LAAM (levo-alpha-acetyl-methadol) is a synthetic opioid agonist that has recently
been approved by the Food and Drug Administration (FDA) for the maintenance
treatment of opiate addiction (Food and Drug Administration, 1993). It is not approved for opiate detoxification
treatment for either short- or long-term detoxification.
Although LAAM is similar to methadone in many ways, it has several features that
make it distinct from methadone. The most significant of these features is
LAAM's longer duration of action, which allows patients to visit the treatment
program less frequently from treatment inception. The approval of LAAM provides
a new treatment alternative in the management of opiate addiction. As such,
it should be evaluated by the same standards by which other treatment options
have been judged. A new medication should, for example, expand accessibility
to treatment, and it should enable more effective and appropriate treatment
for patients already in the treatment system. LAAM therapy offers patients
such possibilities and creates opportunities for staff members to learn about
and provide a new form of care.
In approving LAAM, FDA did not significantly modify the language of the regulations
governing methadone treatment. The word "methadone," for example, was simply changed
to "narcotic drugs" to be more inclusive. However, differences between the
two agents with respect to dosing schedules, prohibition of LAAM take-home
doses, and eligibility for LAAM treatment are spelled out in detail in the FDA
regulations. As the States begin to approve LAAM and develop their own regulations,
many may wish to follow the Federal example. Introduction of LAAM does not
require States to develop extensive new regulations. (See Chapter 6 for a discussion of regulations and their development.)
This chapter describes the medication LAAM, including its metabolization, interactions
with drugs of abuse and other medications, safety and side effects, and use
with certain patient groups, such as women.
The clinical utility of LAAM is based primarily on the activity of two metabolites,
rather than on that of the parent drug alone. In the body, LAAM, metabolized
by the liver, changes sequentially to nor-LAAM and dinor-LAAM. (Throughout
this document, the term LAAM refers to the parent compound and its two active
metabolites, nor-LAAM and dinor-LAAM.) Of these three compounds, nor-LAAM is the most
potent. The combined duration of activity of all three of these compounds accounts
for LAAM's long-acting properties. Knowledge of the basics of steady-state
pharmacology is important for understanding the action of LAAM in the body. Steady-state
pharmacology is described in Chapter 3 in the section "Induction Onto LAAM."
In practical terms, LAAM's longer action makes it possible for patients to
visit the clinic less often than they would for daily methadone treatment. LAAM
can be given either every other day or three times a week. Under current FDA
regulations, LAAM cannot be given more frequently than every other day, 21 C.F.R. Part
291 Section 291.505(k)(1)(i) (1993), and no take-home doses can be given under any circumstances, 21 C.F.R.
Part 291 Section 291.505 (k)(1)(iii) (1993).
Federal regulations also require clinics that use both LAAM and methadone to ensure
that "dosage forms of LAAM and methadone are easily distinguished," 21 C.F.R.
Part 291 Section 291.505 (1993). LAAM must be different in color and taste from methadone. Methadone is
currently available in powder, tablet, and liquid forms, whereas LAAM is currently
prepared only in liquid formulation for oral use. The manufacturer provides LAAM
as a colorless liquid.
At present, LAAM is available only from Roxane Laboratories, Inc. Methadone
can be purchased from three different companies: Mallinckrodt Chemical, Inc.;
Roxane Laboratories, Inc.; and UDL Laboratories, Inc. Each company markets
different forms of methadone that vary in color and taste from the others.
LAAM's interactions with drugs of abuse have not been systematically studied in
human populations, but data from the clinical studies do not suggest any unusual
risk of LAAM versus other opiates in terms of drug-drug interactions with drugs
of abuse. The effects of LAAM would be expected to be similar to the effects
of methadone and other opioid drugs under the same conditions. However, until
conclusive data from systematic studies are available, interactions cannot be predicted
with certainty.
LAAM, like methadone and other opioids, may have additive or synergistic effects
when used in combination with commonly used drugs of abuse. Because of LAAM's
long-acting nature, both patients and clinic staff should be aware that special caution
is necessary when it is combined with drugs that depress the central nervous
system, including alcohol. For this reason, clinic staff should ensure that all
patients who are known to abuse sedatives, tranquilizers, propoxyphene, antidepressants,
benzodiazepines, or alcohol are told in very clear language of the dangers of adverse additive
effects if they take these substances while being stabilized or maintained on LAAM.
Experience during the Labelling Assessment Study (LAS) of LAAM indicated that LAAM's
delayed onset of effect (from 24 to 36 hours) may lead some patients to take benzodiazepines
or other drugs including opiates in an attempt to create an additive effect.
Patients receiving LAAM should be counseled very specifically about its
delayed onset and prolonged duration of activity, as well as the associated extra
risk of effects that can induce withdrawal if patients take other drugs, even
on days when they do not receive a LAAM dose. Some patients may not be candidates
for LAAM if they are unable to tolerate the slow onset.
