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AT Forum NEWS NOTES & UPDATES #108

November-December 2006

Compiled & Edited by Stewart B. Leavitt, PhD

List of all News/Updates

All URL links noted in documents at this AT Forum website were active at the time of publication.  Since the Internet is constantly changing, some linked sites may have moved or become inactive, which is beyond the control of AT Forum.

Contents

FDA Issues Advisory on Methadone

Cardiac Effects of Methadone Recently Reported

Israeli Study Reports on Cardiac QT Intervals in MMT Patients

Study Examines Effects of (R)- and (S)-Methadone on QT Interval

Death Rates Low in Patients on Methadone, Buprenorphine

Methadone Medical Maintenance (MMM) Examined

5-Year Evaluation Shows MMM Beneficial

MMM Enhances Employment and Family/Social Activities

Interim Methadone Maintenance Provides Long-Term Benefits

Benefits of Early MMT During Pregnancy Noted

Depression in MMT Patients Assessed

U.S. Government Releases Data on Opioid Treatment Programs

Addiction Treatment Reduces Psychiatric Disorders

Warning Issued on Venlafaxine (Effexor®)

Two Free Books for Learning More About MMT

Book Aids Understanding of MMT: Highly Recommended

Updated Methadone Primer for Patients from DPA

Voriconazole Increases Methadone Levels

 

FDA Issues Advisory on Methadone

On November 27, 2006, the U.S. Food and Drug Administration issued a Public Health Advisory for methadone 5 mg and 10 mg tablets. The warning noted that there have been reported incidents of cardiac arrhythmia, respiratory depression, and death in patients taking methadone. Healthcare professionals are asked to review the prescribing information carefully to avoid toxicity that can occur due to the challenging complexities of prescribing this product. The deaths and life-threatening adverse effects were reported in patients new to methadone treatment and in patients who were converted to methadone from another opioid analgesic. The adverse events could have been caused by unintentional overdose, drug interactions, or cardiac toxicity. Healthcare professionals, caregivers, and patients should become aware of the prescribing information and the signs of overdose. Along with the FDA advisory, a revised package insert (PI) for 5 mg and 10 mg methadone tablets was released.

For more information, see the FDA Public Health Advisory and link to the PI at: http://www.fda.gov/cder/drug/advisory/methadone.htm. Access checked 12/10/06.

[Comment: The adverse events reported by the FDA are not new and have been repeatedly emphasized during the past several years in AT Forum publications (sponsored by Mallinckrodt Inc., a manufacturer of methadone). See the special reports at: http://www.atforum.com/SiteRoot/pages/rxmethadone/rxmethadone.shtml.
Increases in methadone overdose and deaths in recent years have coincided with its growing use as a pain reliever; especially, in the 5 mg and 10 mg tablet formulations that are the subject of the FDA advisory. Dosing recommendations for methadone analgesia in the original PI were misleading and many prescribers did not fully understand necessary safety precautions. Along with that, many patients were not properly instructed in using methadone to avoid adverse events. Expectedly, these deficiencies can be remedied via better education of healthcare providers and patients, and further methadone-associated overdoses and deaths can be greatly curtailed. – Ed (Stewart B. Leavitt, MA, PhD)]

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Cardiac Effects of Methadone Recently Reported

Israeli Study Reports on Cardiac QT Intervals in MMT Patients

The recent FDA advisory (see above) and prior reports have suggested that in select patients methadone may prolong the QT interval – a portion of the electrocardiogram (ECG) reflecting heart rhythm – and possibly increase the risk for a serious and potentially fatal arrhythmia called torsade de pointes (TdP). The aim of this study was to determine and evaluate QTc intervals (QT corrected for heart beat) in the ECGs of former heroin addicts in methadone maintenance treatment (MMT).

Between January 2003 and September 2004, a total of 138 patients in MMT from 100 days up to 10.7 years, and receiving 40–290 mg/day of methadone, participated. Patients had an ECG at the same time blood was drawn for determination of trough serum methadone levels (SMLs), at around 24 hours after the last oral methadone dose.

Of the 138 patients studied, 98 (71%) were male, mean QTc interval was 418.3 +/- 32.8 milliseconds (ms), average methadone dose was 170.9 +/- 50.3 mg/day, and mean SML was 708.2 +/- 363.1 ng/ml. More than half (55%) the subjects were HCV positive and 8% were HIV positive.

Neither methadone dose nor SMLs correlated directly with QTc values. Of interest, however, in a subgroup of 31 patients who were abusing cocaine, there was a strong correlation of methadone dose and QTc elevations.

