LAAM (levo-alpha-acetyl-methadol) is a synthetic opioid agonist medication for
use in the treatment of opiate addiction. It was approved by the Food and
Drug Administration (FDA) in July 1993 and became commercially available in
August 1993. Like methadone, LAAM creates a pharmacologic cross-tolerance to
other opioids and therefore blocks the euphoric effects of those drugs while
also controlling opiate craving. Methadone suppresses opiate withdrawal symptoms
for 24 hours or longer, whereas LAAM achieves this effect for 48 to 72 hours
or longer. Under FDA regulations, LAAM must be dispensed by approved opioid
substitution therapy programs. Each program must receive approval from the single State
agency (SSA) to dispense LAAM and must ensure that program staff receive training
in its use.
Because of LAAM's long duration of action, after a patient's tolerance to LAAM
has been established, it can be administered no more frequently than every
other day. In humans, LAAM is metabolized into two active metabolites, nor-LAAM
and dinor-LAAM. Both are metabolized more slowly than the parent drug. It
is believed that this slow metabolism is the basis for LAAM's long duration
of action. Like methadone, LAAM is similar in action to morphine. Its effects
include analgesia, sedation, and respiratory depression. Tolerance to these effects
develops with prolonged use, and an abstinence syndrome similar to that observed
with morphine and other opiates occurs with cessation of regular use. However,
with LAAM, the syndrome has a slower onset and lasts longer, with less acute
symptoms (Fraser and Isbell, 1952).
LAAM is a Schedule II controlled substance and is sold under the name ORLAAM
(levomethadyl acetate hydrochloride oral solution). LAAM was first developed in 1948
as an analgesic. The first study of LAAM was published a few years later
by Fraser and Isbell (1952); they observed that LAAM suppressed opiate withdrawal
symptoms for more than 72 hours.
In the late 1960s and early 1970s, as a response to widespread heroin use,
interest in narcotic maintenance treatment resulted in the expansion of methadone
treatment and its approval by FDA in 1972 for use in opioid substitution therapy.
At the same time, clinicians began to examine its effects. Interest in
LAAM during the 1970s resulted in 27 separate studies that involved a total
of more than 6,000 patients. The studies varied in methodology and quality.
The two major studies were conducted by the Veteran's Administration (Ling et al., 1976) and the Special Action Office on Drug Abuse Prevention
(SAODAP) (Klett, 1978). Taken overall, the 27 studies established the safety and efficacy
of LAAM as a maintenance medication in doses up to 100 milligrams dispensed
at 48- to 72-hour intervals for extended periods (National Institute on Drug Abuse, 1993).
During the 1980s, little research was conducted or completed on LAAM, primarily
because of lack of funding. However, as the human immunodeficiency virus/acquired
immunodeficiency syndrome (HIV/AIDS) epidemic began to be centered in the injecting-drug-using
population, interest in expanding treatment programs for this population increased.
This interest, coupled with evidence that methadone maintenance treatment
provided access to this hard-to-reach population, led Federal officials to reexamine
the use of LAAM. In 1990, with the establishment of the Medications Development
Division at the National Institute on Drug Abuse (NIDA), Biometric Research Institute
was engaged to develop a New Drug Application (NDA) for LAAM. After reviewing
the submitted materials, the Drug Abuse Advisory Committee at FDA requested
a study of the proposed package insert and a draft of treatment regulations
for the use of LAAM in opioid substitution therapy programs.
Taken overall, 27 separate studies in the 1970s established the safety and efficacy
of LAAM as a maintenance medication in doses up to 100 milligrams dispensed
at 48- to 72-hour intervals for extended periods.
The final study, called the LAAM Labelling Assessment Study (LAS), was conducted
in 26 methadone treatment programs throughout the United States. A total
of 623 patients were recruited for the study. Seventy percent were patients
transferred from methadone treatment programs; the remaining 30 percent were opiate-addicted
individuals, 15 percent of whom were stabilized on methadone for less than 30 days and
15 percent of whom were not in methadone treatment. Based on results of the
study and comments from treatment programs on the draft regulations, NDA 20-315
was submitted to FDA by the manufacturer in June 1993. Minor changes were
made to the package insert, and FDA approved LAAM for use on August 18, 1993
(National Institute on Drug Abuse, 1993).
LAAM was approved for use in approved opioid substitution therapy programs for
dosing every other day or three times per week. No take-home doses of the medication
are currently allowed, but equivalent doses of methadone can be substituted
to allow for travel or other emergencies. FDA regulations require that all
women of childbearing potential who are taking LAAM be tested monthly for pregnancy
because not enough data are available from the various preliminary studies to determine
the effects of LAAM in pregnant women. The package insert recommends that
women who become pregnant while receiving LAAM be transferred to methadone maintenance
until they give birth, at which time they may resume taking LAAM.
