The Safety of Methadone, LAAM, Buprenorphine
in the Treatment of Opioid Dependency

By Stewart B. Leavitt, PhD, Editor
Addiction Treatment Forum

Alternatives Heralded

New medications have been proposed as welcome, superior, less addictive alternatives to methadone in the treatment of opioid dependency.[1] This was particularly heralded by "Heroin's new fix," a cover story in the May 31, 2000 edition of USA Today, the largest daily circulation U.S. newspaper.[2] 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 diminish 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. A combination product, buprenorphine-naloxone, was mentioned as 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 "gold standard" opioid agonist for the treatment of opioid dependency since the mid-1960s? Perhaps even more important, and the primary focus of this report, are the newer agents safe alternatives?

Pivotal Research

In November 2000, a pivotal article appeared in the New England Journal of Medicine [3] promoted as the first head-to-head comparison of opioid agonist therapies for heroin addiction. This study by a research group at Johns Hopkins University School of Medicine concluded that LAAM (levomethadyl acetate, also called levacetylmethadol or levo-alpha-acetyl-methadol) and buprenorphine were generally equivalent to methadone.

To test the three medications, researchers recruited 220 heroin addicts and treated them for 17 weeks during 1996-97. Patients randomly assigned to 3 experimental groups were given either methadone daily, or LAAM or buprenorphine 3 times per week (since they can be longer-acting agents). Medication doses were adjusted to be the approximate equivalent of 60 to 100 mg of daily methadone, which was considered "high dose." A fourth, control group was treated with a fixed low dose of methadone each day (20 mg). Researchers tracked patients' continued use of heroin and the participants graded the severity of their drug problem. No psychosocial therapy in conjunction with medication was reported in the article.

High-dose methadone was the best at retaining patients in treatment, with 73% completing the 17-week study versus 53% for LAAM and 58% for buprenorphine. Only 20% of the control group could complete the study at the low dose and, as would be expected, the remaining control patients demonstrated the highest rates of continued opioid abuse and the highest ratings of drug problem severity. The percentage of patients with 12 or more consecutive illicit-opioid-free urine specimens was 36% in the LAAM group, 28% for high dose methadone, and 26% for buprenorphine compared with only 8% in the control group.

The researchers concluded that buprenorphine, LAAM, and high dose methadone were all effective in treating opioid dependence and were superior on multiple measures to low-dose methadone. What makes this research of greatest concern is that an Associated Press misinterpretation of study results [4] became the subject of widespread newspaper articles appearing under such headlines as, "Methadone alternatives may be better."[5]

Premature Enthusiasm

Unfortunately, the media attention fueled by the Johns Hopkins research overlooked concerns about LAAM published in the medical literature (described below) and the fact that buprenorphine was still awaiting FDA approval. Although all 3 opioid agonists were described as effective therapies for opioid dependence, the research results for buprenorphine and LAAM were only modest in terms of treatment retention and heroin abstinence. There also were other unacknowledged inadequacies in the study, and some were later expressed in follow-up letters to the New England Journal of Medicine critical of the study.[6]

The maximum allowable "high" methadone dose of 100 mg/day may have been subtherapeutic for many patients,[7] and this was acknowledged in earlier research by this Johns Hopkins team.[8] Mean maximum doses were 90 mg/day for methadone, and 100 mg LAAM or 27 mg buprenorphine on Monday/Wednesday with higher, 3-day doses given on Friday.

Maximum methadone doses might have been limited by the need to keep it within range of the maximum buprenorphine dose, which reaches a ceiling of opiate agonist activity at approximately 10-12 mg/day.[9] Still, it cannot be assumed that medication doses were truly individualized or optimal for patients in any of the groups, and the 17 week study period, without benefit of psychosocial interventions, may have been an inadequate test of treatment efficacy.

Furthermore, past research over the years has demonstrated that the control group methadone dose – 20 mg/day – was acutely inadequate, possibly only equivalent to placebo or what one critic described as "homeopathic."[6] Hence, the clinical validity of the statistically significant results reported in comparison with this control group is questionable.

Other unresolved questions might be posed regarding the relative costs of treatment and potential for adverse effects with the 3 opioid agonist medications. In a press interview,[4] the Johns Hopkins team said they paid $3.15 a week for methadone and $13.60 a week for LAAM; more than a 4-fold difference. Buprenorphine was expected to cost more than LAAM. Hence, from a medicoeconomic perspective there are questions of cost-effectiveness, which are beyond the scope of this present paper.

In terms of adverse events during their study, the researchers noted that the percentage of patients reporting side effects was similar among groups. At least one side effect was reported by 55% of those administered LAAM, 49% receiving buprenorphine, and 45% of high-dose methadone patients. The most common adverse reactions were constipation in 21% of reports, followed by nausea (8%), and dry mouth (6%).[3]

Although statistically significant differences in side effects between the 3 groups were not noted, the seemingly high incidence of all reports and the 10% range between methadone and LAAM appear noteworthy, especially in these carefully selected patients without serious medical or psychiatric illness requiring any long-term comedications. Also, the somewhat moderate opioid agonist doses observed over only a 17-week period may have provided an inadequate test of potential adverse reactions or responses typical of patients in everyday practice. Hence, the external validity of this investigation is uncertain.

Enthusiasm generated by media reports of the research influenced some observers to propose immediately limiting further expansion of methadone programs in favor of buprenorphine. However, in a newspaper column responding to such proposals, Dr. Mark Boesen, executive director of the Maine Association of Substance Abuse Programs, reminded readers that buprenorphine was still investigational and that several years would be required to gather and assess data.[10] "We currently have no knowledge of the long-term side effects that may be exhibited with the product," he cautioned. "Unknown adverse effects of new drugs are very common after introduction into the marketplace." He cited the recent retractions of troglitazone (Rezulin^®) and cisapride (Propulsid®) as two prominent examples.

FDA Adverse Event Reports

To assess the relative safety of methadone, LAAM, and buprenorphine, AT Forum obtained from the US Food and Drug Administration (FDA) Office of Postmarketing Drug Risk Assessment – via the Freedom of Information Act – all adverse event (AE) reports for November 1, 1997 to November 1, 2000 regarding the 3 opioid agonists. The focus was solely on their use in the treatment of opioid addiction.

