Levo-Alpha-Acetylmethadol (LAAM): Clinical, Research, and Policy Issues of a New Pharmacotherapy for Opiod Addiction

Contents

(Top)

i. Abstract

A number of issues are relevant to the development and use of levo-alpha-acetylmethadol (LAAM) as a treatment alternative to methadone. A brief history of methadone maintenance treatment is provided and variants of standard methadone treatment are discussed. The history and current status of LAAM are discussed, as well as its advantages over methadone. In addition, relevant clinical, research, and policy issues are addressed. LAAM has advantages over methadone specifically with regard to thrice- weekly dosing, potential to reduce HIV/AIDS risk, possible cost savings, and possible improved clinic-community relations. The effective and cost-effective implementation of LAAM as a new treatment for opioid addiction requires attention to a number of issues: (1) LAAM as an HIV prevention measure through its potential risk-reduction effects, (2) the use of LAAM with specific high-risk subgroups, (3) causes of differential rates of treatment dropout and their amenability to intervention, (4) the role of patient choice in long-term maintenance treatment, (5) the impact of LAAM on clinic operations, (6) the potential for LAAM as a take-home medication, and (7) the costs of implementing and sustaining LAAM maintenance services.

(Top)

I. Introduction

Methadone treatment has been developed in the United States over the past 30 years. Currently about 750 programs treat approximately 115,000 patients at any one time in the 42 states and territories where such services are provided (Institute of Medicine 1995). Methadone treatment is the predominant treatment available for opioid addiction in this country, and has been delivered primarily through community-based programs, but also in medical clinics, hospitals, and even mobile vans. The effectiveness of methadone treatment(1) in reducing injection drug use and criminal behavior and in improving social stability and productivity has been well documented in numerous research studies (see summaries of this literature in Powers & Anglin 1993; Ward, Mattick & Hall 1992; Ball & Ross 1991; Anglin & Hser 1990; Gerstein & Harwood 1990; Office of Technology Assessment 1990; Anglin & McGlothlin 1985).

After its introduction by Dole and Nyswander in New York City in 1965 (Dole, Nyswander & Kreek 1966), methadone maintenance soon became the primary treatment modality for heroin addiction with the support of the Nixon administration and the Special Action Office for Drug Abuse prevention (SAODAP) (Goldberg 1980). By 1973, 73,000 patients were in methadone treatment nationwide (Strategy Council on Drug Abuse 1973). The advent of the AIDS epidemic in the 1980s led to a reassessment of methadone treatment because of the need to intervene with injection drug users (IDUs) at risk for HIV infection (Cooper 1989). In addition to the demonstrated reductions in injection behavior associated with methadone treatment (Ball et al. 1988), the existing structure of methadone treatment programs and services provided an infrastructure for the implementation of HIV prevention, education, and treatment protocols (Magura et al. 1989; Sorensen et al. 1989). Consequently, methadone treatment, while still controversial within the community-at-large (as evidenced by opposition to the siting of new clinics), became the subject of renewed interest among experts in public health and drug policy.

Beginning in the mid-1980s, several variations on standard methadone treatment were introduced in an effort both to upgrade the quality of treatment and to address the needs of particular types of patients. Enhanced methadone programs, often funded as research demonstration projects, offered a wider range of services as compared with standard methadone treatment, including vocational rehabilitation, treatment for cocaine use, individual and group counseling, and HIV/AIDS prevention and education (Inciardi, Tims & Fletcher 1993). The demand for treatment improvement competed with pressures for cost containment, however, and several variants have been introduced that involve using methadone treatment more efficiently. One of these approaches is medical maintenance, in which patients who are stabilized and have high levels of social functioning are provided methadone in medical clinics or physicians' offices rather than at a methadone program (Novick & Joseph 1991). Alternatively, in an effort to provide services more broadly, low-threshold maintenance approaches have been assessed in the form of interim maintenance (Yancovitz et al. 1991) as well as mobile dispensing clinics (Brady 1993). None of these variations on standard methadone treatment is in wide use, either because it was conducted under an exception to FDA regulations (e.g., medical maintenance) or has not been accepted by the treatment community despite FDA approval (e.g., interim maintenance).

Within the midst of these developments, the Food and Drug Administration's approval of levo-alpha-acetylmethadol (LAAM) for opioid treatment in July 1993 offered a new alternative to the maintenance treatment of heroin dependence. This article discusses a number of clinical, research, and policy issues that will need to be addressed by federal and state officials, program staff, and treatment researchers if LAAM is to become widely used in an effective and cost-effective manner. To place the discussion in context, a brief survey of the history and current status of LAAM treatment is provided first.

(Top)

II. Historical Development and Current Status of LAAM

LAAM is a long-acting synthetic opioid agonist of the morphine type; it has been developed and tested over the past 25 years as an addiction treatment medication, and recently received approval for general clinical use in treating opioid addiction in adult males and nonpregnant, nonnursing adult females (Federal Register 1993). LAAM is administered to patients on a dosing schedule of three days a week instead of the daily dosing that is typically required for methadone treatment. LAAM exerts its clinical effects in the treatment of opioid addiction through two mechanisms. First, LAAM substitutes for opioids and suppresses symptoms of withdrawal in persons dependent on opioids. Second, long-term oral administration of LAAM produces sufficient tolerance to block the subjective "high" of typical doses of illicit opioids. As with methadone, the consequence is a marked reduction in, and in some patients the elimination of, the use of illicit opioids (mainly heroin) (Ling, Rawson & Compton 1994).

