A.T.F. Volume VI, #1. Winter, 1997

Optimal Methadone Dose?
CSAT: Medical Maintenance
From the Editor
Meetings to Note
Physician with a Mission
Survey: Managed Care and MMT
Addiction Treatment on the Internet
Feedback: Horrifying Attitudes
Patient Perspectives

Optimal Methadone Dose?

Research Needs Careful Interpretation
Sometimes, practices regarding optimal methadone dosages are accepted by various groups medical professionals, clinic operators, regulating agencies as indicating that certain approaches work or don't work. This has been the case over the years, despite the limited clinical research regarding optimal dosage AND the disclaimers of the researchers themselves that there are always limitations to their work and gaps remaining for further investigation.
Recent discussions with Eric Strain, M.D, Associate Professor, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, and some research findings from Australia bring to light several points in this regard worth considering.

Exploring Dose-Dependent Effects
The Hopkins group began in the late 1980s doing clinical trials comparing various methadone doses to explore two aspects of current knowledge about optimal dose. For one thing, they suspected exceptionally low doses were being used during the '80s. The GAO report of methadone maintenance, surveying 24 programs, found there was a wide range of average doses. Some programs had low average dosages of as little as 20 mg/day, while most MMT programs were averaging 50-60 mg/d.
Later research published by D'Aunno and Vaughn1 in 1992 found an average dose of 50 mg/d, and an upper average limit of 79 mg/d. A survey conducted by A.T. Forum and reported in late 1993 [Vol. II, #3] found the low average dose = 22 mg/d; average mean dose = 57 mg/d; high average dose = 89 mg/d [see chart].

	Low Avg. Dose	Average Dose	High Avg. Dose
GAO Report	20 mg/d	50-60 mg/d	N/A
D'Aunno/Vaughn	N/A	50 mg/d	79 mg/d
A.T. Forum	22 mg/d	57 mg/d	89 mg/d

N/A = Not Available

It should be noted, that none of the research mentioned above was experimental in nature; rather, it was based upon survey data. There were no attempts to provide patients different doses in clinical settings to see which worked best. Given the wide, but somewhat consistent, variations in the survey data, Strain and colleagues were wondering just what an average dose should be and how to test some hypotheses via controlled experiments.
Second, as part of any well-controlled experimentation, these investigators were interested to know if there would be some sort of placebo response in opiate addicts related to methadone. That is, if the patient merely thought he was getting methadone would there be a positive response. Knowledge of this could also be important when developing new treatments, for there might be a positive response just based on the fact that the patient thought he was getting some sort of helpful medication no matter what it was. Might a sugar pill be relatively as effective as methadone, or LAAM, or some new medicament?
To explore the issues, a clinical research study with 247 street addicts was conducted(2). It compared three dosages:

• · 50 mg/d methadone (average dose);
• · 20 mg/d methadone (low dose);
• · a placebo dose which looked like methadone (cherry syrup) but had none of the medication.

The experiment was double-blind: neither the clinic staff nor the patients were aware of which dose was being administered. It should be noted, however, that patients did give prior consent to be part of an experimental program.
Patients were admitted randomly to one of the experimental conditions and first stabilized on a 25 mg/d dose of methadone. After a week, doses were gradually changed and over the next six weeks the dose was either taken from 25 mg/d up to 50 mg/d, reduced to 20 mg/d, or decreased down to zero. For the subsequent 14 weeks patients were kept at the experimental dose levels.
The entire study ran 20 weeks, and if patients skipped three consecutive days of dosing they were discharged from the experiment. Urines were collected three times a week, but there were no contingencies based on urine results "dirty urines" did not result in dismissal or any other actions. All patients received conjunctive therapy and counseling.
What happened? As expected from prior research, a dose-response effect on treatment retention was found [see chart].