Only 3 patients had QTc intervals above 500 ms, which is considered to be prolonged. After about 2 years of follow-up, 2 of those patients died; however, causes of death were not attributed to cardiac origin. An additional 19 patients had QTc intervals of between 450 and 499 ms (possibly prolonged). None of these patients with QTc greater than or equal to 450 ms had any cardiac problems. Methadone doses of all 22 patients in this group were greater than 120 mg/day; however, all but one of those patients were also either taking prescribed medications or abusing benzodiazepines, cocaine, and or other opioids.

The authors concluded that MMT is generally safe. However, despite the many complicating factors, they also suggest that methadone doses of 120 mg/day or more might influence prolongation of the QT interval and the cardiac health of those patients should be monitored for such changes.

Reference: Peles E, Bodner G, Kreek MJ, Rados, Adelson M. Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients—a cross-sectional study. Addiction. 2006; e-publication prior to print. See: http://dx.doi.org/10.1111/j.1360-0443.2006.01668.x. Access checked 12/12/06.

[Comment: This research group based in Israel has produced a number of reports on the benefits of adequate methadone dosing. The present study is one of the few large, prospective examinations of methadone’s effects on cardiac rhythm, demonstrating that a relatively small proportion of patients may experience non-life-threatening prolongation of the QT interval. Other investigations have shown that methadone itself may play only a minor role in such QTc prolongation and other factors in these patients, as yet undetermined, may be of more significance. Since methadone dose does not appear to correlate directly with variations in the QT interval, it may be inappropriate to select any particular dose ceiling as warranting special cardiac monitoring until more definitive research is done. Still, since comedications and continued substance abuse may affect cardiac function, and in light of the recent FDA advisory concerning possible methadone adverse effects (see item above), it may be sound medical practice to assess cardiac health in patients receiving higher doses of methadone during MMT.
See also: Leavitt SB, Krantz MJ. Cardiac Considerations During MMT. Special Report. Addiction Treatment Forum. 2003(Oct). Available at: http://www.atforum.com/SiteRoot/pages/addiction_resources/DosingandSafetyWP.pdf.  Access checked 12/14/06.  – Ed (Stewart B. Leavitt, MA, PhD).]

Study Examines Effects of (R)- and (S)-Methadone on QT Interval

Some reports have suggested that higher daily doses of methadone have been responsible for QT interval prolongation in the electrocardiogram (ECG) and possible ventricular arrhythmias. Because there are considerable differences in how methadone is managed within the bodies of individual patients (its pharmacokinetics) and because methadone is subject to numerous drug-drug interactions, the serum methadone level (SML), or blood concentration, might be more predictive than the dose for increases in the QT interval – or, more precisely, the QTc, which is the QT interval corrected to take into account variations in heart beat.

Furthermore, methadone is a molecule with two forms, called (R)- and (S)-enantiomers, and it is administered to patients undergoing methadone maintenance treatment (MMT) as a mixture of the two. (R)-methadone has a 10-fold higher activity at the opioid receptor and possesses up to 50 times more analgesic activity compared with (S)-methadone.

To investigate the relationship between the serum concentrations of (R)-methadone, (S)-methadone, and total methadone – the sum of (R)- and (S)-methadone – on the QTc interval, Norwegian researchers performed a retrospective study based on medical records from 78 patients in an MMT program. There were 56 men and 22 women, with a mean age of 38 years. The overall mean QTc interval during treatment with methadone was 417 milliseconds. Average methadone dose was 130 mg/day, ranging between approximately 48 mg/d and 212 mg/d.

There were statistically significant correlations between the total trough SML and QTc (r = 0.22; p = 0.049) and between the (R)-methadone trough concentration and QTc (r = 0.24; p = 0.036). The correlation between the (S)-methadone trough concentration and QTc was essentially non-significant (r = 0.20; p = 0.084). Importantly, there was no significant correlation of daily methadone dose and QTc.

Using 430 milliseconds as a cutoff level for QTc in men and 450 milliseconds in women, considered as normal, 13 subjects had QTc values above these limits. The SML specifically of (R)-methadone was significantly higher in the group with QTc values in the upper range, whereas no significant effects were found for total methadone or (S)-methadone alone. Only 1 subject had a QTc interval of above 500 milliseconds, which is considered a risk factor for torsades de pointes arrhythmia. Interestingly, this patient’s SMLs were the highest of the whole group, despite a moderate dosage of 150 mg/d.