(Top)

III. Clinical Trials of LAAM

The initial interest in developing LAAM as a treatment for opioid addiction in the late 1960s and early 1970s was a response to the disadvantages of daily attendance for methadone treatment and the problems of diversion with methadone take-home doses (e.g., street use, accident poisoning, and other public health concerns). Thus, the search for a long-acting medication became a federal priority in the early 1970s for SAODAP and then for NIDA. The first clinical trials using LAAM in an opioid treatment program were carried out by Jaffe and his colleagues in Chicago in the late 1960s and early 1970s (Senay et al. 1974; Jaffe et al. 1972; Jaffe & Senay 1971; Jaffe et al. 1970). These studies found that LAAM was equal or superior to methadone in outcome measures, such as dropout rate, employment arrests, illicit drug use, clinic attendance, and request for dosage changes. Subsequent evaluations of LAAM, which included both double-blind studies and multicenter open-label studies, confirmed these results, although the later studies were more likely than the earlier ones to find higher dropout rates for LAAM than for methadone patients in the initial weeks of the study (Tennant et al. 1986; Hough, Washton & Resnick 1983; Freedman & Czertko 1981; Marcovici et al. 1981; Blaine et al. 1978; Ling, Klett & Gillis 1978; Trueblood, Judson & Goldstein 1978; Senay, Dorus & Renault 1977; Ling et al. 1976).

In one of the main clinical trial — called the "VA Study" (Ling et al. 1976), which was a 40-week double-blind trial conducted at 12 sites with 430 subjects-treatment with LAAM was found to be comparable to treatment with methadone with respect to reduction in heroin use. LAAM doses in the range of 60 mg to 100 mg dispensed three times a week reduced the average frequency of opioid positive urine samples to 15% to 20%, which was comparable to daily methadone doses of 50 mg and 100 mg. Although more subjects dropped out of LAAM treatment than methadone treatment in the first four weeks of treatment (16% dropouts for LAAM versus 12% dropouts for methadone), the dropout rates for both groups rapidly declined over time, and rates were in the range of 1% to 2% per week for the remaining subjects by the third month of the study. Global ratings of acceptability and response to treatment were similar for both LAAM and methadone. In terms of differential response, LAAM was more effective for those subjects perceived by staff to benefit from reduced frequency of clinic visits, while it was less effective for those perceived as needing the added support of daily clinic visits.

Clinical trials of LAAM generally ended in the early 1980s with the Reagan administration's shift in federal drug policy priorities. A Medline search for the period 1985-1994 identified only three published clinical reports on LAAM (Tennant et al. 1986; Zangwell et al. 1986; Crowley et al. 1985). With the establishment of the Medications Development Division at NIDA in 1990, which had been authorized by the Anti Drug Abuse Act of 1988, pharmacotherapeutic options received renewed attention. NIDA sponsored a multisite study of LAAM, called the "Labeling Assessment Study" (LAS), that focused on product labeling and adverse reactions. The results of this study were considered in the final FDA approval process of LAAM, but have not been published (see National Institute on Drug Abuse, n.d.).

LAAM has been studied in a total of 2,666 street addicts and 3,319 methadone maintenance patients, including 5,697 men and 288 women (the LAS included an additional 204 women) (Ling, Rawson & Compton 1994). In 27 studies, 4,610 patients received orally administered LAAM for up to three years (though most patients received LAAM treatment for less than one year) in thrice-weekly doses ranging from 10 mg to 140 mg. Most patients in these studies received LAAM three days a week (usually Monday, Wednesday, and Friday), although some were on an every-other-day dosing schedule. Many of the sites that dispensed LAAM on a three-days-a-week schedule increased the Friday dose, prior to the 72-hour interdose interval over the weekend, to prevent patients from experiencing opioid withdrawal symptoms on Monday morning.

Most LAAM trials were designed to last for less than a year (usually 40 weeks), and little information has been published on the effectiveness of LAAM delivered over periods in excess of a year. A major exception is a study conducted in Los Angles in the early 1980s (Tennant et al. 1986), which involved clinical experience with 959 male and female patients treated with LAAM for up to three years. However, only 7.8% of the patients remained in treatment for over two years, and the mean time in treatment was five months. Effects of LAAM measured in terms of time in treatment were not reported, except for selected liver function tests. Despite this extensive history, the long-term effectiveness of LAAM with respect to various treatment outcome measures remains to be determined; these include heroin and other drug use, criminality, employment, HIV status and risk behaviors, psychological status, and reported side effects.

(Top)

IV. Current Status of LAAM

Since it received FDA approval in July 1993, the diffusion of LAAM into the existing methadone clinic system appears to be a slow process at several levels, including state regulatory changes, clinic licensing by the FDA and the DEA, program staff ambivalence, and client interest. As of September 2, 1994, 22 of the 42 states (including the District of Columbia) that authorize narcotic treatment programs (i.e., methadone clinics) had approved the use of LAAM. These 22 states have 228 methadone clinics, of which 43 had made application to the FDA for registration to use LAAM. The FDA approved 35 of these applications and was processing the rest, but only about 20 of the approved methadone clinics were treating patients with LAAM. The FDA received an additional 23 applications from clinics located in states that permit the use of LAAM under an exemption process. The remaining states, including the two with the largest number of methadone maintenance programs (New York and California), will likely approve the use of LAAM in 1995 or 1996.(2) By the end of 1994, only about 200 patients were receiving LAAM.(3)

(Top)

V. Advantages of LAAM Treatment

LAAM's pharmacological properties allow for a number of demonstrated and potential advantages over methadone in the treatment of opioid addiction:

Owing to its thrice-weekly rather than daily medication schedule, LAAM may be less disruptive to patients' normal activities and routines.
Some evidence suggests that LAAM has a milder, more consistent effect which enables patients to feel more normal and less "like an addict" (Karp-Gelernter, Wurmser & Savage 1976). LAAM seems to provide less sedation and little or no euphoria. Patients do not experience as much "nodding" as with methadone (Resnick et al. 1976).
Because current federal regulations do not allow take-home doses of LAAM, the potential for overdose deaths from prescribed LAAM in nontolerant individuals, such as children, is virtually eliminated; in addition, the potential for diversion of LAAM to street markets is greatly reduced.
Cost savings from the reduced frequency of dispensing may enable clinics to redirect staff time to provide more counseling and other rehabilitative services.
The use of LAAM by a significant proportion of patients could promote improved relations between clinics and the local community since fewer LAAM patients attend the clinic on any given day, thus reducing the loitering, illegal parking, drug dealing, and other problems that neighbors often complain about.
LAAM may not (yet) have the negative reputation of methadone among certain segments of the street-addict population who avoid methadone treatment. Thus, LAAM may offer a way to attract untreated addicts into treatment (Ling, Rawson & Compton 1994).

