- Email: [email protected]
QTc prolongation: methadone's efficacy-safety paradox
Comment
in patients with renal disease, renin-angiotensin-system inhibitors have nephroprotective properties that exceed what one might expect on the basis of reduction of blood pressure alone. Head-to-head comparison of the above meta-analyses and their related paradox teaches an important lesson: that a-priori definition of inclusion and exclusion criteria do not in themselves assure selected trials of sufficient homogeneity for a reliable meta-analysis. As a result, conclusions might even misdirect important decisions on treatment.
3
4 5
6
7
8
*Giuseppe Remuzzi, Piero Ruggenenti Mario Negri Institute for Pharmacological Research and Unit of Nephrology and Dialysis, Ospedali Riuniti, Bergamo 24125, Italy [email protected] We declare that we have no conflict of interest. 1
2
Flather MD, Yusuf S, Kober L, for the ACE-Inhibitor Myocardial Infarction Collaborative Group. Long-term ACE-inhibitor therapy in patients with heart failure or left ventricular dysfunction. Lancet 2000; 355: 1575–81. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145–53.
9
10 11 12
The European trial on Reduction Of cardiac events with Perindopril in patients with stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events in stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003; 362: 782–88. The PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004; 351: 2058–68. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, for the Collaborative Study Group. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329: 1456–62. Ruggenenti P, Perna A, Gherardi G, on behalf of Gruppo Italiano di Studi Epidemiologici in Nefrologia. Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Lancet 1998; 352: 1252–56. Ruggenenti P, Fassi A, Ilieva AP, for the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators. Preventing microalbuminuria in type 2 diabetes. N Engl J Med 2004; 351: 1941–51. Al-Mallah MH, Tleyjeh IM, Abdel-Latif AA, Weaver WD. Angiotensinconverting-enzyme inhibitors in coronary artery disease and preserved left ventricular systolic function. J Am Coll Cardiol 2006; 47: 1576–83. Dagenais GR, Pogue J, Fox K, Marteen I, Yusuf S. Angiotensinconverting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials. Lancet 2006; 368: 581–88. Thompson SG, Sharp SJ. Explaining heterogeneity in meta-analysis: a comparison of methods. Stat Med 1999; 18: 2693–708. Hardy RJ, Thompson SG. Detecting and describing heterogeneity in meta-analysis. Stat Med 1998; 17: 841–56. Casas JP, Chua W, Loukogeorgakis S, et al. Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet 2005; 366: 2026–33.
QTc prolongation: methadone’s efficacy-safety paradox For decades, methadone has been the most widely prescribed treatment for heroin addiction worldwide. In 1973, clinicians in New York sought an explanation for a perceived increase in the risk of sudden death in heroin addicts, even in those successfully treated with methadone.1 The rate-corrected QT interval (QTc) was found to be prolonged in many patients, which was attributed to illicit polysubstance abuse. Careful inspection of that dataset, however, suggests a striking alternative: QTc prolongation occurred in 34% of methadone-treated individuals compared with only 3% of heroin addicts who were not treated with methadone. This difference did not pique further consideration because at the time there was no evidence that methadone possessed any cardiac-repolarisation activity. Indeed, the notion that methadone might independently alter cardiac repolarisation was not widely appreciated until nearly 30 years later, when torsade de pointes, a form of ventricular tachycardia associated with QTc prolongation, was reported in a small series of US and Canadian patients receiving very high doses of oral methadone.2 556
A recent European study by Georg Ehret and colleagues has raised additional interest about methadone dose and QTc prolongation.3 In this retrospective study, the researchers analysed 247 hospitalised patients with a history of intravenous drug use and found significant QTc prolongation (defined as more than 500 ms) in 16% of the 167 patients on chronic methadone maintenance. By contrast, in 80 age-matched intravenous drug users, not receiving methadone during the study period, no QTc value exceeded 500 ms. Ehret and colleagues’ selection of a 500 ms criteria for significant QTc prolongation is reasonable, because most cases of drug-induced torsade de pointes occur after this threshold is exceeded. In multivariate regression, factors that predicted QTc prolongation included hypokalaemia, liver disease, and concomitant use of inhibitors of hepatic cytochrome P450, which increase the serum methadone concentration. Most intriguing, however, the researchers saw a positive correlation between the prescribed (absolute) methadone dose and the QTc interval. This relation between drug dose and QTc interval parallels the findings of previous studies of www.thelancet.com Vol 368 August 12, 2006
Comment
Endpoint
Correlation
Levacetylmethadol4 Absolute dose vs change in QTc from baseline
r=0·32
Levacetylmethadol4 Serum trough concentration of nor-levacetylmethadol* vs change in QTc from baseline
r=0·45
Methadone5
Serum trough concentration of methadone vs change in QTc from baseline
r=0·37
Methadone3
Absolute dose vs absolute QTc
r=0·20
Methadone6
Absolute dose vs absolute QTc
r=0·51
*Nor-levacetylmethadol is levacetylmethadol metabolite with 10-fold higher biological activity in vivo than levacetylmethadol.
