TREATING OPIOID DEPENDENCE

To the Editor: The article by Johnson et al. on the treatment of opioid
dependence (Nov. 2 issue) (1) and the accompanying editorial by O'Connor
(2) serve an important purpose in making physicians and, one hopes, the
public more aware of the effectiveness of methadone maintenance for heroin
dependence. It is discouraging, however, that the ineffectiveness of
low-dose methadone therapy still has to be demonstrated. The effectiveness
of methadone, at an average dose of 100 mg per day, was shown by Dole et
al. (3) more than 30 years ago and has been repeatedly confirmed since
then, with some patients needing a dose higher than 100 mg per day. (4) If
the high-dose group in the study by Johnson et al. had actually received a
high dose of methadone (i.e., higher than 100 mg per day), its
effectiveness might have been even more impressive. The low-dose group
received a daily dose of 20 mg of methadone, which would not even be an
analgesic dose if used for chronic pain. Unfortunately, most programs are
using inadequate doses of methadone with, not surprisingly, poor results.

Buprenorphine has been shown to be effective as maintenance therapy for
heroin dependence; however, the authors do not mention its high potential
for abuse. It is one of the most frequently abused drugs in Australia and
Scotland. (5) It would have been helpful if Johnson et al. and O'Connor had
mentioned the risk of addiction with buprenorphine as well as its
effectiveness as maintenance therapy.

Barry Stimmel, M.D. Mount Sinai School of Medicine New York, NY 10029-6574

References

1. 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.

2. O'Connor PG. Treating opioid dependence -- new data and new
opportunities. N Engl J Med 2000;343:1332-4.

3. Dole VP, Nyswander ME, Kreek MJ. Narcotic blockade. Am J Intern Med
1966;188:304-9.

4. Barnett PG, Hui SS. The cost-effectiveness of methadone maintenance. Mt
Sinai J Med 2000;67:365-74.

5. Lavelle TL, Hammersley R, Forsyth A, Bain D. The use of buprenorphine
and temazepam by drug injectors. J Addict Dis 1991;10(3):5-14.

To the Editor:
A maintenance dose of 20 mg of methadone per day is homeopathic. A dose of
60 to 100 mg per day is not high; it is a standard dose. Daily doses above
110 mg are high. The state of California permits a dose of up to 180 mg per
day.

A policy of allowing private physicians to prescribe methadone to addicts
has both positive and negative aspects. It assists addicts who live in
states that do not have methadone treatment programs, and it is appealing
because of the dosing schedule and privacy. But how many private physicians
want patients with opioid dependence in their waiting rooms or want to
assume the responsibility for their primary care?

As methadone maintenance has evolved, we now realize that opioid dependence
is a complex problem and needs more attention. It is not enough to give an
addict methadone every day. There are other, large problems associated with
opioid dependence. Most heroin addicts did not graduate from high school,
are functionally illiterate, do not have job skills, and have serious
emotional problems, and at least a third of them abuse alcohol. (This last
fact is not mentioned in the article or editorial, nor is the fact that
most heroin addicts are positive for hepatitis C virus.) Few medical
offices are equipped to address these problems. Addicts need help in
learning the coping skills required for living in the community. In the
past decade, treatment centers began seeing the addict as a whole person,
not just a needle user. The problems associated with opioid dependence are
addressed in many of the large clinics, with even dietary counseling provided.

Thomas V. Reese, Sr., M.D. 3120 Nahenahe Pl. Kihei, HI 96753

The authors reply:

To the Editor:

Both Stimmel and Reese object to the term "high dose" for a dose of 60 to
100 mg of methadone per day. We used the term in its relative, not
absolute, sense, and we agree that for some patients, even higher doses may
be necessary and appropriate.

Both Stimmel and Reese also criticize our use of a lower-dose control
treatment. However, inclusion of this treatment was critical for
documenting the effectiveness of the other study treatments, and our rescue
procedure made it ethically acceptable. We agree that higher doses should
be considered, and our findings support their use. It is our hope that
well-controlled clinical trials (1,2) will help accomplish what 35 years of
uncontrolled clinical experience has not.

Stimmel and Reese err in suggesting that a 20-mg dose of methadone is
ineffective or homeopathic. In the group of patients who received this
dose, there was a large reported reduction in heroin use, and in an earlier
study, patients who received this dose reported substantial improvements in
both symptoms and drug use. (3) The effectiveness of low methadone doses in
suppressing opioid withdrawal probably contributes to the frequent failure
of physicians to increase doses to a level that optimally reduces heroin use.