Reference: Skjervold B, Bathen J, Spigset O. Methadone and the QT Interval: Relations to the Serum Concentrations of Methadone and Its Enantiomers (R)-Methadone and (S)-Methadone [letter]. J Clin Psychopharmacol. 2006;26(6):687-689.

[Comment: It is noteworthy that the researchers did not report any episodes of arrhythmia, despite what were interpreted as prolonged QTc intervals in 17% of patients studied. Furthermore, similar to other investigations (see item above), daily methadone dose was not a predictor of who might experience prolonged QTc, so it is difficult to say that higher methadone dose in itself is harmful in this regard. The SML seems to be a better predictor of potential QTc prolongation; although, the fact that (R)-methadone had the primary effect on QTc is largely of academic interest, since methadone is only administered currently as a mixture of (R)- and (S)-enantiomers. Finally, as the authors concede in their letter, the low correlation coefficients, or r values, suggest that other factors besides methadone itself might be expected to have a significant impact on QTc, such as genetic influences on cardiac conduction. For example, with an r value of 0.22 for total SML vs QTc, as in this study, methadone concentration alone accounts for only about 5% of any QTc prolongation and other factors, as yet undetermined by research, may have greater influence. – Ed (Stewart B. Leavitt, MA, PhD)]

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Death Rates Low in Patients on Methadone, Buprenorphine

Mortality (death) rates in drug-dependent patients participating in opioid agonist therapy (OAT) remain a matter of debate. Although several retrospective toxicological or forensic postmortem studies on this issue have been conducted, few prospective studies have addressed this problem.

In a nationally representative sample from Germany, 2,694 opioid dependent patients in OAT, either with methadone or buprenorphine at baseline, were monitored during a 12-month period. A total of 1,629 (60.4%) were still in treatment after 12 months.

The overall mortality rate was 1.04%. In total, 28 patients from the initial sample died within the 1-year follow-up period. Eleven (0.4%) of these deaths were due to a fatal drug overdose. Three patients (0.1%) died of HIV/AIDS, and 3 (0.1%) committed suicide. Thirteen of these patients (4 with overdose/polydrug intoxication) were not in OAT at the time of death. Other reasons included accidents and deaths due to other medical conditions. Only in 1 case could the reason not be determined. The mortality rate was similar in both methadone and buprenorphine patients. Taking into account the high comorbidity of opioid dependent patients and the severity of drug addiction, the mortality rate of approximately 1% confirms that OAT could be regarded as a reasonably safe treatment for opioid addiction.

Source: Soyka M, Apelt SM, Lieb M, Wittchen HU. One-year mortality rates of patients receiving methadone and buprenorphine maintenance therapy: a nationally representative cohort study in 2694 patients. J Clin Psychopharmacol. 2006;26(6):657-660.

[Note: This is one of the few large, prospective studies of this sort, and it is significant that the safety outcomes for OAT were so favorable. However, the authors of this study used the term “substitution treatment” for what has been changed to “Opioid Agonist Therapy (OAT)” for addiction in the above description. The use of “substitution” is common outside the U.S.; however, it has the stigmatizing implication of substituting one addictive drug (e.g., heroin) with another (e.g., methadone or buprenorphine), which is misleading and inappropriate. – Ed (Stewart B. Leavitt, MA, PhD)].

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Methadone Medical Maintenance (MMM) Examined

5-Year Evaluation Shows MMM Beneficial

Methadone medical maintenance (MMM) is a model for the treatment of opioid addiction in which a monthly supply of methadone is distributed in an office setting, in contrast to more highly regulated methadone maintenance treatment (MMT) settings where more frequent observed dosing is the norm. Researchers at the Albert Einstein College of Medicine, Bronx, New York examined patient characteristics and treatment outcomes of an MMM program by conducting a retrospective chart review.

Participant characteristics were compared with those of patients enrolled in affiliated conventional MMT programs. MMM patients had diverse ethnicities, occupations, educational backgrounds, and income levels. Urine toxicology testing detected minimal illicit opiate and cocaine use. The MMM retention rate was 98%, which compares favorably with the 4 other MMM programs that have been reported in the medical literature. This study demonstrates that selected patients from a socioeconomically disadvantaged population remained clinically stable and engaged in MMM, in a far less intensive setting than traditional MMT.

Reference: Harris KA, Arnsten JH, Joseph H, et al. A 5-year evaluation of a methadone medical maintenance program. J Subst Abuse Treat. 2006;31(4):433-438.