Table: Concentration dependent effects of levacetylmethadol and methadone on QTc interval
methadone and of its long-acting derivative compound levacetylmethadol.4–6 Each study shows a modest concentration-dependent effect of these synthetic opioids on cardiac repolarisation (table). We believe that this dose-dependent effect of methadone on the QTc interval represents an increasingly important issue facing clinicians who prescribe methadone for either chronic pain or opioid dependence. Higher doses of methadone have been shown to improve cancer-related pain,7 as well as improve abstinence from illicit drugs. In one trial, patients randomised to high-dose (80–100 mg a day) methadone had a significant decrease in illicit drug use compared with patients assigned to a low dose (40–50 mg a day).8 Herein lies the dilemma. Ehret’s study identified 27 methadone-treated patients in whom the QTc interval exceeded 500 ms, but only one patient was receiving low-dose methadone (less than 40 mg a day). Similarly, in 59 cases of methadone-associated QTc prolongation or torsade de pointes reported to the US Food and Drug Administration, only one patient received low-dose methadone (less than 40 mg a day).9 What is the clinician to do? Higher doses of methadone may increase the risk of cardiac arrhythmia, but also reduce illicit heroin abuse. The latter in turn positively affects public health by reducing the transmission of viral hepatitis and HIV.10 One option is the substitution of buprenorphine in cases of methadone-related QTc prolongation or torsade de pointes. We successfully moved such a patient from methadone to buprenorphine under hospital supervision and saw normalisation of the QTc interval during induction and follow-up.11 Although buprenorphine is a www.thelancet.com Vol 368 August 12, 2006
reasonable alternative to methadone, buprenorphine is expensive, less widely used, and may be less effective than methadone in treating severe heroin addiction. Methadone therefore remains the most cost-effective and well-validated agent for opioid maintenance. Although QTc prolongation associated with higher doses of methadone is an important safety concern, we do not believe that routine ECG screening is warranted for heroin addicts entering treatment. However, individuals with structural heart disease (eg, left ventricular dysfunction) and those with additional risk factors for QTc prolongation (eg, hypokalaemia, cytochrome P450 inhibitors, other QT-prolonging drugs) may benefit from ECG screening. Although there is presently no arbitrary ceiling dose for methadone in opioid dependency, we believe the current evidence suggests that the decision for ECG screening should not only be informed by the patient’s arrhythmia risk factors but also by the dose of methadone received. This paradox about methadone dose may be of added clinical importance with the movement of methadone maintenance into the realm of primary care. Mori J Krantz, *Philip S Mehler Denver Health Medical Center, Denver, CO 80204, USA [email protected] We declare that we have no conflict of interest. 1 2
3
4
5
6
7 8
9
10 11
Lipski J, Stimmel B, Donoso E. The effect of heroin and multiple drug abuse on the electrocardiogram. Am Heart J 1973; 86: 663–68. Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, Robertson AD, Mehler PS. Torsade de pointes associated with very-high dose methadone. Ann Intern Med 2002; 137: 501–04. Ehret GB, Voide C, Gex-Fabry M, et al. Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors. Arch Intern Med 2006; 166: 1280–87. Huber A, Ling W, Fradis J, Charuvastra VC. Comparison of the effects of methadone and LAAM on the electrocardiogram. Drug Alcohol Depend 2001; 63: S70. Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN. Impact of oral methadone treatment on cardiac repolarization and conduction in opioid users. Am J Cardiol 2005; 95: 915–18. Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS. Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy 2003; 23: 802–05. Hays H, Woodroffe MA. Use of methadone in treating chronic noncancer pain. Pain Res Manag 1999; 4: 23–27. Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med 2000; 343: 1290–97. Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmacoepidemiol Drug Saf 2005; 14: 747–53. Krantz MJ, Mehler PS. Treating opioid dependence: growing implications for primary care. Arch Intern Med 2004; 164: 277–88. Krantz MJ, Garcia JA, Mehler PS. Effects of buprenorphine on cardiac repolarization in a patient with methadone-related torsade de pointes. Pharmacotherapy 2005; 25: 611–14.