The FDA-provided data records for the 3 years were summarized and tabulated for each agent. Duplicate reports, incidents of accidental exposure to the drug (as in a child), and administration of the agent for pain management unrelated to addiction treatment were deleted from the analysis.

The FDA advises that accumulated AE reports should not be used to calculate incidence rates or specific estimates of drug risk. Consequently, the data were used in this analysis as indicative of reporting frequencies to suggest trends in AEs differentially associated with each of the 3 opioid agonists. Table 1 provides an overview of all data.

Table 1: All Adverse Event - Overview

* P < 0.0001 vs methadone and LAAM

Using methadone as the benchmark, there appear to be inordinately high numbers of AEs associated with LAAM and buprenorphine. This considers that, in the US, there were an estimated 179,000 patients receiving methadone [11] and possibly 4,000 receiving LAAM [12] during the 1997-2000 FDA-reporting period. Therefore, the proportionate number of AEs associated with LAAM should only be about 4 (4000/179,000 x 170), rather than the 10 times greater number reported. (Worldwide, there are possibly 10,000 LAAM patients,[13] compared to a conservative estimate of 450,000 patients receiving methadone,[14] or a ratio equivalent to that in the US only.)

Considering that buprenorphine was still an investigational drug in the US for opioid dependency treatment during the 3-year reporting period, and certainly there were far fewer persons treated in the US or worldwide with this agent than with methadone, the 178 AEs associated with buprenorphine may be extremely high. One possibility is that, because buprenorphine was considered investigational, clinicians were more diligent in observing and reporting adverse events. On the other hand, the trend may signal particular complications associated with this drug worthy of further and closer scrutiny.

AE reports classify the possible culpability of a drug for the respective event in several ways: 1) primary suspect as a sole agent that the person submitting the report deemed likely to be associated with the reaction, 2) primary suspect with comedications present concurrently, 3) secondary suspect, with another agent listed as the primary suspect and the possible presence of other comedications.

AE reports for buprenorphine were not only the most numerous but the majority of those cases (57%) involved the drug as a sole agent, compared with 45% for LAAM and only 26% for methadone. This is important, because 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.

Although age and gender data were not reported for all AEs, there were slightly fewer females represented in the buprenorphine group; however, the gender mix did not appear to be a distinguishing factor between groups. Buprenorphine-treated patients were significantly (P < 0.0001) 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 these patients, generally with addictions of less longevity and severity, might have less comorbidity and would potentially experience fewer adverse events in association with buprenorphine. This was not evident. It is also likely that more women of childbearing age were treated with buprenorphine, which would reveal potential effects on fetal development and/or neonatal health (described below).

The vast majority of the FDA-provided reports were from the US, with 15% (26/170) of methadone cases, 14% (25/178) for buprenorphine, and 2.5% (1/40) for LAAM reported as "foreign" in origin. These were included in the overall analyses, although it should be noted that all foreign reports involved the respective opioid agonist with comedications, so these had no impact on analyses of the drugs as sole agents.

AE Outcomes Summary

FDA reports categorize AEs according to several general outcomes: death (mortality), hospitalization (intervention to prevent permanent impairment or damage, and disability), and "other"(less severe reactions of assorted types).[15] For purposes of analyses in this paper, hospitalizations, interventions, disability, and the "other" category were combined under "Patient Morbidity."

Cardiac-related AEs, which might otherwise be considered morbidity, were analyzed as a separate category. This was in deference to recent concerns about potential arrhythmogenic effects associated with opioid agonists.

Additionally, the reports specify if the event occurred in a fetus or neonate as a complication of maternal exposure to the drug(s) in question. Outcomes in these cases are summarized in this paper as either "Fetal Mortality" or "Neonatal Complications."

Table 2: Adverse Event Outcomes - Totals

Outcomes for total AEs are summarized in Table 2. From the overall percentages, each agent at first glance appears to have a particular weakness: e.g., patient mortality with methadone, cardiac-related events with LAAM, and fetal death and neonatal complications with buprenorphine. However, it is important to consider AEs reported for each medication as a sole agent since, as noted above, this could more accurately depict respective opioid agonist effects without confounding drug interactions.

Focusing on each medication as a sole agent within each outcome category, mortality associated with methadone and buprenorphine appear roughly equivalent. However, morbidity, fetal deaths, and neonatal complications are higher for buprenorphine, and cardiac-related AEs remain highest for LAAM. Table 3.

Table 3: Adverse Event Outcomes - Sole Agent

Percentages rounded to the nearest 0.5% do not add to 100%

These "sole agent effects" are analyzed further below, along with more detail regarding specific physical reactions. In the FDA reports, outcomes are typically accompanied by one or more reported adverse reactions describing signs/symptoms associated with the event in medical terminology, using the Medical Dictionary for Regulatory Activities (MedDRA).

Patient Mortality

As sole agents, there were 6 deaths each reported with methadone and buprenorphine, and none with LAAM. Table 4. However, mortality attributed to opioid agonists is often questionable.

Table 4 : Patient Mortality

* LAAM was not listed as a Secondary Suspect in any reports.

One death associated with methadone was for unspecified reasons, organ failure was named in 2 cases, and 3 were attributed to "overdose." For 2 of the overdose deaths, methadone doses were moderate: one case involved 60 mg on day one and 80 mg on day 2 (possibly overmedication during methadone induction); the second case merely reported 6 doses ranging from 21 to 30 mg. Other dosages were not specified.

Overdose also was specified as the most common event in methadone deaths in conjunction with other medications (18 cases). From the comedications involved, it appeared many subjects were HIV/AIDS patients. Reported methadone doses in these cases ranged from 30 to 100 mg/d; well within usually nontoxic limits, although methadone blood levels might have been affected by the comedications.

Sole agent buprenorphine-associated deaths were equally ambiguous and dosage information was missing. Two deaths involved traffic accidents, a third was a completed suicide, and a fourth noted "foreign body trauma." There also was one overdose and one case providing incomplete data. Notably, 2 of the deaths involved IV maladministration of sublingual buprenorphine tablets (discussed further below).

