EDITORIAL
doi:10.1111/j.1360-0443.2007.01976.x
Can LAAM, like Lazarus, come back from the dead? LAAM (levo-alpha-acetylmethadol) is no longer approved for use in Europe and is not available for clinical use in the United States. In Europe, reports of several cases of ventricular tachycardia (torsade de pointes: TdP) occurring in patients treated with LAAM led the European Medicines Evaluation Agency (EMEA) to suspend authorization for its marketing in 2001. In the same year, responding to the reports of LAAM-related cases of TdP, the United States Food and Drug Administration (FDA) required the addition of a ‘black box’ warning on the LAAM label. The label states that LAAM should be used only for patients who failed treatment with other agents and that all patients receiving LAAM should have baseline electrocardiogram (ECG) screening and periodic monitoring [1]. Because most clinics were reluctant to initiate such ECG assessments, the use of LAAM (not very high to begin with), dropped sharply. In 2003, Roxane Laboratories, the sole distributor of LAAM, announced its decision to discontinue its sale. However, it remains an FDA-approved therapeutic agent. In this issue, Anglin and coworkers report on a 1-year study that compared heroin addicts assigned randomly to treatment with daily doses of methadone or thriceweekly LAAM [2]. Patients assigned to LAAM were more likely than those assigned to daily methadone to complete the planned 52-week course of treatment, less likely to submit urine specimens positive for illicit opiates and less likely to discontinue treatment because of incarceration. Baseline and monthly ECG monitoring of patients receiving LAAM revealed no abnormalities. These findings, which show that LAAM is more effective than methadone in suppressing heroin use, are consistent with the findings from other comparisons of these two agents [3–6]. The FDA’s decision to place a ‘black box’ warning on the label for LAAM was appropriate, as was the directive to conduct baseline and periodic ECG monitoring. However, given that there had already been reports of methadone causing QT prolongation and TdP, the advice to use LAAM only when patients had failed to respond to methadone was perhaps not as well justified. Most of the factors associated with methadone and LAAM-induced QT interval prolongation and TdP risk are known. In addition to high dosage of opioid agonists and prolonged QT baseline they include agents that raise serum drug levels, being female, electrolyte imbalance (hypokalemia, hypomagnesemia), HIV infection and structural heart disease [7,8]. Quality treatment of opiate addiction with either methadone or LAAM ought to include screening for these risk factors and, in most cases,
ECG screening at baseline and periodic monitoring at steady state whenever the dosage exceeds accepted ordinary doses. Such ECG screening might be problematic in less developed countries, where opioid maintenance is employed. However, it should not have presented a significant obstacle in developed countries where ECG machines are in common use. Perhaps it speaks to our attitude towards this patient population that these extra steps were not taken for LAAM and are not currently being taken for those treated with methadone. Most (but not all) cases of methadone-related TdP occurred in patients treated with unusually high doses of methadone [7–9]. A common reason for prescribing high doses is an effort to prolong therapeutic plasma levels in patients who metabolize methadone rapidly. This produces a higher peak plasma level of methadone. These are the very patients for whom LAAM at less elevated doses might have provided adequate control [10]. Thus, one irony in the unavailability of LAAM is the likelihood that more patients on full agonist therapy will be at risk for TdP. Another problem for both physicians and policy makers is how to balance the welfare of the opioiddependent patient and the welfare of the community at large. There appears to be an inevitable link between the extent of unsupervised provision of full agonists such as methadone and overdose toxicity (sometimes fatal) among patients in treatment, and often among nonpatients who ingest the high doses of opioids prescribed legitimately for heroin-dependent patients. This problem can be minimized and treatment effectiveness enhanced by requiring that all such opioids be ingested under supervision at a clinic or a community pharmacy. However, such a policy is costly, and it also imposes an unreasonably high compliance burden on patients, a burden so high that