(Top)

VI. Clinical, Research, and Policy Issues

While the pharmacological and treatment effects of LAAM have been well documented generally, the published research on LAAM has given little or no attention to a number of psychosocial and health services issues. These issues include (1) LAAM as an HIV prevention measure through its potential risk-reduction effects, (2) use of LAAM with specific high-risk subgroups, (3) causes of differential rates of dropout between LAAM and methadone treatment and their amenability to intervention, (4) the role of patient choice in long-term maintenance treatment, (5) the impact of LAAM on clinic operations, (6) the potential for LAAM as a take-home medication, and (7) the costs of implementing and sustaining LAAM maintenance services.

(Top)

VII. LAAM as an HIV Risk-Reduction Measure

In issuing regulations for the use of LAAM, the FDA and NIDA anticipated that LAAM might offer an alternative to methadone treatment as an HIV prevention measure (Federal Register 1993:38706): "This additional treatment [LAAM] can help to reduce the mortality rate among addicts and the possible spread of HIV and other diseases among addicts and the general population by decreasing IV drug abuse." Empirical studies of the impact of LAAM on AIDS-risk behavior are lacking, but certain properties of LAAM and LAAM treatment suggest that it is generally as effective as methadone (and possibly more so) in reducing HIV transmission through injection drug use; other considerations suggest that LAAM may have greater effectiveness in reducing high-risk behavior than methadone for specific subgroups of patients.

Clinical studies have shown that LAAM is as effective as methadone in reducing illicit heroin use. In addition, plasma levels of the active metabolites of LAAM, nor-LAAM, and dinor-LAAM remain higher for a longer period of time than do plasma levels of methadone, thereby delaying the onset of withdrawal symptoms and lengthening the period during which the effects of heroin are "blocked" (Blaine et al. 1981). At lower doses (30 mg to 60 mg), LAAM suppresses symptoms of withdrawal for 24 to 48 hours, with the suppression period extending to 48 to 72 hours at higher doses (80 mg and above). By contrast, an adequate dose of methadone (generally 60 mg and above) is effective for 24 to 36 hours.

Patients receiving methadone, however, do not always receive a dose that is sufficient to prevent interdose opioid withdrawal symptoms, either because of the low-dose policies of many clinics or because some patients metabolize methadone at a more rapid rate than is typical of most patients (which can be addressed by a split daily dose, although federal and state regulations make it difficult for clinics to provide split dosing). Thus, on a more or less daily basis, some methadone patients are likely to begin experiencing withdrawal symptoms hours in advance of their arrival at the clinic, which amounts to a window of vulnerability for using heroin (probably by injection) to alleviate withdrawal symptoms. Similar considerations regarding inadequate dosing and variations in metabolism apply to LAAM, but because of its longer period of effect the window of vulnerability occurs less frequently in the course of a week than is the case with methadone. Thus, during a given period, the cumulative time that patients (or at least some patients) may be at risk for using heroin is likely to be less for LAAM than it is for methadone, consequently, all other things being equal, the risk of HIV transmission by injection drug use will be lower.(4)

In addition, every day that a patient does not come to the clinic for a scheduled methadone dose is a day at risk for injecting heroin. The number of such at-risk days for methadone patients can be high. Data from the Enhanced Methadone Maintenance Project, a five-year study conducted by the Drug Abuse Research Center and the Matrix Institute on Addictions, indicate that during the first 90 days of treatment 76% of patients (n=500) had at least one no-show period of one or more days, 73% had at least one no-show of one day; 30% had at least one no-show of two consecutive days; and 26% had at least one no-show of three or more consecutive days (unpublished data, Drug Abuse Research Center). In the General Accounting Office (1990) report on methadone maintenance, the percentage of patients who missed a daily dose of methadone in a 30-day period at 24 programs ranged from 4% to 51%. Ball and Ross (1991) reported that 16% of patients across six clinics missed at least one dose in the course of a one-week period, with a range among clinics of 1% to 27%. Direct comparison of the percentages from the three reports is not possible, but the data do suggest that a substantial number of methadone patients miss at least one dose in a given week and consequently are likely to be injecting heroin on those days to prevent withdrawal symptoms.

As with methadone, some patients on LAAM are also likely to miss a dosing day. The 40-week VA study found that among all subjects enrolled for at least seven days, the LAAM group had similar rates of missed appointments as the two methadone groups (Blaine et al. 1981). However, because of the longer action of LAAM, a missed day may be associated with lower risk of injection than is the case with methadone, particularly if the patient is able to come in for a make-up dose on the following day.

Another consideration in regard to HIV risk behavior is patient absenteeism on weekends, which appears to be more common than on weekdays. Several circumstances contribute to a more than double rate of absenteeism on Saturdays and Sundays compared with weekdays (personal communication, Richard Rawson, October 22, 1994): dispensing hours are shortened on weekends, in many cases to a period of only one or two hours; buses run less frequently on weekends and certain routes may not operate at all; and social activities often occur on Friday and Saturday nights, which may interfere with clinic attendance on Saturday and Sunday. A missed weekend dose may produce even greater risk for injection drug use than a missed weekday dose because clients are more likely to associate with drug-using peers on weekends than on weekdays. LAAM's prolonged duration of action may reduce injection risk during these high-risk weekend days.