During the 1980s, opiate addiction treatment programs changed dramatically. The
epidemic of HIV/AIDS and the proliferation of cocaine abuse required that programs
reconsider their goals and objectives. Increased availability of cocaine and crack
cocaine raised concerns among some officials that take-home doses of methadone
would be sold to purchase these illegal drugs. In addition, research and evaluation
reports indicated that opioid substitution therapy programs were excellent sites
to provide information, education, and treatment related to HIV and AIDS.
Education about safer sex practices, counseling and testing, primary health care,
family planning, and other relevant services can be made available in a "one stop
shopping" model at a treatment center, where addicted patients can feel comfortable
and safe and not experience the hostility they often encounter in mainstream
health or social service settings.
As a result of these factors, public policymakers have begun to look at ways
to expand substitution therapy to engage more opiate-addicted persons in treatment
and service systems. Women are now entering treatment in greater numbers than
ever before, and services have been initiated to meet the needs of women as
well as the children who often accompany them to the treatment site.
Use of LAAM allows patients to visit the treatment site every other day or
three times a week from the inception of treatment. For methadone, FDA regulations
require daily visits to the clinic (at least six visits per week) during the first
3 months of treatment; after 3 months, take-home doses of methadone are
appropriate for some patients. Use of LAAM can allow programs to admit more patients
or focus on services other than medication dispensing.
Daily clinic visits are frequently an obstacle to a patient's ongoing treatment
and rehabilitation, especially if the patient is working or attending school.
Because take-home doses of LAAM are not permitted, LAAM cannot be accidentally
ingested by nontolerant individuals. In addition, some patients in the Labelling
Assessment Study reported a preference for LAAM over methadone; they described LAAM
as having a smooth action that allowed them to feel more "normal."
Medications have been used in the treatment of opiate dependence and other substance
use disorders for more than three decades. While some people continue to find
their use for such purposes problematic, the value of medications in alcohol
and other drug (AOD) abuse treatment has been well established over time.
As this Treatment Improvement Protocol (TIP) was being prepared for publication,
the Institute of Medicine published a report that further validated the concept
of medication use in narcotics treatment programs (Institute of Medicine, 1995). As the use of new medications such as LAAM grows,
we must continue to communicate our experiences to improve the quality of
care.
Until more patients have experienced stabilization on both methadone and LAAM,
comparative data will not be available to determine whether patients with certain characteristics
do better on LAAM than on methadone. Previous trials of LAAM have not included
sufficient numbers of new patients (i.e., those who have never been in treatment)
or noncompliant patients to allow definitive statements to be made about which
patients are appropriate for LAAM. As more patients receive LAAM in clinical settings
and programs perform evaluation and outcomes studies, including interviews
with patients to learn their preferences, these data will accumulate.
Many of the treatment professionals and administrators who reviewed the first
draft of this TIP called for the document to provide very specific guidelines
for deciding which patients would do better on LAAM than on methadone. Some
expressed disappointment that the precise target population for LAAM was not delineated
in the document. A few reviewers even asked that this TIP cite the specific
percentage of opiate-addicted persons who would most benefit from LAAM treatment.
Although these concerns are understandable, the response at this time is
that data are not available to answer these types of questions. After more
widespread experience in the use of LAAM with different groups of patients, it may
be possible to select specific subgroups of those for whom LAAM would be appropriate.
Some readers of the TIP will be among the clinicians, administrators, and
investigators who are gaining and examining LAAM experience as it accumulates.
However, research and experience with methadone have led to some certainties about
the role of maintenance medications: methadone and LAAM are useful medications,
but they cannot meet all the health and social needs a patient may have. Both
medications should be dispensed in a therapeutic setting and in conjunction with comprehensive
health and social services that are structured to meet individual patient needs.
In recent years, it has been increasingly recognized that patients who
seek treatment through opioid substitution therapy programs have a wide variety
of needs and a range of strengths and weaknesses that challenge the clinical
skills and abilities of treatment providers. The Center for Substance Abuse Treatment
(CSAT) has created this series of TIPs to document the current state of knowledge
in particular areas, to provide practice guidelines, and to suggest future
directions for research and investigation.
This TIP LAAM in the Treatment of Opiate Addiction is an attempt to provide
single State agencies, treatment providers, clinicians, administrators, and patients
with current knowledge about LAAM. Members of two panels--a Federal resource
panel and a consensus panel of experts--provided input for the TIP. These two
groups met in April and June, respectively, of 1994. The panels agreed that the
TIP should provide guidance on current practice and objectively address issues
and concerns that remain unanswered.
