TREATING OPIOID DEPENDENCE -- NEW DATA AND NEW OPPORTUNITIES Heroin use in the United States has grown considerably over the past decade. Approximately 3 million Americans have used heroin, (1) a fact that has led to increasing concern about heroin-related problems such as overdose, human immunodeficiency virus (HIV) infection, unemployment, and crime. Finding effective treatments for heroin dependence is critical. The report by Johnson et al. in this issue of the Journal (2) represents an important step toward expanding the options for treatment. Patients who are dependent on opioids may come to physicians with health problems and may request help finding treatment. The first step is careful screening to identify underlying substance-abuse problems. Screening may be hampered by several barriers, including reluctance on the part of patients and physicians to discuss a problem that is considered stigmatizing. Once opioid dependence is identified, the patient should be assessed for the medical and psychosocial problems that typically accompany it. It is also important to determine whether the patient is motivated to change his or her drug-use behavior and enter treatment. Patients who lack such motivation should be counseled about the risks of continuing to use drugs and the benefits of treatment. Patients who are so motivated should be promptly referred to treatment programs. Opioid detoxification and maintenance therapy with an opioid agonist are the two main approaches to treatment. Detoxification can be performed by a variety of techniques with use of opioids (e.g., methadone) and nonopioids (e.g., clonidine), followed by referral to ongoing drug treatment with the ultimate goal of discontinuing all opioid use. Some detoxification-based approaches may have merit. Nonetheless, there is little research that supports their long-term efficacy in keeping patients free from opioid use beyond the acute withdrawal phase (generally a few days or weeks). One recent study found that even under optimal conditions for detoxification, patients treated with methadone-assisted detoxification for 180 days fared much worse in terms of continuation in the treatment program and illicit drug use than those who received maintenance therapy with methadone. (3) Thus, the effectiveness of detoxification-based treatment for most patients, especially those who use heroin daily, is questionable. The goal of maintenance therapy with an opiate agonist is to decrease the use of illicit opioids by the use of a long-acting opioid in combination with counseling. Methadone and levomethadyl acetate have been approved by the Food and Drug Administration (FDA) for maintenance treatment in the United States. Methadone has been the primary medication for maintenance programs since it was developed by Dole and Nyswander in the mid-1960s. (4) Methadone maintenance can decrease the use of illicit drugs and crime and help patients function better, gain employment, and contribute to society. (5,6) It can also prevent health problems such as HIV infection and is thus a cost-effective public health intervention. (7) Research during the past decade has provided important information about how to optimize the effectiveness of methadone maintenance. For example, the amount of psychosocial services provided concurrently can have a significant effect on outcomes. (8) In addition, a sufficient dose of methadone (typically more than 60 mg per day) is necessary for effective treatment. (2,5,9) Although methadone has been the mainstay of opioid maintenance, both levomethadyl acetate and buprenorphine are also highly effective for this purpose. Levomethadyl acetate, a synthetic opioid, was first studied in the 1970s but was not approved by the FDA until 1993. Because it is longer-acting, levomethadyl acetate has an advantage over methadone in that it can be administered three times a week, rather than daily. The effectiveness of levomethadyl acetate is similar to that of methadone and, as with methadone, a sufficient dose is needed to produce an optimal effect. (10) Despite these findings, levomethadyl acetate is not as widely used as methadone in the United States. The reasons include lack of familiarity with the medication on the part of treatment-program staff, concern about inadequate relief of symptoms and the possibility of overdose, the fact that patients cannot take doses at home because of federal regulations, and regulatory barriers that exist in some states. (11) Because buprenorphine is a partial opioid agonist, it is thought to have some advantages over methadone and levomethadyl acetate, including fewer withdrawal symptoms and a lower risk of overdose. Buprenorphine is as effective as methadone if a sufficient dose is used. (12) Like levomethadyl acetate, buprenorphine has the advantage of being long-acting; it can also be effectively administered three times per week. (13) Buprenorphine is available for maintenance treatment in some European countries and is currently available in the United States in a parenteral form for the treatment of pain. The FDA is reviewing applications for two orally active formulations of buprenorphine (the drug alone and the drug combined with naloxone) for the treatment of opioid dependence. (14) Johnson et al. report in this issue the results of a large randomized comparison of two doses of methadone, levomethadyl acetate, and buprenorphine. (2) Their study demonstrates that maintenance treatment with any one of these three medications is effective in reducing illicit opioid use. Future research should include an evaluation of which medication might be most appropriate for specific groups of patients or in specific clinical situations. In addition, Johnson et al. provide further