Treatment of Alcohol and Other Drug Dependence

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1 LIVER TRANSPLANTATION 13:S59-S64, 2007 SUPPLEMENT Treatment of Alcohol and Other Drug Dependence Richard Saitz Departments of Medicine and Epidemiology, Youth Alcohol Prevention Center, Clinical Addiction Research and Education Unit, Section of General Internal Medicine, Boston University and Boston Medical Center, Boston, MA KEY CONCEPTS Addiction (e.g., alcohol or drugs) is a chronic disease. Specific behavioral and pharmacological treatments have proven efficacy. Addressing addiction includes intervention for risky and problem use. Clinicians who are not addiction specialists can play important roles in addressing addiction. Liver Transpl 13:S59-S64, AASLD. Unhealthy alcohol and drug use are associated with substantial morbidity, disability, mortality, and costs. 1,2 They are among the leading preventable causes of death and disability. Most cases of esophageal cancer, 60% of chronic pancreatitis, 50% of cirrhosis and chronic hepatitis, 42% of acute pancreatitis, and substantial proportions of other medical illnesses including human immunodeficiency virus (HIV) and injuries are attributable to alcohol and other drugs. More than 100,000 people in the United States die each year as a result of alcohol and illicit drugs. In the United States, substance (alcohol and drug) use cost far more than other common medical illnesses over $400 billion a year, compared with approximately a quarter of that sum for coronary heart disease and an eighth of that sum for obstructive lung disease and asthma. Despite these consequences and costs, and despite the fact that over a third of hospital admissions are related to unhealthy alcohol and other drug use, most such patients do not receive addiction treatment. But efficacious treatments exist. Tobacco addiction is more common and causes more deaths than alcohol or other drug use. It can be treated effectively with brief advice, individual and group counseling, and several medications (nicotine replacement, bupropion, varenicline). But this review of addiction treatment focuses on alcohol and other drug use, excluding tobacco, a topic worthy of separate focus. For alcohol and other drug disorders, behavioral and pharmacological treatments have proven efficacy. A number of these treatments have been proven effective relatively recently, have not yet been widely disseminated into practice, and can be implemented outside of addiction specialty treatment settings. 3,4 Finally, unhealthy use of substances by people who have not yet met diagnostic criteria for a substance use disorder can also be effectively treated with brief interventions. These interventions are of particular importance to clinicians who are not addiction specialists because they are brief and can be done by nonspecialists. These clinicians also have critical roles in facilitating receipt of addiction treatment by their patients. But before discussing specific treatments, it is important to consider the fact that addiction is a chronic disease, so that expectations of treatment outcome are appropriate. 5 Treating addiction is perhaps more like treating and managing asthma and diabetes than it is like curing a bacterial infection. ADDICTION IS A CHRONIC DISEASE Alcohol and drug (substance) dependence share a number of features in common with other common chronic illnesses. 6 These include the following: physiologic basis; diagnosis; definable risk factors; heritability; poor adherence to treatment; no cure; relapse common; longitudinal care required; and denial. Substance dependence has a physiologic basis. For example, people with alcohol dependence, even during abstinence, have reduced gamma-aminobutyric acid Abbreviations: HIV, human immunodeficiency virus; GABA, gamma-aminobutyric acid; AA, Alcoholics Anonymous. Address reprint requests to: Richard Saitz, Departments of Medicine and Epidemiology, Youth Alcohol Prevention Center, Clinical Addiction Research and Education Unit, Section of General Internal Medicine, Boston University and Boston Medical Center, 91 East Concord Street 200, Boston, MA Telephone: ; Fax: ; DOI /lt Published online in Wiley InterScience (www.interscience.wiley.com). Liver Transplantation, Vol 13, No 11, Suppl 2 (November), 2007: pp S59-S64 S59

