotransmitters. naltrexone to assess its tolerability and efficacy. A group of patients receiving IM The injectable naltrexone plasma con­ injection of 380 mg of injectable naltrex­ centration peaks approximately 2 hours one (along with psychosocial support) had after IM injection followed by a second a 25-percent decrease in the event rate of peak approximately 2 to 3 days later. heavy drinking days compared with those Beginning approximately 7 days after receiving placebo. Patients receiving a dosing, plasma concentrations slowly lower dose (190 mg) of injectable naltrex­ decline, maintaining a therapeutic nal­ one also had a significant decrease (17 trexone blood level over 4 weeks and percent) in the event rate of heavy drink­ avoiding daily peaks and troughs that ing days compared with those receiving occur with oral naltrexone. Steady state placebo. is reached at the end of the dosing inter­ val following the first injection. The FDA Center for Drug Evaluation and Research (CDER) analysis of the Unlike oral naltrexone, injectable nal­ study data concluded that injectable trexone does not undergo first-pass naltrexone is effective only in those who metabolism in the liver. As a con­ were abstinent at baseline. CDER’s sequence, the total monthly dose of analysis emphasized the proportion of naltrexone administered is considerably patients who did not relapse to heavy less for extended-released (380 mg) com­ drinking (FDA CDER, personal commu­ pared with oral naltrexone (1,500 mg). nication, 2008). O’Malley and colleagues Therefore, the peak concentration of (2007) conducted a secondary analysis the drug to which the liver is exposed is of outcomes from the Garbutt study to substantially less for injectable naltrex­ determine whether patients with lead- one than for oral naltrexone. Because in abstinence of 4 or more days also naltrexone-induced hepatotoxicity is dose experienced particularly good treatment dependent, injectable naltrexone would outcomes—a practical issue in U.S. detox­ be expected to show less hepatotoxic­ ification settings, where detoxification ity than the oral form; however, a direct commonly takes 4 days. They found that comparison of relative hepatotoxicity of injectable naltrexone prolongs abstinence

38 Chapter 5 exposure to the drug, reducing the risk of Enhanced Medication Compliance potential liver toxicity. A major benefit of using an extended-release for­ mulation in the treatment of AUDs is decreased concern about compliance with daily administra­ How Is Extended-Release tion, thus ensuring efficacy of naltrexone delivery and therapeutic effect. In a randomized, double- Injectable Naltrexone blind, clinical trial, there were no differences in drinking outcomes in 175 patients with alcohol Used? dependence assigned to minimal psychosocial Treatment with injectable naltrexone treatment and treated with either oral naltrex­ should be part of a management program one or placebo (Chick et al., 2000). However, that provides patient education, address­ when only those subjects demonstrating greater es the psychological and social problems than 80-percent medication compliance were of patients, and encourages attendance at included in the analysis, oral naltrexone was 12-Step or mutual-help meetings or other found to be effective. community support. The importance of medication compliance is fur­ ther supported by a clinical trial that compared Before initiating treatment with inject­ oral naltrexone with placebo in 97 individuals able naltrexone, healthcare practitioners with alcohol dependence receiving weekly one- should do the following: on-one counseling. Among individuals who were treatment compliant, those receiving oral nal­ • Conduct a physical examination trexone reported fewer episodes of heavy drink­ • ing (14 percent vs. 52 percent) and had fewer Determine liver function (alanine ami­ drinking days (2.8 percent vs. 11 percent) than notransferase [ALT], aspartate amin­ those receiving placebo, whereas the drinking otransferase [AST], gamma glutamyl­ outcomes in the noncompliant individuals did transferase [GGT], and bilirubin) not differ from individuals who received placebo (Volpicelli et al., 1997). • Obtain toxicological screening tests. Naltrexone is an opioid antagonist, so individuals who are opioid dependent and reduces both the number of drinking may experience opioid withdrawal. days and the number of heavy drinking Treatment with injectable naltrexone days in patients who are abstinent for as should not be initiated unless the patient few as 4 days before starting treatment. is opioid free for 7 to 10 days (or at least 14 days for patients who have been The online literature review provides taking methadone for more than 3 to 4 more detailed information on these and weeks), as determined by medical history other efficacy studies. or toxicological screening. Patients being maintained on Safety buprenorphine (Suboxone® or Subutex®) Injectable naltrexone appears to be well or methadone for the treatment of opioid tolerated, with a side effects profile dependence cannot undergo treatment similar to that of oral naltrexone (with with naltrexone. Before administering the exception of injection-site reactions). injectable naltrexone, physicians should Like oral naltrexone, the injectable for­ advise patients of the unpleasant physical mulation carries a black-box warning effects of opioid withdrawal that will regarding liver toxicity (see Chapter 4, result if patients are not completely page 29). However, because of its lack detoxified from opioids. Injectable of first-pass metabolism, injectable naltrexone is available through specialty naltrexone significantly reduces liver pharmacies.

Extended-Release Injectable Naltrexone 39 How To Administer Exhibit 5-1 Injectable naltrexone should be adminis­ tered only by a medical professional (e.g., Extended-Release Injectable physician, nurse, physician assistant) Naltrexone Side Effects who can administer IM (gluteal) injec­ Injection site reactions Fatigue tions. Injectable naltrexone comes in a (sometimes severe) Back pain kit that contains a vial of naltrexone as Nausea a dry powder that must be reconstituted Upper abdominal with a liquid diluent immediately before Vomiting pain use. The kits must be refrigerated during Headache Decreased appetite storage but should be brought to room Dizziness temperature 30 to 60 minutes before the injection. The reconstituted microspheres Injectable naltrexone carries the same in solution must be mixed vigorously to contraindications as oral naltrexone (see prevent clumping, which can clog a nee­ Exhibit 4-3 on page 31) plus those listed dle during injection. A syringe and two in Exhibit 5-2. There are no data on use needles are provided—one for mixing the of naltrexone in children or adolescents; microspheres with the diluent and one for treatment of these populations with nal­ injecting the suspension into the upper trexone is not recommended. outer quadrant of the gluteal muscle. The medication is administered every Injectable naltrexone should be used with 4 weeks. If a dose is delayed or missed, many of the cautions applicable to oral the next injection should be administered as soon as possible. However, it is not recommended that medication be read- Exhibit 5-2 ministered earlier than 4 weeks or at a Extended-Release Injectable higher dose than 380 mg. Naltrexone Contraindications Proper IM injection technique is Patient Condition Treatment essential. Serious injection site reactions, or Circumstance Recommendation sometimes requiring extensive surgi­ History of sensitivity Do not administer cal debridement, have been observed to PLG, carboxym­ injectable naltrexone with Vivitrol. CDER reports that these ethylcellulose, or any severe reactions may be more common components of the if the product is inadvertently admin­ diluent istered subcutaneously, rather than Anticipated need Do not administer intramuscularly (FDA CDER, personal for opioid analgesics injectable naltrexone communication, 2008). within the next 30 days Patient obesity Do not administer Side Effects, Contraindications, injectable naltrexone and Cautions if patient’s body mass precludes IM injection Exhibit 5-1 lists the most common side with the provided 1.5­ effects experienced by patients treated inch needle with injectable naltrexone. As when using oral naltrexone, patients should contact Inadvertent subcutane­ their physician if they experience signs or ous injection may cause a severe injection-site symptoms of liver disease (see Exhibit 4-6 reaction on page 32).

40 Chapter 5 naltrexone (see Exhibit 4-4 on page 31) small lump at the injection site frequently plus the cautions listed in Exhibit 5-3. occurs and resolves over 2 to 4 weeks. Injectable naltrexone should be used However, patients should be instructed to cautiously with individuals with current seek immediate medical attention if skin or recent opioid dependence for two rea­ at the injection site becomes painful, red, sons. First, these individuals are at risk and swollen and does not improve within for overdose of opioids if they use large 1 week after the injection. As noted amounts of opioids to overcome naltrex­ above, severe injection-site reactions are one’s opioid blockade (to feel the effects of possible. the drugs). Second, naltrexone blockade can decrease tolerance for opioids, making Patients taking injectable naltrexone also a person more sensitive to their effects. should be monitored for depression. The If a person stops taking naltrexone, then package label states: takes what used to be a “normal” dose of In controlled clinical trials of Vivitrol, opioids, overdose with respiratory depres­ adverse events of a suicidal nature sion can result. (suicidal ideation, suicide attempts, completed ) were infrequent Patient Management overall, but were more common in Possible adverse reactions are the same patients treated with Vivitrol than in as those for oral naltrexone (see Exhibit patients treated with placebo (1% vs. 4-5 on page 32). In addition, injection-site 0). In some cases, the suicidal thoughts reactions are common adverse reactions or behavior occurred after study discon­ to administration of injectable naltrexone. tinuation, but were in the context of an Some pain and tenderness at the injection episode of depression which began while site are common and are similar to those the patient was on study drug. In the occurring after any IM injection. Usually, 24-week, placebo-controlled pivotal trial, this pain resolves within several days. A adverse events involving depressed mood were reported by 10% of patients treated with Vivitrol 380 mg, as com­ Exhibit 5-3 pared to 5% of patients treated with Extended-Release Injectable placebo injections. Naltrexone Cautions Patients who take injectable naltrexone Patient Condition Treatment should undergo the same tests as those or Circumstance Recommendation required for patients taking oral naltrex­ Thrombocytopenia Monitor carefully for 24 one (see page 32). or coagulation hours after injection disorders Overdose should not be a concern for Recent opioid Explain to the patient the patients receiving injectable naltrexone dependence risk of precipitated with­ because it is unlikely that patients will drawal if the patient has receive more than one IM injection per used opioids recently month.

Explain to the patient that the opioid-blocking Patient Education effects last for at least 30 days and that the In addition to the general patient educa­ risks associated with a tion guidelines discussed in Chapter 6, return to opioid use are patient education specific to injectable significant naltrexone should precede use.

Extended-Release Injectable Naltrexone 41 Healthcare providers should ensure that sensitivity to lower doses of opioids patients understand the following: after injectable naltrexone treatment is discontinued; this increased sensitivity • Once naltrexone is injected, it is could result in overdose and respiratory impossible to remove it from the body; depression. if problems occur, the effects can last up to 30 days. • Injectable naltrexone is more likely to reduce drinking if it is used in conjunc­ • The onset of naltrexone’s effects will tion with psychosocial interventions, probably occur within several hours such as specialized substance abuse although full effectiveness may not treatment and community supports occur for 2 to 3 days following first (e.g., counseling, 12-Step, or other injection. The duration of the effects mutual-help groups). appears to be 30 days. • Patients should carry a safety ID card • Injectable naltrexone blocks the effects that indicates they are taking injectable of opioids and opioidlike drugs (e.g., naltrexone. heroin, opioid analgesics, opioid-based antidiarrheals, and antitussives) for up to 30 days, which may complicate the Who Is Appropriate treatment of pain if it occurs during this period. Patients should be assured that for Treatment With other options for analgesia exist. Extended-Release • Injectable naltrexone blocks low to mod­ Injectable Naltrexone? erate doses of opioids, but large doses of This medication should be considered for heroin or other opioids may lead to seri­ individuals with alcohol dependence who ous injury, coma, or death. For patients have not responded to other pharma­ with a history of opioid use, the use of cological and behavioral treatments, in injectable naltrexone may lower toler­ particular those who have problems with ance for opioids, resulting in a greater treatment adherence. The medication

Pain Management As an opioid antagonist, injectable naltrexone blocks the effects of opioid analgesics. Pain manage­ ment for patients taking naltrexone is discussed in Chapter 4, page 34. Pain management for patients using injectable naltrexone can be even more complicated because the medication is long acting. The package insert offers the following advice: In an emergency situation in patients receiving Vivitrol, a suggested plan for pain manage­ ment is regional analgesia, conscious sedation with a , and use of non-opioid analgesics or general anesthesia. In a situation requiring opioid analgesia, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged. A rapidly acting opioid analgesic which minimizes the duration of respiratory depression is preferred. The amount of analgesic administered should be titrated to the needs of the patient. Non-receptor mediated actions may occur and should be expected (e.g., facial swell­ ing, itching, generalized erythema, or bronchoconstriction), presumably due to histamine release. Irrespective of the drug chosen to reverse Vivitrol blockade, the patient should be monitored closely by appropriately trained personnel in a setting equipped and staffed for cardiopul­ monary resuscitation.

42 Chapter 5 could be considered a first-line therapy in this population is available, and inject­ for any patient who is alcohol depen­ able naltrexone has not been approved for dent, interested in treatment, and not the treatment of opioid dependence. subject to the contraindications listed in Exhibit 4-3 and Exhibit 5-2. However, the monthly cost of injectable naltrexone is Treatment Duration and significantly higher than that of oral nal­ Discontinuing Extended- trexone and may not be a viable choice for many patients. Release Injectable For optimal results with injectable nal­ Naltrexone trexone, candidates for treatment should Research has not yet clearly defined meet several criteria: the optimal duration of treatment with injectable naltrexone. Healthcare • They must be medically appropriate to providers may consider discontinuing receive naltrexone. injectable naltrexone once a patient • They should not be using opioids cur­ has achieved stable abstinence from rently or have evidence of recent use. alcohol and has established a sound plan and support for ongoing recovery • They should not be anticipating surgery or if a patient is not compliant with the or have a condition, such as chronic medication regimen. Like oral naltrexone, pain, for which opioid analgesics may be injectable naltrexone may be useful for required in the future. short periods when a patient in stable recovery is at particular risk for relapse • They should not have severe liver or to problem alcohol use. kidney disease, although naltrexone can be used cautiously in persons with mild Patients discontinuing injectable naltrex­ to moderate hepatic impairment or mild one should be reminded that they should renal insufficiency. not take any opioid medications for at least 30 days from the date of their last • They should not have a condition, such injection. Patients also should be warned as a disorder or obesity, that that after discontinuing treatment they prevents them from receiving a deep IM may be more sensitive to the effects of injection. opioid drugs (see Patient Education on • They should have been abstinent for at page 41). least 4 days. • They should be motivated to maintain Final Clinical Thoughts abstinence or to reduce their drinking. Physicians may be concerned that the • They should be willing to participate in decreased frequency of required medical psychosocial substance abuse treatment visits that comes with monthly medi­ such as counseling and support groups. cation will result in decreased use of medical and psychosocial services, The consensus panel believes that the making patients less likely to attend opioid antagonist properties of injectable counseling, 12-Step, or mutual-help group naltrexone may make it a good treatment meetings. Treatment with injectable nal­ option for individuals who are seeking trexone is new, but the experience of the treatment for alcohol dependence and consensus panel suggests that patients who are in recovery from co-occurring opi­ who return monthly for their injectable oid use. However, no evidence for efficacy

Extended-Release Injectable Naltrexone 43 naltrexone continue to participate in the treatment of AUDs, the optimal treatment and to attend these groups. situations for its use remain to be defined. However, it combines two Possible target patients include those attractive features: a medication for who are unable to maintain medication which there is substantial evidence adherence for some reason (e.g., poor for efficacy and a delivery system that memory) and those who would prefer not eliminates daily medication compliance. to have the burden of remembering to As such, it represents an important take medication daily. addition to the list of medications for the Because injectable naltrexone is treatment of alcohol dependence. the newest form of a medication for

44 Chapter 5 6 Patient Management

In This Integrating Medication for Alcohol Dependence Into Clinical Practice Chapter . . . Settings Integrating Medication Pharmacotherapy for alcohol use disorders (AUDs) is underused for Alcohol Dependence both in specialized substance abuse treatment programs and in Into Clinical Practice office-based medical practice. The consensus panel acknowledges Settings that much resistance to pharmacotherapy exists—from third- Initial Assessment party payers, some clinicians, some individuals participating in self-help groups who view medications as substituting a pill for Choosing a Medication self-empowerment and self-responsibility, and some patients and Combination Therapy their families. The diagnoses of alcohol dependence and abuse, as well as hazardous alcohol use, continue to carry significant Choosing a Psychosocial social stigma that affects both the person who is alcohol depen- Intervention dent and healthcare providers. This stigma continues to exist, in part, because of a lack of understanding of alcohol dependence Developing a Treatment Plan as a treatable medical disorder. In addition, providers often worry that persons who are alcohol dependent have complicated Patient Awareness conditions that take too much time to treat. Monitoring Patient Healthcare providers are, however, in ideal practice settings Progress to identify and treat AUDs among users of healthcare services. AUDs are associated with many medical (e.g., hypertension, Modifying the Treatment Strategy ) and behavioral (e.g., major depressive disorder, psychoses) health conditions. Screening, identifying, and treating Discontinuing patients with AUDs have the potential to improve the health Pharmacotherapy of many primary care patients, decrease healthcare costs, and prevent the serious sequelae of alcohol misuse. A full discussion Final Clinical Thoughts of reimbursement issues is outside the scope of TIP 49; however, healthcare practitioners can find useful information in SBI Reimbursement Guide: How to Use Existing Codes to Bill for Alcohol Screening and Brief Intervention/Counseling, prepared by Ensuring Solutions for Alcohol Problems at the George Washington University Medical Center. The guide is available at http://www.ensuringsolutions.org/resources/resources_show. htm?doc_id=385233.