In addition, for patients who prefer LAAM to methadone or who do better on LAAM, treatment with LAAM may promote longer treatment retention, which is associated with progressive declines in illicit drug use (Ball & Ross 1991). Also, the less frequent required attendance for LAAM dosing provides the opportunity for patients to establish a more prosocial, stable, less drug-involved, and lower-risk lifestyle. For opioid addicts with AIDS, LAAM treatment is likely to make it easier for them to schedule and keep appointments at primary care facilities and other agencies for services to meet their multiple needs.

Thus, there are a number of reasons for believing that LAAM is at least as effective as methadone as an AIDS containment intervention, and possibly more so. While this remains speculative, it is important because of its relevance to the overall strategy of AIDS prevention. Clinical studies comparing patients on methadone and on LAAM, using measures of injection and other high-risk behavior and HIV serostatus, need to be conducted to determine whether LAAM does, in fact, have such an advantage over methadone. Such an advantage would not, of course, obviate the need or importance of methadone treatment but it should prompt policymakers to implement LAAM protocols in narcotic treatment programs more aggressively through such means as expedited license approval, special funding, technical training for programs, and patient education.

(Top)

VIII. LAAM Treatment Among Specific High-Risk Subgroups

The acceptability and effectiveness of LAAM among specific subgroups of patients (e.g., women, members of racial/ethnic groups, cocaine/crack-abusing heroin addicts, and HIV-positive patients or persons with AIDS) have not been well studied in previous research. The early clinical trials of LAAM usually excluded women because of concerns over reproductive consequences; in all, less than 300 women were included in the original LAAM trials. While the major clinical Studies of LAAM did include racially and ethnically mixed subject samples, the published reports on the studies did not provide differential outcome findings by race/ethnicity. Furthermore, during the time of the early trials, the use of cocaine was much less than at present, and crack was nonexistent; thus little or no information is available on the efficacy of LAAM among opioid addicts who are heavily involved in cocaine or crack use. Finally, the clinical trials of LAAM were conducted in the 1970s and early 1980s, before the AIDS epidemic, and did not include subjects who were HIV positive or who had AIDS. Clinical and long-term outcome research is needed to determine whether LAAM exhibits differential effects among these and other subgroups of patients and whether clinics need to modify their standard LAAM treatment protocols to address the special characteristics and needs of these groups.

(Top)

IX. Reasons for Patient Termination (Drop Out) from LAAM Treatment

In a study by Ling, Klett and Gillis (1978), 31% of the LAAM dropouts cited "medication not holding" as the reason for dropping out of the LAAM trial, compared with none of the methadone dropouts. In the VA study, retention varied widely among clinics that were using a common protocol, suggesting the importance of nonmedication factors to account for dropping out of LAAM treatment (Whysner & Levine 1978). A number of factors may be responsible for the high dropout rate in the early LAAM clinical studies, for the desire of some LAAM patients to switch to methadone, or for patients being reluctant to enter LAAM treatment in the first place. One may conjecture that these may be related to the physical and subjective effects of LAAM, to patient (and possibly staff) prejudicial attitudes about LAAM, to improper LAAM dosing procedures by clinic staff, or to some other factors. Research on retention in treatment programs that use LAAM will help to identify the more salient reasons for drop out, which can then be addressed in improved treatment protocols.(5)

One issue of particular concern is the negative attitudes toward treatment approaches that develop among street addicts and treatment patients. Popular myths and stigma regarding methadone create barriers to treatment for addicts who might otherwise benefit from methadone treatment (Rosenblum, Magura & Joseph 1991; Hunt et al. 1985-86). Similar negative attitudes toward LAAM are likely to affect the acceptance and success of LAAM maintenance. For example, in the FDA-required Phase 11 clinical trials of LAAM, researchers found that staff acceptance and support of patients as well as patient willingness to accept such support were important in retention, especially during the early stage of treatment (Resnick et al. 1976). In the early 1980s, it was rumored that LAAM caused cancer (Zangwell et al. 1986). A recent study conducted for NIDA noted that negative rumors about LAAM are likely to create patient resistance to trying this new medication (Swan 1994). Thus, it is important to document perceptions and beliefs held by street addicts, treatment patients, and clinic staff about LAAM and to develop educational materials for wide dissemination that address misconceptions and negative attitudes early in the period of LAAM's general clinical use.

(Top)

X. The Role of Patient Choice and Preference in LAAM Treatment

An array of patient-related issues contributes to successful long-term maintenance treatment. Among the most primary are (1) physical health, especially as it relates to the ability of patients to participate fully in the treatment program and to physiological response to medications (2) mental health, especially in terms of psychiatric functioning, which influences the patient's ability to sustain behaviors necessary for engaging in treatment (e.g., regular visits to the clinic and the ability to maintain a counselor/ patient relationship); (3) involvement in a lifestyle or in a social network that supports and sanctions drug use and discourages participation in treatment; and (4) motivation to comply with treatment (Prochaska & DiClemente 1992, 1986, 1982; Miller 1989). Several studies have shown that providing clients with a selection of treatment alternatives decreases dropout rates, reduces resistance to treatment, increases compliance, and improves the overall effectiveness of the treatment program (Miller 1989; Miller & Hester 1980, Parker, Winstead & Willi 1979). With the introduction of LAAM as an additional maintenance treatment for heroin addiction, the role of patient choice or preference will become an important issue in evaluating outcomes of long-term maintenance treatment.

