Treating opioid dependence: Growing implications for primary care

Almost 3 million Americans have abused heroin. The most effective treatment for this concerning epidemic is opioid replacement therapy. Although, from a historical perspective, acceptance of this therapy has been slow, growing evidence supports its efficacy. There are 3 approved medications for opioid maintenance therapy: methadone hydrochloride, levomethadyl acetate, and buprenorphine hydrochloride. Each has unique characteristics that determine its suitability for an individual patient. Cardiac arrhythmias have been reported with methadone and levomethadyl, but not with buprenorphine. Due to concerns about cardiac risk, levomethadyl use has declined and the product may ultimately be discontinued. These recent safety concerns, specifics about opioid detoxification and maintenance, and new federal initiatives were studied. Opioid detoxification has a role in both preventing acute withdrawal and maintaining long-term abstinence. Although only a minority of eligible patients are engaged in treatment, opioid maintenance therapy appears to offer the greatest public health benefits. There is growing interest in expanding treatment into primary care, allowing opioid addiction to be managed like other chronic illnesses. This model has gained wide acceptance in Europe and is now being implemented in the United States. The recent Drug Addiction Treatment Act enables qualified physicians to treat opioid-dependent patients with buprenorphine in an office-based setting. Mainstreaming opioid addiction treatment has many advantages; its success will depend on resolution of ethical and delivery system issues as well as improved and expanded training of physicians in addiction medicine.

[1]  S. Deitchman,et al.  Report of the Council on Scientific Affairs , 2001, Journal of addictive diseases.

[2]  P. O'Connor,et al.  Pharmacologic Treatment of Heroin-Dependent Patients , 2000, Annals of Internal Medicine.

[3]  M. Kreek,et al.  Methadone‐Related Opioid Agonist Pharmacotherapy for Heroin Addiction: History, Recent Molecular and Neurochemical Research and Future in Mainstream Medicine , 2000, Annals of the New York Academy of Sciences.

[4]  M. Stitzer,et al.  Dose-Response Effects of Methadone in the Treatment of Opioid Dependence , 1993, Annals of Internal Medicine.

[5]  E. Khantzian,et al.  DSM-III psychiatric diagnosis of narcotic addicts. Recent findings. , 1985, Archives of general psychiatry.

[6]  L. Poretsky,et al.  Absence of antibody to human immunodeficiency virus in long-term, socially rehabilitated methadone maintenance patients. , 1990, Archives of internal medicine.

[7]  W. Ling,et al.  A 3-year progress report on the implementation of LAAM in the United States. , 1998, Addiction.

[8]  P. Mehler,et al.  Torsade de Pointes Associated with Very-High-Dose Methadone , 2002, Annals of Internal Medicine.

[9]  Alan Ross,et al.  The Effectiveness of Methadone Maintenance Treatment , 1991, Springer New York.

[10]  Negrete Jc The role of medical schools in the prevention of alcohol-related problems , 1990 .

[11]  M. Kreek Opioid receptors: Some perspectives from early studies of their role in normal physiology, stress responsivity, and in specific addictive diseases , 1996, Neurochemical Research.

[12]  J. Prichard,et al.  Torsades de Pointes Associated with High Dose Levomethadyl Acetate (ORLAAM®) , 2001, Journal of Addictive Diseases.

[13]  D. Lewis,et al.  The role of the generalist in the care of the substance-abusing patient. , 1997, The Medical clinics of North America.

[14]  D. Shanson Chapter 18 – Infections of the heart , 1989 .

[15]  M J Kell,et al.  Methadone maintenance. , 1988, JAMA.

[16]  A. Washton,et al.  Clonidine for opiate detoxification: outpatient clinical trials. , 1980, The American journal of psychiatry.

[17]  J. Hedges,et al.  Community-wide emergency department visits by patients suspected of drug-seeking behavior. , 1996, Academic emergency medicine : official journal of the Society for Academic Emergency Medicine.

[18]  L. Harris,et al.  Toxicological evaluation of μ‐agonists. Part II: Assessment of toxicity following 30 days of repeated oral dosing of male and female rats with levo‐alpha‐noracetylmethadol hcl (norlaam) , 1994 .