45 Patients with AUDs may be more likely The reader can refer to Helping Patients to see a healthcare provider than to seek Who Drink Too Much: A Clinician’s Guide treatment at a specialty addiction treat- (National Institute on Alcohol Abuse and ment program; these patients represent Alcoholism [NIAAA], 2006), available an untapped reservoir of individuals at http://www.niaaa.nih.gov. An online who are not receiving needed treatment. course (worth one continuing medical Medications can be a potent means of education unit) based on the guide is also enhancing treatment for many persons available at http://www.niaaa.nih.gov/ who are alcohol dependent; medications Publications/EducationTrainingMaterials/ present healthcare providers a unique VideoCases.htm. NIAAA’s A Pocket way to contribute to treatment. Some Guide for Alcohol Screening and Brief aspects of using maintenance medications Intervention is in Appendix B of this TIP. (e.g., the need for concurrent psychosocial treatment and for monitoring drinking Once an AUD diagnosis has been made, behavior) may seem different from usual thorough assessments for substance medical practice. However, integrating use and social, medical, and psychiatric maintenance medications into practice histories are essential in evaluating the should not present any more difficulty consequences of dependence and iden- than, for example, beginning to prescribe tifying problems that can be addressed antidepressant or antihypertensive concurrently with treatment. Evaluation medications. Monitoring a patient’s main- can identify or rule out contraindications tenance medication regimen is typically to therapy with specific medications. less complicated than medication regi- At the very least, a clinician consider- mens for other chronic conditions, such as ing a patient’s pharmacologic treatment diabetes or coronary disease. for alcohol dependence should per- form a physical exam; order laboratory Healthcare providers may find that using tests; assess psychiatric status; obtain maintenance medication provides them substance use, treatment, and social his- with an opportunity to have a significant tories; and assess motivation for change. effect on patients’ overall health status, social functioning, and family relation- ships. This chapter describes information Physical Exam and Laboratory needed for choosing maintenance medi- Testing cations for patients, making effective Because alcohol dependence can harm referrals, and monitoring patients’ many organ systems and certain condi- progress. tions may preclude pharmacotherapy with a particular maintenance medica- tion, a physical exam and laboratory Initial Assessment testing should be performed before any Persons with AUDs often have physi- treatment is initiated. cal and social sequelae from excessive alcohol consumption. AUDs influence the Medical complications of excessive alcohol incidence, course, and treatment of many consumption are common and numer- medical and behavioral health conditions. ous, and TIP 49 cannot discuss them all. Identifying, assessing, and treating AUDs However, common medical conditions can occur concurrently with assessment such as hypertension and gastritis and and treatment of other medical problems. common psychiatric conditions such as As noted in Chapter 1, a thorough dis- depression can be incited or exacerbated cussion of screening and assessment for by AUDs. Various patient complaints AUDs is outside the scope of this TIP. can be related to alcohol consumption,

46 Chapter 6 including dyspepsia, sleep problems, blackened veins, and abscesses in the sexual difficulties, depressed mood, and arms, hips, buttocks, thighs, or calves irritability. AUDs also contribute to may indicate concomitant injection drug progression of morbidity for many use. Inhaled drugs, such as , diseases. For instance, according often cause a brown tongue, nasal septum to a recent review of the literature abnormalities, or diffuse wheezes. (Conigliaro, Justice, Gordon, & Bryant, 2006), excessive alcohol consumption Laboratory testing increases the morbidity associated with In addition to helping healthcare practi- HIV and viral hepatidies and can tioners assess a patient’s overall health complicate medical treatment for these status, initial laboratory testing can iden- conditions. In addition, existing condi- tify the presence of AUDs, alcohol-related tions, such as hepatic or renal disease damage, and contraindications for use of or pain syndromes, either acute or chron- particular medications. Initial and fol- ic, may contraindicate treatment with lowup laboratory testing may motivate particular maintenance medications. patients and reinforce their progress in treatment. Exhibit 6-1 provides a list Physical exam of useful laboratory tests that can iden- Although physical exam findings may tify patients with significant alcohol not be specific to alcohol consumption consumption. or alcohol disorders, a thorough physi- cal exam can often corroborate clinician suspicions of an AUD and may help with Exhibit 6-1 disease monitoring. Patients with AUDs Useful Laboratory Tests may have no specific abnormal exam find- Breath or blood alcohol tests ings. However, when present, abnormal exam findings provide evidence of the Urine toxicology severity of a patient’s AUD. Longstanding Gamma glutamyltransferase (GGT) alcohol consumption may present with Liver function tests, including serum aspartate many “classic” physical exam features, aminotransferase (AST) including physical manifestations of cir- Complete blood count rhosis, encephalopathy, and vitamin Testing for vitamin deficiencies deficiencies. Alcohol consumption can Renal function tests: Standard panel for urea incur tachycardia (including supraven- (blood urea nitrogen), electrolytes, and serum tricular tachycardias), tremor (hand or creatinine tongue), elevated blood pressure, hepa- Pregnancy test (women of childbearing age) tosplenomegaly, a tender liver edge, peripheral neuropathy, spider angiomata, conjunctival injection, and unexplained trauma (Conigliaro, Delos Reyes, Parran, Identifying AUDs and illicit drug & Schulz, 2003). use. Laboratory tests are more specific than sensitive for detecting alcohol prob- Because AUDs often co-occur with drug lems, and there is no single laboratory use, the physical exam may help the cli- test that is sensitive or specific for AUD nician identify comorbid substance use diagnoses. Detection of AUDs is improved problems. For example, smoking ciga- when laboratory tests are combined with rettes frequently co-occurs with excessive other screening strategies (Escobar, Espi, alcohol use; smoking, along with alcohol & Canteras, 1995; Gordon et al., 2001). use, may increase heart rate and promote However, certain tests help healthcare tachyarrhythmias. Needle marks, hard

Patient Management 47 providers identify AUDs and possible those found in some foods and cosmetic alcohol-related abnormalities. items) can trigger a positive test result. Blood/breath/urine alcohol and toxico- More detailed information about the use logical screening. Blood alcohol levels and (and misuse) of biomarkers for identi- urine/breath tests for alcohol are useful fying AUDs and other substance use measures of recent alcohol consumption. disorders can be found in the Substance They determine acute physical or legal Abuse Treatment Advisory, The Role of incapacity to do specific tasks. Initial Biomarkers in the Treatment of Alcohol laboratory work also should include a Use Disorders (Center for Substance urine toxicology screen to assess for other Abuse Treatment [CSAT], 2006b). substances. Identifying alcohol-related damage Biomarkers for AUDs. Alcohol biomark- and medication contraindications. ers are physiological indicators of alcohol Several laboratory tests help healthcare exposure or ingestion and may reflect the practitioners establish a patient’s overall presence of an AUD. Although tests such health status as well as identify alcohol- as serum carbohydrate-deficient trans- related damage and contraindications for ferin (CDT) levels are not often used in using certain medications. primary care practice, some evidence sug- gests that they might be used to screen Complete blood count. Alcohol overuse for chronic alcohol consumption and to causes and has direct toxic effects monitor consumption during treatment on . An assessment of hema- under certain conditions (Bell, Tallaksen, tologic laboratory indices is essential Try, & Haug, 1994). For example, an when considering pharmacologic treat- increase in CDT over time may sug- ment of AUDs. Many persons who are gest an increase in alcohol consumption alcohol dependent have macrocytosis, and (Sorvajarvi, Blake, Israel, & Niemela, the is often 1996). elevated. In addition to assessing impairment in Testing for vitamin deficiencies. People liver functioning, AST and GGT can be with AUDs may not eat well, and several used as biomarkers because they are vitamin deficiencies can occur that lead often elevated in persons who recently to abnormal cellular functions. Thiamine, consumed significant amounts of alco- folic acid, and pyridoxine deficits are com- hol (Aithal, Thornes, Dwarakanath, & mon in people with chronic AUDs, and Tanner, 1998; Bell et al., 1994; Yersin these deficiencies contribute to abnormal et al., 1995). Some studies suggest that cell growth. Vitamin deficiencies may biomarkers such as AST, GGT, and lead to Wernicke-Korsakoff’s/amnestic CDT are most useful for screening when syndrome in patients with severely exces- used in combination (Aithal et al., 1998; sive alcohol consumption. Sillanaukee, Aalto, & Seppa, 1998). Hepatic and renal testing. Consideration Testing for another biomarker, ethyl of treatment of AUDs with pharma- glucuronide (EtG), is becoming widely cotherapy requires the clinician to available in the United States and is consider evaluating organ systems that increasingly being used for screen- are involved in the metabolism and excre- ing. This marker is highly sensitive for tion of these medications. For example, alcohol. This sensitivity is a potential naltrexone and disulfiram should be used drawback as well as a strength, as expo- with caution in patients with liver dis- sure to even small amounts (such as ease, and naltrexone and acamprosate

48 Chapter 6 should be used with caution in patients Substance Use Assessment with renal impairment. Therefore, hepat- After healthcare providers have ascer- ic and renal system testing should be tained that a patient has an AUD, they done before initiating use of these medi- should obtain an adequate history of cations. Finally, all four medications used the patient’s substance use and of prior to treat AUDs are U.S. Food and Drug treatments for AUDs. Providers should Administration (FDA) pregnancy category determine whether the patient has expe- C; women of childbearing age should rienced alcohol withdrawal syndrome receive a pregnancy test before pharma- because this syndrome can indicate a cotherapy is initiated. need for more specialized care than Motivating patients for treatment primary care providers can typically and reinforcing progress. Providing provide. More information about alcohol feedback about patients’ initial test withdrawal and detoxification is in TIP results, compared with norms, and 45, Detoxification and Substance Abuse the health risks associated with these Treatment (CSAT, 2006a). Excerpts of the results can be a powerful way to increase Quick Guide for Clinicians based on TIP patients’ motivation and adherence 45 are in Appendix C. to treatment. Laboratory tests help During the assessment, providers should healthcare providers objectively monitor assess the quantity and frequency of patients’ progress in treatment and pro- alcohol consumption, patterns of alcohol vide patients with objective reinforcement consumption (e.g., persistent, occasional, by demonstrating biologic evidence of binge use), episodes of use, duration of their improving health status. use, and consequences of alcohol con- sumption. The NIAAA clinician’s guide Psychiatric Assessment suggests a stepwise approach that con- sists of assessment of any use, quantity/ Psychiatric conditions (such as major frequency of use, and harm associated depression, generalized anxiety disorder, with alcohol consumption (NIAAA, 2006). posttraumatic stress disorder, schizophre- NIAAA’s A Pocket Guide for Alcohol nia, and personality disorders) frequently Screening and Brief Intervention, a con- co-occur with excessive alcohol consump- densed version of the clinician’s guide, tion (Kranzler & Rosenthal, 2003). Some is in Appendix B. Exhibit 6-2 lists key psychiatric symptoms resolve with absti- questions to quickly assess quantity and nence, and others lessen. Nonetheless, frequency of alcohol use, based on a “stan- the prescribing professional should assess dard drink” in the United States that the patient for these disorders and for contains 14 grams of pure alcohol (about suicidal ideation or intent (or refer the 0.6 fluid ounces or 1.2 tablespoons). More patient for assessment). Untreated psy- detailed information about what consti- chiatric conditions can seriously interfere tutes a is in Appendix B. with a patient’s ability to comply with pharmacotherapy and psychosocial treat- The history also should include use of ment for alcohol dependence and can substances other than alcohol, especially cause the patient preventable suffering. opioids, as well as the patient’s history More information on co-occurring psychi- of use, misuse, or abuse of prescription atric disorders can be found in TIP 42, medications. Misuse of opioid medications Substance Abuse Treatment for Persons may complicate or contraindicate With Co-Occurring Disorders (CSAT, 2005).

Patient Management 49 work, legal, living, and family situations Exhibit 6-2 can yield information that is critical to Questions To Assess Quantity and treatment planning: Frequency of Consumption • What is the patient’s family situation? How often do you have a drink containing Who should be included in treatment alcohol? planning? Who can monitor a patient’s How many drinks containing alcohol do you medication compliance? have on a typical day when you are • drinking? Is the patient on probation at work? Could this be a means of motivating How often do you have five or more drinks medication compliance? on one occasion? So u r c e : Babor, Higgins-Biddle, Saunders, & • What is the patient’s living situation? Monteiro, 2001. Are extra measures required to ensure medication compliance? Are psychoso- cial treatment modalities (residential treatment with naltrexone. Abuse vs. outpatient) recommended? of sedatives and tranquilizers may com- plicate detoxification and treatment. Assessing Motivation for Change A complete assessment includes a patient’s current involvement in or Before offering treatment for alcohol history of professional treatment or dependence, providers should assess mutual-help group involvement, includ- patients’ readiness to change drink- ing the following: ing behavior. Through this assessment, patients and providers develop mutually • Detoxification episodes agreeable intervention and treatment plans. Exhibit 6-3 provides questions that • Pharmacotherapy interventions determine patients’ readiness for change. • Specialty substance abuse treatment Regardless of patients’ readiness to episodes (including when, where, change, they should, at a minimum, be modality, duration, and outcome) willing to be in a supportive relation- ship with their healthcare provider. If • Individual therapy the relationship is strained by dishon- • 12-Step (e.g., ) esty or mistrust, initial willingness to or other mutual- or self-help program take medication and ongoing compliance involvement. with a medication regimen may suffer. In addition, patients should be willing This information can assist the provider to consider adjunctive options including in treatment planning and advocating specialty treatment, other independent for psychosocial treatment as an adjunct psychosocial treatment providers, or to pharmacologic treatment for alcohol forms of community support. A review dependence. of the literature suggests that although psychosocial interventions increase rates Social History of abstinence and decrease alcohol con- sumption, a significant proportion of Understanding a patient’s social situation patients relapse to drinking within 1 year identifies problems that may interfere (Mason, 2005a). Healthcare providers, with treatment and that necessitate however, can play a significant role in referral for ancillary services. Asking a motivational enhancement and relapse patient basic questions about his or her prevention. More information about

50 Chapter 6 matching is found in the TIP’s online lit- Exhibit 6-3 erature review (http://www.kap.samhsa. Questions To Assess Patients’ gov). In addition to considering the char- Readiness for Change acteristics that research has indicated may be relevant to choosing a medication, In what ways are you concerned about your providers need to consider the patient’s: drinking? How much does this concern you? • Past experience with particular mainte- What are the reasons you see for making a nance medications change? • Opinion about which medication may be How do you feel about changing your most helpful drinking? How ready are you to change your drinking? • Level of motivation for abstinence What do you think will happen if you don’t • Medical status and contraindications for make a change? each medication What do you think you want to do about your drinking? • History of medication compliance. What do you think would work for you, if you Exhibit 6-4 provides a decision grid to needed to change? help providers make decisions about pharmacotherapy. This grid is based on existing evidence regarding patient– stages of change and motivational medication matching, medication enhancement is in TIP 35, Enhancing contraindications, and the clinical experi- Motivation for Change in Substance ences of consensus panelists. Exhibit 6-5 Abuse Treatment (CSAT, 1999b). provides a quick-reference guide for com- paring maintenance medications. Choosing a Medication Combination Therapy Scant research exists to guide clinicians in choosing the best medication for a A number of studies have found that particular patient. This lack of guidance treatment outcomes improve when nal- results in part from the inconsistent find- trexone is combined with acamprosate or ings of pharmacotherapy efficacy trials disulfiram, particularly for patients who among subsets of patient populations. responded poorly to therapy with any These inconsistent results may be related of these medications alone (reviewed by to the multiple factors associated with Kiefer et al., 2003; Kiefer & Wiedemann, the effectiveness of these medications. 2004). Besson and colleagues (1998) Further research with larger patient reported that co-administration of samples is necessary before the proposed disulfiram improved the action of acamp- relationships can have a definitive influ- rosate. One study reports that combining ence in the individual decisionmaking acamprosate with naltrexone boosted process. plasma levels of acamprosate, which may have clinical benefits not achieved by Each chapter in this TIP that discusses monotherapy with either drug (Mason, a particular medication for treating AUDs 2005a). The Combining Medications and summarizes the evidence that is avail- Behavioral Interventions (COMBINE) able regarding the type of patient most study (Anton et al., 2006) did not support appropriate for the medication; a more the efficacy of combination therapy with detailed discussion of patient–medication acamprosate and naltrexone, although

Patient Management 51 this combination has been used in more motivated. Because patients were Europe and with some reported not assigned randomly to the disulfiram– success (Feeney, Connor, Young, Tucker, acamprosate regimen, it is unclear & McPherson, 2006; Kiefer et al., 2003; whether the combination of disulfiram Kiefer & Wiedemann, 2004). More infor- and acamprosate or motivation was mation is needed about the efficacy of this responsible for the results. Another study strategy, although it may be worth try- (Petrakis et al., 2005) found no advantage ing with patients who have not benefited for the combination of naltrexone and from single-drug therapy. disulfiram in a randomized, placebo- controlled study of patients with a One placebo-controlled but not random- co-occurring Axis I mental disorder and ized trial of acamprosate also prescribed alcohol dependence, but it did find that disulfiram to patients who requested active medication with either drug pro- it (Besson et al., 1998). Patients who duced greater benefit than placebo in this received the disulfiram–acamprosate population. combination had significantly more abstinent days than those who received Although no absolute contraindications acamprosate only. However, those who exist for using disulfiram with either requested disulfiram may have been naltrexone or acamprosate, no clear

Exhibit 6-4 AUD Medication Decision Grid

Medications Injectable Pretreatment Indicators Acamprosate Disulfiram Oral Naltrexone Naltrexone (Campral®) (Antabuse®) (ReVia®, Depade®) (Vivitrol®) Renal failure X A A A Significant liver disease A C C C Coronary artery disease A C A A Chronic pain A A C C Current opioid use A A X X Psychosis A C A A Unwilling or unable to sustain total A X A A abstinence Risk factors for poor medication adherence C C C A Diabetes A C A A Obesity that precludes IM injection A A A X Family history of AUDs A A + + Bleeding/other coagulation disorders A A A C High level of craving A A + + Opioid dependence in remission A A + + History of postacute withdrawal syndrome + A A A Cognitive impairment A X A A A = Appropriate to use C = Use with caution X = Contraindicated + = Particularly appropriate