The question of patient preference for LAAM or methadone has not been examined in detail in previous studies, although some LAAM patients in these studies tacitly indicated dissatisfaction with LAAM by switching to methadone. In one study (Tennant et al. 1986), 39% of 897 subjects who had been admitted over a three and one-half year period chose to discontinue LAAM to enter methadone treatment but the remaining subjects chose to continue LAAM treatment. In other studies, dropout rates in the early phase of treatment tended to be higher for subjects on LAAM than for those on methadone. In one of the major clinical studies (Ling, Klett & Gillis 1978), the average length of stay prior to termination for the LAAM group was 72 days, compared with 122 days for the methadone group. At the same time, a subset of patients finds LAAM an acceptable medication and prefers it to methadone. In the Tennant study, 39% of the subjects (n=191) questioned about their preference for LAAM replied that if LAAM were not available they would try to become abstinent or would return to heroin use rather than switch to methadone treatment. The two most common reasons given for preferring LAAM over methadone were the need for less frequent attendance at the clinic (67%) and the feeling that LAAM "holds better" than methadone (43%).

(Top)

XI. Delivery of LAAM Within Established Clinical Settings

Limited information is available on how the introduction of LAAM affects the overall operation of established clinics, in particular possible changes in the type and frequency of interactions between patients and staff and in clinic operations resulting from the reduced number of clinic visits associated with LAAM's dosing schedule. For instance, in a report on clinical experience in a LAAM-only opioid treatment program, Goldstein (1976) noted changes that occurred in the (former methadone) clinic due to the no take-home policy for LAAM: the conflict between staff and patients over the granting or withholding of take-home doses and over urine results (which determined take-home privileges) was eliminated; the time that had been spent in staff-patient disputes over take-homes could be devoted to more productive tasks, such as counseling and patient welfare. Goldstein also pointed out that when staff presented LAAM to patients as "48-hour methadone," patients became anxious about whether the medication would "hold" over the weekend, and often came in sick on Monday; by contrast, when patients were allowed to select their own dose of LAAM (within limits), many patients asked for no increase on Friday and others requested an increase of only a few milligrams. These two examples suggest that the introduction of LAAM into a methadone clinic may require ongoing assessment of program operations, staff attitudes, patient education, and dosing procedures.

(Top)

XII. LAAM as a Possible Take-Home Medication

Since the early 1970s, LAAM has been viewed as a way to avoid the problems associated with methadone take-home doses.(6) Methadone take-home doses were authorized to reinforce progress in treatment and compliance with program rules, to offer an alternative to daily attendance, and to free up staff resources for other patients. Depending on state regulation, methadone patients can earn take-home privileges of up to six days and thus need come into the clinic only once a week. At the same time, however, take-home doses are associated with the diversion of methadone to the street market. Thus, LAAM appeared to be a way to limit diversion, while at the same time reducing the inconvenience of daily attendance.

Federal regulations governing the clinical use of LAAM prohibit take-home doses of LAAM under any circumstances. While this may reduce the problem of diversion and thereby make LAAM more acceptable to the surrounding community, it may also make LAAM less desirable to patients and less effective clinically. Patients who receive more than a three-day supply of methadone may not want to switch to LAAM. A number of researchers have demonstrated that contingent take-home methadone privileges are an effective reinforcement to reduced illicit drug use (Stitzer, Iguchi & Felch 1992; Iguchi et al. 1988; Magura et al. 1988; Milby et al. 1978). The availability of a take-home medication option provides a convenience to the patient and an important treatment tool for the clinician in reducing illicit drug use and reinforcing progress in treatment. FDA regulations prohibit LAAM take-home doses eliminate this useful tool. In addition, LAAM would appear to be a more suitable medication than methadone for take-home doses because less of it is provided to the patient and its slow-acting effect and lack of euphoria limit its appeal to street addicts.

The main justification for not permitting LAAM take-home doses is to prevent diversion and to reduce the likelihood of overdose in naive opioid users or in street users who may combine LAAM with other drugs. However, the same procedures that clinics use to reduce the likelihood of take-home doses of methadone being diverted can also be used with LAAM take-home doses. Such procedures include ensuring that new patients understand dosing procedures, take-home policies, and the consequences of diversion; requiring presentation of' an identification card before dosing, having patients take their dose under observation; requiring patients receiving take-home doses to return with empty bottles, and making random calls to ask that all issued bottles (empty and filled) be brought in for inspection; testing-urine specimens for the presence of methadone or LAAM metabolites; and dealing with suspected and confirmed cases of diversion through established fair hearing procedures, which may result in program discharge.(7)

The possibility of providing take-home doses of LAAM will need to be addressed at the federal level by the agencies involved in the development and approval of regulations for opioid addiction medications; namely, the FDA, NIDA, and the DEA. A recent Institute of Medicine (1995) report on federal regulation of methadone treatment recommended that restrictions on the delivery of methadone treatment be eased. The report did not examine LAAM in detail, but many considerations that informed the committee's recommendations regarding methadone also apply to LAAM. Federal support for allowing LAAM take-home doses is likely to be forthcoming (if at all) only upon presentation of research results that take-home doses of LAAM improve patient acceptability, foster treatment goals, and do not result in significant diversion of LAAM and the potential for overdoses from street use.

(Top)

XIII. Cost of Initial and Sustained LAAM Treatment

Cost, both initial and recurring, is an important issue for clinics considering whether to offer LAAM to their patients, and for those clinics that do offer LAAM, cost enters into issues of reimbursement, either from public sources or in calculating fee-for-service rates to be charged to patients. NIDA has estimated that the cost of purchasing LAAM is about $2.85 more per patient per week than the cost of methadone (Federal Register 1993). In addition, federal regulations require female patients of childbearing age who are taking LAAM to have a monthly pregnancy test that must be performed by a certified laboratory. Each test costs about $7.50, or about $90 per year per patient tested. On the other hand, increased costs for medication and pregnancy monitoring may be more than offset by the fact that LAAM patients come to the clinic three times a week rather than daily. The less frequent attendance by LAAM patients should free up staff time to treat more patients, or to expand and improve the delivery of services for existing patients. However, for clinics that have a large portion of their patients on a three- to six-day methadone take-home schedule, LAAM may offer few economic advantages to the clinic or convenience incentives to patients. These issues regarding cost need to be investigated further in order to clarify the relative costs and cost benefits of LAAM and methadone.