MMM Enhances Employment and Family/Social Activities

Methadone medical maintenance (MMM) reduces the reporting schedule for stable and well-functioning methadone maintenance treatment (MMT) patients to once a month. Researchers from Johns Hopkins University reported on 12-month outcomes of 92 highly stable MMT patients randomly assigned to 1 of 3 study conditions: A) routine care, B) MMM at the MMT clinic, and C) MMM at a physician's office.

The MMM-group patients received a 28-day supply of methadone, whereas routine care patients received 5 or 6 take-home methadone doses each week. All patients performed a medication recall once a month and submitted 2 urine samples each month. An adaptive stepped-care system of treatment intensification was used for patients who failed recall or who had drug-positive urine specimens.

Seventy-seven patients completed the 12-month study period. Dropout was caused primarily by problems with handling methadone and disliking the recall frequency. There were low rates of illicit-drug use or failed medication recall. Treatment satisfaction was high in all groups, but the MMM patients initiated more new employment or family/social activities than did routine care patients during the study period. The stepped-care approach was well tolerated and matched patients to an appropriate step of service within a continuum of treatment intensity.

Reference: King VL, Kidorf MS, Stoller KB, et al. A 12-month controlled trial of methadone medical maintenance integrated into an adaptive treatment model. J Subst Abuse Treat. 2006;31(4):385-393.

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Interim Methadone Maintenance Provides Long-Term Benefits

This study compares interim methadone maintenance (IM) to a waiting list condition at a methadone maintenance treatment (MMT) program in Baltimore. As defined by U.S. federal regulations, IM provides observed methadone dosing and emergency counseling only for a maximum of 120 days. Participants included 319 individuals enrolled on an MMT waiting list who were randomly assigned to either IM or wait-list control. Outcomes were measured at MMT entry (or at 4 months from baseline for those who did not enter treatment), and 6 months thereafter.

At the second follow-up, 129 (64.8%) of the IM participants reported being enrolled in an MMT, versus only 33 (27.5%) of the controls, p < 0.001. IM participants had significantly fewer heroin-positive drug tests (IM 48.1% versus control 72.3%, p = 0.001) but not for cocaine-positive drug tests. At 10 months after study enrollment, there were sustained benefits of having participated in IM as compared with wait-list in terms of increased treatment entry and reduced heroin use and criminal behavior.

Reference: Schwarz RP, Jaffe JH, Highfield DA, Callaman JM, O’Grady KE. A randomized controlled trial of interim methadone maintenance: 10-Month follow-up. Drug Alcohol Depend. 2007;86(1):30-36.

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Benefits of Early MMT During Pregnancy Noted

A study from Australia examined the association between early entry and retention in methadone maintenance treatment (MMT) during pregnancy and key neonatal outcomes. Obstetric and perinatal characteristics of women who were retained continuously in MMT throughout their pregnancy were compared with those who entered late in their pregnancies (less than 6 months prior to birth) and those whose last treatment episode ended at least 1 year prior to birth.

There were 2,993 births to women recorded as being on methadone at delivery, increasing from 62 in 1992 to 459 births in 2002. Compared with mothers who were maintained continuously on methadone throughout their pregnancy, those who entered treatment late also presented later to antenatal services, were more likely to arrive at hospital for delivery unscheduled, were more often unmarried, indigenous, and smoked more heavily. A higher proportion of neonates born to late entrants were born at less than 37 weeks gestation and were admitted to special care nurseries more often.

The authors conclude that continuous MMT during pregnancy is associated with earlier antenatal care and improved neonatal outcomes. Innovative techniques for early engagement in MMT by pregnant heroin-using women or those planning to become pregnant should be identified and implemented.

Reference: Burns L, Mattick RP, Lim K, Wallace C. Methadone in pregnancy: treatment retention and neonatal outcomes. Addiction. e-Pub ahead of print, see: http://dx.doi.org/10.1111/j.1360-0443.2006.01651.x.

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Depression in MMT Patients Assessed

Depression is widely prevalent among former heroin addicts in methadone maintenance treatment (MMT). However, risk factors for depression in MMT patients have not been well characterized.

In a cross-sectional study during 2004-2005, 90 MMT patients were evaluated for depression by the 21-item Hamilton Rating Scale for Depression (21-HAM-D) and the Brief Psychiatric Rating scale (BPRS). To study possible induction of depression by drug abuse, urine samples were tested for opiates, cocaine, benzodiazepines (BDZ), cannabis (THC), amphetamines, and methadone metabolite during 1 month preceding study entry.