2 S60 SAITZ (GABA) receptors in the brain, as measured by single positron emission tomography, than do people without alcohol dependence. Alcohol potentiates inhibitory GABA transmission in the central nervous system. These decreases in central GABA receptors may therefore be related to the uncontrollable desire to drink seen in people with dependence. Whether these changes are a cause or effect of heavy drinking is not known. Physiologic characteristics that do appear to have causal roles are enzymatic activities that lead to higher levels of serum acetaldehyde after drinking (e.g., aldehyde dehydrogenase deficiency). These higher amounts of acetaldehyde that are unpleasant (e.g., nausea) are associated with a lower risk for alcohol dependence. Substance dependence can be reliably diagnosed. Although there is no laboratory test, structured interviews (and expert clinicians) yield diagnoses with consistency. These diagnoses have prognostic value in terms of natural history and treatment response. Substance dependence has definable risk factors, and like other common chronic illnesses has a substantial genetic etiology although also similarly, there is no single gene responsible for the risk. Just over 50% of alcohol dependence is related to nonshared environmental influences (e.g., peers, bad childhood experiences). The remainder is related to genetics. In adoption studies, having a parent with alcohol dependence doubles the risk. About one-third of identical twins will have alcohol dependence if their twin has it. Epidemiologic studies have identified specific genes that increase risk. For example, genes involved in dopamine synthesis, which is critical for the reward pathway where all substances of abuse have action, increase the risk. And the gene that includes the locus that codes for alcohol dehydrogenase has been identified as a risk factor for alcohol dependence. As with other chronic medical illnesses, treatments are effective but are often not adhered to, there are no cures, and relapse is common. Similarly, substance dependence affects physical, social, and emotional well-being, and requires longitudinal health care. After alcohol-dependence treatment, 40-60% of patients are abstinent 1 year later, and an additional 15-30% have not returned to dependent drinking. In comparison, adherence to medication regimens in diabetes, hypertension, and asthma are 30-50% and are generally even worse for nonpharmacological treatments. Relapse, or recurrence of symptoms requiring additional medical care to establish remission of symptoms of these diseases, is actually similar to that seen in substance dependence (up to 70%). And these observations are true despite that fact that in practice, substance dependence treatment is often short term. Despite this, relapse rates are not 100%, as would be the case for diabetes treated only in the short term. Last, even one of the classic characteristics of alcoholism, denial, is a common feature among patients with other chronic illnesses like diabetes and hypertension. Denial is a common response to being accused of (or diagnosed with) having an undesirable characteristic. In the United States, although there are addiction medicine specialists, most addiction treatment is delivered in specialty treatment programs by substance abuse counselors. The view from outside this system is often that patients should go to detox. Detoxification is useful when patients are beginning to cut down or abstain, and it is valuable as a first step in treatment. Physical and emotional symptoms of withdrawal can be ameliorated by using medications cross-tolerant to the substance being used (e.g., benzodiazepines for alcohol withdrawal). But detoxification alone (most often done in ambulatory settings) is not addiction treatment, in that it does not prevent relapse. For example, 20% of patients with opioid dependence are abstinent 1 year after detoxification alone. Unfortunately, most patients who undergo detoxification in the United States do not receive further addiction treatment. Addiction treatment is aimed at decreasing the chronic consequences of uncontrolled substance use, including physical and interpersonal consequences, and social, psychological, legal, and employment problems. In addition, treatment aims to reduce substance use, including lapses (usually defined as use on one occasion) and relapses (usually defined as more than one occasion of heavy use). TREATMENT What Is Addiction Treatment? Alcohol treatment includes access to psychological, medical, employment, legal, and social services, sometimes removal from a drinking or otherwise harmful environment, use of mutual (self)-help groups, pharmacotherapy, and counseling by both specialists and nonspecialists. This counseling includes brief counseling by physicians in medical settings. 7,8 Of note, as would be the case for heart disease or gastrointestinal disease, a single lecture or review article such as this one cannot even briefly mention all known efficacious addiction treatments, and certainly cannot provide detailed indications, prescribing information, and counseling ingredients. As a result, this article focuses on principles and the best proven treatments, particularly those of relevance to those who are not addiction physicians or counselors. How Effective Is Treatment? At 1 year, two-thirds of patients have a reduction in alcohol consequences (injury, unemployment) and consumption (by 50%). 9 One-third are abstinent or drinking moderately without consequences. Monetary benefits of alcohol and drug treatment to society outweigh costs 4-12-fold (depending on drug and treatment type). For opioid dependence, pharmacotherapy and counseling can achieve abstinence rates of 60-80%. Principles of Treatment The National Institute on Drug Abuse has published 13 principles of effective treatment. 10 These are:

3 TREATMENT OF ALCOHOL AND DRUG DEPENDENCE S61 1. No single treatment is appropriate for all individuals. Treatments should be individualized according to patient needs. 2. Treatment needs to be readily available. Patients ready for treatment can be lost if treatment is not immediately accessible. 3. Effective treatment attends to multiple needs of the individual, not just his or her drug use. These needs include addressing substance use and any associated medical, psychological, social, vocational, and legal problems. 4. As with any chronic illness, an individual s treatment and services plan must be assessed continually and modified as necessary to ensure that the plan meets the person s changing needs. 5. Remaining in treatment for an adequate period of time is critical for treatment effectiveness. The appropriate duration for an individual depends on the problems and needs but is usually at least 3 months. Treatment should include strategies to keep patients in treatment. 6. Counseling (individual and/or group) and other behavioral therapies are critical components of effective treatment for addiction. These therapies address motivation, problem solving, relationships, social functioning, and skills useful for avoiding drug use. 7. Medications are an important element of treatment for many patients, especially when combined with counseling and other behavioral therapies. 8. Addicted or drug-abusing individuals with coexisting mental disorders should have both disorders treated in an integrated way. 9. Medical detoxification is only the first stage of addiction treatment and by itself does little to change long-term drug use. 10. Treatment does not need to be voluntary to be effective. Mandated treatment can increase treatment entry and retention. 11. Possible drug use during treatment must be monitored continuously, with results presented to patients. Monitoring helps patients resist urges to use substances, and positive results can signal a need to intensify treatment. 12. Treatment programs should provide assessment for HIV acquired immunodeficiency syndrome, hepatitis B and C, tuberculosis, and other infectious diseases, and counseling to help patients modify or change behaviors that place themselves or others at risk of infection. 13. Recovery from drug addiction can be a long-term process and frequently requires multiple episodes of treatment, or long-term treatment. Behavioral Treatments Behavioral treatments for addiction with proven efficacy are not simply generic counseling sessions. A number of therapies with specific content and doses, often clearly laid out in manuals, have been proven effective in well-designed studies. Motivational interviewing (or manualized 4-session motivational enhancement therapy) is a client-centered, directive method for enhancing intrinsic motivation to change by exploring and resolving ambivalence. Cognitive behavioral therapies emphasize skills to cope with situations that might precipitate substance use. Twelve-step facilitation emphasizes the disease model of addiction and encourages and facilitates full participation in 12-step groups like Alcoholics Anonymous. Contingency management (sometimes referred to as involving motivational incentives) provides rewards for treatment adherence or negative drug testing results. Marital and family therapy can also be effective treatments for addiction. In the context of medication prescription for alcohol dependence, medical management by patients physicians, physician assistants, or nurses, a relatively brief form of repeated counseling similar to what medical physicians routinely do for other medications, appears to effective. 