(Top)

XIV. Conclusion

LAAM is the first maintenance medication for opioid addiction approved by the FDA since methadone over 25 years ago. It provides an alternative treatment for those patients who may prefer LAAM over methadone or who have less interdose withdrawal on LAAM than on methadone. LAAM's pharmacological effect is preferred by some patients because it produces less sedation and allows them to function more effectively. LAAM may allow some patients to develop lives that are less tied to the clinic than is possible with methadone. LAAM's reduced clinic visit schedule may also benefit clinic administrators by reducing the personnel costs associated with daily medication and take-home dose preparation. Moreover, the not uncommon pattern of methadone clients missing a scheduled dose and injecting heroin to prevent withdrawal symptoms may occur less frequently with LAAM because of its longer duration of action. This, and other characteristics of LAAM treatment, may give LAAM certain advantages over methadone as an HIV risk-reduction measure, at least for some patients.

The successful implementation of LAAM treatment throughout the system of narcotic treatment programs will require discussion among providers, policymakers, and researchers regarding experiences with LAAM, as well as research into the health services issues associated with introducing a new medication for addiction treatment. Such issues include differential effects among subgroups of patients, ways to improve retention, factors involved in patient preference for LAAM or methadone, the impact of LAAM on clinic operations and treatment protocols, and the costs and cost benefits of LAAM treatment. Although the FDA, NIDA, and the DEA may regard the issue of LAAM take-home doses as closed, should they decide to consider it, their deliberations will need to be informed by the experience and findings of clinicians and researchers.

(Top)

Notes

Throughout this article, methadone treatment should be understood to mean methadone maintenance treatment and not to include methadone detoxification.
This information was provided by George R. DeVaux, BioDevelopment Corporation, personal communication, October 13, 1994.
Based on a telephone survey of 27 clinics that had ordered LAAM by December 1994 (Richard Rawson, Maxtrix Center/UCLA Alcoholism and Addiction Medicine Service, unpublished data).
LAAM requires more patient education than methadone, both to warn patients against other drug use (especially CNS depressants) in the early induction period and to reassure patients that any initial discomfort will ease in two to three weeks. In this sense, LAAM may have a higher window of vulnerability than methadone in the early weeks of treatment, a problem that can be addressed by transitioning patients from methadone to LAAM rather than by inducting them directly to LAAM.
The higher dropout rate for LAAM observed in a number of the studies of the 1970s needs to be considered in light of the protocols for the studies. In an open-label study, when both subjects and study staff know which drug each subject is taking, the new drug (in this case, LAAM) will be viewed with more suspicion than the familiar drug (methadone); thus, a higher dropout rate would be expected. Patients tended to blame adverse symptoms and other problems on the new, experimental drug. In the Phase II and III clinical studies on LAAM, patients could switch from LAAM to methadone if they found the former unacceptable, but methadone patients who wished to end their participation were discharged to the street. Thus, the consequences of dropping out of LAAM treatment were less severe than dropping out of methadone treatment. This may have led clinic staff to work harder with, or to be more forgiving of, methadone patients who were not doing well. Thus, certain problems of LAAM noted in the literature were inherent to its experimental status (Whysner & Levine 1978); these problems may disappear now that LAAM is no longer experimental.
In 1973, Peter Bourne, Director, Office of Programs, SAODAP, argued that "the introduction of l-alpha-acetylmethadol will make [methadone] take home unnecessary" (Bourne 1973:841). Zaks, Fink and Freedman (1972:209), in a report on one of the early clinical studies of LAAM, noted that studies to validate the long-term effectiveness of LAAM were "made urgent by the actual and potential increase in illicit diversion of methadone as maintenance of this narcotic expands."
Al Hasson, clinic director, Matrix Institute on Addictions, provided the information on methods that clinics use to discourage diversion.

(Top)

References

Anglin, M.D. & Hser, Y. 1990. Treatment of drug abuse. In: M. Tonry & J.Q. Wilson (Eds.) Drugs and Crime. Chicago; University of Chicago Press.

Anglin, M.D. & McGlothlin, W.H. 1985. Methadone maintenance in California: A decade's experience. In: L. Brill & C. Winick (Eds.) The Yearbook of Substance Use and Abuse. New York: Human Sciences Press.

Ball, J.C.; Lange, W.R.; Myers, C.P. & Friedman, S.R. 1988. Reducing the risk of AIDS through methadone maintenance treatment. Journal of Health and Social Behavior 29:214-26.

Ball, J.C. & Ross, A. 1991. The Effectiveness of Methadone Maintenance Treatment: Patients, Programs, Services, and Outcomes. New York: Springer-Verlag.

Blaine, J.D.; Renault, P.F; Levine, G.L. & Whysner, J.A. 1978. Clinical use of LAAM. Annals of the New York Academy of Sciences 311:214-31.

Blaine, J.D.; Thomas, D.B.; Barnett. G.; Whysner, J.A. & Renault. P.F. 1981. Levo-alpha-acetylmethadol (LAAM): Clinical utility and pharmaceutical development. In: J.H. Lowinson & P. Ruiz (Eds.) Substance Abuse: Clinical Problems and Perspectives. Baltimore: Williams & Wilkins.