In the literature, there has been one report from France of 6 deaths with buprenorphine in combination with benzodiazepines [16] and another in which benzodiazepine comedications played a role in 17 of 20 buprenorphine-related deaths.[17] Reynaud and colleagues [16] proposed that if further research confirmed the number of deaths linked to such drug misuse was high, it could be necessary to review how freely buprenorphine was dispensed.

The single death associated with LAAM in the FDA reports was an overdose in conjunction with benzodiazepines. There also has been a published report of sudden death for unspecified reasons associated with LAAM in Europe.[18]

Some past attempts to quantify deaths attributable to methadone have been confounded by a lack of scientific validation, the presence of comedications, and other factors. An investigation by Karch and Stevens [19] of 3317 coroner's cases in San Francisco during 1997-1998 found 38 cases (1.0%) involved methadone, although less than half (17) were deemed caused by methadone toxicity. They also found considerable coexisting morbidity and illicit drugs in these 17 subjects, and methadone serum levels were no different between cases in which methadone toxicity was considered the cause of death and in those in which it was merely an incidental finding.

One study of more than 1,500 MMT patients during a 10-year period [20] and another of patients in methadone medical maintenance spanning 15-years [21] found no deaths directly related to methadone [Herman Joseph, PhD, e-mail communication February 2, 2001]. Other investigations of drug-related fatalities in the US,[22] Australia,[23] and Switzerland [24] have noted very low fatality rates possibly associated with methadone. The various researchers also reached similar conclusions that polydrug toxicity was the leading cause of death among persons in whom methadone was detected postmortem. Further, Zador and Sunjic in Australia [23] noted that the first 7 days of MTT – during the methadone induction phase – is a high risk period due to over estimation of the patients' tolerance to methadone and/or the subjects' concurrent use of other central nervous system depressant drugs.

The methadone induction phase and its relationship to patient mortality has been problematic. According to J. Thomas Payte, MD, a widely respected authority in the field, about 80% of deaths might be attributed to mixed-drug overdose not solely due to methadone, but the remainder might involve actual methadone intoxication. [25] In many of those cases, however, patients were found to misrepresent or distort their medical histories to obtain higher opioid agonist doses. "The unwary examining physician may believe the patient has more opioid tolerance than is actually the case," Payte noted. Whether this might be even more of a problem with buprenorphine, widely administered by physicians in office-based practices, remains to be determined.

Recently, Auriacombe and colleagues [26] reported on deaths attributable to methadone versus buprenorphine in France from 1994 to 1998. During that period, the number of patients administered methadone increased from 50 to 5360, whereas buprenorphine-treated patients increased from 1000 to 55,000. France currently appears to have the world's largest population of patients treated with buprenorphine for opioid addiction.

Using reports of all sudden deaths associated with use of an illegal substance or misuse of a legal substance, and based on cursory evidence rather than laboratory results, Auriacombe et al. concluded that the yearly death rate associated with methadone was at least 3 times greater than deaths related to buprenorphine.

For example, in 1998 they reported 4 deaths related to methadone in 5360 methadone-treated patients (0.07%) compared with 13 deaths in conjunction with buprenorphine in 55,000 buprenorphine-treated patients (0.02%). However, the researchers conceded there were several potential sources of data inaccuracy, including biases in determining death causation and recording. Also, there apparently were no adjustments made for the presence of concomitant drugs, preexisting physical comorbidity, drug dose or route of administration, or source of the drug (illicit or from a treatment program). Hence, the reported incidence rates may have been inappropriately calculated and distorted.

Morbidity (Hospitalization/Interventions/Other)

Table 5 shows that, as sole agents, there was a high proportion of morbidity associated with buprenorphine (60%) compared with methadone (28%), while LAAM was intermediate (48%). Hence, comedications appeared to be the most important factor in methadone-related morbidity.

Table 5: Patient Morbidity

* LAAM was not listed as a Secondary Suspect in any reports.

The most commonly reported events (with multiple mentions and with/without comedications) were similar for the 3 agents: sedation, nausea, vomiting, headache, abdominal pain, constipation, anxiety, agitation, respiratory depression, sexual dysfunction, coma, edema, skin rash, diaphoresis, and vertigo. AEs involving cardiac complications are considered separately below.

Many signs/symptoms are characteristic of opioid agonist withdrawal effects and, in fact, a number of cases simply indicated "abstinence syndrome." Other effects might be commonly attributed to opioid agonist overmedication. "Drug interaction" also was mentioned multiple times without further elaboration.

Unexpectedly, buprenorphine AEs included 5 mentions of non-viral hepatitis, 3 listings of hepatotoxicity, and 1 case of abnormal liver function test results. There were no specific mentions of hepatitis or hepatotoxicity associated with LAAM or methadone.

The significance of this is unknown at present; however, concerns regarding buprenorphine hepatotoxicity have been expressed by practitioners using the agent in Australia (A. Byrne, MD, Redfern, NSW, Australia, e-mail communications December 19, 2000 and January 4, 2001). Furthermore, a prospective investigation by Petry et al.[27] in 120 buprenorphine-treated opioid addicts found that those with a history of hepatitis C exhibited significantly increased AST and ALT levels (p < 0.05) in a dose-dependent fashion. They recommended that liver enzyme levels be closely monitored in such patients.

Reported methadone dosages associated with morbidity ranged from 5 to 100 mg, plus one case of 220 mg. Buprenorphine dosages ranged from 0.6 to 28 mg, with 900 mg in one nonfatal overdose case. Three times weekly LAAM doses ranged from 36 to 90 mg Monday/Wednesday and 30 to 110 mg Friday. With few exceptions, opioid agonist doses appeared to be within normally accepted ranges; however, administered doses might not correspond to blood serum levels due to individual differences in metabolism, comorbid physical conditions, and/or comedications.