3 Medical management involves asking about medication side effects and adherence, and encouraging abstinence. A number of other behavioral treatments have proven efficacy. These include but are not limited to the following: relapse prevention counseling, supportive-expressive psychotherapy, individualized drug counseling, behavioral therapy for adolescents, multidimensional family therapy for adolescents, multisystemic therapy, community reinforcement approach plus vouchers, voucher-based reinforcement therapy in methadone maintenance treatment, day treatment with abstinence contingencies and vouchers, and the Matrix model. The details of these and other treatments are beyond the scope of this article. Pharmacological Treatments Pharmacological treatments for opioid dependence include methadone maintenance, buprenorphine, and naltrexone. 11 As with other pharmacotherapies, drug use should be monitored, and patients should participate in counseling and obtain any needed social support. Naltrexone is a synthetic opioid antagonist that blocks the euphoria associated with opioid use. To avoid precipitating withdrawal, it is given after an opiate-free period, and it is given daily or 3 times a week. It does not prevent craving, and nonadherence is common. This medication is best used in patients who are highly motivated to maintain abstinence (such as impaired physicians or people on parole) who receive counseling and careful monitoring. Methadone is a long-acting opioid agonist taken orally. 12,13 To be effective, it must be given over a long period of time at a dose sufficient to prevent withdrawal, block effects of illicit use, and decrease craving (generally 60 mg once a day). Patients stabilized on doses of methadone do not experience any euphoria from taking the drug; they feel normal and can function normally (or as normal as someone not receiving psychoactive medication can feel). In the United States, methadone can only be prescribed as a treatment for

4 S62 SAITZ opioid dependence by physicians in licensed methadone maintenance programs or by physicians with specific permission to prescribe it as office-based opioid therapy, currently an unusual exception. In these programs, to which access is limited, patients tend to be subject to stigma and to inconvenient and even punitive rules, such as needing to present daily at a particular time for dosing. Nonetheless, as part of a comprehensive drug treatment program, methadone treatment increases survival, increases treatment retention, decreases illicit opioid use, decreases hepatitis and HIV seroconversion, decreases criminal activity, increases employment, and improves birth outcomes. As with detoxification, 80% of patients who undergo treatment will relapse to illicit opioid use in a year. Of note, methadone is also an excellent choice for short-term prevention of withdrawal in general hospital settings. The goal of methadone treatment in those settings is to allow the treatment of the underlying medical or surgical condition. In these cases, the dose is mg in 24 hours, usually initially provided as mg followed by an additional 5-10 mg after 2-3 hours, until symptoms of withdrawal abate. Buprenorphine is a partial opioid agonist provided sublingually for maintenance. 14 With the exception of pregnant women, patients should be treated with a combination tablet of buprenorphine and naloxone. Naloxone is a short-acting opioid antagonist that is not absorbed sublingually but that prevents the tablets from being abused intravenously because it would precipitate withdrawal. Buprenorphine itself can precipitate withdrawal, so induction involves waiting for marked withdrawal symptoms (from the abused opioid) to appear, after which buprenorphine can be initiated at a low dose, then titrated higher to the usual maintenance doses of 8-16 mg once daily. Buprenorphine is quite safe, in part because the opioid effect has a ceiling: after a certain dose, no additional effect accrues. Although experience with buprenorphine is more limited than that with methadone, clinical trials have found that buprenorphine increases abstinence from illicit opioids, increases retention in treatment, and decreases opioid craving and even mortality. Some patients maintained on methadone can be switched to buprenorphine. Those less likely to succeed on buprenorphine are those requiring higher doses of methadone or requiring more structured treatment programs. Pharmacological treatments for alcohol dependence include disulfiram, acamprosate, naltrexone, and longacting injectable naltrexone. These medications reduce heavy drinking and increase abstinence. Disulfiram, an inhibitor of aldehyde dehydrogenase, results in increased levels of acetaldehyde and an unpleasant reaction after consumption of ethanol. The usual oral daily dose is 500 mg. In one of the largest studies of this medication, disulfiram was no better than placebo in achieving abstinence. But it is not clear whether a placebo-controlled trial is the best way to test a drug whose efficacy depends largely on the patient knowing that they may experience a very unpleasant reaction. Of note, in post hoc analyses, the drug