Fifty percent of the subjects were found to be suffering from depression. Fifteen new patients in MMT had lower depression scores than continuous patients in MMT, independent of treatment duration. Higher depression scores were found in 74 patients abusing and or using prescribed BDZ, and in 36 who were prescribed more than one type of medication during MMT. Females (n=40) had more depression than males, especially 12 admitted into treatment while pregnant.

The authors noted that patient drug abuse and withdrawal could distort evaluations and lead to a misclassification of depression. However, the major risk factors for depression were already being in MMT, female gender, taking any psychotropic medication, abuse or using prescribed BDZ, and methadone dose >120 mg/day.

Reference: Peles E, Schreiber S, Naumovsky Y, Adelson M. Depression in methadone maintenance treatment patients: Rate and risk factors. J Affect Disord. 2006 [Epub ahead of print].

[Note: Other research has found that, if methadone is adequately dosed, patients with depression often require higher doses for stabilization. Therefore, methadone dose >120 mg/day as a factor in this study is not surprising and should not be taken as causing depression in itself. – Ed (Stewart B. Leavitt, MA, PhD)].

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U.S. Government Releases Data on Opioid Treatment Programs

According to the most recent data, in 2005, 1,069 (8%) of the 13,371 substance abuse treatment facilities in the U.S. that responded to the government’s National Survey of Substance Abuse Treatment Services (N-SSATS) operated an Opioid Treatment Program (OTP) certified by the Substance Abuse and Mental Health Services Administration (SAMHSA). Currently, methadone and buprenorphine are the only opioid medications approved for the treatment of opioid addiction in OTPs.

Facilities may offer more than one type of care, but most facilities with OTPs offered outpatient care (92%), while 11% offered hospital inpatient care, and 9% offered non-hospital residential care. Close to two fifths (37%) of facilities with OTPs operated maintenance-only programs, and 8% operated detoxification-only programs, but the majority (55%) had OTPs with both maintenance and detoxification programs.

Among all OTP patients on March 31, 2005, nearly half (47%) were in OTPs operated by private for-profit organizations, 40% were in OTPs operated by private nonprofit organizations, and 13% were in government operated OTPs. Most patients were receiving methadone treatment (n=235,836) in contrast to the small number receiving buprenorphine treatment (n=1,165, which does not include those receiving buprenorphine from private practice physicians).

To locate facilities operating Opioid Treatment Programs, the SAMHSA Substance Abuse Treatment Facility Locator (http://www.findtreatment.samhsa.gov) can be a helpful resource. A detailed search provides facility information on treatment services, type of care, special programs/groups, and types of payment accepted. Addresses of clinics within a given radius and maps are included.

Data Source: DASIS (Drug and Alcohol Services Information System) Report (Issue 36, 2006). Available at: http://oas.samhsa.gov/2k6/OTP/OTP.htm.  Access checked 12/15/06.

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Addiction Treatment Reduces Psychiatric Disorders

This study investigated changes in psychiatric symptoms after drug addiction treatment, and relationships between pretreatment problems, illicit drug use, and treatment retention. The sample comprised 662 drug-addicted adults recruited at admission to treatment in residential rehabilitation programs (15 agencies) or outpatient methadone treatment (16 methadone maintenance programs and 15 methadone reduction programs). Data were collected by structured interviews at intake to treatment and at 1-month and 6-month follow-ups.

Reductions were found in a range of psychiatric symptoms after admission to drug addiction treatment and among patients treated in outpatient and in residential programs. These reductions occurred rapidly (during the first month) and were maintained at subsequent follow-up. At intake to treatment, 39% of the residential sample overall met criteria for psychiatric disorders. This figure dropped to 3% at both 1-month and 6-month follow-up. Among methadone-treated patients, 15% met criteria for psychiatric disorders at intake, and this dropped to 5% at 1 month and 3% at 6 months. Improvement in psychiatric symptoms was positively related to treatment retention. The authors conclude that some of the psychiatric symptoms presented by drug-addicted patients at admission to treatment are associated with drug misuse and show rapid remission after addiction treatment.

Source: Gossop M, Marsden J, Stewart D. Remission of psychiatric symptoms among drug misusers after drug dependence treatment. J Nerv Ment Dis. 2006;194(11):826-832.