Bourne, P.G. 1973. Methadone diversion. In: Proceedings of the Fifth National Conference on Methadone Treatment, Washington, D.C., March 17-19.

Brady, J. 1993. Enhancing drug abuse treatment by mobile health service. In: J. Inciardi, F.M. Tinis & B. Fletcher (Eds.) Innovative Strategies in the Treatment of Drug Abuse: Program Models and Strategies. Westport, Connecticut: Greenwood Press.

Cooper, J.R. 1989. Methadone treatment and acquired immunodeficiency syndrome. Journal of the American Medical Association 262 (12): 1864-868.

Crowley, T.J.; Macdonald. M.J.; Wagner, J.E. & Zerbe, G. 1985. Acetylmethadol versus methadone: Human mood and motility. Psychopharmacology 86 (4): 458-63.

Dole, V.P.; Nyswander, M. & Kreek, M.J. 1966. Narcotic blockade. Archives of Internal Medicine 118:304-9.

Federal Register. 1993. Levo-alpha-acetyl-methadol (LAAM) in maintenance; revision of conditions for use in the treatment of narcotic addiction. Federal Register 58 (137): 38704-711.

Freedman, R.R, & Czertko, G. 1981. A comparison of thrice weekly LAAM and daily methadone in employed heroin addicts. Drug and Alcohol Dependence 8:215-22.

Gerstein, D.R. & Harwood. H.J. (Eds.) 1990. Treating Drug Problems Washington, D.C.: National Academy Press.

Goldberg, P. 1980. The federal government's response to illicit drugs. 1969-1978. In: Drug Abuse Council. The Facts About "Drug Abuse." New York: The Free Press.

Goldstein, A. 1976. A clinical experience with LAAM. In: J.D. Blaine & P.F. Renault (Eds.) Rx: 3x/Week LAAM: Alternative to Methadone. NIDA Research Monograph 8. Rockville, Maryland: National Institute on Drug Abuse.

Hough, G.; Washton, A.M. & Resnick, R.B. 1983. Addressing the diversion of take-home methadone: LAAM as the sole treatment choice for patients seeking maintenance therapy. In: L.S. Harris (Ed.) Problem of Drug Dependence. NIDA Research Monograph 43. Rockville, Maryland: National Institute on Drug Abuse.

Hunt, D.E.; Lipton, D.S.; Goldsmith, D.S.; Strug, D. L. & Spunt, B. 1985-86. It takes your heart: The image of methadone maintenance in the addict world and its effect on recruitment into treatment. International Journal of the Addictions 21 (11-12): 1751-771.

Iguchi, M.Y.; Stitzer, M.L.; Bigelow, G.E. & Liebson, I.A. 1988. Contingency management in methadone maintenance: Effects of reinforcing and aversive consequences on illicit polydrug use. Drug and Alcohol Dependence 22:1-7.

Inciardi, J.; Tims, F.M. & Fletcher, B. (Eds.) 1993. Innovative Strategies in the Treatment of Drug Abuse: Program Models and Srategies. Westport, Connecticut: Greenwood Press.

Institute of Medicine. 1995. Federal Regulation of Methadone Treatment. Washington, D.C.: National Academy Press.

Jaffe, J.H.; Schuster, C.R.; Smith, B.B. & Blachly, P.H. 1970. Comparison of acetylmethadol and methadone in the treatment of long-term heroin users. Journal of the American Medical Association 211:1834-836.

Jaffe, J.H. & Senay, E.C. 1971. Methadone and L-methadyl acetate: Use in management of narcotics addicts. Journal of the American Medical Association 216:1303-305.

Jaffe, J.H.; Senay, E.C.; Schuster, C.R.; Renault, P.R.; Smith, B. & DiMenza, S. 1972. Methadyl acetate vs. methadone: A double-blind study in heroin users. Journal of the American Medical Association 222:437-42.

Karp-Gelernter, E.; Wurmser, L. & Savage, C. 1976. Therapeutic effects of methadone and l-alpha-acetylmethadol. American Journal of Psychiatry 133 (8): 955-57.

Ling, W.; Charuvastra, C.; Kaim, S.C. & Klett, C.J. 1976. Methadyl acetate and methadone as maintenance treatment for heroin addicts. Archives of General Psychiatry 33:709-20.

Ling, W.; Klett, C.J. & Gillis, R. 1978. A cooperative clinical study of methadyl acetate. Archives of General Psychiatry 35:345-53.

Ling, W.; Rawson, R. & Compton, M.A. 1994. Substitution pharmacotherapies for opioid addiction: From methadone to LAAM and buprenorphine. Journal of Psychoactive Drugs 26 (2): 119-28.

Magura, S.; Casriel, C.; Goldsmith, D.S.; Strung, D.L. & Lipton, D.S. 1988. Contingency contracting with polydrug-abusing methadone patients. Addictive Behaviors 13 (1): 113-18.

Magura, S.; Shapiro, J.L.; Grossman, J.I. & Lipton, D.S. 1989. Education/ support groups for AIDS prevention with at-risk clients. Social Casework: The Journal of Contemporary Social Work 70 (1): 10-20.

Marcovici, M.; O'Brien, C.; McLellan, A.T. & Kacian, J. 1981. A clinical controlled study of L-alpha-acetylmethadol in the treatment of narcotic addiction. American Journal of Psychiatry 138:234-36.

Milby, J.B.; Garrett, C.; English, C.; Fritschi, O. & Clarke, C. 1978. Take home medication: Contingency effects on drug-seeking and productivity of narcotic addicts. Addictive Behaviors 3:215-20.

Miller, W.R. 1989. Increasing motivation for change. In: R.K. Hester & W.R. Miller (Eds.) Handbook of Alcoholism Treatment Approaches: Effective Alternatives. New York: Pergamon.

