A.T.F. Volume X #2 Spring 2001

Clinical Concepts - How Safe Are Methadone, LAAM, Buprenorphine?
MMT & Beyond - Office-Based Methadone Prescribing
From the Editor: Where's the Evidence?!

Events to Note
Brainstorm: Voices of Dissent- Part 8

Survey: Supervised WIthdrawal

Clinical Concepts - How Safe Are Methadone, LAAM, Buprenorphine?

Alternatives Praised

Newer medications have been proposed as superior alternatives to methadone in the treatment of opioid dependency. This especially came to light in "Heroin's new fix," a cover story in the May 31, 2000 edition of USA Today, the largest daily circulation U.S. newspaper. The article began, "New drugs, younger addicts fuel push to shift treatment from methadone clinics."

The news article quoted scientists and health officials as claiming newer opioid agonists could reduce methadone's role as well as that of methadone maintenance treatment (MMT) clinics. In particular, buprenorphine was portrayed as a "cutting-edge" medication, effective and safe, and destined to move addiction treatment into doctors' offices nationwide. Additionally, a combination buprenorphine-naloxone product was mentioned as being under investigation. LAAM, approved by the FDA in 1993, also was cited as a newer alternative to methadone.

Are buprenorphine and LAAM improvements over methadone, the foremost or "gold standard" opioid agonist for the treatment of opioid dependency since its introduction in the mid-1960s?

Even more important, are the newer agents really safe alternatives?

Unexpected Findings

To examine these safety issues, AT Forum analyzed adverse event reports concerning methadone, LAAM, and buprenorphine that were submitted to the U.S. Food & Drug Administration during a 3-year period, November 1997 to November 2000. A medical literature search also was conducted to identify published evidence supporting or opposing the findings.

Adverse events (AEs) associated with drugs are unanticipated reactions or consequences that are considered medically harmful to the patient, or a female patient's unborn baby. Sometimes they are called drug "side effects," although these generally tend to be less severe.

During the 3-year period, there were 170 AE reports submitted for methadone, 40 for LAAM, and 178 for buprenorphine. Compared with methadone, for which the AE reports represented only 0.03% of all methadone-treated persons during the 3 years, there were an unexpectedly high number of AEs associated with LAAM and buprenorphine.

This considers that, in the U.S., persons on methadone outnumbered LAAM patients by 45 to 1 so, proportionately, there should only have been about 4 reports for LAAM. And, since buprenorphine was not yet FDA-approved and still under study for opioid-dependency therapy in even fewer patients than for LAAM, the 178 AEs for buprenorphine seem extremely high and of concern.

Buprenorphine-treated patients were significantly younger than those receiving either LAAM or methadone. Younger patients have been suggested as a primary target population for buprenorphine (as also noted in the news articles mentioned above). It might be expected that such patients, generally with addictions of less longevity and severity, might be healthier and would potentially experience fewer adverse events with buprenorphine. This was not evident.

Comedication Effects

The AE reports noted whether methadone, LAAM, or buprenorphine was the only drug – the "sole agent" – involved, or if the patient also was taking other drugs, "comedications." Only about a quarter (26%) of total AEs associated with methadone involved the drug as a sole agent, suggesting that interactions with other drugs play the major role in adverse reactions with methadone.

Compared with methadone, more than twice as many buprenorphine AEs occurred with the drug by itself (57%), possibly suggesting a more harmful effect of buprenorphine. Similarly, 45% of LAAM-related AEs were as a sole agent. See Figure 1.

From this information, it appears that methadone, by itself, is by far the safest of the 3 medications. Furthermore, these findings suggest that the vast majority of AEs associated with methadone might be avoided by more careful prescribing of any comedications used in a particular patient's treatment.

Troublesome Trends

The best indication of a drug's accountability in producing AEs might be in viewing it as a sole agent, unaffected by interactions with other drugs, prescribed or illicit.

Looking at each medication as a sole agent, FDA AE reports were further organized into several categories more clearly describing what happened – i.e., outcomes – as a result of drug effects. The outcomes included death, morbidity (which includes reactions often requiring emergency care or hospitalization), and cardiac-related effects (such as irregular heartbeat or heart attack). Additionally, as a result of the mother's exposure to the drug, some AEs reported fetal death or neonatal complications (e.g., abstinence syndrome in the newborn, tremor, or problems feeding or breathing).

The trends are summarized and displayed in Figure 2.

Deaths

Patient deaths were roughly equal for methadone and buprenorphine; however, this may be misleading, considering the much greater number of patients treated each year with methadone. Also, due to a number of factors, there have been questions about the accuracy of deaths attributed solely to methadone in the past and most reports indicate other causes or medications were present. Long-term studies of MMT patients have found no deaths directly caused by methadone.