[19]  Kreek Mj Plasma and urine levels of methadone. Comparison following four medication forms used in chronic maintenance treatment. , 1973 .

[20]  V. Dole,et al.  A MEDICAL TREATMENT FOR DIACETYLMORPHINE (HEROIN) ADDICTION. A CLINICAL TRIAL WITH METHADONE HYDROCHLORIDE. , 1965, JAMA.

[21]  D. Charney,et al.  The clinical use of clonidine in abrupt withdrawal from methadone. Effects on blood pressure and specific signs and symptoms. , 1981, Archives of general psychiatry.

[22]  M. Kreek,et al.  Methadone plasma level: sustained by a reservoir of drug in tissue. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[23]  T. Kosten,et al.  Rapid and ultrarapid opioid detoxification techniques. , 1998, JAMA.

[24]  A. Katchman,et al.  Influence of Opioid Agonists on Cardiac HumanEther-a-go-go-related Gene K+ Currents , 2002, Journal of Pharmacology and Experimental Therapeutics.

[25]  D. Jasinski,et al.  Physiological parameters of morphine dependence in man--tolerance, early abstinence, protracted abstinence. , 1969, Journal of psychiatric research.

[26]  R. Rettig,et al.  Federal regulation of methadone treatment , 1995 .

[27]  J. Blaine,et al.  CLINICAL USE OF LAAM , 1978, Annals of the New York Academy of Sciences.

[28]  M. Kreek Clinical Update of Opioid Agonist and Partial Agonist Medications for the Maintenance Treatment of Opioid Addiction , 1997 .

[29]  R. Brooner,et al.  Smoking habits and attitudes in a methadone maintenance treatment population. , 1997, Drug and alcohol dependence.

[30]  A. Goldstein Blind Dosage Comparisons and Other Studies in a Large Methadone Program , 1971 .

[31]  D. Himmelstein,et al.  Care denied: US residents who are unable to obtain needed medical services. , 1995, American journal of public health.

[32]  H. Isbell,et al.  The addiction liability of methadon (amidone, dolophine, 10820) and its use in the treatment of the morphine abstinence syndrome. , 1949, The American journal of psychiatry.

[33]  B. Ludes,et al.  Buprenorphine-related deaths among drug addicts in France: a report on 20 fatalities. , 1998, Journal of analytical toxicology.

[34]  H. Harwood,et al.  Economic costs of alcohol abuse and alcoholism. , 1998, Recent developments in alcoholism : an official publication of the American Medical Society on Alcoholism, the Research Society on Alcoholism, and the National Council on Alcoholism.

[35]  Gleeson Rk HIV/AIDS report. , 1995, Medical Section proceedings : the ... annual Meeting of the Medical Section of the American Council of Life Insurance. American Council of Life Insurance. Medical Section. Meeting.

[36]  K. Barry,et al.  Tobacco, alcohol, and drug use in a primary care sample: 90-day prevalence and associated factors. , 1998, Journal of addictive diseases.

[37]  D. Simpson,et al.  Gender, cocaine and during-treatment HIV risk reduction among injection opioid users in methadone maintenance. , 1996, Drug and alcohol dependence.

[38]  K. Offord,et al.  Point prevalence of alcoholism in hospitalized patients: continuing challenges of detection, assessment, and diagnosis. , 2001, Mayo Clinic proceedings.

[39]  D. Epstein,et al.  Methadone dose increase and abstinence reinforcement for treatment of continued heroin use during methadone maintenance. , 2000, Archives of general psychiatry.

[40]  J. Strang,et al.  Double-blind randomised controlled trial of lofexidine versus clonidine in the treatment of heroin withdrawal. , 1997, Drug and alcohol dependence.

[41]  W. Ling,et al.  A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence. , 1996, Archives of general psychiatry.

[42]  M. Stitzer,et al.  Moderate- vs high-dose methadone in the treatment of opioid dependence: a randomized trial. , 1999, JAMA.

[43]  R. Hubbard,et al.  Overview of 1-year follow-up outcomes in the Drug Abuse Treatment Outcome Study (DATOS). , 1997 .

[44]  D. Redmond,et al.  CLONIDINE BLOCKS ACUTE OPIATE-WITHDRAWAL SYMPTOMS , 1978, The Lancet.