The Federal resource panel consisted of representatives of Federal agencies
as well as other organizations (see Appendix C), concerned with the regulation and practice of substance
abuse treatment and prevention. Representatives of NIDA, FDA, the Drug Enforcement
Administration (DEA), CSAT, the Center for Substance Abuse Prevention (CSAP), the National
Association of State Alcohol and Drug Abuse Directors (NASADAD), and others concluded
that a document was needed that presented the current state of knowledge about
LAAM in a balanced and objective manner.
The consensus panel of experts was nominated, selected, and convened soon after.
It was composed of clinicians and researchers who were involved in both
the early studies of LAAM and the more recent Labelling Assessment Study.
Representatives from treatment programs and single State agencies were included, as was
a medical ethicist. To ensure open and honest communication during the panel's
deliberations, each participant signed a statement of confidentiality and a statement
of disclosure of conflict of interest. The goal of the consensus panel was
to describe the clinical, administrative, managerial, and regulatory issues
raised by LAAM therapy and to achieve consensus on these issues when possible.
This TIP represents the panel's effort to assemble the current knowledge about
the use of LAAM to help single State agencies and treatment providers understand
this new medication. Those interested in the use of LAAM in narcotic treatment
programs will find this TIP valuable, particularly front-line program staff working
directly with patients and their families. Patients receiving LAAM therapy may
also find the TIP helpful.
As the consensus panel discussed and debated the clinical, pharmacological,
administrative, regulatory, and practical value of LAAM as it is currently approved for
use, several issues emerged. There was consensus that more experience and knowledge
are needed than now exist. In addition, it is the expressed wish of the panel
that NIDA, CSAT, and the other agencies concerned with the problem of substance
abuse and HIV/AIDS help to address the concerns described here.
The panel recommends that training be available for all levels of staff
in programs that introduce LAAM therapy. Experience in the Labelling Assessment
Study indicates that patients experience improved outcomes in programs that make
a concerted effort to create an informed interdisciplinary treatment staff.
Counselors, nurses, physicians, and others must all support treatment
decisions and work together to help patients attain treatment goals. Two resources for training and technical assistance in the use of LAAM are described in Appendix B.
It is clear that LAAM will not replace methadone in maintenance treatment.
As indicated above, the details of what works, for whom, and when, are
still not known. The consensus panel agreed that a thorough discussion of patient-treatment
matching issues in opiate addiction treatment was needed. The panel was pleased
to learn that another TIP in this series -- Matching Treatment to Patient Needs in Opioid Substitution Therapy --
was being developed to address these issues. The panel has no doubt that the
TIP on matching will also be applicable to LAAM therapy. The TIP on matching,
along with the previously published TIP State Methadone Treatment Guidelines and the TIP on Assessment and Treatment
of Cocaine-Abusing Methadone-Maintained Patients, will provide valuable
information for understanding the elements of comprehensive treatment and for developing
individualized treatment plans. As expertise and experience in the use of LAAM grow,
this body of knowledge will be periodically updated.
The two issues that most concerned the consensus panel were the use of LAAM
by women of childbearing potential and the lack of take-home availability
of LAAM. The panel recommends that research begin quickly to determine the
safety and efficacy of LAAM during pregnancy as well as the safety and efficacy
of providing take-home doses for self-administration under certain circumstances.
The requirement for monthly pregnancy testing caused concern and discussion
among some panel members. FDA has not imposed this requirement on any other
newly approved drug. No reason exists for researchers or clinicians to believe
that LAAM would affect the mother or fetus any differently than other narcotic
drugs taken under supervision during pregnancy, including methadone. Therefore,
the panel was concerned that the required monthly pregnancy testing would be
viewed with suspicion by patients and seen as an additional and perhaps unnecessary
expense by program administrators.
Therefore, the panel recommends that the necessary studies in animals and humans be
conducted and evaluated quickly and that the results be made widely available to
patients, clinicians, and administrators. If warranted, the current requirement
for monthly testing should be revised based on these studies. In addition,
family planning services should be available to all patients maintained on both
LAAM and methadone, as part of a comprehensive women's health program either
onsite or by referral to a cooperating facility.