A single death with LAAM in the FDA AE reports was in association with benzodiazepines. Similarly, there have been a number of deaths reported in the literature with buprenorphine in combination with benzodiazepines.

Morbidity

A considerably higher frequency of morbidity was reported for LAAM and buprenorphine than for methadone. In fact, there were twice as many hospitalizations, emergency care situations, and other reactions requiring treatment for buprenorphine as for methadone.

An important concern is that twice as many buprenorphine AEs in this category were due to patients dissolving tablets in liquid for IV injection, rather than sublingual administration (dissolving tablets under the tongue) as prescribed. Reactions specifically associated with IV abuse of buprenorphine involved injection site complications, such as blood vessel inflammation or clots, abscesses, edema, and pain.

This IV abuse potential of buprenorphine has been widely reported in the literature, along with a black market for the drug in countries where it has been available. This has raised concerns about the liberal prescription of take-home buprenorphine tablets, and it is uncertain that a buprenorphine-naloxone combination product in development would resolve the problem.

Cardiac Related

FDA-reported cardiac-related events were minimal for methadone and buprenorphine, but disproportionately much greater for LAAM. Due to concerns about cases of life-threatening heart rhythm disturbances, European authorities recently advised against using LAAM.

There were only 4 cases of heart disturbances associated with methadone. Practitioners in the field have noted that most such events in methadone patients might be traced back to preexisting medical conditions or an inherited tendency to develop heart problems.

A single cardiac-related event was reported for buprenorphine as a sole agent and it is possible that this might be a safety advantage of the medication. Further research in this area concerning all 3 opioid agonist medications seems appropriate.

Fetal Deaths/Neonatal Complications

Surprisingly, there were unusually high percentages of fetal deaths and neonatal complications associated with buprenorphine. This is a particular concern because the medication has been proposed for major use in younger addicts, which would include women of prime child-bearing age.

There were 4 deaths and 27 neonatal complication cases reported with buprenorphine, or proportionately 9 times more neonatal complications than with methadone. There has been relatively little research into the safety of buprenorphine during pregnancy and further investigations of this issue seem needed.

There were no fetal deaths and only 3 complications in newborns associated with methadone as a sole agent, which was noteworthy considering the very large numbers of women maintained on methadone each year. LAAM has been prohibited in pregnancy since its FDA approval, so there were no reports of fetal or neonatal AEs with this medication as a sole agent.

Research Limitations

AEs reported to the FDA for methadone, LAAM, and buprenorphine might have been just the tip of the iceberg. Some have suggested that, in general, only 1% of all serious adverse reactions to drugs are reported to the FDA. Adjusting for this, however, it still would have resulted in only a very small percentage of all persons on methadone experiencing reactions to the drug during the 3-year period; for LAAM it would have been a third (33%) of all patients, and possibly much greater for buprenorphine.

Furthermore, the FDA reports do not provide information regarding illness prior to drug administration, so there is no way of knowing the relative impact of a patient's medical history. Substance dependent persons, especially older patients, often have multiple physical problems and symptoms that might make accurate reporting difficult.

Finally, AE reports sent to the FDA might be characterized as a collection of anecdotal cases. Still, in lieu of a better information-gathering system, such accounts do often carry considerable weight, as in the European warnings about LAAM mentioned above.

Methadone Still "Gold Standard"

In its approximately 35-year history as the "gold standard" treatment for opioid dependency, methadone has proved to be a safe medication. In the millions of patients treated during that time, extending more than 20 years in some patients, severe adverse reactions requiring emergency care or hospitalization have been relatively rare.

Medication side effects have been more common during the early days of MMT and easily managed. Women stabilized on methadone generally have more healthful pregnancies and healthier newborns than would be observed without such therapy.

Recently noted concerns about LAAM affecting heart health may limit its use to only special cases in which risks are overshadowed by specific advantages, such as its longer action permitting less- frequent dosing.

Buprenorphine and a buprenorphine-naloxone combination may offer advantages in carefully selected patients. However, risks of potential IV abuse must be considered and possible hazards of buprenorphine in pregnancy need to be better understood.

Robert Newman, MD, president emeritus of Continuum Health Partners, New York, and a leader in the addiction treatment field, has observed that there is no reason to believe that buprenorphine will be superior to methadone maintenance or other modalities for treating opioid dependence.

One major proposed advantage of buprenorphine would be its widespread and easy accessibility to patients in community-based medical practices. However, there do not appear to be any research-proven safety advantages that make buprenorphine better suited to this treatment approach than methadone. As Newman stressed, the same rationale for permitting buprenorphine to be prescribed by all licensed practitioners applies equally well to methadone.

Certainly, if multiple agents were available for opioid-dependency treatment, patients could benefit; just as multiple forms of antibiotics offer advantages in treating infection. However, patient safety should remain a prime concern.

