- Email: [email protected]
Methadone and QTc prolongation – Authors' reply
Correspondence
were regular smokers at the beginning of the study.3 Therefore, it is not likely that smoking status had any effect on the observations as a whole. Owing to the low numbers, subgroup analyses by smoking are not rational. Two-thirds of the DPS participants were middle-aged women, among whom smoking is relatively uncommon.4 A low prevalence of smoking might be a marker of health-consciousness among the volunteers willing to participate in the DPS. In future programmes for the prevention of chronic diseases, the focus of lifestyle interventions might need to be adjusted according to smoking status. Additionally, because atherosclerotic vascular diseases are the most common cause of death among people with different degrees of glucose abnormality, stopping smoking should always be one of the main goals in prevention strategies dealing with these high-risk groups. We declare that we have no conflict of interest.
*Jaana Lindström, Pirjo Ilanne-Parikka, Markku Peltonen, Matti Uusitupa, Jaakko Tuomilehto jaana.lindstrom@ktl.fi Diabetes Unit, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Mannerheimintie 166, 00300 Helsinki, Finland (JL, MP, JT); The Diabetes Centre, Finnish Diabetes Association, Tampere, Finland (PI-P); and Department of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland (MU) 1
2
3
4
366
Tuomilehto J. Primary prevention of type 2 diabetes: lifestyle intervention works and saves money, but what should be done with smokers? Ann Intern Med 2005; 142: 381–83. Davey Smith G, Bracha Y, Svendsen KH, Neaton JD, Haffner SM, Kuller LH. Incidence of type 2 diabetes in the randomized multiple risk factor intervention trial. Ann Intern Med 2005; 142: 313–22. Lindström J, Louheranta A, Mannelin M, et al. The Finnish Diabetes Prevention Study (DPS): Lifestyle intervention and 3-year results on diet and physical activity. Diabetes Care 2003; 26: 3230–36. Dobson AJ, Kuulasmaa K, Moltchanov V, et al. Changes in cigarette smoking among adults in 35 populations in the mid-1980s. WHO MONICA Project. Tob Control 1998; 7: 14–21.
Methadone and QTc prolongation Mori Krantz and Philip Mehler (Aug 12, p 556)1 write about preventable cardiac risks of methadone treatment. They state: “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”.2 We have re-read this reference (one of us, BS, was co-author) and find no reference to unexplained deaths in methadone patients. Of more importance, however, is that the patients in the methadone group were all using several other drugs in addition to heroin for at least 3 days before the cardiography. There was no group in that study that was only using methadone. The frequency of QTc prolongation was 18% in those using heroin versus 34% in those misusing several drugs while on methadone maintenance. We could find no other series of unexplained deaths of addicts in treatment at that time, nor in the decades since. After widespread use throughout the world, often under close medical supervision, it is hard to accept that a serious side-effect would be entirely overlooked. Most of the small number of reported torsades cases have involved other risk factors or doses averaging nearly 400 mg daily for pain management3—ie, more than four times the average used in addiction treatment. Krantz and Mehler’s implication that high doses of methadone should be avoided could paradoxically lead to more cocaine use and other highrisk behaviour, far outweighing any possible cardiac side-effect.4 It seems more reasonable to monitor the changes in QT intervals when the need for high doses arises, especially in circumstances where multiple drugs are needed to control pain, depression, or other complex disorders. We declare that we have no conflict of interest.
*Andrew Byrne, Barry Stimmel [email protected] 75 Redfern Street, Redfern, New South Wales 2016, Australia (AB); and Mount Sinai Medical Center, 5th Avenue, New York City, NY, USA. 1
2
3
4
Krantz MJ, Mehler PS. QTc prolongation: methadone’s efficacy-safety paradox. Lancet 2006; 368: 556–57. 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. Borg L, Broe DM, Ho A, Kreek MJ. Cocaine abuse sharply reduced in an effective methadone maintenance program. J Addictive Dis 1999; 18: 63–75.