Methadone Treatment Dose Retention Rate (through 20 weeks)

50 mg/d	52%
20 mg/d	42%
Placebo (0 mg/d)	21%

More patients on 50 mg/d (52 percent) remained in treatment than those on 20 mg/d (42 percent) and this was greater than those in the placebo group (0 mg/d). Somewhat surprisingly, however, 21 percent of patients in the placebo condition who were not getting any methadone, but thought they were stayed the full 20 weeks. Granted that this retention rate was lower than for the two other groups, but Strain believes this is testimony to the nonpharmacologic aspects of the methadone treatment modality attesting to the value of counseling and other services.
There was also a dose-response relationship regarding opiate positive urines corresponding to methadone dose level. That is, as would be expected, the higher the dose the fewer the number of positive urines.
Strain stresses, however, that the interpretation of such research must proceed with caution. While it demonstrates that methadone treatment is more than JUST methadone, due to the demonstrated placebo effect, one also needs to consider several points relating to the study:

• · "Dirty urines" were not cause for dismissal, and Strain found that those remaining in treatment were indeed supplementing their dose (or lack of it in the placebo group) with outside drugs.
• · Even the high dose 50 mg/d was below what many have considered to be an optimal average dose, and nearly half of the subjects in that group did drop out of treatment.
• · The entire study only ran for about five months, so it is not known how retention rates might have been affected over a longer period of time.
• · The study also used a fixed dosing schedule that was not adjusted for individual patient needs.
• Hence, while the results of this study are quite interesting, there were limitations and actual clinical practice (by allowing for higher average dosages) might result in better outcomes.

Urine Tests: Poor Indicator of Progress
To overcome at least one limitation of the study described above, a follow-up experiment by the Hopkins group used a more flexible methadone dosing schedule to compare the advantages of moderate dose versus high dose. Patients were assigned to either a 40 mg/d dose (moderate) or an 80 mg/d dose (high) group. In the moderate range group, patients were allowed clinically determined (i.e., patients had no input in the dosing decisions) increases up to a maximum of 50 mg/d; doses could also be decreased if there were clinical signs of over-medication. In the 80 mg/d group, increases were allowed up to 100 mg/d.
Retention in treatment for the two groups was identical. Superficially, this suggested that, beyond a certain level of dose, retention rates are not dramatically improved. However, in the higher dose group the investigators did find a lower rate of opiate positive urines.
Strain does note a very important qualifier here: In the second study, urines were tested only twice weekly. This will detect illicit drug use, but it will NOT show subtle changes in the amount or frequency of such use. So, there may have actually been dramatic changes in illicit drug taking among the higher dose group that were not detected by the study.
Strain observes that urine test results may be an inadequate indicator of progress in any treatment program. The Hopkins group also looked at Addiction Severity Index (ASI) results, and those did show marked decreases in the frequencies of illicit drug use during the program. Hence, there may be an argument made, using this research, for the higher methadone doses.

Patient-Determined Dose in Australia
Related and recent research(3) conducted by Jason M. White, Ph.D. and colleagues from the University of Adelaide in South Australia, explored the notion that when patients have some control over their treatment including helping to determine the methadone dosage itself they are significantly more likely to remain in treatment for up to a year. The authors arrived at their conclusions by comparing patient records at an Australian methadone maintenance treatment (MMT) program before (in 1991) and after (in 1993) program changes were implemented that allowed greater patient input.
In 1993, the MMT instituted several levels of treatment intensity, with each allowing the methadone dosage to be increased gradually during the first weeks of treatment until the patient decided that the dose was optimal. When patients determined their own methadone dose, the average dose did increase, but not as much as one might expect [see chart].

So. Australian MMT Program

	1991	1993
Average Methadone Dose	45.2mg/d	62.8 mg/d
Pts. In Treatment @12 Months	59%	78%

Of interest, the average doses arrived at by patient input (62.8 mg/d) were only modestly higher than the average dose (57 mg/d) found by the above mentioned A.T. Forum survey, and the doses are consistent with the lowest average dose (60 mg/d) recommended by CSAT's 1992 State Methadone Maintenance Treatment Guidelines. While the study's authors make no mention of this, it seems that patients in the Australian program settled on self-determined dose levels that were well within reasonable ranges in fact, even lower than many in the treatment community might expect or recommend.
Perhaps most important, along with increases in average dose from 1991 to 1993, the retention rates also increased dramatically. The chances of a patient dropping out of the program in 1993 were 27 percent lower than in 1991. The study's authors believe that retention rates may have reached the maximum that could be achieved, and exceeded those experienced by similar MMT programs in the U.S. [See chart].