Full Report Available: This research was sponsored by an educational grant from Mallinckrodt Inc., a manufacturer of methadone. The complete report, including 80 resource references, is available by checking the appropriate box and mailing the feedback card in this issue. It is also readily available in electronic format at under the "Current/Past Issues" tab, at the bottom of the contents page in the "Unpublished Reports" section.

MMT & Beyond - Office-Based Methadone Prescribing

In 1997, NIDA funded a 3-year research project on "Office-Based Methadone Prescribing" at Montefiore and Beth Israel Medical Centers, and the Albert Einstein College of Medicine. Following is a report from project director Ellen L. Tuchman, CSW, PhD (cand) and principal investigator Ernest Drucker, PhD.

More than 30 years since its inception, most methadone maintenance treatment (MMT) in the U.S. continues to be delivered only through clinics that are heavily regulated. After years of MMT, patients may still be attending the clinic 4 to 5 times per week, even though they are making every effort to avoid being in places that have any association with drugs or their previous lifestyle.

Methadone for addiction treatment remains a medication that cannot be prescribed by physicians outside of MMT programs. Furthermore, many MMT patients do not receive primary medical care and, if they do, that care is often divorced from their treatment for addiction.

The goal of our study was to explore the possibility of extending options available for methadone treatment by determining the safety, practicality, and efficacy of a primary care model for prescribing methadone.

Study Design

We enrolled 151 women in a randomized trial comparing "Office-Based Prescribing" (OBP) with usual care in MMT clinics. Fifty-three (53) patients were assigned to OBP (the experimental group ) and 100 were followed as controls at their MMT clinics. Only women were included in this preliminary study to simplify the research design and reduce costs. In a subsequent stage men will be included.

To be eligible for the study, patients had to be on a stable dose of methadone for at least 6 months and at a reduced pickup schedule of 5 times or less per week. Patients with an existing primary care physician were excluded, so as not to interrupt already established medical care relationships.

The experimental and control groups were demographically equivalent. Average age and time in MMT for all subjects was roughly 41 years and 13 years, respectively. On average, the women were attending their clinics 3 to 4 days per week for methadone dosing at the start of the study. Methadone dispensing for both groups of patients continued to take place at participating MMT program clinics.

The objective of this study was to demonstrate equivalence: i.e., that the OBP patients would do as well as the MMT clinic controls. Two treatment outcomes were examined: retention and illicit drug use.

Results Twelve medical practitioners were recruited from primary care community practices and health clinics at Montefiore and Beth Israel Medical Centers. Physicians were trained in all aspects of methadone treatment.

Prescribing authority over methadone dosage and pickup schedules for the 53 OBP patients was then transferred to participating practitioners. OBP patients made monthly visits to these primary care providers, who could alter dosages and pickup schedules within the practice guidelines and regulations operative in the MMT programs. All OBP patients continued to attend their MMT clinics for regular methadone dispensing, urine tests, and ancillary clinic services.

For treatment retention, with 12-months follow-up, 5.7% of OBP patients left treatment compared with 6.1% of MMT patients.

For use of illicit drugs, with 12-months follow-up, 82.3% of the women in OBP vs 71.1% of the women in MMTP had not used heroin or cocaine. We defined "illicit use" as two or more positive urine screens.

Differences between groups for retention and illicit drug use were not statistically significant, demonstrating that office-based physicians apparently can safely manage methadone prescribing for stable patients. However, to be of practical significance and to help increase total MMT capacity, office-based prescribing must be coupled with community pharmacy dispensing of methadone.

Integrating Community Pharmacy Dispensing

During the next 4 years our research will be expanded under a new NIDA grant, "Office Based Prescribing and Community Pharmacy Dispensing of Methadone."

We have worked with the Pharmacists Society of the State of New York to identify and recruit 4 well-regarded community pharmacies that have agreed to participate in the study. All are already serving many methadone patients' general pharmacy needs and have submitted required applications for appropriate licensing to administer methadone.

Participating pharmacies are open at least 6 days and for an average of 70 hours per week. The pharmacist will obtain methadone on a weekly basis and be responsible for preparing observed and take-home doses.

Twenty-five (25) current study patients, who completed at least one year with an office-based prescribing physician, will be eligible for the new pharmacy program. Patients will select one of the participating pharmacies, which will serve as a "medication unit."

Each patient will have a case manager – a social worker who coordinates care and provides all required psychosocial services, and all documentation required by state and federal rules. The women will see this case manager at least once each month and as needed.

Patients will begin receiving medication at the pharmacy at their current dosage and pickup schedule. As is the case in MMT clinics, doses administered at the pharmacy will be observed. Participating pharmacies will have a private consultation area where these doses will be administered.