52 Chapter 6 Exhibit 6-5 Comparison of Approved Medications for Maintenance of Abstinence From Alcohol*

Extended- Acamprosate Disulfiram Oral Naltrexone Release Injectable Naltrexone Mechanism Not clearly understood; Inhibits aldehyde dehy- Not clearly understood; Same as oral of action appears to restore to drogenase, causing a opioid antagonist; naltrexone normal the altered reaction of flushing, blocks the effects of balance of neuronal sweating, nausea, and endogenous opioid excitation and inhibi­ tachycardia when alco­ peptides; appears to tion induced by chronic hol is ingested attenuate euphoria alcohol exposure, possi­ associated with alcohol bly through interaction use; may make alcohol with the glutamate use less rewarding; may neurotransmitter reduce craving system Examples No clinically relevant Metronidazole; medi- Opioid medications; Presumed same as of drug interactions cations containing cough/cold medications; oral naltrexone; clini­ interactions alcohol; anticoagu­ antidiarrheal medica­ cal drug interaction lants such as warfarin; tions; thioridazine; studies have not been amytripyline; isoniazid; yohimbine performed diazepam Common Diarrhea and Transient mild drowsi- Nausea; vomiting; Same as oral naltrex­ side effects somnolence ness; metallic taste; anxiety; headache; one, plus injection site dermatitis; headache; dizziness; fatigue; reactions; joint pain; impotence somnolence muscle aches or cramps Contra- Severe renal impair- Hypersensitivity to Currently using opi- Same as oral naltrex­ indications ment (creatinine rubber derivatives; sig­ oids or in acute opioid one, plus inadequate clearance ≤ 30 mL/min) nificant liver disease; withdrawal; anticipated muscle mass for deep alcohol still in system; need for opioid analge­ intramuscular injec­ coronary artery disease sics; acute hepatitis or tion; body mass that liver failure precludes deep intra­ muscular injection; rash or at injection site Cautions Dosage may be modi­ Hepatic cirrhosis or Renal impairment; Same as oral nal­ fied for moderate renal insufficiency; cere­ chronic pain; pregnancy trexone, plus impairment (creatinine brovascular disease; category C† hemophilia or other clearance 30–50 mL/ psychoses; diabetes bleeding problems min); pregnancy cat­ mellitus; epilepsy; renal egory C† impairment; pregnancy category C† Serious Rare events include Disulfiram–alcohol Precipitates opioid Same as oral naltrex­ adverse suicidal ideation; severe reaction; hepato­ withdrawal if the one plus inadvertent reactions persistent diarrhea toxicity; peripheral patient is dependent on neuropathy; psychotic opioids; hepatotoxicity may cause a severe reactions; optic neuritis (although it does not injection-site reac­ appear to be a hepato­ tion; depression; rare toxin at recommended events including aller­ doses) gic pneumonia and suicidal ideation and behavior *Based on information in the FDA-approved product labeling or published medical literature. †FDA pregnancy category C: Animal studies have indicated potential fetal risk OR have not been conducted and no or insufficient human studies have been done. The drug should be used with pregnant or lactating women only when potential benefits justify potential risk to the fetus or infant.

Patient Management 53 current evidence indicates that one com- (reviewed by McCaul & Petry, 2003). bination is more efficacious than any of Medical management (MM) is often the three agents alone. There is some practiced by primary care physicians in concern about concurrent use of nal- patients with diabetes and hypertension trexone with disulfiram because of the treatment. NIAAA developed an MM possibility of additive liver toxicity. In treatment as part of its COMBINE study addition, disulfiram should not be used (NIAAA, 2004). MM was designed spe- unless the patient’s goal is complete cifically to accompany pharmacotherapy abstinence, a goal not necessary when for AUDs and be delivered by medically treating with naltrexone or acamprosate. trained clinicians in a medical setting. Finally, the literature is not clear that MM provides the structure and materials combining disulfiram with either nal- to enable clinicians to do the following: trexone or acamprosate improves patient outcomes. Therefore, at this time the con- • Provide patients with strategies for sensus panel does not recommend using taking their medications and staying disulfiram in combination with either nal- in treatment trexone or acamprosate. • Provide educational materials about alcohol dependence and Choosing a Psychosocial pharmacotherapy Intervention • Support patients’ efforts to change drinking habits Any pharmacologic treatment for alcohol dependence should be used as an adjunct • Make direct recommendations for to, not a replacement for, psychosocial changing drinking behaviors. treatment. The literature suggests that the medication–psychosocial therapy An MM manual is available through combination is more effective than either NIAAA at http://www.niaaa.nih.gov. alone. For example, Anton and colleagues Providers in psychiatric practice may (2005, 2006) reported the benefits of provide psychosocial therapies on site. In combining naltrexone and behavioral the context of the primary care setting, interventions for alcohol dependence, however, delivering particular psychoso- including longer time to relapse and cial therapies (e.g., group therapy) may increased time between relapse episodes. be difficult because of time constraints, Psychosocial treatments are likely to patient population, and lack of training. enhance compliance with pharmaco- Brief interventions, motivational enhance- therapy; likewise, pharmacotherapies, ment therapy, and MM treatment are to the extent that they reduce craving more conducive to primary care settings and help maintain abstinence, may make (Anton et al., 2005, 2006). Sources of the patient more open to psychosocial information about these interventions are interventions. listed in Exhibit 6-6. If these types of in- office interventions are not effective with a patient, or if the provider does not have Types of Psychosocial Therapies the resources to offer them, providers As with pharmacotherapy, there is no may need to refer the patient for more psychosocial “magic bullet.” However, intensive or specialized services. a number of modalities of psychosocial therapy have been studied and validated for treatment of alcohol use disorders

54 Chapter 6 • Referral to mutual-help groups. Exhibit 6-6 Resources for Office-Based The underlying basis for a specialty Psychosocial Approaches program is that optimal outcomes are achieved through a range of comple- TIP 34, Brief Interventions and Brief Therapies mentary services and that, as abstinence for Substance Abuse (CSAT, 1999a) lengthens, other issues related to alcohol KAP Keys for Clinicians Based on TIP 34 (CSAT, use become clearer and more amenable 2001a) Quick Guide for Clinicians Based on TIP 34 to treatment. (CSAT, 2001c) A practitioner who is planning to treat TIP 35, Enhancing Motivation for Change in patients with alcohol dependence should Substance Abuse Treatment (CSAT, 1999b) become familiar with a range of local KAP Keys for Clinicians Based on TIP 35 (CSAT, treatment resources. Developing relation- 2001b) ships with treatment staff will facilitate Quick Guide for Clinicians Based on TIP 35 smooth referrals and followup. In addi- (CSAT, 2001d) tion, understanding something about a Helping Patients Who Drink Too Much: A program’s treatment duration, modality, Clinician’s Guide (NIAAA, 2006) philosophy, and continuing-care options NIAAA’s A Pocket Guide for Alcohol Screening helps the practitioner better match a and Brief Intervention (see Appendix B) patient to appropriate treatment; practi- Medical Management Treatment Manual: A tioners can prepare the patient for what Clinical Research Guide for Medically Trained to expect, enhancing compliance with the Clinicians Providing Pharmacotherapy as Part referral. Practitioners can find programs of the Treatment for Alcohol Dependence in their areas or throughout the United (NIAAA, 2004) States by using the interactive Substance Abuse Treatment Facility Locator on the Substance Abuse and Mental Health Referring Patients for Specialty Services Administration (SAMHSA) Web Treatment site at http://dasis3.samhsa.gov. Primary care practitioners may need to refer patients for psychosocial therapies, Mutual- or Self-Help Programs including to specialty substance abuse treatment programs. Many specialty sub- Mutual- or self-help group support can be stance abuse treatment programs provide critical to long-term recovery. The oldest, comprehensive treatment services, either best-known, and most accessible mutual- directly or through referrals, that address help program is Alcoholics Anonymous multiple factors affecting recovery. Such (AA) (http://www.aa.org). Patients may programs address not only immediate resist attending AA meetings and may withdrawal and craving but manage- fear that disclosure of medication use ment of long-term abstinence through the may be unwelcome. Although some AA following: members may have negative attitudes toward medications, the organization • Pharmacotherapy itself supports appropriate medication use (AA, 1984). Providers should • Case monitoring encourage patients to try different • Individual, group, and family/couples group meetings if they meet with counseling and therapy negativity. Lists of local meetings can be obtained from http://www.aa.org • Other psychosocial services (e.g., and given to patients. Dual Recovery vocational counseling) Anonymous (http://www.draonline.org)

Patient Management 55 is a 12-Step program for patients with egy and has a greater chance of long-term co-occurring psychiatric disorders. Other success. mutual- or self-help groups include Self Management and Recovery Training Certain conditions warrant advising (http://www.smartrecovery.org) and a patient to abstain from rather than Women for , Inc. (http://www. reduce drinking. As noted in the NIAAA womenforsobriety.org). Although groups (2006) clinician’s guide, these conditions other than AA are not available in every include when drinkers: community, they do offer a number of • Are or may become pregnant online resources. For patients’ family members, there are Al-Anon and Alateen • Are taking a contraindicated medication meetings (http://www.al-anon.alateen. org). • Have a medical or psychiatric disorder caused or exacerbated by drinking Providers should have a working knowledge of the most common groups • Have an AUD. so that they can suggest these groups For those who drink heavily and who do to their patients and discuss patients’ not have an AUD, the practitioner should participation. use professional judgment to determine whether cutting down or abstaining is Developing a Treatment more appropriate, based on factors such as (NIAAA, 2006): Plan • A family history of alcohol problems Setting Goals: Abstinence or • Advanced age Reduction? • Injuries related to drinking. Each patient–provider interaction should assess and clarify outcome goals for the patient. A patient initially may seek to Elements of a Treatment Plan reduce alcohol consumption. Another A comprehensive pharmacotherapy treat- patient may be motivated for total absti- ment plan for a patient with an AUD nence. Investigations into prescribing of should include the following: pharmacotherapy employ both alcohol use reduction outcomes and abstinence • The medication to be used and a ratio- outcomes to assess the efficacy of medica- nale for its use tions to treat alcohol dependence. Clinical • Initial and maintenance dosages outcomes to assess progress include the length of time to first drink, time to • A schedule for followup office visits and heavy drinking, cumulative abstinence laboratory testing for monitoring health days, and drinks per drinking episode. status and progress Each provider and patient should set an initial goal and be willing to refine that • Criteria for discontinuing the goal as treatment progresses. medication If a patient with an AUD is unwilling to • A referral and followup plan for be completely abstinent, he or she may concurrent specialty substance abuse be willing to cut down on alcohol use. treatment, psychiatric treatment, and/ Practitioners can work with this while or family therapy noting that abstinence is the safer strat-

56 Chapter 6 • A plan for mutual- or self-help group attendance Exhibit 6-7 Elements of Patient Education • Clarification of family or significant other involvement in treatment Information about alcohol dependence as a chronic medical disorder • A plan for treating alcohol-related or other concurrent conditions. Description of what to expect in recovery, including symptoms of postacute withdrawal Special attention must be paid to devel- oping a medication compliance plan with List of the possible benefits of a particular the patient. This plan may include the medication following: Information about the medication itself:

• Specific strategies for remembering to • How and when to take it and the impor­ take medications tance of complying with the regimen

• Using blistercard packs or pill boxes • When the medication will become fully effective • Monitoring medication compliance on an appropriate schedule given the • Possible common side effects and their patient’s history of compliance with expected duration maintenance and other medication • Under what conditions the patient should regimens immediately call the provider

• Involving the patient’s family members • Any cautions regarding daily activities in monitoring compliance. • Medication interactions

Explanation of the importance for women Patient Awareness of childbearing age to use an effective birth Patient awareness is critical to successful control method pharmacotherapy. When starting any new medication, the patient should under- Information about what to do if the patient stand how the medication works and what starts drinking after a period of abstinence to expect while taking it. Particularly Description of the importance of concurrent when prescribing maintenance medi- psychosocial treatment and mutual- or self- cations, treatment providers need to help programs offer that information and guidance to patients. Patients also need to understand Followup plans that alcohol dependence is a chronic medi- Specific patient education unique to each medica­ cal disorder. They need to know that they tion is in the medication chapters. may experience protracted effects from their alcohol use, including postacute withdrawal symptoms (e.g., sleep difficul- Monitoring Patient ties). When patients do not feel good, it is a challenge to keep them in treatment. Progress Providers should educate patients to As it is with any chronic illness, moni- manage their concerns and anxieties. toring of AUDs and pharmacologic Exhibit 6-7 contains elements of effective treatment is important. Providers should patient education, and Exhibit 6-8 is a monitor patients’ ongoing treatment com- brief list of information resources pliance, abstinence or reduced drinking, providers can give patients.

Patient Management 57 Exhibit 6-8 Information Resources for Patients

Al-Anon/Alateen SMART Recovery http://www.al-anon.alateen.org http://www.smartrecovery.org 1 (888) 425-2666 1 (866) 951-5357 General information about how to find local Information about recovery, online recovery tools, meetings online meetings/chat groups/message boards, how to find face-to-face meetings, and publications Alcoholics Anonymous http://www.aa.org SAMHSA (212) 870-3400 (U.S. General Service Office) http://www.samhsa.gov General information, publications, and how to find 1 (800) 662-HELP (Substance Abuse Treatment local meetings Facility Locator) 1 (800) 273-TALK (8255); 1 (800) 799-4889 (TTY) Dual Recovery Anonymous (National Suicide Prevention Lifeline) http://www.draonline.org Information about substance abuse and self-tests General information, publications, and how to find local meetings FDA http://www.fda.gov National Council on Alcoholism and Drug 1 (888) INFO-FDA Dependence Patient information about medications to treat http://www.ncadd.org AUDs (212) 269-7797 Publications about AUDs and information about Women for Sobriety, Inc. advocacy http://www.womenforsobriety.org (215) 536-8026 NIAAA Online recovery tools, online chat groups, how to http://www.niaaa.nih.gov find face-to-face meetings, and publications Information about AUDs, information for families, and publications levels of craving, health status, social • Requesting periodic status reports from functioning, and use of other substances specialty substance abuse treatment so that necessary adjustments in treat- programs, psychiatric referrals, and ment plans can be made. other psychosocial therapy or support.

Monitoring Adherence Monitoring Abstinence Several means exist for a provider to or Reduction in Alcohol monitor patients’ compliance with treat- Consumption ment plans, including the following: The ways in which providers can monitor • Tracking patients’ record of keeping patients’ drinking behavior include the (or not keeping) appointments for following: medication monitoring • Patient self-reports can be useful indi- • Monitoring prescription refills cators of treatment success. The pro- vider should discuss with the patient • Noting whether patients are keep- the quantity and frequency of drink- ing agreements about payment for ing, especially during stressful periods treatment (e.g., holidays, celebrations, major life changes).

58 Chapter 6 • Laboratory tests may include AST, GGT, Monitoring Health Status and CDT, EtG, and urine drug screening. Social Functioning In addition, providers can use periodic Ultimately, the goal of treatment is BreathalyzerTM tests (although these improved quality of life. It is important detect only for a short period following to monitor patients’ progress over time in ingestion) to monitor alcohol intake and the following areas: provide positive feedback to patients who are successful in maintaining abstinence. • Health – Normalization of previously elevated Monitoring Craving blood pressure Greatly diminished craving to drink alco- – Improvement of liver function hol is an optimum outcome of treatment. To assess craving, a physician can rely – Stabilization of related medical largely on the patient’s subjective reports, problems that the patient was although measures such as the Alcohol experiencing before treatment (e.g., Urge Questionnaire (Bohn, Krahn, & control of blood glucose, stabilization Staehler, 1995) may prove useful. of asthma, cardiomyopathy, encepha- lopathy, gastritis, ascites and ) More important than the method of moni- toring is consistency in how the patient is – Signs of increased concern about asked about craving patterns and trends. health care, such as seeing a Patients should be asked about current physician for the first time in years craving as well as how they felt over the and/or increased compliance with past week (e.g., as a rating between 1 prescribed medication regimens and 10, with 1 being no craving and 10 not related to AUD treatment (e.g., the most intense craving the patient has asthma or blood pressure medications) ever experienced). Patients may be asked • Family/social activities whether any episodes have caused par- ticular problems for them. – Spending more positive time with children and/or spouse The patterns of craving over time can be useful. Both the provider and the patient – Greater involvement/participation can see that the patient’s patterns of with family members craving may fluctuate throughout the day and over longer periods; these pat- – Improved intimate relationships terns can assess the appropriateness to continue, adjust, supplement, enhance, or – Reduced family conflict terminate pharmacologic treatment. – Engagement in nondrinking leisure Providers should educate the patient and recreational activities about the role of craving in relapse. • Work/vocational status Learning from and responding optimisti- cally to relapse may increase the patient’s – Obtaining employment if previously motivation to reduce or eliminate alcohol unemployed consumption. – Improved attendance at work – Fewer job-related and financial problems – Improved job performance

Patient Management 59 • Legal status age further escalation of consumption. A patient’s goals may change over time, – No parole or probation violations (in a and providers should adapt to these new patient with legal problems) objectives. – No new driving-under-the-influence As with patients who receive treatment charges for other chronic diseases, patients receiv- • Mental status ing treatment for AUDs may relapse. If this occurs, the provider should consider – Decreased irritability and anxiety several options: – Improved mood • Increase monitoring of medication adherence – Improved sleep • Increase the dose of the medication – Getting appropriate treatment for anxiety disorders, suicidal ideation, • Change the medication depression, or schizophrenia rather • than self-medicating with alcohol. Increase or change the intensity of psy- chosocial treatment to include referring the patient to specialty care Monitoring Other Substances • Examine social, medical, or behav- of Abuse ioral factors that contribute to alcohol It is important to address other sub- consumption. stances of abuse that pose the same level of concern and possible adverse conse- Even after patients and providers have quences. The abuse of other substances examined the reasons for relapse and can be evaluated by random urinalysis have intensified or modified psychosocial collection and testing and self-reports treatment or pharmacotherapy, some from the patient. Use of illicit substances, patients may continue to resist reducing tobacco use, and abuse of prescription alcohol consumption. A small propor- and nonprescription medications should tion of patients with AUDs may simply be addressed. The patient’s agreement or be resistant to treatment. For example, resistance to continuing treatment may chronic relapsing patients are gener- indicate his or her willingness to consider ally defined as patients who persistently other substance use a problem. consume alcohol despite regular and intensive social and medical interven- tions. These patients frequently use Modifying the Treatment emergency services (Thornquist, Biros, Olander, & Sterner, 2002). They may Strategy resist or cannot effectively use pharma- An AUD is a chronic illness that, despite cological and psychosocial interventions treatment, may wax and wane in intensi- because of poor social or environmental ty over time. Some patients may respond situations or other personal factors. These to psychosocial interventions, others to patients, often labeled as “difficult,” con- pharmacotherapy. Because a patient may tribute to the perception of providers that respond to one medication and not to treating AUDs is unlikely to be success- another, the provider should be flexible ful. Dealing with any chronic condition in modifying the medical regimen based and changing harmful behavior are on the patient’s needs. Furthermore, difficult. Understanding and accepting a patient may choose to be treated for these difficulties can help providers keep AUDs to reduce, eliminate, or discour- patients moving forward, even if the pace

60 Chapter 6 is slow. Because treatment of chronic (such as attendance at mutual-help relapsing patients is difficult, it should group meetings). be undertaken by addiction professionals in specialty treatment settings that use None of the medications discussed in this a multifaceted approach incorporating TIP are associated with a withdrawal social, environmental, medical, behavior- syndrome, and they do not need to be al, and motivational interventions. tapered.