[45]  T. Kosten,et al.  Clinical utility of rapid clonidine-naltrexone detoxification for opioid abusers. , 1988, British journal of addiction.

[46]  David S. Metzger,et al.  The Effects of Psychosocial Services in Substance Abuse Treatment , 1993, JAMA.

[47]  M A Gerber,et al.  The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team. , 1992, The New England journal of medicine.

[48]  R. Brooner,et al.  Psychiatric and substance use comorbidity among treatment-seeking opioid abusers. , 1997, Archives of general psychiatry.

[49]  E. Kharasch,et al.  Metabolism of levo-alpha-Acetylmethadol (LAAM) by human liver cytochrome P450: involvement of CYP3A4 characterized by atypical kinetics with two binding sites. , 2001, The Journal of pharmacology and experimental therapeutics.

[50]  Rapid and ultrarapid opioid detoxification , 1998 .

[51]  J. Camí,et al.  Follow-up after a six-month maintenance period on naltrexone versus placebo in heroin addicts. , 1991, British journal of addiction.

[52]  W. Bickel,et al.  A clinical trial of buprenorphine: Comparison with methadone in the detoxification of heroin addicts , 1988, Clinical pharmacology and therapeutics.

[53]  D. Ziedonis,et al.  Buprenorphine versus Methadone Maintenance for Opioid Dependence , 1993, The Journal of nervous and mental disease.

[54]  C. Kasser Current and future prospects for rapid opioid detoxification with opioid antagonists. , 1997, Journal of addictive diseases.

[55]  S. B. Sells,et al.  Effectiveness of treatment for drug abuse: An overview of the DARP research program. , 1982 .

[56]  R. Rosenheck,et al.  Day treatment versus enhanced standard methadone services for opioid-dependent patients: a comparison of clinical efficacy and cost. , 1999, The American journal of psychiatry.

[57]  Buprenorphine Treatment of Heroin Dependence (Detoxification and Maintenance) in a Private Practice Setting , 2001, Journal of addictive diseases.

[58]  S. Viskin Long QT syndromes and torsade de pointes , 1999, The Lancet.

[59]  A T McLellan,et al.  Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. , 2000, JAMA.

[60]  M. Alter,et al.  The importance of preventing hepatitis C virus infection among injection drug users in the United States. , 1998, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[61]  J. Micallef,et al.  Recent evolution in opiate dependence in France during generalisation of maintenance treatments. , 2001, Drug and alcohol dependence.

[62]  D. L. Simon Rapid opioid detoxification using opioid antagonists: history, theory and the state of the art. , 1997, Journal of Addictive Diseases.

[63]  W. Ling,et al.  Substitution pharmacotherapies for opioid addiction: from methadone to LAAM and buprenorphine. , 1994, Journal of psychoactive drugs.

[64]  D. Ziedonis,et al.  Buprenorphine vs methadone maintenance treatment for concurrent opioid dependence and cocaine abuse. , 1997, Archives of general psychiatry.

[65]  A Cowan,et al.  Buprenorphine: combatting drug abuse with a unique opioid , 1995 .

[66]  S. Holmberg,et al.  The estimated prevalence and incidence of HIV in 96 large US metropolitan areas. , 1996, American journal of public health.

[67]  G. Henderson,et al.  Metabolism and disposition of l-alpha-acetylmethadol in the rat. , 1977, Drug metabolism and disposition: the biological fate of chemicals.

[68]  R. Stohler,et al.  Double-blind randomized trial of buprenorphine and methadone in opiate dependence. , 2001, Drug and alcohol dependence.

[69]  S. Holmberg,et al.  Health services use by urban women with or at risk for HIV-1 infection: the HIV Epidemiology Research Study (HERS). , 1998, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[70]  V. Dole On federal regulation of methadone treatment. , 1995, JAMA.

[71]  C. Inturrisi,et al.  Disposition of acetylmethadol in relation to pharmacologic action , 1975, Clinical pharmacology and therapeutics.

[72]  R. Batey,et al.  Methadone Maintenance in Australia , 1992 .

[73]  B. Rounsaville,et al.  A randomized trial of buprenorphine maintenance for heroin dependence in a primary care clinic for substance users versus a methadone clinic. , 1998, The American journal of medicine.