The absolute prohibition against take-home doses of LAAM may prevent acceptance
by patients and staff. In States that prohibit or limit the use of take-home
methadone, use of LAAM would provide more clinical flexibility and allow patients
a degree of freedom from daily visits that they do not now enjoy. In States
where narcotic treatment regulations are similar to Federal regulations, LAAM
therapy would allow treatment professionals to adjust the frequency of clinic visits
during the first 2 years of treatment. After 2 years, patients receiving methadone
are eligible for twice-weekly visit schedules; after 3 years, schedules with
once-weekly visits are possible if patients have made substantial progress in treatment.
In such situations, even if patients prefer LAAM to methadone, they may
want to take advantage of having fewer visit schedules and be transferred to
methadone maintenance treatment.
Once patients being treated with LAAM begin to experience stability and advance
in treatment, they will need take-home doses for a variety of valid personal
and vocational reasons. Constant changes between LAAM and methadone could
present administrative and clinical problems, including problems related to physician
orders and documentation. Therefore, the consensus panel believes that the prohibition
against take-home doses of LAAM should be openly discussed and considered. Studies
and trials to explore the possibility of take-home doses of LAAM for appropriately
screened patients should be conducted and evaluated.
It is hoped that when patients and clinicians gain experience and knowledge,
LAAM therapy will provide treatment professionals and patients with another
medication to add to the treatment system. After a period of clinical use, the treatment
field will eventually understand where LAAM fits into the treatment system.
Such knowledge will maximize the ability to match patients to appropriate treatment
and assist greater numbers of persons in need of treatment.
Patient selection issues and other unanswered questions about LAAM therapy should
help focus research and evaluation efforts as LAAM treatment is implemented
across the country. Issues concerning pregnant women, take-home LAAM, the relationship
of staff attitudes to successful treatment, use of LAAM and methadone after
relapse, and the use of LAAM in difficult-to-treat or noncompliant patients and
others must be examined by carefully designed studies. Focused research efforts
will help resolve some of these issues and improve treatment for all patients
in opioid substitution therapy.
The TIP is organized into six chapters. The remaining chapters are described
below.
Chapter 2 Clinical Profile of LAAM reviews the pharmacology of LAAM and
its actions and effects, both in the laboratory and in treatment settings.
Medications that should be avoided by patients taking LAAM are discussed,
as well as the side effects, indications, and contraindications of LAAM.
Although this chapter may be more technical than others, the panel feels that direct
treatment providers should read it carefully and understand the pharmacology of LAAM.
These front-line staff are often the first to discuss such issues with
patients and to respond to their concerns. Anecdotal information from the Labelling
Assessment Study indicated that LAAM maintenance worked best in programs where direct
treatment staff were fully trained and briefed about all aspects of LAAM therapy
and had a positive attitude toward it.
Chapter 3 Clinical Application of LAAM Therapy explains the use of LAAM
and describes practical concerns for clinicians in prescribing LAAM, including
dosage and build-up schedules and whether to provide LAAM every other day or three
times weekly. It reviews the LAS results as they pertain to different patient
subgroups. Ways to approach and solve frequently occurring clinical issues concerning
dosing are described.
Chapter 4 Treatment Planning reviews the first 30 days of LAAM treatment
and issues and concerns that may arise. An approach to patient education that
maximizes acceptance of this new maintenance therapy is described.
Chapter 5 Management and Administrative Issues provides an overview of administrative
and managerial requirements for programs to become approved to use LAAM and
addresses the practical application of these requirements. Issues that contribute
to successful treatment programming are discussed as are issues specific to
LAAM therapy, such as monthly pregnancy testing and transfer of patients from
LAAM to methadone. The costs of LAAM therapy and issues involved with reimbursement,
especially in managed care environments, are discussed.
Chapter 6 Regulatory and Ethical Issues provides an overview of the regulatory
process for States and programs to become approved to use LAAM. The future of
LAAM (and methadone) treatment regulations is discussed. NIDA's development
of the Methadone Quality Assurance System, designed to assess the feasibility
of a performance-based reporting and feedback system for methadone treatment
programs, has led to more emphasis on treatment outcomes and quality of care than
is found in traditional process reviews currently performed by FDA. In addition,
the Institute of Medicine's recently published review of regulations governing
methadone treatment calls for less government regulation and the adoption of practice
guidelines for opioid substitution therapy (Institute of Medicine, 1995). The costs of LAAM therapy and the economic issues
raised by the approval and use of LAAM are also reviewed.
Appendix A lists references cited in the TIP as well as other materials on LAAM.
Training and informational materials available from the manufacturer of LAAM, as ewll as technical assistance available through the CSAT-implemented Opiod Addiction Treatment Improvement Project, are described in Appendix B.Appendix C
is a list of individuals who participated in the Federal resource panel that
helped develop this TIP. Names of those who participated in field review of an
early draft of this document are listed in Appendix D.
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