557
in patients with renal disease, renin-angiotensin-system inhibitors have nephroprotective properties that exceed what one might expect on the basis of reduction of blood pressure alone. Head-to-head comparison of the above meta-analyses and their related paradox teaches an important lesson: that a-priori definition of inclusion and exclusion criteria do not in themselves assure selected trials of sufficient homogeneity for a reliable meta-analysis. As a result, conclusions might even misdirect important decisions on treatment.
3
4 5
6
7
8
*Giuseppe Remuzzi, Piero Ruggenenti Mario Negri Institute for Pharmacological Research and Unit of Nephrology and Dialysis, Ospedali Riuniti, Bergamo 24125, Italy [email protected] We declare that we have no conflict of interest. 1
2
Flather MD, Yusuf S, Kober L, for the ACE-Inhibitor Myocardial Infarction Collaborative Group. Long-term ACE-inhibitor therapy in patients with heart failure or left ventricular dysfunction. Lancet 2000; 355: 1575–81. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145–53.
9
10 11 12
The European trial on Reduction Of cardiac events with Perindopril in patients with stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events in stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003; 362: 782–88. The PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004; 351: 2058–68. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, for the Collaborative Study Group. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329: 1456–62. Ruggenenti P, Perna A, Gherardi G, on behalf of Gruppo Italiano di Studi Epidemiologici in Nefrologia. Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Lancet 1998; 352: 1252–56. Ruggenenti P, Fassi A, Ilieva AP, for the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators. Preventing microalbuminuria in type 2 diabetes. N Engl J Med 2004; 351: 1941–51. Al-Mallah MH, Tleyjeh IM, Abdel-Latif AA, Weaver WD. Angiotensinconverting-enzyme inhibitors in coronary artery disease and preserved left ventricular systolic function. J Am Coll Cardiol 2006; 47: 1576–83. Dagenais GR, Pogue J, Fox K, Marteen I, Yusuf S. Angiotensinconverting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials. Lancet 2006; 368: 581–88. Thompson SG, Sharp SJ. Explaining heterogeneity in meta-analysis: a comparison of methods. Stat Med 1999; 18: 2693–708. Hardy RJ, Thompson SG. Detecting and describing heterogeneity in meta-analysis. Stat Med 1998; 17: 841–56. Casas JP, Chua W, Loukogeorgakis S, et al. Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet 2005; 366: 2026–33.
QTc prolongation: methadone’s efficacy-safety paradox For decades, methadone has been the most widely prescribed treatment for heroin addiction worldwide. In 1973, clinicians in New York sought an explanation for a perceived increase in the risk of sudden death in heroin addicts, even in those successfully treated with methadone.1 The rate-corrected QT interval (QTc) was found to be prolonged in many patients, which was attributed to illicit polysubstance abuse. Careful inspection of that dataset, however, suggests a striking alternative: QTc prolongation occurred in 34% of methadone-treated individuals compared with only 3% of heroin addicts who were not treated with methadone. This difference did not pique further consideration because at the time there was no evidence that methadone possessed any cardiac-repolarisation activity. Indeed, the notion that methadone might independently alter cardiac repolarisation was not widely appreciated until nearly 30 years later, when torsade de pointes, a form of ventricular tachycardia associated with QTc prolongation, was reported in a small series of US and Canadian patients receiving very high doses of oral methadone.2 556
A recent European study by Georg Ehret and colleagues has raised additional interest about methadone dose and QTc prolongation.3 In this retrospective study, the researchers analysed 247 hospitalised patients with a history of intravenous drug use and found significant QTc prolongation (defined as more than 500 ms) in 16% of the 167 patients on chronic methadone maintenance. By contrast, in 80 age-matched intravenous drug users, not receiving methadone during the study period, no QTc value exceeded 500 ms. Ehret and colleagues’ selection of a 500 ms criteria for significant QTc prolongation is reasonable, because most cases of drug-induced torsade de pointes occur after this threshold is exceeded. In multivariate regression, factors that predicted QTc prolongation included hypokalaemia, liver disease, and concomitant use of inhibitors of hepatic cytochrome P450, which increase the serum methadone concentration. Most intriguing, however, the researchers saw a positive correlation between the prescribed (absolute) methadone dose and the QTc interval. This relation between drug dose and QTc interval parallels the findings of previous studies of www.thelancet.com Vol 368 August 12, 2006
Comment
Endpoint
Correlation
Levacetylmethadol4 Absolute dose vs change in QTc from baseline
r=0·32
Levacetylmethadol4 Serum trough concentration of nor-levacetylmethadol* vs change in QTc from baseline
r=0·45
Methadone5
Serum trough concentration of methadone vs change in QTc from baseline
r=0·37
Methadone3
Absolute dose vs absolute QTc
r=0·20
Methadone6
Absolute dose vs absolute QTc
r=0·51
*Nor-levacetylmethadol is levacetylmethadol metabolite with 10-fold higher biological activity in vivo than levacetylmethadol.