Patients receiving LAAM should also be cautioned not to use or abuse alcoholic beverages.
Patients should be advised that chronic use of alcohol damages the liver
and that liver dysfunction may interfere with the metabolism of LAAM. If alcohol
abuse is evident, the program should ensure that the patient receives counseling
and assistance in discontinuing alcohol use. If a patient abuses alcohol consistently,
a switch to methadone may be warranted because daily clinic attendance will
permit closer monitoring, and research has indicated that methadone may be safely
prescribed for patients with severe liver damage. Although similar research on LAAM
has not been completed, there is every reason to believe that use of LAAM by
patients with severe liver damage is not problematic. LAAM may be used concurrently
with disulfiram (Antabuse).
Mixed agonists and antagonists, such as pentazocine (Talwin), butorphanol (Stadol),
nalbuphine (Nubain), and buprenorphine (Buprenex), and pure antagonists, such as naltrexone
and naloxone, all may precipitate withdrawal in LAAM-maintained patients.
FDA has recently approved the narcotic agonist naltrexone for use in treating
alcohol craving. Clinicians must be aware and must inform patients that the use
of naltrexone will precipitate withdrawal symptoms in patients maintained
on LAAM or methadone. Naltrexone must not be used by patients in opioid substitution
therapy.
As a result of cross-tolerance, LAAM (like other mu agonists) reduces
the effectiveness of narcotic analgesics in normal doses. Clinicians may need
to adjust medications and patient pain management accordingly. As with methadone,
when other narcotics, such as morphine, are used for analgesia and anesthesia,
dosages should be adjusted upward to achieve the same level of pain relief or anesthesia.
With the rise in the prevalence of tuberculosis, many more patients are being
prescribed rifampin, the bactericidal drug currently widely used to treat this disease.
Rifampin has been found to reduce methadone levels in serum by up to 50
percent in patients who have been stabilized on methadone maintenance. This reduction
in serum levels of methadone often results in symptoms of withdrawal. A recent
study of an alternate antituberculosis medication, mycobutin (Rifabutin), showed
that this medication did not alter plasma levels of methadone. Some participants
had subjective complaints of discomfort, which may have resulted from suggestivity
to remarks of the researchers, as noted at the consensus panel by B. Primm,
M.D. Further studies of this type should be effects.
When a new medication is introduced to the market, all potential side effects
must be reported. The most frequently reported side effects in the LAAM trials
were insomnia, nervousness, and constipation. Other side effects observed in
clinical trials are shown in Exhibit 2-1. Side effects probably caused by LAAM that occurred in less than
1 percent of patients in clinical trials include a drop in blood pressure
when the patient stands (postural hypotension), muscle pain (myalgia), and tearing
of the eyes.
In addition, several other reactions appeared in both controlled and uncontrolled
LAAM trials. Although they were seen infrequently and their relationship to
LAAM is unknown, clinic staff should be aware that these effects have been reported:
hypertension, changes in cardiac activity patterns on electrocardiogram
(specifically, prolongation of the QT interval and nonspecific ST-T wave changes), bradycardia,
hepatitis and test indications of abnormal liver functions, absence of menstruation
(amenorrhea), and the presence of pus in the urine (pyuria). Close monitoring by counselors,
nurses, and medical staff in the first several months of adjustment to LAAM therapy
will ensure that any side effects are addressed promptly.
Clinicians may want to provide symptomatic treatment of side effects resulting from
LAAM. Of the three most commonly reported side effects of LAAM, constipation
is probably the most persistent and problematic. It also raises the potential
problem of laxative dependence when patients treat themselves. Patients should
be told to avoid the use of strong or harsh chemical laxatives. Stool softeners,
lubricants (such as mineral oil), bulk and fiber laxatives (such as Metamucil), and
naturally occurring laxatives such as prunes may provide symptomatic relief. However,
it should be noted that chronic use of mineral oil can lead to malabsorption
of fat-soluble vitamins and result in a vitamin deficiency. Adequate fluid
intake also is important.
The other two most frequent reactions to LAAM therapy, insomnia and nervousness,
usually disappear with continued treatment. Other side effects, for example, muscle
and joint pain, can be treated with nonsteroidal anti-inflammatory agents,
such as ibuprofen.
Further research is needed on the impact of liver disease on patients in opioid
substitution therapy programs. Although the presence of liver disease is not currently
a reason to exclude a patient from treatment, the presence of severe persistent
liver disease does indicate the need for caution in treatment and monitoring
and may require special patient counseling. In patients with a severely impaired
liver, the parent drug, LAAM, may not be as easily converted into the more active
metabolite, nor-LAAM, because this process occurs in the liver. This difficulty in
conversion could delay the drug's onset of effect. Such patients should be monitored
closely for signs of excessive accumulation of LAAM and its metabolites.