Stimmel suggests that buprenorphine may have a high potential for abuse. It
does have a potential for abuse, but it is probably less than that of
methadone or heroin. Buprenorphine has typically been abused in
circumstances of limited regulation, limited availability of other opioids,
or both. Once it has been approved by the Food and Drug Administration
(FDA), the primary formulation for the treatment of heroin dependence will
be a combination product containing the antagonist naloxone, which
dramatically reduces the potential for abuse through injection by
opioid-dependent persons. (4)

Reese notes that many heroin-dependent patients have serious behavioral and
medical problems. We certainly concur. Increasing the array of treatment
options should result in a larger proportion of patients who receive some
form of treatment and should enhance opportunities to address these problems.

Rolley E. Johnson, Pharm.D. Eric C. Strain, M.D. George E. Bigelow, Ph.D.
Johns Hopkins University School of Medicine Baltimore, MD 21224

References

1. Strain EC, Bigelow GE, Liebson IA, Stitzer ML. Moderate-vs high-dose
methadone in the treatment of opioid dependence: a randomized trial. JAMA
1999;281:1000-5.

2. 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.

3. Strain EC, Stitzer ML, Liebson IA, Bigelow GE. Methadone dose and
treatment outcome. Drug Alcohol Depend 1993;33:105-17.

4. Mendelson J, Jones RT, Welm S, et al. Buprenorphine and naloxone
combinations: the effects of three dose ratios in morphine-stabilized,
opiate-dependent volunteers. Psychopharmacology (Berl) 1999;141:37-46.

The editorialist replies:

To the Editor:

As Stimmel and Reese point out, the dose of methadone is clearly related to
its effectiveness in treating opioid dependence. (1) For example, one study
found that a "high" dose, in the range of 80 to 100 mg per day, was
superior to a "moderate" dose, in the range of 40 to 50 mg per day, in
reducing illicit opioid use. (2) Even higher doses (more than 100 mg per
day) may be necessary for some patients.

Like other opioids, buprenorphine has a potential for abuse, although as a
partial opioid agonist, buprenorphine may have less potential for abuse
than pure opioid agonists such as methadone. A preparation that is likely
to be approved in the United States is a combination of buprenorphine and
naloxone, which may further decrease (but not eliminate) the potential for
abuse, especially among opioid-dependent injection-drug users. (3)

Office-based maintenance therapy for opioid dependence has the potential to
provide greatly increased access to treatment. Although I agree with Reese
that this approach may be especially useful in areas that do not have
maintenance programs, it will also be useful in areas where programs exist
but access to them is limited because of an insufficient number of
treatment slots or other barriers. Studies of office-based methadone
maintenance in Connecticut and elsewhere suggest that finding private
physicians who are willing and able to provide such treatment and primary
care for stabilized patients may not be difficult. I agree that the simple
act of dispensing a medication is generally not sufficient and that
counseling and other services are critical elements of treatment for opioid
dependence and other medical disorders. However, studies of office-based
methadone maintenance suggest that selected patients can do well in the
office setting. (1,4) Nonetheless, it is unlikely that office-based
methadone maintenance will be broadly available in the near future.

In 2000, President Bill Clinton signed legislation (Public Law 106-310)
that authorizes appropriately trained physicians to prescribe Schedule III,
IV, and V controlled substances that have been approved for the treatment
of opioid dependence. Although as of this writing the FDA has yet to
approve such medications, it is likely that buprenorphine will eventually
be approved for this purpose. (5) Critical issues remain to be addressed.
These include the training of physicians, the selection of patients, the
appropriate level of counseling, the effectiveness and safety of
office-based treatment, satisfaction on the part of patients and
physicians, and links with substance-abuse programs.

Patrick G. O'Connor, M.D., M.P.H. Yale University School of Medicine New
Haven, CT 06520-8025

References

1. O'Connor PG, Fiellin DA. Pharmacologic treatment of heroin-dependent
patients. Ann Intern Med 2000;133:40-54.

2. Strain EC, Bigelow GE, Liebson IA, Stitzer ML. Moderate-vs high-dose
methadone in the treatment of opioid dependence: a randomized trial. JAMA
1999;281:1000-5.

3. Robinson GM, Dukes PD, Robinson BJ, Cooke RR, Mahoney GN. The misuse of
buprenorphine and a buprenorphine-naloxone combination in Wellington, New
Zealand. Drug Alcohol Depend 1993;33:81-6.

4. 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.

5. Department of Health and Human Services. Opioid drugs in maintenance and
detoxification treatment of opiate addiction: conditions for use of partial
agonists treatment medications in the office-based treatment of opiate
addiction. Fed Regist 2000;65:25894-5.