Miller, W.R. & Hester, R.K. 1980. Treating the problem drinker: Modern approaches. In: W.R. Miller (Ed.) The Addictive Behaviors: Treatment of Alcoholism, Drug Abuse, Smoking, and Obesity. Oxford, England: Pergamon.

National Institute on Drug Abuse. (n.d.) Information on LAAM. Rockville, Maryland: Medications Development Division, National Institute on Drug Abuse.

Novick, D.M. & Joseph, H. 1991. Medical maintenance: The treatment of chronic opioid dependence in general medical practice. Journal of Substance Abuse Treatment 8:233-39.

Office of Technology Assessment. 1990. The Effectiveness of Drug Abuse Treatment: Implications for Controlling AIDS/HIV Infection. (AIDS-related issues background paper 6; OTA-BP-H- 73). Washington, D.C.: U.S. GPO.

Parker, M.W.; Winstead, D.K. & Willi, F.J.P. 1979. Patient autonomy in alcohol rehabilitation. I. Literature review. International Journal of the Addictions 14 (7): 1015-22.

Powers, K.I. & Anglin, M.D. 1993. Cumulative versus stabilizing effects of methadone maintenance: A quasi-experimental study using longitudinal self-report data. Evaluation Review 17 (3): 243-70.

Prochaska, J.0. & DiClemente, C.C. 1992. Stages of change in the modification of problem behaviors. In: M. Hersen, R.M. Eisler & P.M. Miller (Eds.) Progress in Behavior Modification. Newbury Park, California: Sage.

Prochaska, J.0. & DiClemente, C.C. 1986. Toward a comprehensive model of change. In: W.R. Miller & N. Heather (Eds.) Treating Addictive Behaviors: Processes of Change. New York: Plenum.

Prochaska, J.0. & DiClemente, C.C. 1982. Transtheoretical therapy: Toward a more integrative model of change. Psychotherapy: Theory, Research and Practice 19:276-88.

Resnick, R.B.; Orlin, L.; Geyer, G.; Schuyten-Resnick, E.; Kestenbaum, R.S. & Freedman, A.M. 1976. l-alpha-acetylmethadol (LAAM): Prognostic considerations. American Journal of Psychiatry 133 (7): 814-19.

Rosenblum, A.; Magura, S. & Joseph. H. 1991. Ambivalence toward methadone treatment among intravenous drug users. Journal of Psychoactive Drugs 23 (1): 21-27.

Senay, E.C.; Dorus, W. & Renault, R.F. 1977. Methadyl acetate and methadone: An open comparison. Journal of the American Medical Association 237:138-42.

Senay, E.C.; Jaffe, J.H.; DiMenza, S. & Renault, P.F. 1974. A 48-week study of methadone, methadyl acetate, and minimal services. In: S. Fisher & A.M. Freedman (Eds.) Opioid Addiction: Origins and Treatment. Washington, D.C.: V.H. Winston & Sons.

Sorensen, J.L.; Batki, S.L.; Good, P. & Wilkinson, K. 1989. Methadone maintenance program for AIDS-affected opioid addicts. Journal of Substance Abuse Treatment 6:87-94.

Stitzer, M.L.; Iguchi, M.Y. & Felch, L.J. 1992. Contingent take-home incentive: Effects on drug use of methadone maintenance patients. Journal of Consulting and Clinical Psychology 60 (6): 927-34.

Strategy Council on Drug Abuse. 1973. Federal Strategy for Drug Abuse and Drug Traffic Prevention 1973. Washington, D.C.: U.S. GPO.

Swan, N. 1994. States slow to approve LAAM. NIDA Notes 9 (3): 12-13.

Tennant, F.S., Jr.; Rawson, R.A.; Pumphrey, E. & Seecof, R. 1986. Clinical experiences with 959 opioid-dependent patients treated with levo-alpha-acetylmethadol (LAAM). Journal of Substance Abuse Treatment 3 (3): 195-202.

Trueblood, B.; Judson, B.A. & Goldstein, A. 1978. Acceptability of methadyl acetate (LAAM) as compared to methadone in a treatment program for heroin addicts. Drug and Alcohol Dependence 3:125-132.

U.S. General Accounting Office. 1990. Methadone Maintenance: Some Treatment Programs Are Not Effective; Greater Federal Oversight Needed. (GAO/HRD-90-104) Washington, D.C.: U.S. GPO.

Ward, J.; Mattick, R. & Hall, W. 1992. Key Issues in Methadone Maintenance Treatment. Kensington, Australia: New South Wales University Press.

Whysner, J.A. & Levine, G.L. 1978. Phase III clinical study of LAAM: Report of current status and analysis of early terminations. In: R.C. Petersen (Ed.) The International Challenge of Drug Abuse. NIDA Research Monograph 19. Rockville, Maryland: National Institute on Drug Abuse.

Yancovitz, S.R.; Des Jarlais, D.C.; Peyser, N.P.; Drew, E.; Friedmann, P., Trigg, H.L. & Robinson, J.W. 1991. A randomized trial of an interim methadone maintenance clinic. American Journal of Public Health 81 (9): 1185-191.

Zaks, A.; Fink, M. & Freedman, A.M. 1972. L-alpha-acetylmethadol in maintenance treatment of opioid dependence. In: Proceedings of the Fourth National Conference on Methadone Treatment. New York: National Association of the Prevention of Addiction to Narcotics.

Zangwell, B.C.; McGahan, P.; Dorozynsky, L. & McLellan, A.T. 1986. How effective is LAAM treatment? Clinical comparison with methadone. In: L.S. Harris (Ed.) Problems of Drug Dependence, 1985. NIDA Research Monograph 67. Rockville, Maryland: National Institute on Drug Abuse.

Back to Focal Point: Drug Substitution and Maintenance Approaches

(Top)

ΕΛΛΗΝΙΚΑ