It has been suggested that, compared with other opioids, buprenorphine causes significantly less sedation and respiratory depression even at high doses. Buprenorphine is actually a partial opioid agonist with very high affinity for the mu-opioid receptor and lower opioidergic activity than methadone. Thus, buprenorphine expectedly has a favorable safety profile if accidentally overdosed or if used with other opioids, such as heroin, since it would block respiratory-depressant effects of those agents.[28]

However, the FDA data did report nonfatal sedation (7 cases), overdose (6 cases), and respiratory depression/distress (4 cases) in conjunction with buprenorphine. This compared with 15, 1, and 8 cases, respectively, for methadone. Considering the proportionately smaller number of patients treated with buprenorphine, the agent's presumed safety in this regard may be worthy of further evaluation.

A potential difficulty with buprenorphine is that, due to its strong mu-opioid receptor affinity, there appears to be no specific, completely reliable antagonist for its respiratory depressant effects when they do occur. There have been reports that even very high doses of the potent opioid antagonist naloxone may produce only partial reversal.[29,30]

Another concern is that many of the total AEs associated with buprenorphine involved maladministration of sublingual tablets. They apparently were crushed to a powder for nasal inhalation by 3% (5/178) or dissolved in liquid for intravenous (IV) administration by 36% (64/178) of users. Figure A.

Considering only morbidity outcomes for buprenorphine as a sole agent, there were about twice as many AEs due to IV abuse as with prescribed sublingual administration (41 Vs 21 cases, respectively). Reactions specifically associated with IV abuse of buprenorphine involved injection site complications (21 cases) included vasculitis, necrosis, abscess, thrombosis, edema, and pain.

One report from France described 8 deaths and 10 nonfatal poisonings (37% of 49 total studied cases) associated with IV injection of crushed buprenorphine tablets.[17] A recent large survey of patients maintained on buprenorphine in that country [31] found that 3% of all persons taking buprenorphine were IV abusers of the drug. The medication was taken without supervision in 10% of cases and illicitly injected by 28% of those unsupervised patients. More than a third (37%) of all patients were being prescribed buprenorphine by general practitioners.

A very recent report from France [32] examined 343 injection drug users and found that nearly 34% were polydrug users who occasionally injected buprenorphine in parallel with heroin and/or cocaine. Another approximately 24% only injected buprenorphine in the prior 6 months and many received the drug via participation in buprenorphine maintenance treatment programs. The authors concluded that there is substantial risk of injecting misuse associated with buprenorphine and that more stringent regulation may be necessary in other countries than the current French system allowing prescription by all physicians, including general practitioners.

There also have been numerous reports of a widespread black market for buprenorphine in countries where it has been available, such as: the United Kingdom,[33] Scotland,[34] New Zealand,[35] and Germany.[36] At the request of the National Institute on Drug Abuse (NIDA), a study was conducted in the US to forecast if buprenorphine might play a role in drug "street markets."[37] The authors of this prognostic analysis determined that buprenorphine would indeed have desirable qualities in the US from a street addict point of view.

Recognizing buprenorphine's potential for misuse, it has been suggested that the drug might be unsuitable as a take-home medication in the US Hence, development of a combination buprenorphine-naloxone product was proposed to prevent maladministration, since the naloxone component, an opioid antagonist, would presumably diminish opioid effects and/or produce undesirable withdrawal symptoms in the user.[28]

However, IV abuse of the buprenorphine-naloxone product might still appeal to patients maintained on buprenorphine. Since quite large doses of naloxone may be required to displace buprenorphine strongly bonded to mu-opioid receptors (as mentioned above), these patients might still experience desirable opioid effects via IV injection, without significant antagonist effects from the naloxone component.

None of the FDA-provided AE reports mentioned a buprenorphine-naloxone formulation. Therefore, the validity of the assumption that the combination product would not be abused, the extent to which patients might "test" it via injection, or its propensity to produce adverse events similar to buprenorphine as a single agent cannot be determined from available FDA data.

There were no FDA-AE reports of methadone or LAAM IV injection; however, there has been one report from New Zealand of MMT patients injecting their methadone via large-bore needles and with subsequent complications: e.g., abscess, headache, "asthma."[38] In this small number of studied patients (19) the methadone mixture involved was primarily an aqueous solution particular to that region, rather than the sugar-based syrup commonly prescribed throughout the rest of the world.

A final concern with buprenorphine, whether used sublingually by itself or in the combination product, might be interactions with full-agonist pain medications. Due to its powerful affinity for the mu-opioid receptor, buprenorphine might either displace or block certain medications, such as morphine, leading to acute withdrawal syndrome or rendering the pain medication ineffective. This has not been the case with methadone-maintained patients in whom opioid pain medications are effective, although higher than usual doses of analgesic agents may be required in some cases.

Cardiac-Related Events

There has been recent concern regarding a potential for opioid agonists to trigger cardiac conduction disturbances and/or dysrhythmias. As Table 6 shows, the greatest total proportion of cardiac-related AEs in the FDA data was exhibited by LAAM – 33% (13/40). Whereas, only 3.5% (6/170) and 3.9% (7/178) of total methadone and buprenorphine cases, respectively, involved cardiac events.

Table 6: Cardiac-Related Events

* LAAM was not listed as a Secondary Suspect in any reports.

Cardiac events associated with buprenorphine included cardiac failure, hypotension, tachycardia, and bradycardia. The single case with buprenorphine as a sole agent involved myocardial infarction.

Cardiac events associated with methadone included cardiac failure/arrest, syncope, pacemaker insertion, arrhythmia, and bradycardia. There was one case of prolonged QTc (i.e., QT segment measurement corrected for heart rate).And one report of torsade de pointes (TdP, a sometimes life-threatening ventricular tachycardia) with methadone, both in conjunction with comedications.

Methadone daily doses associated with cardiac complications ranged up to 800 mg/day. As a sole agent, dose ranges were from 130 to 740 mg/day. Some practitioners have noted instances of cardiac arrhythmia associated with methadone at doses greater than 500 mg/day, although patient medical history (including prolonged QTc interval at baseline), family history of cardiac conditions, and comedications appeared to play critical roles in many cases (M. Shinderman, MD, Chicago, IL, personal communications August 2000, March 2001).