[74]  L. Markson,et al.  Use of Antiretroviral Therapies by HIV-Infected Persons Receiving Methadone Maintenance , 2000, Journal of addictive diseases.

[75]  M. Kreek,et al.  Rifampin-induced methadone withdrawal. , 1976, The New England journal of medicine.

[76]  T. Chalmers,et al.  Methadone vs. L-alpha-acetylmethadol (LAAM) in the Treatment of Opiate Addiction: A Meta-Analysis of the Randomized, Controlled TriaIs , 1997 .

[77]  P. Friedmann,et al.  Screening and intervention for alcohol problems , 2000 .

[78]  S. Schnoll Treatment of Opioid Addiction in Physicians' Offices , 2001, Journal of Addictive Diseases.

[79]  M L Brandeau,et al.  HIV transmission and the cost-effectiveness of methadone maintenance. , 2000, American journal of public health.

[80]  S. B. Sells,et al.  THE EFFECTIVENESS OF TREATMENT FOR DRUG ABUSE , 1996 .

[81]  M. Anglin,et al.  Long-term Follow-up of Clients of High- and Low-Dose Methadone Programs: Dr McGlothlin died shortly after this article was accepted. For the field and for many colleagues it is a loss that is keenly felt.—ED. , 1981 .

[82]  W. Bickel,et al.  Buprenorphine treatment of opioid dependence: A review. , 1995 .

[83]  G. Woody,et al.  Sociopathy and psychotherapy outcome. , 1985, Archives of general psychiatry.

[84]  D. Charney,et al.  Clonidine in outpatient detoxification from methadone maintenance. , 1985, Archives of general psychiatry.

[85]  H. Klingemann,et al.  Drug treatment in Switzerland: harm reduction, decentralization and community response. , 1996, Addiction.

[86]  J. R. Cooper,et al.  Including narcotic addiction treatment in an office-based practice. , 1995, JAMA.

[87]  H. W. Clark,et al.  Methadone maintenance vs 180-day psychosocially enriched detoxification for treatment of opioid dependence: a randomized controlled trial. , 2000, JAMA.

[88]  R. Freedman,et al.  A comparison of thrice weekly LAAM and daily methadone in employed heroin addicts. , 1981, Drug and alcohol dependence.

[89]  P. Hjemdahl,et al.  Subjective and objective symptoms in relation to plasma methadone concentration in methadone patients , 1995, Psychopharmacology.

[90]  P. Friedmann,et al.  Screening and intervention for alcohol problems. A national survey of primary care physicians and psychiatrists. , 2000, Journal of general internal medicine.

[91]  E. Senay,et al.  Withdrawal from methadone maintenance. Rate of withdrawal and expectation. , 1977, Archives of general psychiatry.

[92]  D. Asch,et al.  Are supplementary services provided during methadone maintenance really cost-effective? , 1997, The American journal of psychiatry.

[93]  W. Hauck,et al.  Regular outpatient medical and drug abuse care and subsequent hospitalization of persons who use illicit drugs. , 2001, JAMA.

[94]  J. Jaffe,et al.  A controlled trial of buprenorphine treatment for opioid dependence. , 1992, JAMA.

[95]  T. Chalmers,et al.  Methadone vs. L-alpha-acetylmethadol (LAAM) in the treatment of opiate addiction. A meta-analysis of the randomized, controlled trials. , 1997, The American journal on addictions.

[96]  P. O'Connor,et al.  New Federal Initiatives To Enhance the Medical Treatment of Opioid Dependence , 2002, Annals of Internal Medicine.

[97]  E. Senay,et al.  Guidelines for the Management of Hospitalized Narcotic Addicts , 1975 .

[98]  P. Banys,et al.  Liver transplantation and opioid dependence. , 2001, JAMA.

[99]  Washton Am,et al.  Clonidine for opiate detoxification: outpatient clinical trials. , 1980 .

[100]  M. French,et al.  The costs of drug abuse consequences: a summary of research findings. , 1996, Journal of substance abuse treatment.

[101]  C. Gevirtz,et al.  Outcome and Six Month Follow Up of Patients After Ultra Rapid Opiate Detoxification (URODSM) , 2000, Journal of addictive diseases.