was more effective in those who were adherent to it. In at least 5 controlled studies, disulfiram was associated with marked increases in abstinence when administration of the drug was supervised by a concerned other. Disulfiram has numerous contraindications, and the risk-benefit ratio for people at risk of complications should they experience the ethanol reaction (e.g., those with esophageal varices) needs to be considered. High doses can lead to an idiosyncratic fulminant hepatitis and neuropathy. Acamprosate increases continuous abstinence at 1 year by 8%, from 15% to 23%, and increases abstinent days by 27 days. 15 The mechanism of action is unclear, but the drug appears to work by affecting the glutamate system. The usual oral dose is 666 mg 3 times daily. The main side effect is diarrhea, which subsides with continued use, and the medication needs adjustment for renal insufficiency (and is contraindicated in patients with renal failure). Naltrexone decreases relapse to heavy drinking by approximately 11% (decrease in absolute risk from 48% to 37%). 15 Naltrexone is a long-acting opioid antagonist that is absorbed when taken orally. The usual dose is 50 mg daily. The medication blocks endogenous opioids, thus decreasing the reinforcing pleasurable effects of drinking. The main side effects, nausea and dizziness, subside with continued use. Naltrexone cannot be given to patients with opioid dependence or a need for opioids. In the event of an acute need for opioids to treat pain, naltrexone should be discontinued, and in the short term, very high doses of opioids will be required under close monitoring. Monthly injections of naltrexone (380 mg intramuscularly), as established by a placebo-controlled trial, also decreases heavy drinking, and may address the problems with adherence that occur with oral pharmacotherapies that need to be provided daily or more frequently. 4 The manufacturer has a program that coordinates product delivery for all patients being treated and provides information regarding appropriate storage and administration. Most studies of pharmacotherapies have been in patients who have completed detoxification first, but naltrexone appears to be efficacious even in patients who have a short duration of abstinence before beginning treatment. Of course, abstinence must be achieved before beginning disulfiram to avoid the disulfiram-ethanol reaction. During naltrexone or disulfiram treatment, liver enzymes should be monitored periodically. Although the drugs can cause increases in liver enzymes, most studies of alcohol dependence pharmacotherapy find decreases or no difference in levels in treated patients compared with control patients. All alcohol-dependence pharmacotherapies are category C; they should only be prescribed during pregnancy if risks will clearly outweigh benefits. Combinations of naltrexone and acamprosate do not appear to offer clear additional efficacy compared with either drug alone. For dependence on drugs other than alcohol, tobacco, and opioids, there are no well-established pharmacotherapies, although many are under investigation.

5 TREATMENT OF ALCOHOL AND DRUG DEPENDENCE S63 CO-OCCURRING MENTAL HEALTH CONDITIONS Diagnosis of co-occurring mental health problems can be challenging in people with addictions because there is substantial overlap in symptoms, and sometimes the temporal relations are difficult to sort out. Nonetheless, patients with co-occurring mental health conditions should have the conditions treated, regardless of whether the condition preceded the addiction or not. Psychiatric illness can interfere with adherence to and participation in addiction treatment, and it can trigger relapse. Psychiatric treatment can decrease these effects. For example, for those with anxiety disorders, buspirone can decrease heavy alcohol consumption. Fluoxetine is similarly effective in those with alcohol dependence and major depression. ADDRESSING ADDICTION What Is Risky and Problem Use? Excessive use of alcohol (e.g., 14 standard drinks per week or 4 drinks per occasion by men, 7 and 3 for women and the elderly) and use of drugs by people who do not meet criteria for substance dependence is more common than addiction. Problem use describes people who are using substances (or drinking heavily) and experiencing consequences of that use but who do not meet dependence criteria. People with risky use have not yet experienced consequences but are at risk (e.g., excessive alcohol use, any illicit drug use). How Can Risky and Problem Use Be Identified? Risky and problem use should be identified because brief intervention has efficacy (proven for alcohol, some evidence for efficacy for drug use), and because the prevalence is higher than that of dependence. Brief