1993 RETENTION RATES

	3 Months	6 Months
So. Australia Program	91%	79%
Comparable U.S. Programs	78%	62%

The Australian researchers also noted in the study that significantly fewer patients during 1993 (36 percent) had a prior history of methadone treatment than those in 1991 (52 percent), despite the fact that drug use was similar in both groups. The authors speculated that the updated program was attracting new patients rather than merely providing services to patients who had previously dropped out of methadone treatment.

Caveat Emptor
Before one "buys-off" on the results of the above research, a further assessment seems appropriate. White and his co-authors recognized that their study relied solely upon "archival information" drawn from clinic case notes. Patients were not randomly assigned to the program and, indeed, there were three levels of intervention for patients to choose among. Furthermore, there was no control group such as patients who had no control over level of dose for comparison purposes. The authors also wondered if there were other, undiscovered, aspects of the 1993 program that might have contributed to the improved treatment outcomes.
Comparing the first Hopkins study with the Australian research, one notes that their retention rate at about five months (52 percent) fell well below the data presented above at six months for either Australia (79 percent) or the U.S. (62 percent). Perhaps, this was because the 50 mg/d dose was too low; but, the second Hopkins experiment found nearly identical retention rates at the higher dose range of 80 mg/d to 100 mg/d. Still, based upon Addiction Severity Index results (but not urine testing) there WAS decreased illicit drug use, if not greater retention, as the dose was increased.
If anything, this analysis shows how difficult (perhaps confusing) it can be to compare and contrast experimental approaches seeking to determine optimal methadone dose, let alone trying to establish field practices or policies based upon such results. When it comes to such experiments, Strain cautions, "You've got to be careful about giving too simplistic an interpretation of results. These are clinical trials, with strengths and weaknesses that must be recognized."
For example, in his own research, Strain wonders what the impact would be of contingencies relating to continued opiate use, as there often are in most MMTPs? Such contingencies might be punitive (e.g., dismissal from the program) or positive (e.g., increases in methadone dose, more intensive counseling, etc.). In those cases, reductions in continued opiate use achieved via higher methadone doses (and, thus, avoiding punishments) and prolonged retention in treatment (with intensive counseling) might provide some dramatic impacts on behavior. The Hopkins research to date does not allow for those other variables, and Strain recognizes the need for further exploration before firm conclusions can be reached.
It should always be kept in mind that most published research reports end with the author's full disclosure of shortcomings and areas for further investigation surrounding the particular issue. Readers often overlook that part of the report and focus more on the brief, bold face, highlights presented in the summary. That can be a serious mistake.
See also From the Editor, and Question of the Month, this issue.

REFERENCES...
1. D'Aunno, T., Vaughn, T.E., "Variations in Methadone Treatment Practices: Results from a National Study." JAMA, Vol. 267, no. 2, (January 8, 1992): 253-258.
2. Strain, E.C., Stitzer, M.L., Liebson, I.A., Bigelow, G.E. "Dose response effects of methadone in the treatment of opioid dependence." Annals Int. Med., Vol. 119, no. 1 (1993): 23-27.
3. White, J.M., Ryan, C.F., Ali, R.L. "Improvements in retention rates and changes in client group with methadone maintenance streaming," Drug and Alcohol Review, (1996): 15:83-88, . (Adapted by The Brown University Digest of Addiction Theory and Application, November 1996 and reported via InfoSage.)


Should patients have input in determining their levels of methadone dose? What might be the outcome in terms of average dose levels? Please respond in the "Question of the Month" section of this site.