evidence that a sufficient dose is critical to ensure optimal outcomes of treatment. The difference in outcomes between the high-dose and low-dose methadone groups was as striking in this study as it has been in others. (5,9) Other studies of levomethadyl acetate (10) and buprenorphine (12) have also demonstrated the importance of using an adequate dose of medication. This study also provides further evidence that buprenorphine is effective when given three times a week. (13) In 1998, a national consensus panel in the United States concluded that "society must make a commitment to offer effective treatment for opiate dependence to all who need it." (6) Currently, only two Schedule II medications -- methadone and levomethadyl acetate -- can be used in opioid-agonist maintenance treatment in the United States, and their use for outpatient treatment is restricted to treatment programs that obtain a special license and comply with extensive rules and regulations. As a result, there are not enough programs, and many people with opioid dependence are denied access to treatment. The consensus panel recommended that unnecessary regulations be reduced and the availability of treatment be expanded. (6) In line with these goals, the future of opioid maintenance treatment should include new approaches, such as enlisting appropriately trained general physicians as direct providers of treatment. Studies of both patients receiving methadone maintenance who were transferred from a methadone program to a physician's office (15) and new entrants into treatment (16) have demonstrated that opioid maintenance treatment can be provided effectively in a physician's office or clinic. This year, both the House and the Senate have approved federal legislation that would amend the federal Controlled Substances Act to allow qualifying physicians with appropriate certification or training to dispense Schedule III, IV and V controlled substances for opioid maintenance treatment or detoxification. If the FDA makes buprenorphine or other medications for the treatment of opioid dependence available as Schedule III, IV, or V controlled substances, then selected physicians may be able to administer these drugs in their offices. The effectiveness of this approach must be assessed, and proper training of physicians and collaboration between them and substance-abuse treatment programs will be needed. In addition, important issues, including the selection of patients and the optimal counseling strategy, must be addressed. However, if it is implemented properly, I believe that office-based opioid maintenance can greatly increase the availability of a highly effective and much-needed treatment. Increasing the access of patients dependent on opioids to high-quality treatment should become an important goal of the medical profession and of society. [FOOTNOTES] 1. Summary of findings from the 1999 National Household Survey on Drug Abuse. Rockville, Md.: Substance Abuse and Mental Health Services Administration, 2000. 2. Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med 2000;343:1290-7. 3. Sees KL, Delucchi KL, Masson C, et al. Methadone maintenance vs 180-day psychosocially enriched detoxification for treatment of opioid dependence: a randomized controlled trial. JAMA 2000;283:1303-10. 4. Dole VP, Nyswander M. A medical treatment for diacetyl morphine (heroin) addiction: a clinical trial with methadone hydrochloride. JAMA 1965;193:646-50. 5. Ball JC, Ross A. The effectiveness of methadone maintenance treatment: patients, programs, services, and outcome. New York: Springer-Verlag, 1991. 6. National Consensus Development Panel on Effective Medical Treatment of Opiate Addiction. Effective medical treatment of opiate addiction. JAMA 1998;280:1936-43. 7. Zaric GS, Barnett PG, Brandeau ML. HIV transmission and the cost-effectiveness of methadone maintenance. Am J Public Health 2000;90:1100-11. 8. McLellan AT, Arndt IO, Metzger DS, Woody GE, O'Brien CP. The effects of psychosocial services in substance abuse treatment. JAMA 1993;269:1953-9. 9. Preston KL, Umbricht A, Epstein DH. Methadone dose increase and abstinence reinforcement for treatment of continued heroin use during methadone maintenance. Arch Gen Psychiatry 2000;57:395-404. 10. Eissenberg T, Bigelow GE, Strain EC, et al. Dose-related efficacy of levomethadyl acetate for treatment of opioid dependence: a randomized clinical trial. JAMA 1997;277:1945-51. 11. Rawson RA, Hasson AL, Huber AM, McCann MJ, Ling W. A 3-year progress report on the implementation of LAAM in the United States. Addiction 1998;93:533-40. 12. Schottenfeld RS, Pakes JR, Oliveto A, Ziedonis D, Kosten TR. Buprenorphine vs methadone maintenance treatment for concurrent opioid dependence and cocaine abuse. Arch Gen Psychiatry 1997;54:713-20. 13. Schottenfeld RS, Pakes J, O'Connor P, Chawarski M, Oliveto A, Kosten TR. Thrice-weekly versus daily buprenorphine maintenance. Biol Psychiatry 2000;47:1072-9. 14. Substance Abuse and Mental Health Services Administration. Opioid drugs in maintenance and detoxification treatment of opiate addiction: conditions for the use of partial agonists treatment medications in the office-based treatment of opiate addiction. Fed Regist 2000;65(87):25894-5. 15. Novick DM, Joseph H, Salsitz EA, et al. Outcomes of treatment of socially rehabilitated methadone maintenance patients in physicians' offices (medical maintenance): follow-up at three and a half to nine and a fourth years. J Gen Intern Med 1994;9:127-30. 16. O'Connor PG, Oliveto AH, Shi JM, et al. A randomized trial of buprenorphine maintenance for heroin dependence in a primary care clinic for substance users versus a methadone clinic. Am J Med 1998;105:100-5.
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