A study in Belgium by Mathot and colleagues [39] reported that roughly 38% of 206 patients with a QTc >420 msec were methadone users. However, virtually all of the methadone patients also received one (22.3%) or more (77.6%) neuroleptic agents. The researchers concluded that methadone patients might be at higher risk for prolonged QTc when certain psychotropic drugs are concurrently administered. However, there were no life-threatening adverse events reported in the investigation and the clinical significance of such cardiac conduction irregularities was undetermined.

For LAAM as a sole agent, there were 3 cases of prolonged QTc interval and one case of TdP in the FDA data. Other events included syncope, angina, tachycardia, and increased ST segment interval. In conjunction with comedications, there were 3 cases of prolonged QTc and 5 cases of TdP. Of interest, LAAM dosages were generally higher in cardiac-related cases than in those involving other morbidity, ranging from 98 to 200 mg Monday/Wednesday and 126 to 300 mg Friday.

Very recently, a report from Europe (where LAAM was approved in 1997),[18] noted 10 case reports of life-threatening cardiac disorders associated with LAAM (Orlaam^®), including: cardiac arrest associated with ventricular arrhythmias (5 cases), cardiac arrhythmia (3 cases), and syncope (2 cases). In 7 patients there was a prolonged QT interval (535-800 msec) and TdP in 4 patients; 3 patients required pacemaker insertion. These cases also occurred in relatively young patients (median age 39 years; range 23-57); however, more complete details regarding patient history, comorbidity, or comedications were unavailable.

Consequently, and based on those cases, the European Medicines Evaluation Agency's (EMEA) scientific committee, the Committee for Proprietary Medicinal Products (CPMP), issued two special warnings in December 2000:[18]

1. "Prescribers are advised not to introduce any new patients to Orlaam therapy."
2. "Patients currently taking Orlaam should contact their doctor for advice regarding their treatment, they must not stop Orlaam suddenly without seeking medical advice."

These warnings followed an announcement a year earlier (December 15, 1999) by the EMEA [40] advising that LAAM should not be administered to patients with known or suspected arrhythmia disorders or in conjunction with other medications known to prolong the cardiac QTc interval. [See ADDENDUM UPDATE at end of this paper.]

In spring 2000,[13] the US manufacturer of LAAM issued a statement advising that all patients should have a 12-lead ECG performed prior to initiating LAAM therapy and the drug should not be administered if there was a prolonged QTc interval. A new package insert was issued in June 2000. [See ADDENDUM UPDATE.]

In November 2000, the American Methadone Treatment Association (AMTA) advised similar precautions regarding LAAM in a memorandum to methadone treatment providers.[41] Additionally, AMTA suggested that all patients should have their medical histories updated, with an emphasis on past or current cardiac conduction defects, arrhythmias, syncopal attacks, seizures, etc. Patients with high risk profiles "may be managed more safely with methadone," the memo stated.

AMTA further recommended that, as part of a patient history, all medications taken currently and during the prior 1 to 3 months should be noted. These should be "checked against lists of medications known to be associated with prolonged QTc intervals," although the source of such lists was not indicated.

Finally, AMTA advised that concern with the prolonged QTc interval phenomenon "should not deter the use of LAAM in individuals who would prefer LAAM and benefit from its use." However, risks/benefits of LAAM therapy should be documented in the patient record and/or the patient may elect to sign an informed consent. AMTA acknowledged that these recommended procedures could be subject to change as more is learned about risks associated with drug-induced prolonged QTc intervals.

It is important to note that there appears to be little agreement in the scientific community on what specifically constitutes a normal versus prolonged QTc interval and its clinical importance. Formal guidelines have not been issued by the US FDA,[42] although the EMEA has issued a guidance document [43] and various researchers have proposed differing parameters for consideration.[44-49]

Age and sex are important factors, with women generally having longer baseline QT intervals than men [49] and accounting for the majority of TdP cases.[50] Specific QTc values observed at any one time in a patient may be of less clinical importance than intraindividual QTc changes over time.[42,43,51] However, researchers have observed that it is not yet possible to define an absolute QTc duration relative to baseline that will predict with high probability the development of TdP,[49,52] and authorities such as the EMEA have suggested that further research is needed to better understand the relationship between QTc interval and TdP.[43]

Fetal Mortality

As Table 7 depicts, there was considerably more fetal mortality associated with buprenorphine than the other opioid agonists. However, since its approval, LAAM (Pregnancy Category C) has been essentially contraindicated for use in pregnancy or in women planning to become pregnant,[53,54] so such reports would be unexpected with this agent.

Table 7: Fetal Mortality

* LAAM contraindicated during pregnancy;
** Mothers with HIV/AIDS

In women taking methadone (also Pregnancy Category C), there was one case each of sudden infant death syndrome and spontaneous abortion. In both cases it appeared that the mothers were being treated for HIV/AIDS with multiple, concomitant antiretroviral medications. One case also involved flunitrazepam (Rohypnol) abuse.

The 5 fetal death cases associated with buprenorphine involved multiple-congenital abnormalities (4 cases), intrauterine death (3 cases), miscarriage (1 case), and cardiac abnormality (1 case). The single case involving comedications was in a woman injecting buprenorphine (14 mg IV) and also taking flunitrazepam and praxinor. Reported sublingual buprenorphine dosages were 4 mg to 8 mg. The only currently FDA-approved formulation of buprenorphine is injectable Buprenex^® classified as Pregnancy Category C: for use during pregnancy only if potential benefits justify potential risks to the fetus.[55]

Neonatal Complications

The single case of LAAM associated with complications in a neonate involved convulsions, apnea, cleft palate, and renal failure. The mother was taking 100 mg LAAM Monday/Wednesday and 130 mg LAAM on Friday, along with 85 mg of daily methadone.

Table 8: Neonatal Complications

* LAAM was not listed as a Secondary Suspect in any reports.
** LAAM has been contraindicated during pregnancy.