[102]  E. Senay,et al.  Medical maintenance: a pilot study. , 1993, Journal of addictive diseases.

[103]  P. Selwyn,et al.  Medical care for injection-drug users with human immunodeficiency virus infection. , 1994, The New England journal of medicine.

[104]  M. Gourevitch,et al.  Integrating primary care and methadone maintenance treatment: implementation issues. , 1997, Journal of addictive diseases.

[105]  T. Kosten,et al.  Buprenorphine detoxification from opioid dependence: a pilot study. , 1988, Life sciences.

[106]  J. Ufkes,et al.  Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts , 2004, European Journal of Clinical Pharmacology.

[107]  K. Richter,et al.  A Case for Addressing Cigarette Use in Methadone and Other Opioid Treatment Programs , 2000, Journal of addictive diseases.

[108]  M. Stitzer,et al.  A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. , 2000, The New England journal of medicine.

[109]  R. Shader,et al.  Guidelines for the withdrawal of narcotic and general depressant drugs. , 1973, Diseases of the nervous system.

[110]  B. Rounsaville,et al.  Cocaine abuse among opioid addicts: demographic and diagnostic factors in treatment. , 1986, The American journal of drug and alcohol abuse.

[111]  D. Lewis,et al.  Access to narcotic addiction treatment and medical care: prospects for the expansion of methadone maintenance treatment. , 1999, Journal of addictive diseases.

[112]  D. Jasinski,et al.  Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction. , 1978, Archives of general psychiatry.

[113]  L. Cabré,et al.  Efficacy and safety of two new methods of rapid intravenous detoxification in heroin addicts previously treated without success , 1997, British Journal of Psychiatry.

[114]  M. Anglin,et al.  Long-term follow-up of clients of high- and low-dose methadone programs. , 1981, Archives of general psychiatry.

[115]  Donald F. Dansereau,et al.  Strategies for Improving Methadone Treatment Process and Outcomes , 1997 .

[116]  K. Schuh,et al.  Dose-response analysis of opioid cross-tolerance and withdrawal suppression during LAAM maintenance. , 1998, The Journal of pharmacology and experimental therapeutics.

[117]  S. Schnoll,et al.  Role of the primary care physician in problems of substance abuse. , 1999, Archives of internal medicine.

[118]  H. Pollack,et al.  Changes in methadone treatment practices: results from a national panel study, 1988-2000. , 2002, JAMA.

[119]  M. Weinrich,et al.  Provision of methadone treatment in primary care medical practices: review of the Scottish experience and implications for US policy. , 2000, JAMA.

[120]  Alan Ross,et al.  The Effectiveness of Methadone Maintenance Treatment: Patients, Programs, Services, and Outcome , 1991 .

[121]  J. Kuper,et al.  Drug Interactions of HIV Protease Inhibitors , 1999, Drug safety.

[122]  B. Rounsaville,et al.  Treatment for opioid dependence: quality and access. , 2000, JAMA.

[123]  D. Vlahov,et al.  Sex differences in risk factors for hiv seroconversion among injection drug users: a 10-year perspective. , 2001, Archives of internal medicine.

[124]  M. Weissman,et al.  Heterogeneity of psychiatric diagnosis in treated opiate addicts. , 1982, Archives of general psychiatry.

[125]  H. Joseph,et al.  Medical maintenance: the treatment of chronic opiate dependence in general medical practice. , 1991, Journal of substance abuse treatment.

[126]  W. H. Hall,et al.  Effective medical treatment of opiate addiction , 1998 .

[127]  M. Fleming,et al.  Medical education about substance abuse: changes in curriculum and faculty between 1976 and 1992 , 1994, Academic medicine : journal of the Association of American Medical Colleges.

[128]  L. Melton,et al.  Mortality following inpatient addictions treatment. Role of tobacco use in a community-based cohort. , 1996, JAMA.

[129]  A. Rosenblum,et al.  Changes in HIV risk behaviors among cocaine-using methadone patients. , 1998, Journal of addictive diseases.

[130]  P. O'Connor Treating opioid dependence--new data and new opportunities. , 2000, The New England journal of medicine.

[131]  Richard E. Sampliner,et al.  The Natural History of Community-Acquired Hepatitis C in the United States , 1993 .