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Warning Issued on Venlafaxine (Effexor®)

Many persons undergoing addiction treatment are prescribed antidepressant medications for cooccurring psychiatric disorders. In late October, the FDA and Wyeth notified healthcare professionals of revisions to the prescribing information for Effexor® (venlafaxine HCl, a serotonin and norepinephrine reuptake inhibitor [SNRI]), indicated for treatment of major depressive disorder. In postmarketing experience, there have been reports of overdose with venlafaxine, occurring predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include: tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis (pupil dilation), seizures, and vomiting. Electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported.

According to the FDA, published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcome compared with that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Healthcare professionals are advised to prescribe Effexor and Effexor XR (extended release capsules) in the smallest quantity of capsules consistent with good patient management to reduce the risk of overdose.

Reference: For more information, see: October 17, 2006 [letter] from the FDA available at: http://www.fda.gov/medwatch/safety/2006/effexor_DHCPletter.pdf.  Access checked 12/12/06.

[Note: Venlafaxine has not been reported to interact with methadone metabolism. However, the potential for venlafaxine to affect cardiac rhythm (e.g., prolong the QT interval) on its own, and possibly to a greater extent in combination with methadone, should be considered. – Ed (Stewart B. Leavitt, MA, PhD).]

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Two Free Books for Learning More About MMT

Book Aids Understanding of MMT: Highly Recommended

Among the many articles, pamphlets, and booklets of all sorts seeking to explain how methadone maintenance treatment (MMT) really works, this book stands out most favorably. Professional Perspectives on Addiction Medicine; Understanding Opioid Addiction and the Function of Methadone Treatment is a long title for a rather brief and compact book (120 pages, 5” x 8”) that is authoritative, comprehensive, and very easy to read.

Edited by two experienced practitioners in the field – Mark Stanford, PhD, and Donald Avoy, MD – they suggest the book would be particularly important for persons outside the methadone treatment field; however, it has importance for everyone with an interest in the treatment of opioid addiction. It definitely should be read by all MMT clinic staff and they should strongly recommend it to community leaders, law enforcement personnel, educators, and others. Many current or prospective MMT patients, and their loved ones, also could benefit.

How to get a copy – a free Adobe® PDF version of this book can be downloaded at the AT Forum website: http://www.atforum.com/SiteRoot/pages/addiction_resources/MMT_book_2006.pdf.

Updated Methadone Primer for Patients from DPA

About Methadone (and Buprenorphine) is a revised (2006) 50-page booklet from the Drug Policy Alliance (DPA) that covers most of the questions patients and their loved ones might have about methadone maintenance treatment. There also is a brief discussion on buprenorphine, added in this 2nd edition. Written in nontechnical language, it gives facts, dispels myths, and also provides helpful tips on such topics as traveling with methadone, storing the drug, concerns about overdose, and much more.

To obtain copies – contact the Drug Policy Alliance at 212-613-8020; e-mail to methadone@drugpolicy.org; or go to http://www.drugpolicy.org/library/bookstore/aboutmethadone.cfm to visit the DPA publications library where a free PDF copy of the booklet can be downloaded.

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Voriconazole Increases Methadone Levels

Certain antifungal agents, such as fluconazole, have been found to significantly increase methadone serum levels and require reducing the methadone dose. A trial was conducted to estimate the interaction between the antifungal voriconazole and methadone at steady-state in male patients on methadone therapy, and to characterize the safety and tolerability profile during coadministration of the agents.

Twenty-three patients on individualized methadone maintenance therapy (30-100 mg once daily) were enrolled in a randomized, patient- and investigator-blind, placebo-controlled, parallel group study. In addition to methadone, subjects received either 200 mg twice daily (BID) voriconazole (400 mg BID loading doses on the first day) (n=16) or matching placebo (n=7) for the next 5 days.

Voriconazole increased methadone concentration overall – and, the inactive (S)-methadone component (enantiomer) was increased more than the active (R)-methadone form – however, patients showed no signs or symptoms of significant methadone withdrawal or overdose. Conversely, methadone appeared to have no effect on voriconazole concentration.

The authors conclude that coadministration of twice-daily 200 mg voriconazole with methadone is generally safe and well-tolerated. Nevertheless, caution should be exercised when voriconazole is coadministered with methadone due to the increase in (R)-methadone, which may require a dose reduction of methadone.

Source: Liu P, Foster G, Labadie R, Somoza E, Sharma A. Pharmacokinetic interaction between voriconazole and methadone at steady-state in patients on methadone therapy. Antimicrob Agents Chemother. 2006(Oct 30); Epub ahead of print.

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