Pubdate: Thu, 02 Nov 2000
Source: New England Journal of Medicine (MA)
Copyright: 2000 by the Massachusetts Medical Society
Contact:  10 Shattuck Street, Boston, MA 02115-6094
Fax: (617) 739-9864
Author: Patrick G. O'Connor, M.D., M.P.H., Yale University School of Medicine
Bookmark: Methadone items:


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.


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 

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 

7. Zaric GS, Barnett PG, Brandeau ML. HIV transmission and the 
cost-effectiveness of methadone maintenance. Am J Public Health 

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 

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 

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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