Discontinuing Final Clinical Thoughts Management of the patient with an AUD Pharmacotherapy may be seen as a series of stages: Because an AUD is a chronic disorder, patients may need long-term use of • Assessing the patient’s suitability for medication or more than one episode treatment with a medication of pharmacotherapy. In addition, some • Determining which medication should patients may benefit from using a medi- be used cation over short periods to help them through a particularly stressful period • Providing and/or referring the patient or a situation that has typically elicited for psychosocial services cravings for alcohol (e.g., a patient may want to take disulfiram or naltrexone • Assessing the patient’s response to while visiting family members who drink medication, including both efficacy (Is excessively). it working?) and side effects (Are there problems?). Ideally, the patient and provider will decide together to discontinue pharma- This process is similar to becoming famil- cotherapy. A patient may simply stop iar with any new treatment regimen. taking the medication. A patient also AUDs may differ from other common may express a desire to discontinue a chronic disorders mainly in that health- medication because of side effects or care providers may perceive that they for other reasons, or a patient will need have few patients with AUDs. However, to discontinue medication because of the pervasiveness of alcohol use and the significant negative changes in labora- substantial rates of AUDs in the United tory findings or physical health status. States make it extremely unlikely that Otherwise, the patient and provider may the clinician is not seeing patients with consider discontinuing medication under AUDs. The provider simply may not rec- the following conditions: ognize patients with problem alcohol use.

• The patient reports substantially The availability of effective medications diminished craving. that can decrease rates of problem alcohol use or help patients maintain abstinence • The patient has maintained stable is an extremely important step forward in abstinence over a sustained period. the treatment of AUDs. Physicians should become familiar with these medications, • The patient feels ready to discontinue with the features of this patient popula- the medication. tion, and with the services that, combined • The patient is engaged in ongoing with medication, can improve treatment recovery, including community supports outcome. AUDs are treatable medical con- ditions, and treatment can improve the patient’s health and quality of life.

Patient Management 61

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70 Appendix A Appendix B— NIAAA’s A Pocket Guide for Alcohol Screening and Brief Intervention

Included with permission from the National Institute on Alcohol Abuse and Alcoholism

71

HOW TO SCREEN FOR HEAVY DRINKING HOW TO ASSESS FOR ALCOHOL USE DISORDERS HOW TO CONDUCT A BRIEF INTERVENTION

STEP 1 Ask About Alcohol Use STEP 2 Assess For Alcohol Use Disorders FOR AT-RISK DRINKING (no abuse or dependence) FOR ALCOHOL USE DISORDERS (abuse or dependence)

Updated Ask: Do you sometimes drink beer, wine, Next, determine if there is a maladaptive pattern of alcohol STEP 3 Advise and Assist STEP 3 Advise and Assist or other alcoholic beverages? use, causing clinically significant impairment or distress. A POCKET GUIDE FOR State your conclusion and recommendation clearly and State your conclusion and recommendation clearly and Determine whether, in the past 12 months, your patient’s drinking relate them to medical concerns or findings. relate them to medical concerns or findings. NO YES has repeatedly caused or contributed to Gauge readiness to change drinking habits. Negotiate a drinking goal. risk of bodily harm (drinking and driving, operating Consider evaluation by an addiction specialist. Alcohol Screening and Screening complete. Ask the screening question about machinery, swimming) Consider recommending a mutual help group. heavy drinking days: Is patient ready to commit to change? relationship trouble (family or friends) For patients who have dependence, consider How many times in the past year role failure (interference with home, work, or school • the need for medically managed withdrawal (detoxification) Brief Intervention have you had . . . obligations) NO YES and treat accordingly. 5 or more 4 or more run-ins with the law (arrests or other legal problems) Updated 2005 Edition drinks in a day? drinks in a day? • prescribing a medication for alcohol dependence for patients who endorse abstinence as a goal. (for men) (for women) If yes to one or more your patient has alcohol abuse. Restate your concern. Help set a goal. Arrange followup appointments, including medication In either case, proceed to assess for dependence symptoms. Encourage reflection. Agree on a plan. management support if needed. This pocket guide is condensed One standard drink is equivalent to Address barriers to change. Provide educational 12 ounces of beer, 5 ounces of wine, Determine whether, in the past 12 months, your patient has from the 34-page NIAAA guide, or 1.5 ounces of 80-proof spirits. Reaffirm your willingness materials. (See www.niaaa. to help. nih.gov/guide.) Helping Patients Who Drink Too Much: not been able to cut down or stop (repeated failed attempts) STEP 4 At Followup: Continue Support A Clinician’s Guide. Is the answer 1 or more times? not been able to stick to drinking limits (repeatedly gone over them) REMINDER: Document alcohol use and review goals at each visit. Visit www.niaaa.nih.gov/guide for related shown tolerance (needed to drink a lot more to get STEP 4 At Followup: Continue Support Was patient able to meet and sustain drinking goal? professional support resources, including: NO YES the same effect) shown signs of withdrawal (tremors, sweating, nausea, REMINDER: Document alcohol use and review goals at each visit. • patient education handouts or insomnia when trying to quit or cut down) NO YES Advise staying within these Your patient is an at-risk limits: kept drinking despite problems (recurrent physical Was patient able to meet and sustain drinking goal? • preformatted progress notes drinker. For a more complete or psychological problems) Maximum Drinking Limits picture of the drinking spent a lot of time drinking (or anticipating or Acknowledge that change Reinforce and support • animated slide show for training For healthy men up to age 65— pattern, determine the weekly average: recovering from drinking) NO YES is difficult. continued adherence. • materials in Spanish • no more than 4 drinks • On average, how spent less time on other matters (activities that had Support efforts to cut down Coordinate care with in a day AND been important or pleasurable) or abstain. specialists as appropriate. • no more than 14 drinks many days a week do you have an Acknowledge that Reinforce and support in a week change is difficult. continued adherence Relate drinking to ongoing Maintain medications alcoholic drink? If yes to three or more your patient has alcohol problems as appropriate. Or contact: dependence. to recommendations. for alcohol dependence For healthy women (and Support positive change for at least 3 months healthy men over age 65)— • On a typical X Consider (if not yet done): drinking day, how and address barriers. Renegotiate drinking and as clinically indicated NIAAA Publications Distribution Center • no more than 3 drinks many drinks do Renegotiate goal and goals as indicated (e.g., • consulting with an thereafter. in a day AND you have? plan; consider a trial of if the medical condition addiction specialist. P.O. Box 10686, Rockville, MD 20849-0686 Does patient meet criteria for abuse or dependence? changes or if an abstain­ Treat coexisting • no more than 7 drinks abstinence. • recommending a mutual dependence. (301) 443–3860 in a week Weekly average ing patient wishes to help group. Consider engaging resume drinking). Address coexisting Recommend lower limits or significant others. • engaging significant www.niaaa.nih.gov Record heavy drinking days NO YES Encourage to return others. disorders—medical and abstinence as indicated: for psychiatric—as needed. example, for patients who take in past year and weekly Reassess diagnosis if if unable to maintain average in chart. • prescribing a medication medications that interact patient is unable to either adherence. for alcohol-dependent cut down or abstain. with alcohol, have a health GO TO Rescreen at least annually. patients who endorse condition exacerbated by GO TO STEPS 3 & 4 STEPS 3 & 4 abstinence as a goal. alcohol, or are pregnant for for Address coexisting (advise abstinence) GO TO AT-RISK ALCOHOL USE disorders—medical and Rescreen annually STEP 2 DRINKING DISORDERS psychiatric—as needed. WHAT’S A STANDARD DRINK? DRINKING PATTERNS PRESCRIBING MEDICATIONS A standard drink in the United States is any drink that The chart below contains excerpts from page 16 of NIAAA’s Helping Patients Who Drink Too Much: A Clinician’s Guide. It does not provide complete information and is not meant to be a contains about 14 grams of pure alcohol (about 0.6 fluid substitute for the patient package inserts or other drug references used by clinicians. For patient information, visit http://medlineplus.gov. ounces or 1.2 tablespoons). Below are U.S. standard drink HOW COMMON equivalents as well as the number of standard drinks in HOW ARE ALCOHOL Naltrexone Extended-Release Injectable Acamprosate Disulfiram different container sizes for each beverage. These are approx­ WHAT‘S YOUR COMMON DISORDERS IN ® ® ® (Campral®) ® imate, since different brands and types of beverages vary in DRINKING IS THIS DRINKERS WITH (Depade , ReVia ) Naltrexone (Vivitrol ) (Antabuse ) PATTERN? PATTERN? THIS PATTERN? their actual alcohol content. Action Blocks opioid receptors, resulting in reduced craving and Same as oral naltrexone; 30-day duration. Affects glutamate and GABA neurotransmitter systems, but Inhibits intermediate metabolism of alcohol, causing a APPROXIMATE reduced reward in response to drinking. its alcohol-related action is unclear. buildup of acetaldehyde and a reaction of flushing, STANDARD Based on the following DRINK NUMBER OF sweating, nausea, and tachycardia if a patient drinks limits—number of drinks: alcohol. EQUIVALENTS STANDARD DRINKS IN: Percentage Combined BEER or COOLER On any DAY—Never more of prevalence Contraindications Currently using opioids or in acute opioid withdrawal; Same as oral naltrexone, plus inadequate muscle mass for Severe renal impairment (CrCl ≤ 30 mL/min). Concomitant use of alcohol or alcohol-containing than 4 (men) or 3 (women) U.S. adults of anticipated need for opioid analgesics; acute hepatitis or deep intramuscular injection; rash or infection at the preparations or metronidazole; coronary artery disease; – and – aged 18 alcohol abuse liver failure. injection site. severe myocardial disease; hypersensitivity to rubber 12 oz. • 12 oz. = 1 or older* and dependence (thiuram) derivatives. In a typical WEEK—No more • 16 oz. = 1.3 than 14 (men) or 7 (women) • 22 oz. = 2 Precautions Other hepatic disease; renal impairment; history of suicide Same as oral naltrexone, plus hemophilia or other Moderate renal impairment (dose adjustment for CrCl Hepatic cirrhosis or insufficiency; cerebrovascular disease attempts or depression. If opioid analgesia is needed, bleeding problems. between 30 and 50 mL/min); depression or suicidal or cerebral damage; psychoses (current or history); • 40 oz. = 3.3 Never exceed the daily or larger doses may be required, and respiratory depression ideation and behavior. Pregnancy Category C. diabetes mellitus; epilepsy; hypothyroidism; renal weekly limits may be deeper and more prolonged. Pregnancy Category impairment. Pregnancy Category C. Advise patients to ~5% alcohol fewer than C. Advise patients to carry a wallet card to alert medical carry a wallet card to alert medical personnel in the event MALT LIQUOR (2 out of 3 people in this group 1 in 100 personnel in the event of an emergency. For wallet card of an emergency. For wallet card information, see abstain or drink fewer than information, see www.niaaa.nih.gov/guide. www.niaaa.nih.gov/guide. 8–9 oz. 12 drinks a year) 72% • 12 oz. = 1.5 • 16 oz. = 2 Serious adverse Will precipitate severe withdrawal if the patient is Same as oral naltrexone, plus infection at the injection Rare events include suicidal ideation Disulfiram-alcohol reaction, hepatotoxicity, optic neuritis, Exceed only the daily limit • 22 oz. = 2.5 reactions dependent on opioids; hepatotoxicity (although does not site; depression; and rare events including allergic and behavior. peripheral neuropathy, psychotic reactions. (More than 8 out of 10 in this 1 in 5 appear to be a hepatotoxin at the recommended doses). pneumonia and suicidal ideation and behavior. • 40 oz. = 4.5 group exceed the daily limit less than once a week) ~7% alcohol 16% Common side effects Nausea; vomiting; decreased appetite; headache; Same as oral naltrexone, plus a reaction at the injection Diarrhea; somnolence. Metallic after-taste; dermatitis; transient mild drowsiness. TABLE WINE dizziness; fatigue; somnolence; anxiety. site; joint pain; muscle aches or cramps. 5 oz. Exceed both daily and Examples of drug Opioid medications (blocks action). Same as oral naltrexone. No clinically relevant interactions known. Anticoagulants such as warfarin; isoniazid; metronidazole; weekly limits almost interactions phenytoin; any nonprescription drug containing alcohol. (8 out of 10 in this group 1 in 2 • a 750-mL (25-oz.) bottle = 5 exceed the daily limit Usual adult dosage Oral dose: 50 mg daily. IM dose: 380 mg given as a deep intramuscular gluteal Oral dose: 666 mg (two 333-mg tablets) three times Oral dose: 250 mg daily (range 125 mg to 500 mg). once a week or more) 10% injection, once monthly. daily; or for patients with moderate renal impairment (CrCl Before prescribing: Patients must be opioid-free for a 30 to 50 mL/min), reduce to 333 mg (one tablet) three Before prescribing: Evaluate liver function. Warn the minimum of 7 to 10 days before starting. If you feel that Before prescribing: Same as oral naltrexone, plus examine times daily. patient (1) not to take disulfiram for at least 12 hours ~12% alcohol there’s a risk of precipitating an opioid withdrawal the injection site for adequate muscle mass and skin after drinking and that a disulfiram-alcohol reaction can *Not included in the chart, for simplicity, are the 2 percent of U.S. adults who Before prescribing: Evaluate renal function. Establish 80-proof SPIRITS (hard liquor) exceed only the weekly limits. The combined prevalence of alcohol use disorders reaction, a naloxone challenge test should be employed. condition. abstinence. occur up to 2 weeks after the last dose and (2) to avoid in this group is 8 percent. Evaluate liver function. alcohol in the diet (e.g., sauces and vinegars), over-the- • a mixed drink = 1 or more* Laboratory followup: Monitor liver function. counter medications (e.g., cough syrups), and toiletries Laboratory followup: Monitor liver function. (e.g., cologne, ). 1.5 oz. • a pint (16 oz.) = 11 Source: 2001–2002 National Epidemiologic Survey on Alcohol and Related • a fifth (25 oz.) = 17 Conditions (NESARC), a nationwide NIAAA survey of 43,093 U.S. adults Laboratory followup: Monitor liver function. • 1.75 L (59 oz.) = 39 aged 18 or older. Note: Whether or not a medication should be prescribed and in what amount is a matter between individuals and their health care providers. The prescribing information provided here is not a substitute for a provider’s judgment in an *Note: Depending on factors such as the type of spirits and individual circumstance and the NIH accepts no liability or responsibility for use of the information with regard to particular patients. the recipe, one mixed drink can contain from one to three or January 2007 ~40% alcohol more standard drinks. Appendix C— Excerpts From Quick Guide for Clinicians Based on TIP 45*

Introduction The “medical model” of detoxification is characterized by the use of physicians and nursing staff and the administration of medi­ cation to assist people through withdrawal safely. The “social model” relies more on a supportive non-hospital environment than on medication to ease the passage through withdrawal.

Definitions Detoxification is a series of interventions aimed at managing acute intoxication and withdrawal. It denotes a clearing of tox­ ins from the body of the patient who is acutely intoxicated and/ or dependent on substances of abuse. Detoxification seeks to minimize the physical harm caused by the abuse of substances. Evaluation entails testing for the presence of substances of abuse in the bloodstream, measuring their concentration, and screening for co-occurring mental and physical conditions. Evaluation also includes a comprehensive assessment of the patient’s medical, psychological, and social situation. Stabilization includes the medical and psychosocial process of assisting the patient through acute intoxication and with­ drawal to the attainment of a medically stable, fully supported, substance-free state. Fostering the patient’s entry into treatment involves preparing a patient for entry into treatment by stressing the importance of following through with a complete continuum of care.

*TIP 45, Detoxification and Substance Abuse Treatment.