For buprenorphine, the majority (64%) of complications in neonates were with the drug as a sole agent. Table 8. Overall (with and without comedications), the most frequently listed buprenorphine-related complications were: neonatal abstinence syndrome (NAS, 35 mentions), tremor (14), hypertonia (4), feeding disorder (4), respiratory disorder (3), vomiting (3), agitation (3), bradycardia (2), cardiac abnormality (2), low birth weight (2), and infection (2). Buprenorphine doses ranged from 1 to 16 mg. Four cases involved IV abuse of buprenorphine (2 to 16 mg) and one case of nasal inhalation. The most frequently cited comedications were: bromazepam, clorazepate, hydroxyzine, imovane, fluoxetine, and heroin.

There were only 3 cases (19%) of neonatal complication with methadone as a sole agent. For all cases (with/without comedications), the most frequently listed complications were: NAS (10), congenital anomaly (6), convulsions (2), and undersized baby (2). Dosages ranged from 40 to 150 mg/day. The most frequently named comedications included various antiretroviral agents (mothers with HIV/AIDS), hydroxyzine, venlafaxine, diazepam, and LAAM.

In total, more than a quarter (26%) of all AE reports concerning buprenorphine involved fetal death or neonatal complications versus only 10% for methadone. Since its approval more than 30 years ago, methadone has proved efficacious and relatively safe for use during pregnancy. When they do occur, complications in the neonate, such as NAS, are generally moderate and effectively managed via protocols established over many years experience with methadone.[56]

Because methadone-related neonatal complications are so readily managed, it is possible that they were underreported. Still, considering that methadone-treated patients vastly outnumbered those treated with buprenorphine, the evident trend of fetal deaths and neonatal complications with buprenorphine seems troublesome. And, there have been limited research reports of buprenorphine's safety in pregnancy.

Two studies from research teams headed by Fischer in Vienna, Austria [57,58] observed that the babies born to buprenorphine-maintained mothers had birth weights and Apgar scores within normal ranges and no or little evidence of opioid-related NAS. However, the 2 studies combined included only 24 subjects and they participated in comprehensive treatment programs covering all aspects of prenatal and perinatal care. The authors stressed that further research was needed to confirm the appropriateness of buprenorphine in pregnant patients.

A small study in France found more equivocal results.[59] In pregnant buprenorphine-maintained women without the benefit of a comprehensive program, the complication rates were 30% prematurity, 46% fetal growth retardation, 23% acute fetal distress, and 69% NAS. However, a second group of pregnant buprenorphine-maintained women enrolled in a comprehensive program, including extensive medical and psychosocial support, fared much better, although the NAS rate was 63% in their newborns. This study enrolled a total of only 24 women in both groups, so it would be inappropriate to make assumptions of external validity in a larger, more diverse population of women.

Interacting Agents

Only about a quarter (26%) of total AEs associated with methadone involved the drug as a sole agent, suggesting that drug interactions play the major role in adverse reactions with this medication. Conversely, compared with methadone, more than twice as many AEs with buprenorphine occurred with the drug as a sole agent (57%), suggesting a potentially more toxic effect of buprenorphine. Similarly, 45% of LAAM-related AEs were as a sole agent. Figure B.

The list of comedications involved in AE reports for the 3 opioid agonists was extensive and varied. It included numerous medications that would be expected in a population with multiple psychiatric diagnoses, and in whom certain illnesses – such as HIV, HCV, TB, etc. – are highly prevalent. Most of the comedications have been demonstrated as substrates for CYP450 enzymes and/or have exhibited inhibitory or inducing effects on selected CYP isoforms.[60,61]

With many patients coming into MMT being HIV-positive, the potential for opioid agonist interactions with antiretroviral regimens may lead to opioid withdrawal side effects or toxicities due to unexpected blood levels. Antiretroviral agents may lose potency due to interactions. For example, pharmacokinetic interactions between methadone and zidovudine, didanosine, stavudine, abacavir, nevirapine, Efavirenz, and nelfinavir have been documented. Others are still undocumented, but might be predicted based upon the various liver enzymes involved in metabolism. Interactions similar to those with methadone are likely with LAAM but may not be as prevalent with buprenorphine.[62]

Interacting drugs receiving multiple mentions included the following (some, but not necessarily all, metabolic mechanisms are indication in brackets):

Some medications are not marketed in US
Unmarked - non-CYP metabolism; ? - unknown metabolic mechanism
• CYP3A4 substrate; § - CYP3A4 inhibitor; - Æ - CYP3A4 inducer
ø - CYP2D6 inhibitor; # - CYP2C9 inhibitor; + - CYP2C19 inhibitor

Methadone is a strongly metabolized by the CYP3A4 isoform,[63] so comedications that induce activity of this liver enzyme may be associated with subtherapeutic plasma methadone concentrations and acute opiate withdrawal symptoms. Conversely, CYP3A4 inhibitors may cause abnormally high methadone levels precipitating toxic adverse reactions (e.g., sedation, respiratory depression, nausea, constipation, etc.).[63,64] Drugs that are merely substrates for CYP3A4, or both inducers/inhibitors of the isoform, could compete with methadone for that enzyme and with unpredictable results.

Methadone also is metabolized by CYP2D6, most likely CYP2C9 and CYP2C19, and to a lesser extent CYP1A2.[63] Many of the above-listed comedications could affect methadone metabolism by those enzymes.

The metabolic pharmacokinetics of LAAM and buprenorphine have been less thoroughly studied. Both agents are reportedly significant substrates for CYP3A4,[60] although other isoforms might be involved to some extent. In general, most of the agents listed above would also be expected to interact with these opioid agonists.

The time frame over which CYP enzyme inducers exert maximum effect is 2-3 weeks, so adverse reactions, such as opioid withdrawal symptoms, associated with inducing comedications might come on gradually. On the other hand, CYP inhibitors produce maximal effects more rapidly, within days, so the onset of toxicity associated with increased levels of opioid agonist could be much more acute and noticeable.[64] Thus, AEs reflecting toxic effects of opioid agonist interactions with other drugs might be more frequently of concern and reported.