[132]  Dole Vp,et al.  Narcotic blockade--a medical technique for stopping heroin use by addicts. , 1966 .

[133]  J. Greenwood Six years' experience of sharing the care of Edinburgh's drug users , 1996 .

[134]  H. Delaney,et al.  AIDS risk behavior in opioid dependent patients treated with community reinforcement approach and relationships with psychiatric disorders. , 1998, Journal of addictive diseases.

[135]  J. Spagnoli,et al.  Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment. , 2000, Drug and alcohol dependence.

[136]  I. Maremmani,et al.  Methadone Dose and Retention During Treatment of Heroin Addicts with Axis I Psychiatric Comorbidity , 2000, Journal of addictive diseases.

[137]  W. Bickel,et al.  A preliminary investigation of outcome following gradual or rapid buprenorphine detoxification. , 1995, Journal of addictive diseases.

[138]  N. S. Miller Comprehensive handbook of drug and alcohol addiction , 1991 .

[139]  S. Darke,et al.  Polydrug dependence and psychiatric comorbidity among heroin injectors. , 1997, Drug and alcohol dependence.

[140]  J. Zweben,et al.  Methadone maintenance treatment: a primer for physicians. , 1991, Journal of psychoactive drugs.

[141]  A. Prince,et al.  Infections of the heart. , 1989, Advances in pediatric infectious diseases.

[142]  M. Max,et al.  Pharmacokinetic‐pharmacodynamic relationships of methadone infusions in patients with cancer pain , 1990, Clinical pharmacology and therapeutics.

[143]  J. Annon,et al.  HIV risk behaviors among women in methadone maintenance treatment. , 1996, Substance use & misuse.

[144]  A. Goldstein,et al.  Heroin addiction: neurobiology, pharmacology, and policy. , 1991, Journal of psychoactive drugs.

[145]  A. Rosenblum,et al.  Gender differences in psychiatric comorbidity among cocaine-using opiate addicts. , 1998, Journal of addictive diseases.

[146]  J. Volavka,et al.  Methadone in man: Pharmacokinetic and excretion studies in acute and chronic treatment , 1975, Clinical pharmacology and therapeutics.

[147]  W. Ling,et al.  Buprenorphine as a Pharmacotherapy for Opiate Addiction: What Dose Provides a Therapeutic Response? , 1996 .

[148]  V. Karir Bradycardia Associated with Intravenous Methadone Administered for Sedation in a Patient with Acute Respiratory Distress Syndrome , 2002, Pharmacotherapy.

[149]  G. Zerbe,et al.  Naltrexone-induced dysphoria in former opioid addicts. , 1985, The American journal of psychiatry.

[150]  K. Seal,et al.  Is it justifiable to withhold treatment for hepatitis C from illicit-drug users? , 2001, The New England journal of medicine.

[151]  S. Kasper,et al.  Buprenorphine versus methadone maintenance for the treatment of opioid dependence. , 1999 .

[152]  P. Rosenberg,et al.  Trends in HIV incidence among young adults in the United States. , 1998, JAMA.

[153]  D. D. Des Jarlais,et al.  HIV incidence among injection drug users in New York City, 1992-1997: evidence for a declining epidemic. , 2000, American journal of public health.

[154]  J. Stephenson Former addicts face barriers to treatment for HCV. , 2001, JAMA.

[155]  W. Colburn,et al.  Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain , 1987, Clinical pharmacology and therapeutics.

[156]  D. Vlahov,et al.  Viral infections in short-term injection drug users: the prevalence of the hepatitis C, hepatitis B, human immunodeficiency, and human T-lymphotropic viruses. , 1996, American journal of public health.

[157]  N. Flynn,et al.  Hepatitis C in Methadone Maintenance Patients , 2001, Journal of addictive diseases.

[158]  J. Strong,et al.  The involvement of cytochrome P450 3A4 in the N-demethylation of L-alpha-acetylmethadol (LAAM), norLAAM, and methadone. , 1997, Drug metabolism and disposition: the biological fate of chemicals.

[159]  J. Zweben,et al.  Methadone maintenance in the treatment of opioid dependence. A current perspective. , 1990, The Western journal of medicine.