Patients should also be monitored for signs and symptoms of dose accumulation, which
include jumpiness or feeling on edge (what some patients describe as "feeling wired"),
poor concentration, drowsiness, and dizziness when moving to a standing position.
When patients exhibit signs of excess accumulation of LAAM, the dosage
should be reduced. If significant signs of sedation are present, the clinician
may omit a dose or slow the buildup.
Data show no differences between the sexes in response to LAAM treatment; women
and men fare equally well. However, until the safety of LAAM during pregnancy
is studied further, the consensus panel that developed this Treatment Improvement
Protocol felt that women of childbearing potential who entered treatment should
receive methadone rather than LAAM. Once treatment has progressed, the required
pregnancy testing can be discussed with the patient. When informed consent is obtained
and pregnancy testing is implemented, the woman can be transferred to LAAM
if this is desirable. As discussed in Chapter 1, the panel recommends that
the necessary studies in animals and humans be conducted and evaluated quickly
and the results made widely available to patients, clinicians, and administrators.
If warranted, the current requirement for monthly testing should be revised
based on these studies.
Until data are evaluated, treatment of pregnant women with LAAM is discouraged.
Monthly pregnancy testing is a requirement for women of childbearing potential
who receive LAAM. Women who become pregnant while on LAAM should be transferred
to methadone maintenance. (More detailed information about considerations for pregnant women and nursing
mothers is given in Chapter 3.)
The effect of LAAM on the immune system is unknown, as is its interaction with
zidovudine (formerly azidothymidine, or AZT) and other drugs prescribed for patients
with human immunodeficiency virus (HIV) infection and acquired immunodeficiency
syndrome (AIDS). Currently, there is no known reason to exclude patients from LAAM
treatment based on HIV-positive status or AIDS.
Patients receiving maintenance therapy with methadone or LAAM are often undertreated
or even denied treatment for pain associated with injury, surgical procedures,
or chronic conditions. It is the ethical obligation of health care providers
to provide adequate pain relief for all patients. Reluctance to provide adequate
treatment for pain is usually based on the belief that the maintenance dose of LAAM
or methadone provides pain relief. This belief is absolutely incorrect.
With long-term administration of LAAM, nearly complete tolerance develops to
any analgesic effects of the medication, and the usual maintenance dose affords
no pain relief.
The inadequate treatment of pain in patients receiving maintenance therapy
often leads to disruptive behavior by angry and frightened patients and discharge
against medical advice, despite the obvious risks to the health of the patient
(Zweben and Payte, 1990). For these reasons, program staff should work cooperatively
with the patient's health care providers to assist in providing proper pain management
and treatment.
Patients on LAAM maintenance therapy for opiate addiction occasionally require treatment
for pain associated with trauma or with medical, surgical, or dental procedures.
Whenever possible, pain management should be discussed with care providers
before surgery or dental procedures take place. Some basic principles should
inform the management of acute pain in patients receiving maintenance therapy:
Maintenance treatment should be continued without interruption during pain management.
When nonnarcotic analgesia is not effective for pain management, standard opioid
agonist drugs, such as codeine and morphine, are appropriate. It is important,
however, for clinicians to be aware that patients will require higher doses of these
drugs at more frequent intervals because of cross-tolerance to LAAM or methadone.
Doses should be adjusted accordingly to achieve adequate pain relief for
the patient. Doses should be administered at regular intervals rather than
"as needed."
Agonist/antagonist drugs may precipitate severe withdrawal reactions and should not be used.
These include pentazocine (Talwin), butorphanol (Stadol), nalbuphine (Nubain),
buprenorphine (Buprenex), and naltrexone. More information on this subject can be found
in the TIP State Methadone Treatment Guidelines.
Patients with chronic opioid addiction and a disorder causing chronic pain pose
a clinical challenge. Those who fail to respond to more conservative management
often benefit from carefully supervised adequate doses of short-acting opioid
agonist drugs, provided within the context of adequate dose maintenance pharmacotherapy.
The two most important areas for additional research on LAAM treatment are
pregnancy (effects on the mother and the fetus, including postpartum issues such
as lactation and breast-feeding) and the feasibility of take-home LAAM. Other
essential research topics related to LAAM are
Immune response
Interactions with drugs of abuse, such as cocaine and alcohol (multidrug interactions)
Coexisting psychological problems or disorders (dual diagnoses)
LAAM as an analgesic for treatment of chronic pain
Interactions with other therapeutic drugs
Medically supervised withdrawal from maintenance therapy with LAAM
LAAM in patients with hepatic or renal disease
LAAM for daily use in special situations, such as in patients who metabolize
the drug rapidly.
Other research areas include quality assurance studies focusing on improved treatment
outcomes (for example, research on patient selection and on staff attitudes) and
cost-effectiveness studies.
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