Table: Concentration dependent effects of levacetylmethadol and methadone on QTc interval
methadone and of its long-acting derivative compound levacetylmethadol.4–6 Each study shows a modest concentration-dependent effect of these synthetic opioids on cardiac repolarisation (table). We believe that this dose-dependent effect of methadone on the QTc interval represents an increasingly important issue facing clinicians who prescribe methadone for either chronic pain or opioid dependence. Higher doses of methadone have been shown to improve cancer-related pain,7 as well as improve abstinence from illicit drugs. In one trial, patients randomised to high-dose (80–100 mg a day) methadone had a significant decrease in illicit drug use compared with patients assigned to a low dose (40–50 mg a day).8 Herein lies the dilemma. Ehret’s study identified 27 methadone-treated patients in whom the QTc interval exceeded 500 ms, but only one patient was receiving low-dose methadone (less than 40 mg a day). Similarly, in 59 cases of methadone-associated QTc prolongation or torsade de pointes reported to the US Food and Drug Administration, only one patient received low-dose methadone (less than 40 mg a day).9 What is the clinician to do? Higher doses of methadone may increase the risk of cardiac arrhythmia, but also reduce illicit heroin abuse. The latter in turn positively affects public health by reducing the transmission of viral hepatitis and HIV.10 One option is the substitution of buprenorphine in cases of methadone-related QTc prolongation or torsade de pointes. We successfully moved such a patient from methadone to buprenorphine under hospital supervision and saw normalisation of the QTc interval during induction and follow-up.11 Although buprenorphine is a www.thelancet.com Vol 368 August 12, 2006
reasonable alternative to methadone, buprenorphine is expensive, less widely used, and may be less effective than methadone in treating severe heroin addiction. Methadone therefore remains the most cost-effective and well-validated agent for opioid maintenance. Although QTc prolongation associated with higher doses of methadone is an important safety concern, we do not believe that routine ECG screening is warranted for heroin addicts entering treatment. However, individuals with structural heart disease (eg, left ventricular dysfunction) and those with additional risk factors for QTc prolongation (eg, hypokalaemia, cytochrome P450 inhibitors, other QT-prolonging drugs) may benefit from ECG screening. Although there is presently no arbitrary ceiling dose for methadone in opioid dependency, we believe the current evidence suggests that the decision for ECG screening should not only be informed by the patient’s arrhythmia risk factors but also by the dose of methadone received. This paradox about methadone dose may be of added clinical importance with the movement of methadone maintenance into the realm of primary care. Mori J Krantz, *Philip S Mehler Denver Health Medical Center, Denver, CO 80204, USA [email protected] We declare that we have no conflict of interest. 1 2
3
4
5
6
7 8
9
10 11
Lipski J, Stimmel B, Donoso E. The effect of heroin and multiple drug abuse on the electrocardiogram. Am Heart J 1973; 86: 663–68. Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, Robertson AD, Mehler PS. Torsade de pointes associated with very-high dose methadone. Ann Intern Med 2002; 137: 501–04. Ehret GB, Voide C, Gex-Fabry M, et al. Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors. Arch Intern Med 2006; 166: 1280–87. Huber A, Ling W, Fradis J, Charuvastra VC. Comparison of the effects of methadone and LAAM on the electrocardiogram. Drug Alcohol Depend 2001; 63: S70. Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN. Impact of oral methadone treatment on cardiac repolarization and conduction in opioid users. Am J Cardiol 2005; 95: 915–18. Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS. Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy 2003; 23: 802–05. Hays H, Woodroffe MA. Use of methadone in treating chronic noncancer pain. Pain Res Manag 1999; 4: 23–27. Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med 2000; 343: 1290–97. Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmacoepidemiol Drug Saf 2005; 14: 747–53. Krantz MJ, Mehler PS. Treating opioid dependence: growing implications for primary care. Arch Intern Med 2004; 164: 277–88. Krantz MJ, Garcia JA, Mehler PS. Effects of buprenorphine on cardiac repolarization in a patient with methadone-related torsade de pointes. Pharmacotherapy 2005; 25: 611–14.
557