CSAT: Medical Maintenance

The past issue of A.T. Forum [Fall 1996] included a summary of reader responses to the survey on "medical methadone maintenance" i.e., primary care physicians treating methadone maintenance patients and prescribing methadone for once or twice monthly pick-up. Previously, David Mactas, director of the Center for Substance Abuse Treatment (CSAT) had promised to review those responses and comment [see Spring 1996]. His agency has been working with the FDA and DEA toward crafting a transition whereby CSAT will assume a dominant role in regulating and accrediting MMT programs.
Mactas comments that he was not surprised to learn A.T. Forum readers, especially patients, were widely in favor of medical maintenance, and he sounds sympathetic regarding their concerns: "We're mindful of the fact that there are clinics that are crowded," he says. "And that there are folks with great tenure on methadone who are doing well, yet they are tethered to a clinic. For them, it is at best an inconvenience, and at worst it is a disincentive for continuing treatment."
While there is no progress to report regarding medical maintenance, Mactas says that CSAT's assuming more responsibility for the accreditation and regulation of methadone maintenance treatment programs is under way, but it will take time to get things really moving forward. Those initiatives are coming under the direction of Dr. Joyce Johnson, D.O. who, as part of a recent reorganization of CSAT, heads the new Office of Pharmacologic & Alternative Therapies. However, Dr. Johnson comments she is in the preliminary stages of looking at methadone issues in general and that there will be nothing to report until February 1997. [A.T. Forum will follow-up with her].
In another area, Mactas believes, "We've begun to pursue the spirit behind medical maintenance by funding and working on a pilot project with pharmacies to distribute methadone." This initiative, under the direction of Dr. Jerome Jaffe, M.D. (head of CSAT's Office for Evaluation, Scientific Analysis & Synthesis), will identify a group of patients for whom methadone distribution by a regular, community-based pharmacy would help make access to the medication more convenient.
Dr. Jaffe notes that test locations in New Jersey, Philadelphia, and Washington, D.C. are being considered. "The pilot program will be open only to stabilized, employed patients who are already eligible for take-home doses," he says. "Patients will still attend their clinics on an appropriate schedule for counseling and urine tests. The clinics are quite in favor of the project, since some have patients traveling great distances several times a week to pick up their methadone, and this will relieve the patients of that burden."

From the Editor

Optimal Methadone Dose Still a Question
Over the years, we've frequently explored research and opinion regarding the optimal some would say "best" or "adequate" methadone dosage levels. There has been quite a diversity of opinions, practices, and policies among treatment professionals, and the topic is still an open question.
During a recent conversation with Dr. Eric Strain regarding his group's research seeking to provide some answers, it became apparent that studies to date have all fallen short of "perfection." That's not the fault of the researchers or their study designs. It's actually inherent in most any scientific investigation and Strain, himself, was honestly quick to point out possible refinements regarding his own work.
So, with an eye toward how research results might be interpreted more cautiously, in this issue we offer assessments of some clinical experiments by Strain's group at Johns Hopkins and a fascinating recent study that came from "down under" in Adelaide, Australia. The most engaging aspects of that study demonstrated some success in allowing patients to determine their own optimal methadone doses, and that those doses on average were lower than some might expect.
The possibility of patients self-determining their methadone doses (within allowable regulatory limits, of course) stirs one's imagination. And, as always, we invite our readers to make their thoughts and opinions known. So, this issue's two-part survey question is:
How much input should MMT patients be allowed in determining their methadone dose levels? · A great deal · Very little · None at all
How might this affect their daily methadone doses? · Levels would probably increase, · Probably decrease, · No change expected
See also "Optimal Methadone Dose?" this issue.
Please provide your responses and comments on the "Question of the Month" page in this site.
A.T. Forum
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Internet: http://www.atforum.com

Stewart B. Leavitt, Ph.D., Editor

Meetings to Note
1997

FEBRUARY 4-7 - 9TH Annual Substance Abuse Conference; Sheraton Hotel, Tulsa; sponsored by the Oklahoma Dept. for Mental Health & Substance Abuse Services. Keynoters include: David Mactas, Terence Gorski, James Sipe. Contact Sue Carlson at 405-325-1447.

APRIL 13-16 - AMTA Conference; Sheraton Hotel and Towers, Chicago; Chaired by Eldoris Mason. For information contact the American Methadone Treatment Association (AMTA) at 212-566-5555; FAX: 212-349-1073.

[To post your meeting or conference announcement in A.T. Forum and/or our Web site, fax the information to: 847-413-0526 or submit it via e-mail from our Web site: http://www.atforum.com.]