77 Guiding Principles/Assumptions 7. Patients seeking detoxification ser­ vices have diverse cultural and The panel of experts who created TIP ethnic backgrounds as well as unique 45 agreed to the following assumptions, health needs and life situations. which served as a basis for their work: Organizations that provide detoxifica­ 1. Detoxification alone is not sufficient tion services need to ensure that they treatment for substance dependence have standard practices in place to but is one part of a continuum of care address cultural diversity. for substance-related disorders. 8. A successful detoxification process 2. The detoxification process consists can be measured, in part, by wheth­ of the following three components: er an individual who is substance dependent enters, remains in, and is • Evaluation compliant with the treatment protocol of a substance abuse treatment/reha­ • Stabilization bilitation program after detoxification. • Fostering patient readiness for and entry into treatment Overarching Principles for Care A detoxification process that does not During Detoxification Services incorporate all three critical compo­ • Detoxification services do not offer a nents is considered incomplete and “cure” for substance use disorders; they inadequate by the consensus panel. are often a first step toward recov­ 3. Detoxification can take place in a wide ery and a “first door” through which variety of settings and at a number of patients pass to treatment. levels of intensity. Placement should • Substance use disorders are treatable be appropriate to a patient’s needs. and there is hope for recovery.

4. Persons seeking detoxification should • Substance use disorders are brain have access to the components of the disorders and not evidence of moral detoxification process described above, weakness. no matter what the setting or the level of treatment intensity. • Patients should be treated with respect and dignity at all times. 5. All persons requiring treatment for substance use disorders should receive • Patients should be treated in a nonjudg­ treatment of the same quality and mental and supportive manner. appropriate thoroughness and should be put into contact with a treatment • Services planning should be completed program for substance use disorders in partnership with the patient and his after detoxification. or her social support network, including family, significant others, or employers. 6. Ultimately, insurance coverage for the full range of detoxification • All health professionals involved in the services and followup treatment care of the patient will maximize oppor­ services is cost-effective. If reim­ tunities to promote rehabilitation and bursement systems do not provide maintenance activities and to link the payment for the complete detoxifica­ patient to appropriate substance abuse tion process, patients may be released treatment immediately after the detoxi­ prematurely, leading to medically or fication phase. socially unattended withdrawal.

78 Appendix C • Active involvement of the family and 4. Level III.7-D: Medically Monitored other support systems, while respecting Inpatient Detoxification (e.g., free­ the patient’s right to privacy and confi­ standing detoxification center). Unlike dentiality, is to be encouraged. Level III.2-D, this level provides 24-hour medically supervised detoxifi­ • Patients are treated with due con­ cation services. sideration for individual background, culture, preferences, sexual orienta­ 5. Level IV-D: Medically Managed tion, disability, vulnerabilities, and Intensive Inpatient Detoxification (e.g., strengths. psychiatric hospital inpatient center). This level provides 24-hour care in an acute care inpatient setting. Levels of Care and It is important to note that ASAM PPC­ Patient Placement 2R criteria are only guidelines and In addition to the general placement that there are no uniform protocols for criteria for the treatment of substance- determining which patients are placed related disorders, the Patient Placement in which level of care. For further infor­ Criteria, Second Edition, Revised (PPC­ mation on patient placement, readers 2R) of the American Society of Addiction are advised to consult TIP 13, The Role Medicine (ASAM) also indicates a second and Current Status of Patient Placement set of placement criteria, which are more Criteria in the Treatment of Substance important for the purposes of TIP 45 Use Disorders (CSAT 1995). and this Quick Guide—the five “Adult Detoxification” placement levels of care within Dimension 1 (ASAM, 2001). These Biomedical and “Adult Detoxification” levels of care are: Psychosocial Issues 1. Level I-D: Ambulatory Detoxification Detoxification presents an opportunity to Without Extended Onsite Monitoring intervene during a period of crisis and to (e.g., physician’s office, home health encourage a client to make changes in the care agency). This level of care is an direction of health and recovery. Hence, organized outpatient service moni­ a primary goal of the detoxification staff tored at predetermined intervals. should be to build a therapeutic alliance and motivate patients to enter treatment. 2. Level II-D: Ambulatory Detoxification This process should begin as the patient With Extended Onsite Monitoring is being medically stabilized. (e.g., day hospital service). This level of care is monitored by appropriately credentialed and licensed nurses. Symptoms and Signs of 3. Level III.2-D: Clinically Managed Conditions That Require Residential Detoxification (e.g., non­ Immediate Medical Attention 21medical or social detoxification • Change in mental status setting). This level emphasizes peer and social support and is intended • Increasing anxiety for patients whose intoxication and/

or withdrawal is sufficient to warrant • Hallucinations 24-hour support. • Temperature greater than 100.4°F (these patients should be considered potentially infectious)

Quick Guide for Clinicians Based on TIP 45 79 • Significant increases and/or decreases Initial Biomedical and in blood pressure and heart rate Psychosocial Evaluation Domains • Insomnia An initial evaluation will help detoxifica­ tion staff foresee any variables that might • Abdominal pain complicate withdrawal. The following • Upper and lower gastrointestinal is a list of biomedical and psychosocial bleeding domains that can affect the stabilization of the patient. • Changes in responsiveness of pupils Biomedical domains • Heightened deep tendon reflexes and ankle clonus, a reflex beating of the foot • General health history: What is the when pressed rostrally, indicating pro­ patient’s medical and surgical history? found central nervous system irritabil­ Are there any psychiatric or medi­ ity and the potential for seizures cal conditions? Any known medication allergies? A history of seizures? Immediate Mental Health Needs • Mental status: Is the patient oriented, alert, cooperative? Are thoughts coher­ The following are mental health issues ent? Are there signs of psychosis or that require immediate attention: destructive thoughts? Suicidality • General physical assessment with neu- • Patients receiving detoxification servic­ rological exam: This will ascertain the es should be evaluated for suicide risk. patient’s general health and identify medical or psychiatric disorders of • During acute intoxication and with­ immediate concern. drawal, it is important to provide an environment that minimizes opportuni­ • Temperature, pulse, blood pressure ties for suicide attempts. (should be monitored throughout detoxification). • Frequent safety checks should be implemented. • Patterns of substance abuse: When did the patient last use? What were • Patients at risk for suicide should be the substances of abuse? How much placed in areas monitored by staff. of these substances was used and how frequently? Anger and aggression • Urine and toxicology screen for com- • All patients who are intoxicated should monly abused substances. be considered potentially violent. • Past substance abuse treatments or • Symptoms associated with increased detoxification. risk for violence include hallucinations, paranoia, anxiety, and depression. Psychosocial domains • Physical restraint should be used as a • Demographic features: Gather informa­ last resort. tion on gender, age, ethnicity, culture, language, and education level. • Living conditions: Is the patient homeless or living in a shelter? Are

80 Appendix C significant others in the home (and, if Parents with dependent children so, can they safely supervise)? • It is of vital importance to ensure that • Violence, suicide risk: Is the patient the children of someone receiving detox­ aggressive, depressed, or hopeless? Is ification services have a safe place to there a history of violence? stay. • Transportation: Does the patient have • Working with patients to identify sup­ adequate means to get to appointments? portive family or friends may uncover Do other arrangements need to be temporary childcare resources. made? • A consult or referral to the treatment • Financial situation: Is the patient able facility’s social services while the to purchase medication and food? Does patient is being detoxified is indicated the patient have adequate employment when the care of children is uncertain. and income? • Dependent children: Is the patient able Alcohol Intoxication and to care for children, provide adequate Withdrawal child care, and ensure the safety of children? The following symptoms of alcohol intoxi­ cation can vary greatly with the patient’s • Legal status: Is the patient a legal resi­ level of tolerance. dent? Are there pending legal matters? Is treatment court ordered? Blood alcohol level is 20–100 mg percent • Physical, sensory, or cognitive disabili- • Mood and behavioral changes ties: Does the client have disabilities • Reduced coordination that require consideration? • Impairment of ability to drive a car or Considerations for Specific operate machinery Populations Blood alcohol level is 101–200 mg percent Adolescents • Reduced coordination of most activities • Adolescents are more likely to drink • Speech impairment large quantities of alcohol in a short period of time, making it important that • Trouble walking staff be alert to escalating blood alcohol • General impairment of thinking and levels. judgment • Adolescents are more likely to use drugs • Somnolence, combative or “psychotic” they cannot identify, to combine mul­ behavior tiple substances with alcohol, to ingest unidentified substances, and to be • “Normal” mental status unwilling to disclose drug use. Blood alcohol level is 201–300 mg percent • Asking open-ended questions and using street terminology for drugs can be • Marked impairment of thinking, memo­ helpful in both establishing rapport and ry, and coordination obtaining an accurate substance use

history. • Marked reduction in level of alertness

Quick Guide for Clinicians Based on TIP 45 81 • Memory blackouts • Delusions, usually of paranoid or perse­ cutory varieties • Nausea and vomiting/aspiration • Grand mal seizures Blood alcohol level is 301–400 mg percent • Hyperthermia • Worsening of above symptoms with reduction of body temperature and blood • Delirium/disorientation with regard to pressure time, place, person, and situation; fluctuation in level of consciousness • Excessive sleepiness/comatose • Amnesia Management of Alcohol • Nausea and vomiting/aspiration Withdrawal Without Medication • • Death Indications for the management of alco­ hol withdrawal without medication have Blood alcohol level is 401–800 mg percent not been established through scientific studies or evidence-based methods. • Difficulty waking the patient (coma) • The course of alcohol withdrawal is • Serious decreases in pulse, temperature, unpredictable; it is impossible to tell blood pressure, and rate of breathing who will or will not experience life- threatening complications. • Urinary and bowel incontinence • Positive aspects of the nonmedication • Death approach are that it is highly cost- The signs and symptoms of acute alcohol effective and provides inexpensive withdrawal generally start 6 to 24 hours access to detoxification for individuals after the patient takes his last drink. seeking aid. Acute withdrawal may begin when the patient still has significant blood alcohol Social Detoxification concentrations. The signs and symptoms may include the following and are highly Social detoxification programs are short- variable: term, nonmedical treatment service for individuals with substance use disorders. • Restlessness, irritability, anxiety, A social detoxification program offers agitation room, board, and interpersonal support to intoxicated individuals and individuals in • Anorexia, nausea, vomiting substance use withdrawal. Social detoxi­ • Tremor, elevated heart rate, increased fication programs vary widely in services blood pressure offered, but there should always be medi­ cal surveillance, including monitoring of • Insomnia, intense dreaming, nightmares vital signs. • Poor concentration, impaired memory TIP 45 provides several guidelines for and judgment social detoxification programs: • Increased sensitivity to sound, light, and • Such programs should follow local gov­ tactile sensations ernmental regulations regarding licens­ ing and inspection. • Hallucinations (auditory, visual, or tactile) • It is highly desirable that individuals entering social detoxification be assessed

82 Appendix C by primary care practitioners with some tion treatment of this group should substance abuse treatment experience. proceed as quickly as possible. • An assessment should determine 2. Patients who are already in with­ whether the patient is currently intoxi­ drawal and demonstrating moderate cated and the degree of intoxication, the symptoms of withdrawal also require type of withdrawal syndrome, severity immediate medication. of the withdrawal, information regard­ ing past withdrawals, and the presence 3. The third group includes patients of co-occurring psychiatric, medical, and who may still be intoxicated, or who surgical conditions that might require have, at the time of admission, been specialized care. abstinent for only a few hours and have not developed signs or symptoms • Particular attention should be paid to of withdrawal. A decision regarding individuals who have undergone mul­ medication treatment for this group tiple withdrawals in the past and for should be based on advancing age, whom each withdrawal appears to be number of years with alcohol depen­ worse than previous ones (the so-called dence, and the number of previously kindling effect). Patients with a history treated or untreated severe with­ of severe withdrawals are not good can­ drawals. If there is an opportunity to didates for social detoxification. observe the patient over the next 6 to 8 hours, then it is possible to delay • All social detoxification programs a decision regarding treatment and should have personnel who are familiar periodically reevaluate a client of this with the features of substance use with­ category. drawal, have training in basic life sup­ port, and have access to an emergency medical system that can provide trans­ Benzodiazepine Treatment for portation to emergency departments. Alcohol Withdrawal These drugs remain the medication Management of Alcohol of choice in treating withdrawal from Withdrawal With Medications alcohol. The early recognition of alcohol withdrawal and prompt administration It is believed that only a minority of of a suitable benzodiazepine will prevent patients with alcoholism will go into sig­ further withdrawal reaction from pro­ nificant alcohol withdrawal requiring ceeding to serious consequences. medication. Identifying that small minor­ ity is sometimes problematic, but there • Loading dose of a benzodiazepine. are signs and symptoms of impending Administration of a metabolized ben­ problems that can alert the caretaker to zodiazepine may be carried out every seek medical attention. 1 to 2 hours until significant clinical improvement occurs or the patient Deciding whether or not to use medi­ becomes sedated. In general, patients cal management for alcohol withdrawal with severe withdrawal may receive 20 requires that patients be separated into mg of diazepam or 100 mg of chlordi­ three groups: azepoxide every 2 to 3 hours until 1. Clients who have a history of the most improvement or sedation prevails. The extreme forms of withdrawal, that of treatment staff should closely monitor seizures and/or delirium. The medica­ blood pressure, pulse, and respiratory features.

Quick Guide for Clinicians Based on TIP 45 83 • Symptom-triggered therapy. Using the progressive worsening of each succes­ CIWA-Ar or similar alcohol withdrawal sive alcohol withdrawal is in question. rating scales, medical personnel can be trained to recognize symptoms of • Benzodiazepine use to treat outpatients alcohol withdrawal, make a rating, and in alcohol withdrawal may “prime” based on the rating administer benzo­ or reinstate alcohol use during their diazepines to their patient only when administration. signs and symptoms reach a particular threshold. A typical routine of adminis­ Other Medications tration is as follows: Administer 50 mg of chlordiazepoxide for CIWA-Ar >9 and The following is a list of other medica­ reassess in 1 hour. Continue admin­ tions sometimes used in detoxification istering 50 mg chlordiazepoxide every from alcohol: hour until CIWA-Ar is <10. • Barbiturates • Gradual, tapering doses. Once the • patient has been stabilized, oral ben­ zodiazepines can be administered on • Beta blockers/alpha adrenergic agonists a predetermined dosing schedule for several days and gradually tapered over • Antipsychotics time. One example of this regimen is • Relapse prevention agents that patients might receive 50 mg of chlordiazepoxide or 10 mg of diazepam every 6 hours during the first day of Management of Delirium and treatment and 25 mg of chlordiazepox­ Seizures ide or 5 mg of diazepam every 6 hours on the second and third days. The major goal of medical detoxification is to avoid seizures and a special state of • Single daily dosing protocol. According delirium called (DTs) to studies, this regimen may be attrac­ with aggressive use of the primary detoxi­ tive in community or social detoxifica­ fication drug. Death and disability may tion settings, particularly if patients result from DTs or seizures without medi­ could be monitored between doses. cal care. For patients with a history of DTs or sei­ Limitations of Benzodiazepines zures, early benzodiazepine treatment in Outpatient Treatment is indicated at the first clinical setting. Patients with severe withdrawal symp­ The interaction of benzodiazepines with toms, multiple past detoxifications (more alcohol can lead to coma and respiratory than three), and co-occurring unstable suppression, motor incoordination, and medical and psychiatric conditions should abuse. Abuse is usually in the context of be managed similarly. the concurrent use of alcohol, opioids, or stimulants. There are two other limita­ tions as well: DTs • Giving the patient a benzodiazepine • Although benzodiazepines have been should not be delayed by waiting for the studied for 30 years and are effective for return of laboratory studies, transporta­ suppressing alcohol withdrawal symp­ tion problems, or the availability of a toms, their ability to halt the hospital bed.

84 Appendix C • Once full DTs have developed, they tend • Benzodiazepine and/or to run their course despite medication intoxication needs to be treated and management. assessed differently, given the potential­ ly life-threatening implications of • Patients presenting in severe DTs withdrawal from either substance in should have emergency medical combination with each other and/or transport to a qualified emergency alcohol. department and generally will require hospitalization. Wernicke-Korsakoff’s Syndrome Seizures • Wernicke-Korsakoff’s Syndrome is composed of Wernicke’s encephalopathy • Seizures usually occur within the first and Korsakoff’s psychosis. 48 hours after cessation or reduction of alcohol, with peak incidence around 24 • Wernicke’s encephalopathy is an hours. acute neurological disorder featuring oculomotor dysfunction (bilateral • Someone experiencing a is at abducens nerve palsy-eye muscle greater risk for progressing to DTs, paralysis), (loss of muscle coordi­ whereas it is extremely unlikely that nation), confusion, and weakness. a patient already in DTs will also then experience a seizure. • Korsakoff’s psychosis is a chronic neu­ rological condition that includes retro­ • The occurrence of an alcohol withdrawal grade and antegrade amnesia (profound seizure happens quickly, usually with­ deficit in new learning and remote out warning to the individual experienc­ memory) with confabulation (patients ing the seizure or anyone around him. make up stories to cover memory gaps). • Predicting who will have a seizure • Both syndromes are related to thiamine during alcohol withdrawal cannot be deficiency. accomplished with any great certainty. • Thiamine initially is given parenter­ • Patients having a seizure can be treated ally (in a manner other than through with intravenous (IV) diazepam or the digestive tract, as by intravenous lorazepam and advanced cardiac life or intramuscular injection). Afterward, support protocol procedures. oral administration is the treatment • Patients who have had a single wit­ of choice. nessed or suspected alcohol withdrawal • Always give thiamine prior to glucose seizure should be immediately given administration. a benzodiazepine, preferably with IV administration.

Quick Guide for Clinicians Based on TIP 45 85

Appendix D— Excerpts From Quick Guide for Clinicians Based on TIP 24*

Introduction Alcohol-related disorders occur in up to 26 percent of general medicine clinic patients, a prevalence rate similar to those for such other chronic diseases as hypertension and diabetes. Since substance abuse disorders are often chronic conditions that progress slowly, primary care clinicians are in an ideal position to screen for alcohol and drug problems. Studies have shown that primary care clinicians can help patients decrease alcohol consumption through office-based interventions that take only 10 or 15 minutes.