Expanded Spectrum of Care

MMT clinics are invaluable for those who first enter treatment, for those who continue abusing heroin and other drugs, and for those who need more intensive psychosocial services and other care.

At the other end of the spectrum, for the most stable patients, we already have medical methadone maintenance. These patients are seen by their physicians monthly and given up to 30 days of take-home methadone at the office visit. This is appropriate for only a small percentage of patients.

OBP and pharmacy methadone dispensing could serve a larger percentage of MMT patients, and would open significant space in existing clinics for new patients. Plus, there are many cities in the US (and 8 states) where there is no methadone treatment or not enough slots in existing methadone clinics for those who want treatment.

Other patients also could benefit. Travel, illness, and disabilities prevent many from remaining in MMT clinics. Working patients sometimes fear their jobs are in jeopardy because MMT clinic hours conflict with work schedules. Women with young children may lack the finances or social support for childcare so that they can attend the clinic. And some stable patients simply no longer need all the structure and support services of a clinic setting.

In one model proposed by the American Methadone Treatment Association, the MMT clinic is seen as the hub of all treatment. Patients in hub clinics would be able to move fluidly from the clinic to an office-based provider with community pharmacy dispensing, and perhaps then to medical maintenance. However, there would always be an option to return to the MMT clinic during a period of instability or relapse.

If this model is to be effective in expanding access to care and maintaining quality, it is imperative that MMT program staff develop the ability to work well with outside physicians and pharmacists. In the next phase of our project we hope to demonstrate the feasibility of this transition, and document the effects on patients and the responses of providers to this new model of care.

This report is based on a poster presentation at the College on Problems of Drug Dependency, (CPDD), in San Juan, Puerto Rico, June 2000. Office Based Methadone Prescribing in Primary Care Practice: Results of a Randomized Trial of Feasibility and Efficacy. E. Drucker, D. Hartel, E. Tuchman, K. Bonuck, P. Vavaglakis, J. Garfield, and W. McCarthy.

From the Editor - Where's the Evidence?!

Evidence-based addiction medicine is a tough taskmaster.

It commands: "Your experience, opinions, and speculations are of limited use. Where's the research evidence to support your claims?"

We're reminded of the boisterous elderly lady (Clara Peller was her name) in TV commercials for a fast food hamburger chain some years ago. "Where's the beef?!" she protested with a look of disgust as she examined her anemic-looking sandwich.

Like the meat in Clara's sandwich, evidence is the substance of science.

Beefier Articles

Perhaps long-time readers of AT Forum have noticed some of our articles have grown a bit longer and more complicated in the interest of providing more substance. Such is the case with this issue's research into the safety of medications for opioid addiction.

We started with an analysis of adverse events reported to the FDA regarding methadone, LAAM, and buprenorphine during a several-year period. Plus, we scoured the research literature to see if there was supporting evidence for our findings.

The results were surprising, although methadone clearly retained its position as the "gold standard."

A summary of our report without documentation and as few intruding numbers as possible is in this edition of AT Forum. The full report is available by request (see the feedback card) and at our Web site – www.atforum.com. But, we must advise readers that there's a lot of "beef" in the full report – it's long and complex.

Credible evidence is rarely served up in quickly digested nuggets.

Slicing Through SPAM

At the other end of the evidence spectrum, this edition also has an article presenting "voices of dissent" – those self-proclaimed experts who argue against the concept of addiction as a disease and downplay the role of medical treatments in recovery. These folks appear to be unhindered by a careful examination of scientific evidence.

We hesitated to devote space to such ideologies, lest anyone think we endorse them. Yet, it is vital that everyone in the addiction treatment field is aware of these viewpoints, for they are a prime breeding ground for what Carlton Erickson, PhD has called SPAM – Stigma, Prejudice and Misunderstanding – surrounding drug addiction and its treatment.

Scientific evidence can slice through SPAM; however, we must be willing to search out and examine it. Indeed, the answer to "Where's the evidence?" is: "It's there if we look for it, and more is becoming available every day."

AT Forum will continue to search on your behalf and hopefully present our discoveries in ways that are easily understood and usable in everyday practice. Let us know how we're doing.

Survey – MMT Attitudes?

As usual, we want to know what our readers think about addiction and methadone treatment. Please respond to the following statements:

1. An MMT patient who continues to use heroin should be given higher doses of methadone. ____ agree; ___ disagree.

2. Complete abstinence from illicit drugs is essential for recovery in MMT. ____ agree; ___ disagree.

3. Many patients need to be maintained on methadone indefinitely. ____ agree; ___ disagree. Are you responding as a ____ staff member; or, ___ patient.

There are several ways for you to reply: A. Provide your answers on the postage-free feedback card in this issue; B. Write or fax us [see info below]; or C. Visit our Web site to respond online. As always, your written comments will also help us discuss the results in our next issue.