Polysubstance abuse, common in opioid addicts, would place these patients at risk for opioid agonist interactions with drugs such as alcohol, cocaine, benzodiazepines, and a variety of other psychotropic agents, prescribed or illicit. Therefore, this patient population may be highly vulnerable to adverse events and/or drug overdose unless comedications and concurrent drug abuse are closely monitored.[64]

As for cardiac complications, some drugs specifically and most frequently mentioned in the FDA AE reports, including prolonged QTc and TdP in the case of LAAM, were:

Of those drugs, only fluconazole and fluoxetine have appeared in review articles listing agents that may influence cardiac conduction disturbances and/or dysrhythmias. A literature survey has found approximately 122 drug/toxins and 28 physical conditions and illnesses, not including hereditary factors, that may adversely affect the QTc interval and/or be associated with severe cardiac rhythm disorders.[65] The potential for certain drugs and drug combinations to have proarrhythmic effects in conjunction with opioid agonist therapy is an area requiring further investigation, and it also is possible that at least some patients in the FDA AE reports had contributing preexisting medical conditions and/or genetic predispositions that were overlooked.

Limitations & Caveats

The FDA's Adverse Event Reporting System (AERS) is purely voluntary on the part of health care professionals, drug manufacturers, and consumers. The system relies upon the reporting person to detect new clinical events, to attribute the appearance of the clinical event to the administration of the drug(s) in question, and to report the event in a timely manner. The interpretation of what constitutes a reportable event and the accuracy of such reports may be variable.

The analyses in this paper relied upon data from submitted reports that were entered by the FDA into a computerized database. Information in the database is not scientifically validated and in some cases data is incomplete and vague. The actual reports, in the formats in which they are submitted, also are scanned into an electronic image-filing system by the FDA but were not accessed for this paper.

There is no certainty that the suspected drug(s) indicated in any report were causative of the reaction and one must be cautious of "guilt by association" conclusions. The AE reports do not provide extensive data regarding morbidity prior to drug administration, so there is no way of determining the relative impact of a patient's medical history on drug effects. Substance dependent persons, especially older patients, often have multiple physical diagnoses and concurrent symptomatology that might confound accurate reporting and analyses.

An extensive underreporting of AEs for all 3 opioid agonists is likely. This might have been particularly true for methadone, wherein less severe adverse reactions might have been routinely accepted as common side effects unworthy of reporting.

Some have suggested that, in general, only 1% of all serious adverse reactions to drugs are reported to the FDA.[66] Still, adjusting for such hypothetically gross underreporting by using the AE frequencies in this report and estimated numbers of patients treated with methadone and LAAM each year (described above), it would have resulted in only a maximum 3% of all persons on methadone experiencing AEs during the 3-year reporting period (1%/year). For LAAM the proportionate percentage would have been 33% of patients (11%/year), and most likely the percentage would have been even greater than LAAM for buprenorphine.

Others have observed that, although adverse drug events are of growing concern, a comprehensive reporting system is currently lacking.[67,68]. Very recently, even the quality and quantity of drug safety reporting in controlled clinical trials has been described as deficient.[69]

Finally, the FDA-provided AE reports used for this paper might be characterized as a collection of anecdotal cases. Due to the inherent limitations and biases of this sort of research, conclusions must be cautiously interpreted as signaling needs and directions for further research. As Alan Leshner, PhD, director of the National Institute on Drug Abuse, very recently observed, "The plural of anecdote is not evidence."[70] Still, in lieu of a more comprehensive and scientifically valid data gathering and analysis system, such anecdotal cases do often carry considerable weight, as in the EMEA's proclamations regarding LAAM mentioned above.

Conclusion - Methadone Still "Gold Standard"

This investigation analyzed adverse event (AEs) reports submitted to the FDA during a 3-year period concerning 3 opioid-agonist medications used for treating opioid dependency – methadone, LAAM, and buprenorphine. A literature search also was conducted to identify published scientific evidence supporting or opposing the findings.

All 3 opioid agonists have proved effective to varying degrees in retaining patients in maintenance treatment and reducing illicit opioid abuse; however, there are still questions about the optimal dosing protocols for producing best results. Along with other criteria, a significant factor in patient selection for each medication might hinge on the agent's relative safety profile.

This report noted that only a quarter (26%) of AE reports for methadone were with the drug as a sole agent; whereas, LAAM and buprenorphine were sole agents in 45% and 57% of cases, respectively. Hence, methadone would appear to have the most favorable overall safety profile. Looking closer at the reported AE outcomes for each medication as a sole agent several important trends may be summarized. Figure C [data from Table 2].

• Patient mortality reports appear roughly equivalent for methadone and buprenorphine; however, this may be misleading considering the much greater number of patients treated each year with methadone. Furthermore, due to a number of potentially confounding factors, there are questions regarding the validity of most deaths attributed solely to opioid agonists.
• A relatively higher frequency of morbidity was reported for LAAM and buprenorphine than for methadone. AEs in buprenorphine-treated patients were exacerbated by IV maladministration of sublingual tablets in a large percentage cases. This might raise concerns about the liberal prescription of take-home buprenorphine tablets, and it is uncertain that a buprenorphine-naloxone combination product would resolve the potential problem.
• Reported cardiac-related events were disproportionately much greater for LAAM, considering that only about 1/45th as many persons were treated with LAAM as with methadone each year. Due to concerns about cardiac conduction disturbances and dysrhythmias, European authorities recently advised against the use of LAAM in new patients. The fewest number of cardiac-related events were reported for buprenorphine as a sole agent and it is possible that a low level of arrhythmogenicity might be a safety advantage of this medication. Further investigations of alleged cardiotoxicity associated with opioid agonists in general seem warranted.
• There were unexpectedly high percentages of fetal deaths and neonatal complications associated with buprenorphine. This appears particularly problematic due to the relatively small numbers of patients being treated with buprenorphine during the FDA-reporting period while it was still an investigational drug, and the fact that the medication has been proposed for major use in a younger population of addicts including women of prime childbearing age. Further research into this issue seems needed. LAAM has been essentially contraindicated in pregnancy since its FDA approval, hence there were no reports of fetal/neonatal AEs with this medication as a sole agent. There were no fetal deaths and only 3 AEs in neonates associated with methadone as a sole agent, which was noteworthy considering the large numbers of women maintained on methadone each year.