intervention can prevent future use and can likely decrease consequences. Screening tests can identify risky and problem use, and all adults should be screened. A single question can identify risky alcohol use: How many times in the past year have you had 5 (4 for women) or more drinks in a day? (a positive test is one or more times). Although screening tests are less well validated for drug use, several questionnaires have been developed, and a consensus panel recommended the following single question as a screening test: Have you ever used street drugs more than 5 times in your life? Longer screening questionnaires include the Alcohol Use Disorders Identification Test, a 2-item conjoint (drug and alcohol) screening test, the World Health Organization Alcohol Smoking and Substance Involvement Screening Test. Laboratory tests are generally insensitive and nonspecific when used for screening for unhealthy alcohol use. Laboratory testing for drug use is similarly not very useful for screening patients because of short half-lives and the need to test for many drugs of abuse. Brief Intervention Brief intervention generally refers to minutes of counseling, with feedback about use, advice, and goal setting, and follow-up contact with a clinician. The advice should be appropriate to the patient s readiness to change. Randomized trials in diverse clinical settings have found that brief interventions can reduce risky drinking amounts by 11%. Decreased heroin and cocaine use may result from brief intervention. 16 Although not consistently found in controlled studies, brief intervention may also decrease consequences of alcohol and other drug use, including serum gammaglutamyltransferase levels, hospitalization, and death. Most People With Addictions Do Not Receive Treatment Most people with addictions do not receive effective treatment. Most are not identified in medical settings. Even when patients with addictions are identified in medical settings, they often do not receive any efficacious interventions. And even when patients enter addiction care via detoxification, the initial steps are most often not followed by efficacious addiction treatment. For example, 80% of people with opioid addiction do not receive medication-assisted treatment. Screening and Brief Intervention Clinicians who are not addiction specialists can play critical roles in improving identification and management of patients with addictions. Universal screening can identify patients with addictions. Brief interventions can reduce substance use and/or recommend linkage to addictions care. Follow-up and support of specialty addiction treatment plans can contribute to relapse prevention efforts. 1 Referral to Mutual Help Groups Mutual or self-help groups such as Alcoholics Anonymous (AA) provide social support and an alcohol- and drug-free social network. Observational studies suggest that AA can increase abstinence for people with alcohol dependence who participate. Clinicians can refer patients to these groups, and they can help by suggesting that patients try groups until they find one they are comfortable with, and by asking about meeting attendance and participation. 1 Pharmacotherapy for Alcohol Dependence Clinicians who are not addiction specialists can become familiar with prescribing pharmacotherapies for alcohol dependence, and can then do so while having addiction specialists manage the many other interventions needed for successful addiction treatment (e.g., counseling, assistance with employment or housing). Buprenorphine Clinicians who are not addiction specialists can also become familiar with prescribing buprenorphine for opioid

6 S64 SAITZ dependence and prescribe this treatment. In the United States, a waiver is required from the Drug Enforcement Administration. 17,18 Obtaining the waiver requires certification in addiction medicine or psychiatry, or evidence of training (at least 8 hours) specifically acceptable for this purpose. Then, as with pharmacotherapy for alcohol dependence, the clinician can prescribe, knowing that other aspects of addiction treatment are addressed either in their practice or by addiction specialty clinicians or programs. Prescribing this effective opioid treatment in a medical office represents a dramatic contrast with the requirement to attend a program to receive methadone. Buprenorphine has the potential to be more accessible to patients than methadone because it can be prescribed in a doctor s office. Access is currently limited in the United States by the numbers of physicians prescribing this treatment and by a regulatory limit of 30 patients per physician, which can be increased to 100 after the first year. Integrating Care Clinicians who are not addiction specialists can help