it no doubt contributes substantially to some patients’ decision to discontinue opioid agonist treatment. The high rate of relapse to heroin use and the increase in morbidity and mortality for those who do drop out of treatment is well established. When LAAM was developed it was hoped that because it allowed for dosing only two or three times a week the compliance burden on patients would be reduced without increasing the risks associated with unsupervised use. Reducing direct medication observation to twice weekly would require five take-home doses of methadone, but only a single dose of LAAM. Currently, only methadone (a full agonist) and buprenorphine (a partial agonist) are approved and available for use in agonist maintenance programs. There is a
© 2007 The Author. Journal compilation © 2007 Society for the Study of Addiction
Addiction, 102, 1342–1343
Editorial
general consensus that while buprenorphine has a better safety profile than methadone (is less likely to be associated with fatal overdose), it is for many heavily dependent patients less effective than methadone in reducing heroin use [11,12]. It is now clear that methadone as well as LAAM can prolong the QT interval, and that instances of TdP have been reported with both agents. Screening to identify patients at risk for unacceptable degrees of QT prolongation ought to be a part of agonist treatment with any agent known to be a torsadogen. With proper screening and ECG monitoring it seems likely that arrhythmias associated with agonist therapy can be reduced substantially or prevented. Once such screening becomes routine there may be an opportunity in the United States, where LAAM is still approved, to persuade a pharmaceutical company or the government to make it available again. Many clinicians believe that LAAM adds an important therapeutic option. Perhaps even the EMEA would reconsider its decision to withdraw its approval of LAAM.
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JEROME H. JAFFE
Department of Psychiatry, Division of Alcohol and Drug Abuse, University of Maryland School of Medicine, Baltimore, MD, USA. E-mail:
[email protected]
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References 1. FDA letter to Roxane Laboratories. Available at: http:// www.fda.gov/cder/foi/appletter/2001/20315S6LTR.PDF (accessed 24 June 2007). 2. Anglin M. D., Conner B. T., Annon J., Longshore D. Levo-alpha-acetylmethadol (LAAM) versus methadone maintenance. One-year treatment retention, outcomes, and status. Addiction 2007; 102: 1432–42. 3. Clark N., Lintzeris N., Gijsbers A., Whelan G., Dunlop A., Ritter A., Ling W. LAAM maintenance vs methadone
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maintenance for heroin dependence. Cochrane Database Syst Rev 2002; 2: CD002210. Ritter A., Lintzeris N., Clark N., Jozica J., Kutin J. J., Bammer G. et al. A randomized trial comparing levo-alphaacetylmethadol with methadone maintenance for patients in primary care settings in Australia. Addiction 2003; 98: 1605–13. Ling W., Charuvastra V. C., Kaim S. C., Klett C. J. Methadyl acetate and methadone as maintenance treatments for opiate addicts. Arch Gen Psychiatry 1976; 33: 709–20. Marsch L. A., Stephens M. A. C., Mudric T., Strain E. C., Bigelow G. E., Johnson R. E. Predictors of outcome in LAAM, buprenorphine, and methadone treatment for opioid dependence. Exp Clin Psychopharmacol 2005; 13: 293–302. Pearson E. C., Woosley R. L. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmacoepidemiol Drug Saf 2005; 14: 747–53. Justo D., Gal-Ox A., Paran Y., Goldin Y., Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction 2006; 101: 1333–8. Krantz M. J., Lewkowiez L., Hays H., Woddroffe M. A., Robertson A. D., Mehler P. S. Torsade de Pointes associated with very-high-dose methadone. Ann Intern Med 2002; 137: 501–4. Newcombe D. A., Bochner F., White J. M., Somogyi A. A. Evaluation of levo-alpha-acetylmethadol (LAAM) as an alternative treatment for methadone maintenance patients who regularly experience withdrawal: a pharmacokinetic and pharmacodynamic analysis. Drug Alcohol Depend 2004; 76: 63–72. Mattick R. P., Kimber J., Breen C., Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev 2004; 3: CD002207. Schottenfeld R. S., Chawarski M. C., Pakes J. R., Pantalon M. V., Carroll K. M., Kosten T. R. Methadone versus buprenorphine with contingency management or performance feedback for cocaine and opioid dependence. Am J Psychiatry 2005; 162: 340–9.
© 2007 The Author. Journal compilation © 2007 Society for the Study of Addiction
Addiction, 102, 1342–1343