General Recommendations for Primary Care Clinicians

Screening 1. Periodically and routinely screen all patients for substance use disorders 2. Ask questions about substance abuse in the context of other lifestyle questions 3. Use the Alcohol Use Disorder Identification Test (AUDIT) to screen for alcohol problems among English-speaking, liter­ ate patients, or use the first three quantity/frequency ques­ tions from AUDIT, supplemented by the CAGE questionnaire

*TIP 24, A Guide to Substance Abuse Services for Primary Care Clinicians.

87 4. Use the CAGE-AID (CAGE Adapted Warning Signs and Risk to Include Drugs) to screen for drugs use among patients Factors for Alcohol and 5. Ask “Have you used street drugs Illicit Drug Use more than five times in your life?” It is important for primary care clini­ A positive answer suggests further cians to know patients’ drinking levels to screening and possibly assessment are gauge their potential risk for developing needed problems. 6. Ask high-risk patients about alcohol and drug use in combination Physical Signs: General 7. Ask pregnant women “Do you use • Dental caries street drugs?” If the answer is yes, • Swollen hands or feet advise abstinence • Swollen parotid glands 8. Use the CAGE, the AUDIT, or the Michigan Alcoholism Screening Test– • Leukoplakia in mouth Geriatric Version (MAST-G) to screen patients over 60 • Gingivitis 9. Screen adolescents for substance • Perforated septum abuse every time they seek medical • Needle track marks services • Skin abscesses, on inside of lips Brief Intervention • Disrupted menstrual cycle 1. Perform a brief intervention with patients whose substance abuse prob­ lems are less severe Physical Signs: Neurological • Dilated or constricted pupils 2. Include in the brief intervention feedback about screening results and • Slurred, incoherent, or too rapid speech risk of use, information about safe

consumption limits and advice about • Inability to focus (both visually and change, assessment of patient’s readi­ mentally) ness to change, negotiated goals and • Unsteady gait strategies for change, and arrange­ ments for followup visits • “Nodding off” • Blackouts or other periods of memory Assessment and Treatment loss Refer high-risk patients to a specialist, if • Insomnia or other sleep disturbances possible, for in-depth assessment • Withdrawal symptoms • Agitation

88 Appendix D Psychiatric Family • Depression • Use of drugs and alcohol by parents, siblings • Anxiety • Inherited predisposition to alcohol or • Low self-esteem drug dependence • Low tolerance for stress • Family dysfunction • Other mental health disorders • Family trauma • Feelings of desperation • Marital/cohabitation status • Feelings of loss of control over one’s life • Domestic violence and other abuse • Feelings of resentment history

Behavioral Demographic • • Use of other substances Male gender • • Aggressive behavior in childhood Inner city or rural residence combined with low-socioeconomic status • Conduct disorders; antisocial • personality Lack of employment opportunities • Impulsiveness and risk taking Low-Risk and At-Risk • Alienation and rebelliousness Low-risk drinkers consume less than an • School-based academic or behavioral average of one to two drinks per day, do problems not drink more than three or four drinks per occasion, and do not drink in high- • Involvement with criminal justice risk situations (while pregnant, driving a system car, etc.). • Poor interpersonal relationships At-risk drinkers occasionally exceed rec­ ommended guidelines for use. While they are at risk for alcohol-related problems, Social and Sexual History they may never experience negative con­ • Legal status (minor, in custody) sequences as a result of their drinking and represent a prime target for preven­ • Alcohol or drug use by friends tive, educational efforts by primary care clinicians. • Level of education • Occupation/work history Screening Instruments

• Sexual preference Asking potentially sensitive questions • Number of sexual relationships about substance abuse in the context of other behavioral lifestyle questions • Types of sexual activity engaged in appears to be less threatening to patients. • Whether the patient practices safe sex

Quick for Clinicians Based on TIP 24 89 CAGE-AID • The questions are easy to understand Asking the following questions of every Health workers should try to estab­ adult routinely and periodically is a cost- lish these conditions before the AUDIT effective way of screening for substance is given. Answers should be recorded abuse and detecting possible problems at carefully. an early stage in their development: In addition to these general consid­ • Have you ever felt you ought to cut erations, the following interviewing down on your drinking or drug use? techniques should be used: • Have people annoyed you by criticizing • Try to interview patients under the best your drinking or drug use? possible circumstances • Have you felt bad or guilty about your • Look for signs of alcohol or drug intox­ drinking or drug use? ication—patients who have alcohol on their breath or appear intoxicated may • Have you ever had a drink or used be unreliable respondents drugs first thing in the morning to steady your nerves or to get rid of a • It is important to read the questions as hangover (eye-opener)? written and in the order indicated Scoring: Item responses on the CAGE Circle the number that comes closest to are scored 0 for “no” and 1 for “yes” the patient’s answer. answers. Consider conducting a brief intervention (see below) with any patient 1. How often do you have a drink who scores a one or higher. containing alcohol? (0) Never The AUDIT Questionnaire (1) Monthly or less The AUDIT is designed to be used as a brief structured interview or self-report (2) Two to four times a month survey that can easily be incorporated into a general health interview, life­ (3) Two to three times a week style questionnaire, or medical history. (4) Four or more times a week Patients tend to answer it most accurate­ ly when: 2. How many drinks containing alcohol do you have on a typical day when • The interviewer is friendly and you are drinking? nonthreatening [Code number of standard drinks.*] • The purpose of the questions is clearly related to a diagnosis of their health (0) 1 or 2 status (1) 3 or 4 • The patient is alcohol- and drug-free at the time of the screening (2) 5 or 6 • The information is considered (3) 7 to 9 confidential (4) 10 or more

*In determining the response categories it has been assumed that one drink contains 10 g of alcohol. In countries where the alcohol content of a standard drink differs by more than 25 percent from 10 g, the response category should be modified accordingly.

90 Appendix D 3. How often do you have six or more 7. How often during the last year have drinks on one occasion? you had a feeling of guilt or remorse after drinking? (0) Never (0) Never (1) Less than monthly (1) Less than monthly (2) Monthly (2) Monthly (3) Weekly (3) Weekly (4) Daily or almost daily (4) Daily or almost daily 4. How often during the last year have you found that you were not able to 8. How often during the last year have stop drinking once you had started? you been unable to remember what happened the night before because (0) Never you had been drinking? (1) Less than monthly (0) Never (2) Monthly (1) Less than monthly (3) Weekly (2) Monthly (4) Daily or almost daily (3) Weekly 5. How often during the last year (4) Daily or almost daily have you failed to do what was nor­ mally expected from you because of 9. Have you or has someone else been drinking? injured as a result of your drinking? (0) Never (0) No (1) Less than monthly (2) Yes, but not in the last year (2) Monthly (4) Yes, during the last year (3) Weekly 10. Has a relative or friend or a doctor or other health worker been concerned (4) Daily or almost daily about your drinking or suggested you 6. How often during the last year have cut down? you needed a first drink in the morn­ (0) No ing to get yourself going after a heavy drinking session? (2) Yes, but not in the last year (0) Never (4) Yes, during the last year (1) Less than monthly Procedures for scoring AUDIT

(2) Monthly Question 1: Never = 0 (3) Weekly Monthly or less = 1 (4) Daily or almost daily Two to four times per month = 2 Two to three times per week = 3 Four or more times per week = 4

Quick for Clinicians Based on TIP 24 91 Question 2: more than five drinks without falling 1 or 2 = 0 asleep or passing out. A positive response 3 or 4 = 1 to the “worry” question scores 2 points, 5 or 6 = 2 and a positive response to the last three 7 to 9 = 3 questions scores 1 point each. A total 10 or more = 4 score of 2 or more indicates a woman is likely to be a risky drinker. Questions 3–8: Never = 0 Screen all adults age 60 or older for alco­ Less than monthly = 1 hol and abuse as part of Monthly = 2 their regular physical. Weekly = 3 Daily or almost daily = 4 Michigan Alcoholism Screening Questions 9–10: Test–Geriatric Version (MAST-G) No = 0 Yes, but not in the last year = 2 The following are yes or no questions: Yes, during the last year = 4 1. After drinking have you ever noticed The minimum score (for non-drinkers) is an increase in your heart rate or beat­ 0 and the maximum possible score is 40. ing in your chest? A score of 8 or more indicates a strong 2. When talking with others, do you ever likelihood of hazardous or harmful alcohol underestimate how much you actually consumption. drink? 3. Does alcohol make you so sleepy that TWEAK Test you often fall asleep in your chair? Use the TWEAK test to screen pregnant women. 4. After a few drinks, have you some­ times not eaten or been able to skip a T Tolerance: How many drinks can meal because you didn’t feel hungry? you hold? 5. Does having a few drinks help W Have close friends or relatives decrease your shakiness or tremors? worried or complained about your drinking in the past year? 6. Does alcohol sometimes make it hard for you to remember parts of the day E Eye-opener: Do you sometimes take or night? a drink in the morning when you first get up? 7. Do you have rules for yourself that you won’t drink before a certain time A Amnesia: Has a friend or family of the day? member ever told you about things you said or did while you were drink­ 8. Have you lost interest in hobbies or ing that you could not remember? activities you used to enjoy?

K Do you sometimes feel the need to 9. When you wake up in the morning, do cut down on your drinking? you ever have trouble remembering part of the night before? Scoring: A 7-point scale is used to score the test. The “tolerance” question scores 10. Does having a drink help you sleep? 2 points if a woman reports she can hold

92 Appendix D 11. Do you hide your alcohol bottles from Suggestions for Screening family members? Risk factors for adolescent drug use 12. After a social gathering, have you ever • felt embarrassed because you drank Physical or sexual abuse too much? • Parental substance abuse 13. Have you ever been concerned that • Parental incarceration drinking might be harmful to your health? • Dysfunctional family relationships 14. Do you like to end an evening with a • Peer involvement with drugs or alcohol ? • Smoking tobacco 15. Did you find your drinking increased after someone close to you died? Red flags 16. In general, would you prefer to have a • Marked change in physical health few drinks at home rather than go out • Deteriorating performance in school or to a social event? job 17. Are you drinking more now than in • Dramatic change in personality, dress, the past? or friends 18. Do you usually take a drink to relax • Involvement in serious delinquency or or calm your nerves? crimes 19. Do you drink to take your mind off • HIV high-risk activities your problems? • Serious psychological problems 20. Have you ever increased your drink­ ing after experiencing a loss in your Pregnant women and women older than life? 60, as well as women who have experi­ enced a major life transition, should be 21. Do you sometimes drive when you queried about their psychoactive prescrip­ have had too much to drink? tion drug use and use of over-the-counter 22. Has a doctor or nurse ever said they sleep aids. were worried or concerned about your Clinicians will want to use the screening drinking? instrument that best meets the needs of 23. Have you ever made rules to manage their patient population. your drinking? When treating patient populations at 24. When you feel lonely does having a high risk for drug abuse, ask questions drink help? regarding alcohol and drug use at the same time. Scoring: 5 or more “yes” responses are indicative of an alcohol problem.

Quick for Clinicians Based on TIP 24 93 Following Up on Selecting Appropriate Patients Screening for Brief Intervention In response to screening questionnaires • All patients who undergo screening for patients can be categorized into one of alcohol or drug use should be told the three groups: results of the screen. 1. Patients who do not appear to have • Patients with positive results to a any alcohol- or drug-related problems. screen will need some type of followup. These patients require no further Assessment questions should cover intervention. severity of the suspected alcohol or drug involvement, the types and frequency of 2. Patients with positive but low problems connected with the patient’s scores on any screening tests or who use, and other special medical and psy­ occasionally use marijuana. These chiatric considerations. patients may be appropriate candi­ dates for brief intervention. • If a patient’s response to a brief assess­ ment suggests a diagnosis of substance 3. Patients with several positive abuse or dependence, the clinician responses to screening questionnaires should initiate a referral for an in-depth and suspicious drinking or drug use assessment. histories, symptoms of substance dependence, or current use of illicit • The clinician can initiate a brief, office- drugs. These patients need further based therapeutic intervention in these assessment. situations:

– Screening reveals only mild to Conducting Brief Interventions moderate substance abuse problems 1. Give feedback about screening – The patient appears to be at risk for results, impairment, and risks experiencing negative consequences as while clarifying the findings a result of current patterns • Give prompt feedback to the – Coexisting illness or conditions may screening. be worsened by continued drinking or other medications • Present results in a straightforward, nonjudgmental manner and in terms – Patient refuses referral for further a patient can readily understand. assessment or treatment. • Concerns about potential or actual health effects should be stressed. Brief Intervention For example, “At this level of con­ Brief interventions as secondary preven­ sumption, you are at increased risk tion tools have the potential to help an for some health problems as well as estimated 15 to 20 million heavy drinkers accidents.” in the U.S. by minimizing serious adverse • Avoid being adversarial and pay consequences such as costly emergency attention to semantics. For example, room visits, domestic violence, or road the phrase “people for whom sub­ accidents. stance abuse is creating a problem” is less off-putting than the labels “alcoholic” or “addict.”

94 Appendix D • Remain tolerant of the range of stages along a continuum that pro­ patient reactions, including aston­ vides a useful framework for moni­ ishment, embarrassment, hostility, toring progress: and denial. – Precontemplation: Not seeing • Try to avoid arguments or discus­ the behavior as a problem or not sions about how much others can wanting to change the behavior. drink without adverse consequences. – Contemplation: Beginning to • Be reassuring that alcohol and drug understand that the behavior is problems are not anyone’s “fault” causing difficulties in living or and can certainly be addressed dur­ taking a toll on their health and ing visits. happiness.

2. Inform the patient about safe con- – Preparation/Determination: sumption limits and offer advice Considering various options for about change change. • Explain what acceptable and safe – Action: Taking concrete steps to use levels are for the relevant sub­ change the behavior in a specific stance. Low-risk drinking is no more way. than two drinks per day for men and one drink per day for women. – Maintenance: Avoiding relapse into problem behavior. • Patients should understand concepts of tolerance and metabolism. • Be prepared for resistance and setbacks. • Clearly state recommendations about consumption goals, keep­ • Avoid the temptation to regard ing these in the context of lifestyle resistance as a challenge to author­ issues and living habits. For exam­ ity or to react in an authoritarian ple, “In reviewing your response to way. our screening questionnaire, I notice • Have an emphatic and supportive that you are drinking a lot of beer attitude and create an atmosphere on weekends. You don’t seem to that the patient will be comfortable have any direct problems as a result, returning to even if goals are not but I’m concerned that driving while successfully achieved. intoxicated is not safe and you have a young family to consider.” 4. Negotiate goals and strategies for change • Clinician authority in offering advice can be strongly motivating. • With alcohol, suggest that the client reduce consumption to below unsafe

3. Assess the patient’s readiness to or potentially hazardous levels. For change example, “Can we set a specific date • A patient’s reaction to initial feed­ to reduce your alcohol use? Could back about screening results offers you cut back, beginning this week?” strong clues about readiness to • If a patient who is using illegal change. drugs does not feel ready to • People with substance abuse disor­ discontinued use, suggest a tapering ders generally fall into one of five schedule.

Quick for Clinicians Based on TIP 24 95 • The clinician can only remind the • The use of any form of objective patient that reducing or stopping monitoring beyond self-reports of alcohol use or abstaining from other substance abuse must be negoti­ drug use will eliminate the health ated between the clinician and the or social problems substance use is patient. causing: Ultimately the patient must choose the goal. • Tell patients exactly who will see their medical charts and what • Suggest that patients keep track information about screening and of consumption in a daily diary intervention will be recorded. to make them more aware of how much they consume. Even patients • One researcher found that reduction who are not ready to change their of alcohol consumption correlated behavior may be willing to keep a with the number of practitioner diary. intervention sessions that were delivered. • Patients will be more motivated to change if they are helping to set goals and develop strategies for Deciding To Refer for Further change. Some studies have found Assessment or Treatment that self-help manuals can be a Clinicians should be prepared for the helpful adjunct for planning change. brief intervention to fail: The patient may • A written contract is a good idea not be able to achieve or maintain the since sometimes patients forget mutually established goal of reducing what they agreed to do. or stopping use after one try, or even several tries. Clinicians cannot force a 5. Arrange for followup treatment patient to undergo further assessment. However, if problem use persists after • Monitor any health problems or a brief intervention, those discussions abnormal physical markers. should serve as a springboard for a • Express trust in the patient. more in-depth assessment or specialized treatment. • Confront the patient if he or she is not honest about reporting substance use.