patients receive the care that they need over time. Patients with addictions often require coordinated, integrated care for addiction, mental health, and medical problems. These services are often delivered in different places by different clinicians, in short-term programs, leading to fragmented, uncoordinated care, and increasing the risk of errors and suboptimal care. Attention to the whole clinical picture and monitoring of all of the care received (e.g., case management) can improve care. Systems that integrate medical, addiction, and psychiatric care have the potential to improve patient outcomes. CONCLUSIONS To manage addictions appropriately, one must recognize that alcohol and other drug dependence are chronic illnesses. As such, the focus should be on longterm management with the goal of relapse prevention. Continued treatment is associated with better outcome than short-term treatment. Behavioral treatments with proven efficacy include motivational enhancement and cognitive behavioral therapy, contingency management, less intense and less specialized medication management, and brief counseling interventions that have efficacy specifically for nondependent unhealthy alcohol use, and perhaps for initiating referral for care. Pharmacological treatments, usually in the context of counseling, also have proven efficacy. The best proven of these include acamprosate, naltrexone (oral and long-acting injectable), and disulfiram for alcohol dependence, and methadone and buprenorphine for opioid dependence. To avoid addressing only the most severely affected patients, attention needs to be directed to the larger proportion of patients with risky use to whom the largest number of health problems can be attributed. Care for addictions should include attention to psychiatric comorbidity. Clinicians who are not addiction specialists can play very important roles in addressing addiction by identifying patients with risky, problem, or dependent use; by providing brief counseling and prescribing efficacious medications; by addressing common comorbidities; and by referring to specialists when needed. BIBLIOGRAPHY 1. Friedmann PD, Saitz R, Samet JH. Management of adults recovering from alcohol or other drug problems. JAMA 1998;279: Saitz R. Unhealthy alcohol use. N Engl J Med 2005;352; Anton RF, O Malley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM, et al, for the COMBINE Study Research Group. Effect of combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE Study: a randomized controlled trial. JAMA 2006;295: Garbutt JC, Kranzler HR, O Malley SS, Gastfriend DR, Pettinati HM, Silverman BL, et al, for the Vivitrex Study Group. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA 2005;293: McLellan AT. Have we evaluated addiction treatment correctly? Implications from a continuing care perspective. Addiction 2002;88: McLellan AT, O Brien CP, Lewis DL, Kleber HD. Drug addiction as a chronic medical illness: implications for treatment, insurance and evaluation. JAMA 2000;284: Kaner EF, Beyer F, Dickinson HO, Pienaar E, Campbell F, Schlesinger C, Heather N, et al. Effectiveness of brief alcohol interventions in primary care populations [review]. Cochrane Database Syst Rev 2007;(2):CD US Preventive Services Task Force. Screening and behavioral counseling interventions in primary care to reduce alcohol misuse: recommendation statement. Ann Intern Med 2004;140: Miller WR, Walters ST, Bennett ME. How effective is alcoholism treatment in the United States? J Stud Alcohol 2001;62: National Institute on Drug Abuse. National Institutes of Health. Principles of Addiction Treatment: A Research- Based Guide. NIH Publication Bethesda, MD: National Institutes of Health; O Connor PG, Fiellin DA. Pharmacologic treatment of heroin-dependent patients. Ann Intern Med 2000;133: Ball JC, Ross A. The Effectiveness of Methadone Maintenance Treatment. New York, NY: Springer-Verlag; Dole VP, Nyswander M. A medical treatment for diacetylmorphine (heroin) addiction: a clinical trial with methadone hydrochloride. JAMA 1965;193: Fiellin DA, O Connor PG. Office-based treatment of opioiddependent patients. N Engl J Med 2002;347: Carmen B, Angeles M, Ana M, Maria AJ. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 2004;99: Bernstein J, Bernstein E, Tassiopoulos K, Heeren T, Levenson S, Hingson R. Brief motivational intervention at a clinic visit reduces cocaine and heroin use. Drug Alcohol Depend 2005;77: Fiellin DA, O Connor PG. New federal initiatives to enhance the medical treatment of opioid dependence. Ann Intern Med 2002;137: Fiellin DA et al. Consensus statement on office-based treatment of opioid dependence using buprenorphine. J Substance Abuse Treat 2004;27:

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