The majority of dosages reported for methadone, LAAM, and buprenorphine in association with AEs were well within accepted, or even low, therapeutic ranges. This is not unusual, since it has been observed in general medical practice that 75% of all adverse drug reactions occur at standard, manufacturer-recommended doses.[71]

However, for many reasons, standard doses may be too high for some patients, resulting in toxic serum levels and adverse reactions, or too low in others, with exacerbation of undermedication symptomatology. Patient response can vary 4-fold to 40-fold with any given drug at any given dose, suggesting that patient-individualized doses are important for minimizing dose-related side effects and/or adverse events.[72] This seems especially critical for opioid agonists with their potential for toxicity at high plasma levels or abstinence syndrome at inadequate doses.

Three-quarters (74%) of AEs involving methadone also involved concomitant drugs, and most of those agents were prescription psychotropic medications. This suggests a relatively high level of safety for methadone itself, but necessary caution when used with comedications. It appears that many methadone-associated adverse reactions, as well as those with LAAM and buprenorphine, might be avoided via more prudent prescribing practices, taking into account potentially hazardous "metabolic cross-talking"[73] – i.e., drug-drug interactions – during the coadministration of multiple drugs transformed by the same enzyme systems.

In its approximately 35-year history as the "gold standard" treatment for opioid dependency, methadone has proved to be a safe medication.[74,75] In the millions of patients treated during that time, extending more than 20 years in some patients, severe adverse reactions have been relatively rare. Long-term prospective and retrospective studies reported by Kreek [76] and others [77,78] have demonstrated that MMT is medically safe, with minimal side effects, and generally without toxic reactions requiring hospitalization. Medication side effects have been more common during early days of maintenance treatment and easily managed. Also, as a result of MMT, improvements in health-related quality-of-life measures have been noted.[79] Women stabilized on methadone generally have more healthful pregnancies and healthier newborns than would be observed without such therapy.

Recently noted reservations about LAAM as an alternative therapy may limit its use to only special cases wherein purported arrhythmogenic risks are overshadowed by perceived clinical advantages, such as its longer mode of action permitting less frequent dosing. Buprenorphine and a buprenorphine-naloxone combination may offer advantages in certain patients; however, patient selection criteria and the particular therapeutic advantages appear in need of further research and cautious definition.

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. "There is nothing to suggest that a 'cure' – i.e., permanent post-treatment abstinence – is more likely to be achieved with buprenorphine than with methadone or any other treatment of addiction," he wrote.[80]

A major advantage of buprenorphine would be its more widespread and easy accessibility to patients in community-based medical practices. However, in view of this report's findings and literature survey, there do not appear to be any safety advantages associated with buprenorphine that make it more amenable to this treatment milieu than for methadone. As Newman stressed, the same rationale for permitting buprenorphine to be prescribed by all licensed practitioners applies equally well to methadone.

As noted above under limitations and caveats, the observations and conclusions of this report should not be construed as a call for action other than further investigation. If multiple agents are available for opioid agonist therapy, patients could greatly benefit; just as multiple forms of antibiotics offer advantages in treating infection. However, patient safety factors should remain a prime concern, along with therapeutic efficacy. Just as patients do not enter treatment for opioid dependency to get just a little bit better, they also most certainly do not want to get worse.

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Addiction Treatment Forum is supported by an educational grant from Mallinckrodt Inc, a manufacturer of methadone. We would like to thank the following persons for their peer reviews and suggestions during development of this report: Andrew Byrne, MD, Redfern, NSW, Australia; Chin Eap, PhD, Prilly-Lausanne, Switzerland; Herman Joseph, PhD, New York, NY; Robert Newman, MD, New York, NY; Marc Shinderman, MD, Chicago, IL. Additionally, this report was circulated to key researchers, government officials, and clinicians for their assessments and comments prior to finalization. We also thank the U.S. Food & Drug Administration for sharing the data that made this research report possible.

This report is available in electronic format at < www.ATForum.com > under the "Current/Past Issues" tab, listed at the bottom of the contents page in "Unpublished Reports."

Finalization Date: March 20, 2001

ADDENDUM UPDATE: LAAM Disparaged in US, Europe

WASHINGTON, DC – FDA Talk Paper T01-15; April 20, 2001 – The US Food & Drug Administration strengthened warnings to physicians about serious cardiac adverse events associated with levomethadyl acetate hydrochloride (LAAM, Orlaam®).

Additionally, the approved indication for Orlaam will be revised to advise that it is not to be used as first line therapy and should be reserved for use only in treatment of opiate-addicted patients who fail to show an acceptable response to other adequate treatments for addiction. As of March 30, 2001, 10 cases of serious arrhythmias had been submitted to FDA through MedWatch – the agency's safety surveillance program.

On April 18, 2001, Roxane Laboratories, Inc., the drug's manufacturer, mailed a "Dear Healthcare Professional" letter to physicians licensed to treat narcotic addiction. The letter noted that Orlaam is contraindicated in patients with known or suspected arrhythmias and in conjunction with any drug known to potentially prolong the QT interval or with drugs that induce or inhibit CYP3A4 enzymes.

Prior to induction/initiation of Orlaam therapy, all patients should undergo a 12-lead ECG to determine if prolonged QT interval is present, ECG should be repeated at 12-14 days thereafter, and then periodically to rule out QT interval alterations. If a patient taking Orlaam experiences palpitations, dizziness, light-headedness, or seizures, the patient should seek immediate medical attention.

LONDON, UK – EMEA Public Statement 8776/01; April 19, 2001 – the European Medicines Evaluation Agency (EMEA) recommended the suspension of the marketing authorization for Orlaam in the European Union. Citing the potential of Orlaam to significantly increase the QTc interval and to be proarrhythmic, the Committee for Proprietary Medicinal Products (CPMP) noted, "it was not possible to identify any ‘niche' indication where the therapeutic benefit would outweigh the occurrence of severe, serious and unpredictable cardiotoxicity associated with the use of Orlaam."

Physicians were advised to "switch their patients from Orlaam to another existing alternative, e.g. methadone." Existing supplies of Orlaam were to be progressively withdrawn from pharmacies.