96 Appendix D Appendix E—Resource Panel

Patricia Allman Allyson T. Gage, Ph.D. Consultant Associate Director Cephalon, Inc. Central Nervous System Therapeutic Dillon Allman & Partners, LLC Area Bethesda, Maryland Forest Research Institute Jersey City, New Jersey David R. Anderson Communications Director David R. Gastfriend, M.D. Ensuring Solutions to Alcohol Problems Vice President, Medical Affairs School of Public Health and Health Alkermes, Inc. Services Cambridge, Massachusetts The George Washington University Washington, D.C. Beverley Goggins, RN, Ed.M. Representing Therapeutic Communities Neil A. Capretto, D.O., FASAM of America Representing the National Association Lead Nurse of Addiction Treatment Providers Second Genesis, Inc. Medical Director Silver Spring, Maryland Aliquippa, Pennsylvania George Kolodner, M.D. Heidi L. Coleman, J.D. Representing the American Society Chief of Addiction Medicine Impaired Driving Division Director National Highway Traffic Safety KOLMAC Clinic Administration 1003 Spring Street Washington, D.C. Silver Spring, Maryland

Carlo C. DiClemente, Ph.D. Stephen LeBlanc Representing the Division on Addictions, Public Health Analyst American Psychological Association Consumer Affairs Professor Office of the Director University of Maryland, Baltimore Center for Substance Abuse Treatment County Substance Abuse and Mental Health Baltimore, Maryland Services Administration Rockville, Maryland

97 Cynthia Moreno-Tuohy, NCAC II, Timothy P. Tunner, Ph.D., M.S.W. CCDC III Senior Policy Associate—Behavioral Executive Director Health NAADAC, The Association for National Association of Social Workers Addiction Professionals Washington, D.C. Alexandria, Virginia Allan Weber Charlotte A. Mullican, M.P.H. General Manager Senior Advisor for Mental Health Odyssey Pharmaceuticals, Inc. Research East Hanover, New Jersey Agency for Healthcare Research and Quality Wendy J. Wilcox Rockville, Maryland American Association for Marriage and Family Therapy Kevin P. Mulvey, Ph.D. Bowie, Maryland Branch Chief Practice Assessment and Applications Mark L. Willenbring, M.D. Branch Director Center for Substance Abuse Prevention Treatment and Recovery Research Substance Abuse and Mental Health Division Services Administration National Institute on Alcohol Abuse Rockville, Maryland and Alcoholism National Institutes of Health Elyse Sharpe, LCSW-C Bethesda, Maryland Manager Work-Life Program Stephen Wing, M.S.W. Washington, D.C. Associate Administrator for Alcohol Policy Robert L. Stephenson II, M.P.H. Division of Policy Coordination Director Substance Abuse and Mental Health Division of Workplace Programs Services Administration Center for Substance Abuse Prevention Rockville, Maryland Substance Abuse and Mental Health Services Administration Wilbur Woodis, M.A. Rockville, Maryland Division of Behavioral Health Indian Health Service Richard T. Suchinsky, M.D. Rockville, Maryland Associate Chief for Addiction Disorders Department of Veterans Affairs Washington, D.C.

98 Appendix E Appendix F—Field Reviewers

David D. Atkins, M.S.M., LISW, ACSW Peter M. Miller, Ph.D. Alcohol/Substance Abuse Program Professor Director Center for Drug and Alcohol Programs Indian Health Service, Phoenix Medical University of South Carolina Area Office Charleston, South Carolina Phoenix, Arizona Paul Nagy, M.S., LPC, LCAS, CCS David A. Fiellin, M.D. Program Director Associate Professor of Medicine Duke Addictions Program Yale University School of Medicine Duke University Medical Center New Haven, Connecticut Durham, North Carolina

Sharon Morgillo Freeman, Ph.D., Charles O’Brien, M.D., Ph.D. APRN-CS, MAC Professor President, Center for Brief Therapy, P.C. Department of Psychiatry and University of Pennsylvania School President, NAADAC, The Association of Medicine for Addiction Professionals Philadelphia, Pennsylvania Fort Wayne, Indiana Ashwin A. Patkar, M.D., MRC Psych Monika A. Koch, M.D. Medical Director, Duke Addictions Addiction Psychiatrist Program Chemical Dependence Recovery and Program Associate Professor, Division The Permanente Medical Group of Biological Psychiatry Vallejo, California Department of Psychiatry and Behavioral Sciences Sandra C. Lapham, M.D., M.P.H. Duke University Medical Center Director Durham, North Carolina Behavioral Health Research Center of the Southwest Pacific Institute for Research and Evaluation Albuquerque, New Mexico

99 James Recktenwald, M.S.W., CADC Ruth Robinson Staten, Ph.D., Substance Abuse Counselor ARNP-CS Carl D. Perkins Vocational Training Associate Professor Center University of Kentucky College Thelma, Kentucky of Nursing Lexington, Kentucky John Scanlon, D.O. Assistant Professor of Family Medicine Scott H. Stewart, M.D. and Addiction Medicine Center for Drug and Alcohol Programs Pikeville College School of Osteopathic Department of Psychiatry and Medicine Behavioral Sciences Pikeville, Kentucky Medical University of South Carolina Charleston, South Carolina Marvin D. Seppala, M.D. Medical Director and CEO Daniel C. Vinson, M.D., M.S.P.H. Beyond Addictions Professor Beaverton, Oregon Department of Family and Community Medicine C. Chapman Sledge, M.D., FASAM University of Missouri-Columbia Medical Director Columbia, Missouri Pine Grove Behavioral Health and Addiction Services Hattiesburg, Mississippi

100 Appendix F Appendix G— Acknowledgments

Numerous people contributed to the development of this TIP, including the TIP Consensus Panel (see page vii), the Knowledge Application Program (KAP) Expert Advisory Panel (see page ix), the Resource Panel (see Appendix E), and TIP Field Reviewers (see Appendix F). This publication was produced under KAP, a Joint Venture of The CDM Group, Inc., and JBS International, Inc. (JBS), for the Substance Abuse and Mental Health Services Administration, Center for Substance Abuse Treatment. Lynne MacArthur, M.A., A.M.L.S., served as the JBS KAP Executive Project Co-Director, and Barbara Fink, RN, M.P.H., served as the JBS KAP Managing Project Co-Director. Other JBS KAP personnel included Candace Baker, M.S.W., MAC, Deputy Director for Product Development; Dennis Burke, M.S., M.A., TIPs, TAPs, and Other Products Manager; Elliott Vanskike, Ph.D., Senior Writer; Frances Nebesky, M.A., Quality Assurance Editor; and Wendy Caron, Quality Assurance Manager.

101

Index

AA. See Alcoholics Anonymous Aggression, 80 Abstinence Al-Anon, 56 defined, 2 Alateen, 56 goal setting, 56 Alcohol challenges, 18 monitoring, 58–59 Alcohol cravings, 34, 59 Acamprosate Alcohol dehydrogenase, 16 adverse reactions, 12, 13, 53, 76 Alcohol dependence, 3 cautions, 12–13, 53, 76 Alcohol intoxication, 81–85 contraindications, 12, 52, 53, 76 Alcohol Urge Questionnaire, 59 discontinuing treatment, 14 Alcohol Use Disorder Identification Test, dosage, 9, 13, 76 87–88, 90–92 duration of treatment, 14 Alcohol use disorders efficacy, 10–11 access to medication-assisted history of development, 9–10 treatment, 4 initiating treatment, 11 assessment, 73 mechanism of action, 53, 76 benefits of medication-assisted medication comparison, 53, 76 treatment, 5–7 overview, 9 costs, 3 patient education, 12 defined, 2 patient management, 12, 13 drinking patterns, 75 patient selection, 13–14 genetic links, 5–6 pharmacology, 10 identifying, 47–48 safety, 11 integrating medication-assisted side effects, 12, 53, 76 treatment into clinical practice, 45–46 storage, 9 medication-assisted treatment, 3–4 treatment decision factors, 52 neuroadaptations, 6 Acetaldehyde, 16–17 patient assessment, 46–50 Adolescents, 56, 81, 93 prevalence of, 3 “Adult Detoxification” levels, 79 primary care treatment advantages, Adverse reactions 1–2 acamprosate, 12, 13 treatment options, 5 comparison, 53, 76 Alcohol withdrawal, 82–85 disulfiram, 17–18, 23 Alcoholics Anonymous, 55 naltrexone, extended release Aldehyde dehydrogenase, 16, 18, 22 injectable, 41 ALDH. See Aldehyde dehydrogenase naltrexone, oral, 32 American Society of Addiction Medicine, 79

103 Anger, 80 CDER. See Center for Drug Evaluation Antabuse®. See Disulfiram and Research ASAM. See American Society of Addiction CDT. See Carbohydrate-deficient Medicine transferin Aspartate aminotransferase, 47–48 Center for Drug Evaluation and Assessment, 46 Research, 38 psychiatric, 49 Center for Substance Abuse Treatment, x substance use, 49 CIWA-Ar scale, 84 AST. See Aspartate aminotransferase COMBINE. See Combining Medications At-risk drinkers, 89 and Behavioral Interventions AUDIT, 87–88, 90–92 Combining Medications and Behavioral AUDs. See Alcohol use disorders Interventions, 4, 51, 54 Contraindications Benzodiazepine, 83–84 acamprosate, 12 Biomarkers, 48 comparison, 53, 76 Biomedical issues, 79–81 disulfiram, 20–21 Black-box warning medication decision grid, 52 disulfiram, 19 naltrexone, extended-release naltrexone, extended release injectable, 40 injectable, 39 naltrexone, oral, 30–31 naltrexone, oral, 29 Cravings, 34, 59 Blood alcohol levels, 81–82 CSAT. See Center for Substance Abuse Blood counts, 48 Treatment Blood tests, 47–48 Breath tests, 47–48 Delirium tremens, 84–85 BreathalyzerTM tests, 59 Depade®. See Naltrexone, oral Brief interventions Detoxification choosing type of treatment, 5 defined, 77 defined, 2 Detoxification and Substance Abuse A Guide to Substance Abuse Services Treatment, TIP 45 for Primary Care Clinicians, TIP 24, alcohol intoxication and withdrawal, 88, 94–96 81–85 A Pocket Guide for Alcohol Screening biomedical issues, 79–81 and Brief Intervention, 49, 74 definitions, 77 Buprenorphine, 6 guiding principles and assumptions, 78 Buproprion, 6 levels of care, 79 patient placement, 79 CAGE Adapted to Include Drugs, 88, 90 principles for care, 78–79 CAGE-AID, 88, 90 psychosocial issues, 79–81 CAGE questionnaire, 87–88 Disulfiram Campral® Delayed-Release Tablets. See absorption and elimination, 18 Acamprosate adverse effects of reaction with alcohol, Carbohydrate-deficient transferin, 48 17–18, 23, 76 Cautions adverse reactions, 21, 23, 53 acamprosate, 12–13 black-box warning, 19 comparison, 53, 76 cautions, 20, 22, 53, 76 disulfiram, 20, 22 contraindications, 20–21, 52, 53, 76 naltrexone, extended-release discontinuing treatment, 25–26 injectable, 41 dosage, 15, 20, 76 naltrexone, oral, 30–31 drug interactions, 21, 24, 53, 76

104 Index duration of treatment, 25–26 warning signs and risk factors, 88–89, efficacy, 18–19 93 hepatic toxicity, 21 history of development, 15–16 Health status, 59–60 initiating treatment, 19–20 Healthcare practitioners laboratory testing, 21, 25 defined, 2 mechanism of action, 53, 76 Hepatic toxicity. See Liver disease medication comparison, 53, 76 Hepatitis, disulfiram-induced, 19 overdose, 21–22 HHS. See U.S. Department of Health and overview, 15 Human Services patient education, 23–25 patient management, 21–23 Information resources, 58 patient selection, 19, 25 Intoxication, 81–85 pharmacology, 16–18 safety, 19 Kindling effect, 83 side effects, 20–21, 53, 76 storage, 15 Laboratory testing supervised ingestion, 20 disulfiram therapy and, 21, 25 treatment decision factors, 52 identifying alcohol-related damage, Disulfiram-alcohol reaction, 17–19, 23, 76 48–49 Drinks, standard, 75 identifying alcohol use disorders, Drug interactions 47–48 comparison, 53, 76 monitoring patient progress, 59 disulfiram and, 21, 24 useful tests, 47 oral naltrexone and, 33 Liver disease Drug use. See Substance use disulfiram-induced, 19–21 DTs. See Delirium tremens oral naltrexone and, 29, 32 Dual Recovery Anonymous, 55–56 Liver function tests, 47–49 Low-risk drinkers, 89 Education. See Patient education EtG. See Ethyl glucuronide MAST-G, 88, 92–93 Ethyl glucuronide, 48 Medical detoxification, 77 Evaluation Medical management defined, 77 benefits of, 54 defined, 2 FDA. See U.S. Food and Drug Medication-assisted treatment. See also Administration specific medications by name access to, 4 Gamma glutamyltransferase, 47–48 benefits of, 5–7 Genetic variants, 5–6 choosing a medication, 51–53 Geriatric screening, 88, 92–93 combination therapy, 51–52, 54 GGT. See Gamma glutamyltransferase discontinuing, 61 A Guide to Substance Abuse Services for FDA-approved medications, 3–4 Primary Care Clinicians, TIP 24 integrating into clinical practice, assessment and treatment, 88 45–46 brief intervention, 88, 94–96 medication combinations, 4 followup, 94 Mental health issues, 80 screening, 87–88 Michigan Alcoholism Screening Test- screening instruments, 89–93 Geriatric Version, 88, 92–93 MM. See Medical management

AppendicesIndex 105 Mutual-help programs, 55–56 safety, 29 side effects, 30, 53, 76 Naltrexone, extended-release injectable storage, 27 administering, 40 treatment decision factors, 52 adverse reactions, 41, 53, 76 National Institute on Alcohol Abuse and benefits of, 39 Alcoholism, 4, 46, 49, 54, 71–76 black-box warning, 39 Neuroadaptations, 6 cautions, 41, 53, 76 NIAAA. See National Institute on Alcohol compliance, enhanced, 39 Abuse and Alcoholism contraindications, 40, 52, 53, 76 discontinuing treatment, 43 Opioids dosage, 37, 76 addiction treatment, 6 drug interactions, 53, 76 oral naltrexone and, 34 duration of treatment, 43 Overdose, disulfiram, 21–22 efficacy, 38–39 history of development, 37–38 Pain management initiating treatment, 39 extended-release injectable naltrexone mechanism of action, 53, 76 and, 42 medication comparison, 53, 76 oral naltrexone and, 34 overview, 37 Parents with dependent children, 81 pain management and, 42 Patient education patient education, 41–42 acamprosate use, 12 patient management, 41 disulfiram use, 23–25 patient selection, 42–43, 44 elements of, 57 pharmacology, 38 information sources, 58 safety, 39 naltrexone, extended-release side effects, 40, 53, 76 injectable, 41–42 storage, 37 naltrexone, oral, 33 treatment decision factors, 52 Patient management Naltrexone, oral acamprosate use, 12, 13 adverse reactions, 32, 53, 76 assessing motivation for change, 50–51 black-box warning, 29 choosing a medication, 51–53 cautions, 30–31, 53, 76 combination therapy, 51–52, 54 contraindications, 30–31, 52, 53, 76 developing a treatment plan, 56–57 discontinuing treatment, 35 discontinuing pharmacotherapy, 61 dosage, 27, 30, 76 disulfiram use, 21–23 drug interactions, 33, 53, 76 fostering patient’s entry into duration of treatment, 35 treatment, 77 efficacy, 28–29 information resources for patients, 58 history of development, 27–28 initial assessment, 46 initiating treatment, 29–30 integrating medication-assisted liver disease signs and symptoms, 32 treatment into clinical practice, mechanism of action, 53, 76 45–46 medication comparison, 53, 76 laboratory testing, 47–49 overview, 27 modifying treatment strategy, 60–61 pain management and, 34 monitoring progress, 57–60 patient education, 33 motivating patients for treatment, 49 patient management, 32–33 naltrexone, extended-release patient selection, 34 injectable, 41 pharmacology, 28 naltrexone, oral, 32–33

106 Index patient awareness, 57 Side effects physical exam, 46–47 acamprosate, 12 psychiatric assessment, 49 common, 53, 76 psychosocial interventions, 54–56 comparison, 53, 76 social history, 50 disulfiram, 20–21 substance use assessment, 49–50 naltrexone, extended-release Patient placement, 79 injectable, 40 Pharmacology naltrexone, oral, 30 acamprosate, 10 Smoking cessation treatment, 6 disulfiram, 16–18 Social detoxification, 77, 82–83 naltrexone, extended-release Social functioning, 59–60 injectable, 38 Social history, 50 naltrexone, oral, 28 Specialty substance abuse treatment/care Pharmacotherapy. See Medication- choosing type of treatment, 5 assisted treatment defined, 2 Physical exam, 46–47 referring patients, 55 A Pocket Guide for Alcohol Screening and Stabilization Brief Intervention, 49, 71–76 defined, 77 Pretreatment indicators, 52 Standard drinks, 75 Psychiatric assessment, 49 Substance Abuse and Mental Health Psychosocial interventions Services Administration, xiii mutual-help programs, 55–56 Substance use referring patients for specialty adolescent risk factors, 93 treatment, 55 assessment, 49–50 resources for office-based approaches, monitoring, 60 55 Suicidality, 80 self-help programs, 55–56 types of, 54 TIP. See Treatment Improvement Psychosocial issues, 79–81 Protocol Tolerance, 92 Reimbursement guide, 45 Toxicological screening, 48 Renal function tests, 47–49 Treatment Improvement Protocol ReVia®. See Naltrexone, oral Detoxification and Substance Abuse Treatment, TIP 45, 77–85 SAMHSA. See Substance Abuse and A Guide to Substance Abuse Services Mental Health Services Administration for Primary Care Clinicians, TIP 24, Screening 87–96 choosing type of treatment, 5 Treatment plan, 56 heavy drinking, 73 Trexan®. See Naltrexone, oral A Guide to Substance Abuse Services TWEAK test, 92 for Primary Care Clinicians, TIP 24, 88 Urine tests, 47–48 A Pocket Guide for Alcohol Screening U.S. Department of Health and Human and Brief Intervention, 49, 71–76 Services, ix Seizures, 84–85 U.S. Food and Drug Administration Self-help programs, 55–56 approval of alcohol use disorder Self Management and Recovery Training, medications, 1 56 Center for Drug Evaluation and Self-reports, 58 Research, 38 pregnancy Category C, 13, 31, 53

Index 107 Vitamin deficiencies, 47–48 Wernicke-Korsakoff’s Syndrome, 85 Vivitrol®. See Naltrexone, extended- Withdrawal, 82–85 release injectable Women for Sobriety, Inc., 56

108 Index CSAT TIPs and Publications Based on TIPs What Is a TIP? Treatment Improvement Protocols (TIPs) are the products of a systematic and innovative process that brings together clinicians, researchers, program managers, policymakers, and other Federal and non-Federal experts to reach con­ sensus on state-of-the-art treatment practices. TIPs are developed under CSAT’s Knowledge Application Program to improve the treatment capabilities of the Nation’s alcohol and drug abuse treatment service system. What Is a Quick Guide? A Quick Guide clearly and concisely presents the primary information from a TIP in a pocket-sized booklet. Each Quick Guide is divided into sections to help readers quickly locate relevant material. Some contain glossaries of terms or lists of resources. Page numbers from the original TIP are referenced so providers can refer back to the source docu­ ment for more information. What Are KAP Keys? Also based on TIPs, KAP Keys are handy, durable tools. Keys may include assessment or screening instruments, check­ lists, and summaries of treatment phases. Printed on coated paper, each KAP Keys set is fastened together with a key ring and can be kept within a treatment provider’s reach and consulted frequently. The Keys allow you—the busy clini­ cian or program administrator—to locate information easily and to use this information to enhance treatment services. TIP 1 State Methadone Treatment Guidelines— TIP 15 Treatment for HIV-Infected Alcohol and Replaced by TIP 43 Other Drug Abusers—Replaced by TIP 37 TIP 2* Pregnant, Substance-Using Women—BKD107 TIP 16 Alcohol and Other Drug Screening of Quick Guide for Clinicians QGCT02 Hospitalized Trauma Patients—BKD164 KAP Keys for Clinicians KAPT02 Quick Guide for Clinicians QGCT16 TIP 3 Screening and Assessment of Alcohol- and KAP Keys for Clinicians KAPT16 Other Drug-Abusing Adolescents—Replaced TIP 17 Planning for Alcohol and Other Drug by TIP 31 Abuse Treatment for Adults in the Criminal TIP 4 Guidelines for the Treatment of Alcohol- Justice System—Replaced by TIP 44 and Other Drug-Abusing Adolescents— TIP 18 The Tuberculosis Epidemic: Legal and Replaced by TIP 32 Ethical Issues for Alcohol and Other Drug TIP 5 Improving Treatment for Drug-Exposed Abuse Treatment Providers—BKD173 Infants—BKD110 Quick Guide for Clinicians QGCT18 TIP 6* Screening for Infectious Diseases Among KAP Keys for Clinicians KAPT18 Substance Abusers—BKD131 TIP 19 Detoxification From Alcohol and Other Quick Guide for Clinicians QGCT06 Drugs—Replaced by TIP 45 KAP Keys for Clinicians KAPT06 TIP 20 Matching Treatment to Patient Needs in TIP 7 Screening and Assessment for Alcohol and Opioid Substitution Therapy—Replaced by Other Drug Abuse Among Adults in the TIP 43 Criminal Justice System—Replaced by TIP 44 TIP 21 Combining Alcohol and Other Drug Abuse TIP 8 Intensive Outpatient Treatment for Alcohol Treatment With Diversion for Juveniles in and Other Drug Abuse—Replaced by TIPs 46 the Justice System—(SMA) 08-4073 and 47 Quick Guide for Clinicians and TIP 9 Assessment and Treatment of Patients With Administrators QGCA21 Coexisting Mental Illness and Alcohol and TIP 22 LAAM in the Treatment of Opiate Other Drug Abuse—Replaced by TIP 42 Addiction—Replaced by TIP 43 TIP 10 Assessment and Treatment of Cocaine- TIP 23 Treatment Drug Courts: Integrating Abusing Methadone-Maintained Patients— Substance Abuse Treatment With Legal Replaced by TIP 43 Case Processing—(SMA) 08-3917 TIP 11*Simple Screening Instruments for Outreach Quick Guide for Administrators QGAT23 for Alcohol and Other Drug Abuse and TIP 24 A Guide to Substance Abuse Services for Infectious Diseases—BKD143 Primary Care Clinicians—(SMA) 08-4075 Quick Guide for Clinicians QGCT11 Concise Desk Reference Guide (SMA) KAP Keys for Clinicians KAPT11 08-3740 TIP 12 Combining Substance Abuse Treatment Quick Guide for Clinicians QGCT24 With Intermediate Sanctions for Adults in KAP Keys for Clinicians KAPT24 the Criminal Justice System—Replaced by TIP 25 Substance Abuse Treatment and Domestic TIP 44 Violence—(SMA) 08-4076 TIP 13 Role and Current Status of Patient A Guide for Treatment Providers MS668 Placement Criteria in the Treatment of A Guide for Administrators MS667 Substance Use Disorders—BKD161 Quick Guide for Clinicians QGCT25 Quick Guide for Clinicians QGCT13 KAP Keys for Clinicians KAPT25 Quick Guide for Administrators QGAT13 TIP 26 Substance Abuse Among Older Adults— KAP Keys for Clinicians KAPT13 (SMA) 08-3918 TIP 14 Developing State Outcomes Monitoring A Guide for Treatment Providers MS669 Systems for Alcohol and Other Drug Abuse Treatment—BKD162 A Guide for Social Service Providers MS670 Physician’s Guide MS671 *Under revision 109 TIP 26 Substance Abuse Among Older Adults— TIP 38 Integrating Substance Abuse Treatment (SMA) 08-3918 and Vocational Services—BKD381 Good Mental Health is Ageless PHD881 Quick Guide for Clinicians QGCT38 (English), (SMA) 08-3897 (Spanish) Quick Guide for Administrators QGAT38 Aging, Medicines and Alcohol (SMA) 08-3169 KAP Keys for Clinicians KAPT38 (English), (SMA) 08-3898 (Spanish) TIP 39 Substance Abuse Treatment and Family Quick Guide for Clinicians QGCT26 Therapy—(SMA) 08-4219 KAP Keys for Clinicians KAPT26 Quick Guide for Clinicians QGCT39 TIP 27 Comprehensive Case Management for Quick Guide for Administrators QGAT39 Substance Abuse Treatment—(SMA) 08-4215 TIP 40 Clinical Guidelines for the Use of A Guide for Treatment Providers MS673 Buprenorphine in the Treatment of Opioid Quick Guide for Clinicians QGCT27 Addiction—(SMA) 07-3939 Quick Guide for Administrators QGAT27 Quick Guide for Physicians QGPT40 TIP 28 Naltrexone and Alcoholism Treatment— KAP Keys for Physicians KAPT40 Replaced by TIP 49 TIP 41 Substance Abuse Treatment: Group TIP 29 Substance Use Disorder Treatment for Therapy—BKD507 People With Physical and Cognitive Quick Guide for Clinicians QGCT41 Disabilities—(SMA) 08-4078 TIP 42 Substance Abuse Treatment for Persons Quick Guide for Clinicians QGCT29 With Co-Occurring Disorders—(SMA) Quick Guide for Administrators (SMA) 08-3992 08-3592 Inservice Training (SMA) 08-4262 KAP Keys for Clinicians KAPT29 Quick Guide for Clinicians (SMA) 07-4034 TIP 30 Continuity of Offender Treatment for Quick Guide for Administrators QGAT42 Substance Use Disorders From Institution KAP Keys for Clinicians (SMA) 08-4036

to Community—(SMA) 08-3920 TIP 43 Medication-Assisted Treatment for Opioid Quick Guide for Clinicians QGCT30 Addiction in Opioid Treatment Programs— KAP Keys for Clinicians KAPT30 (SMA) 08-4214 TIP 31 Screening and Assessing Adolescents for Inservice Training (SMA) 08-4341 Substance Use Disorders—(SMA) 08-4079 Quick Guide for Clinicians QGCT43 See companion products for TIP 32. KAP Keys for Clinicians (SMA) 07-4108 TIP 32 Treatment of Adolescents With Substance TIP 44 Substance Abuse Treatment for Adults in Use Disorders—(SMA) 08-4080 the Criminal Justice System—BKD526 Quick Guide for Clinicians QGC312 Alcohol & Drug Treatment (SMA) 07-4292 KAP Keys for Clinicians KAPT312 (English), (SMA) 08-4320 (Spanish) TIP 33 Treatment for Stimulant Use Disorders— Quick Guide for Clinicians QGCT44 BKD289 KAP Keys for Clinicians (SMA) 07-4150 Quick Guide for Clinicians QGCT33 TIP 45 Detoxification and Substance Abuse KAP Keys for Clinicians KAPT33 Treatment—(SMA) 08-4131 TIP 34 Brief Interventions and Brief Therapies for Inservice Training (SMA) 08-4331 Substance Abuse—(SMA) 07-3952 Quick Guide for Clinicians (SMA) 06-4225 Quick Guide for Clinicians QGCT34 Quick Guide for Administrators (SMA) KAP Keys for Clinicians KAPT34 06-4226 TIP 35 Enhancing Motivation for Change in KAP Keys for Clinicians (SMA) 06-4224 Substance Abuse Treatment—(SMA) 08-4212 TIP 46 Substance Abuse: Administrative Issues in Faces of Change (SMA) 08-4174 Outpatient Treatment—BKD545 Inservice Training (SMA) 08-4190 Quick Guide for Administrators (SMA) Quick Guide for Clinicians QGCT35 07-4232 KAP Keys for Clinicians KAPT35 TIP 47 Substance Abuse: Clinical Issues in TIP 36 Substance Abuse Treatment for Persons Intensive Outpatient Treatment—BKD551 With Child Abuse and Neglect Issues— Quick Guide for Clinicians (SMA) 07-4233 (SMA) 08-3923 KAP Keys for Clinicians (SMA) 07-4251 Helping Women Heal—(SMA) 08-4132 TIP 48 Managing Depressive Symptoms in (English), PHD981S (Spanish) Substance Abuse Clients During Early Helping Men Heal—(SMA) 07-4134 (English), Recovery—(SMA) 08-4353 PHD1059S (Spanish) TIP 49 Incorporating Alcohol Pharmacotherapies Quick Guide for Clinicians QGCT36 Into Medical Practice—(SMA) 09-4380 KAP Keys for Clinicians KAPT36 TIP 50 Addressing Suicidal Thoughts and TIP 37 Substance Abuse Treatment for Persons Behaviors With Clients in Substance Abuse With HIV/AIDS—(SMA) 08-4137 Treatment—(SMA) 09-4381 HIV/AIDS: Is Your Client at Risk? MS965 Drugs, Alcohol and HIV/AIDS (SMA) 08-4127 (English), (SMA) 08-4181 (Spanish) Drugs, Alcohol and HIV/AIDS for African Americans (SMA) 07-4248 Quick Guide for Clinicians QGCT37 KAP Keys for Clinicians KAPT37 110 Treatment Improvement Protocols (TIPs) from the Substance Abuse and Mental Health Services Administration’s (SAMHSA’s) Center for Substance Abuse Treatment (CSAT) Place the quantity (up to 5) next to the publications you would like to receive and print your mailing address below. ___ TIP 2* BKD107 ___TIP 27 (SMA) 08-4215 ___ TIP 38 BKD381 ___ QG† for Clinicians QGCT02 ___ Guide for Treatment Providers ___ QG for Clinicians QGCT38 ___ KK† for Clinicians KAPT02 MS673 ___ QG for Administrators QGAT38 ___ Guide for Administrators MS672 ___ KK for Clinicians KAPT38 ___ TIP 5 BKD110 ___ QG for Clinicians QGCT27 ___ QG for Administrators QGAT27 ___ TIP 39 (SMA) 08-4219 ___ TIP 6* BKD131 ___ QG for Clinicians QGCT39 ___ QG for Clinicians QGCT06 ___ TIP 29 (SMA) 08-4078 ___ QG for Administrators QGAT39 ___ KK for Clinicians KAPT06 ___ QG for Clinicians QGCT29 ___ QG for Administrators ___ TIP 40 (SMA) 07-3939 ___ TIP 11* BKD143 (SMA) 08-3592 ___ QG for Physicians QGPT40 ___ QG for Clinicians QGCT11 ___ KK for Clinicians KAPT29 ___ KK for Physicians KAPT40 ___ KK for Clinicians KAPT11 ___ TIP 30 (SMA) 08-3920 ___ TIP 41 BKD507 ___ TIP 13 BKD161 ___ QG for Clinicians QGCT30 ___ QG for Clinicians QGCT41 ___ QG for Clinicians QGCT13 ___ KK for Clinicians KAPT30 ___ QG for Administrators QGAT13 ___ TIP 42 (SMA) 08-3992 ___ KK for Clinicians KAPT13 ___ TIP 31 (SMA) 08-4079 ___ Inservice Training (SMA) 08-4262 ___ QG for Clinicians (SMA) 07-4034 ___ TIP 14 BKD162 ___ TIP 32 (SMA) 08-4080 ___ QG for Administrators QGAT42 ___ QG for Clinicians QGC312 ___ KK for Clinicians KAPT42 ___ TIP 16 BKD164 ___ KK for Clinicians KAPT312 ___ QG for Clinicians QGCT16 ___ TIP 43 (SMA) 08-4214 ___ KK for Clinicians KAPT16 ___ TIP 33 BKD289 ___Inservice Training (SMA) 08-4341 ___ QG for Clinicians QGCT33 ___ QG for Clinicians QGCT43 ___ TIP 18 BKD173 ___ KK for Clinicians KAPT33 ___ KK for Clinicians (SMA) 07-4108 ___ QG for Clinicians QGCT18 ___ KK for Clinicians KAPT18 ___ TIP 34 (SMA) 07-3952 ___ TIP 44 BKD526 ___ QG for Clinicians QGCT34 ___Alcohol & Drug Treatment ___ TIP 21 (SMA) 08-4073 ___ KK for Clinicians KAPT34 (SMA) 07-4292 ___ QG for Clinicians & Administrators ___Alcohol & Drug Treatment (Spanish) QGCA21 ___ TIP 35 (SMA) 08-4212 (SMA) 08-4320 ___ Faces (SMA) 08-4174 ___ QG for Clinicians QGCT44 ___ TIP 23 (SMA) 08-3917 ___ Inservice Training (SMA) 08-4190 ___ KK for Clinicians (SMA) 07-4150 ___ QG for Administrators QGAT23 ___ QG for Clinicians QGCT35 ___ KK for Clinicians KAPT35 ___ TIP 45 (SMA) 08-4131 ___ TIP 24 (SMA) 08-4075 ___ Inservice Training (SMA) 08-4331 ___ Desk Reference (SMA) 08-3740 ___ TIP 36 (SMA) 08-3923 ___ QG for Clinicians (SMA) 06-4225 ___ QG for Clinicians QGCT24 ___ Brochure for Women ___ QG for Administrators (SMA) 06- ___ KK for Clinicians KAPT24 (SMA) 08-4132 4226 ___ Brochure for Women (Spanish) ___ KK for Clinicians (SMA) 06-4224 ___ TIP 25 (SMA) 08-4076 PHD981S ___ Guide for Treatment Providers ___ Brochure for Men ___ TIP 46 BKD545 MS668 (SMA) 07-4134 ___ QG for Administrators (SMA) 07- ___ Guide for Administrators MS667 ___ Brochure for Men (Spanish) 4232 ___ QG for Clinicians QGCT25 PHD1059S ___ KK for Clinicians KAPT25 ___ QG for Clinicians QGCT36 ___ TIP 47 BKD551 ___ KK for Clinicians KAPT36 ___ QG for Clinicians (SMA) 07-4233 ___ TIP 26 (SMA) 08-3918 ___ KK for Clinicians (SMA) 07-4251 ___ Guide for Treatment Providers ___ TIP 37 (SMA) 08-4137 MS669 ___ Your Client At Risk MS965 ___TIP 48 (SMA) 08-4353 ___ Guide for Social Service Providers ___ Drugs, Alcohol & HIV/AIDS MS670 (SMA) 08-4127 ___TIP 49 (SMA) 09-4380 ___ Physician’s Guide MS671 ___ Drugs, Alcohol & HIV/AIDS ___ Good Mental Health PHD881 (Spanish) (SMA) 08-4181 ___TIP 50 (SMA) 09-4381 ___ Good Mental Health (SMA) 08-3897 –––Drugs, Alcohol & HIV/AIDS for (Spanish) African Americans (SMA) 07-4248 ___ Aging, Medicine (SMA) 08-3169 ___ QG for Clinicians QGCT37 ___ Aging, Medicine (SMA) 08-3898 ___ KK for Clinicians KAPT37 (Spanish) ___ QG for Clinicians QGCT26 *Under revision ___ KK for Clinicians KAPT26 †QG = Quick Guide; KK = KAP Keys

Name: ______Address: ______City, State, Zip: ______Phone and e-mail: ______You can either mail this form or fax it to (240) 221-4292. Publications also can be ordered by calling SAMHSA’s Health Information Network at 877-SAMHSA-7 (877-726-4727) (English and Español) or by visiting http://www.samhsa.gov/shin. TIPs can also be accessed on line at http://www.kap.samhsa.gov. FOLD

STAMP

SAMHSA’s Health Information Network P.O. Box 2345 Rockville, MD 20847-2345

FOLD Incorporating Alcohol Pharmacotherapies Into Medical Practice

TIP 49, Incorporating Alcohol Pharmacotherapies Into Medical Practice, provides clinical guidelines for the proper use of medications in the treatment of alcohol use disorders. The underlying objective is to expand access to information about the effective use of these medications, not only in specialty substance abuse treatment pro­ grams but also in physicians’ offices and other general medical care settings. The TIP includes discussions of acamprosate, disulfiram, oral naltrexone, and extended-release injectable naltrexone. The U.S. Food and Drug Administration has approved these medications for treating alcohol use disorders. The TIP explains each medication’s history, the reasons for its use, how to use it, who should use it, and other clinical information about the medication.

Most of the fundamental research that forms the evidence basis for this TIP is not provided in the TIP itself. Those who wish to review the supporting research can access a full bibliography, an annotated bib­ liography of select references, and a literature review via the Internet at http://www.kap.samhsa.gov. The online bibliography and literature review are updated every 6 months for 5 years after publication of the TIP.

HHS Publication No. (SMA) 09-4380 Printed 2009

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Substance Abuse and Mental Health Services Administration Center for Substance Abuse Treatment

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