Authors‘ reply We thank Andrew Byrne and Barry Stimmel for their insightful comments. However, we stand by our contention that sudden death is not a rarity among heroin addicts, whether treated with methadone or not. Therefore, we feel this is worthy of further investigation, given a report of rising mortality attributed to methadone.1 Regarding the 1973 study by Lipski and Stimmel,2 we agree that there is a confounding effect of poly-drug abuse on the QTc interval that cannot be adjudicated in a post-hoc review of this study. Nonetheless, the fact that clinically important QTc prolongation was nearly twice as common among patients receiving methadone (proven by urine toxicology) than those who were methadone-naive is uncanny. We concur with Byrne and Stimmel that electrocardiographic monitoring seems most appropriate for patients in whom the methadone dose is being escalated and among those on multiple QTc-prolonging drugs. Moreover, we also wholeheartedly agree that highdose methadone is very effective in reducing illicit drug use. However, we believe that a high-dose methadone strategy has a clear safety trade-off. Our field has moved dramatically towards higher methadone doses over the past decade. In our methadone maintenance treatment practice in Denver, CO, www.thelancet.com Vol 369 February 3, 2007
Correspondence
We declare that we have no conflict of interest.
is another risk factor not cited in their review.5 I declare that I have no conflict of interest.
Daniele Focosi [email protected] Division of Hematology, University of Pisa, via Roma 56, I-56100 Pisa, Italy 1 2
3
*Philip Mehler, Mori Krantz [email protected] Denver Health Medical Center, Denver, CO 80204, USA 1
2
3
Ballesteros MF, Budnitz DS, Sanford CP, Gilchrist J, Agyekum GA, Butts J. Increase in deaths due to methadone in North Carolina. JAMA 2003; 290: 40. Lipski J, Stimmel B, Donoso E. The effect of heroin and multiple drug abuse on the electrocardiogram. Am Heart J 1973; 86: 663–68. Roxane Laboratories Inc. Dolophine hydrochloride. http://www.fda.gov/cder/foi/ label/2006/006134s028lbl.pdf (accessed Jan 15, 2007).
Acute myeloid leukaemia In their review, Elihu Estey and Hartmut Döhner (Nov 25, p 1894)1 cite the 1999 paper by Gundestrup and Storm,2 reporting a 5·1-fold increased incidence of acute myeloid leukaemia in 3000 Danish male cockpit crew, a finding arbitrarily attributed to increased cosmic ray exposure. However, in 2003, Pukkala and colleagues showed in the largest study published to date that the incidence of acute myeloid leukaemia was not significantly higher than that of the general population in a cohort of 10 000 North European airline pilots who had served more than 20 years. The only cancers whose incidence has been found consistently increased in airline crew involve the skin.3 A more proven environmental risk factor for radiation-induced acute myeloid leukaemia is indoor radon exposure;4 cigarette smoking www.thelancet.com Vol 369 February 3, 2007
4
5
Estey E, Döhner H. Acute myeloid leukaemia. Lancet 2006; 368: 1894–907. Gunderstrup M, Storm HH. Radiation-induced acute myeloid leukaemia and other cancers in commercial jet cockpit crews: a populationbased cohort study. Lancet 1999; 354: 2029–31. Pukkala E, Aspholm R, Auvinen A, et al. Cancer incidence among 10,211 airline pilots: a Nordic study. Aviat Space Environ Med 2003; 74: 699–706. Evrard AS, Hemon D, Billon S, et al. Childhood leukemia incidence and exposure to indoor radon, terrestrial and cosmic gamma radiation. Health Phys 2006; 90: 569–79. Chelgoum Y, Danaila C, Belhabri A, et al. Influence of cigarette smoking on the presentation and course of acute myeloid leukemia. Ann Oncol 2002; 13: 1621–27.
Barriers against STDs: what about planned pregnancy? We welcome Anne Philpott and colleagues’ proposal that barriers against sexually transmitted diseases should be designed to promote sexual pleasure (Dec 2, p 2028).1 We agree that the uptake and consistency of use of such barriers, and hence their effectiveness, would be thereby enhanced. This is surely a concern to be kept in mind by those who design physical and chemical barriers. Also, those who aim to dispense them to potential users have to work within the cultural constraints of the society to maximise their pleasurable use. An issue no less fundamental and in need of attention, however, is that for many young women and men, conception is also an integral part of sexual relationships. Fertility is not only desirable but essential to the maintenance of the community. There are many individuals who will accept neither physical barriers such as condoms, nor microbicides that
are contraceptive, even if the risk of infection is reported to be high. Perhaps these concerns seem obvious; nevertheless, Philpott and colleagues’ publication, and we hope ours too, go beyond the laboratory considerations that too often seem to take priority in prevention of HIV. We declare that we have no conflict of interest.
Zena Stein, *Joanne Mantell [email protected] HIV Center for Clinical and Behavioral Studies at the New York State Psychiatric Institute and Columbia University, New York, NY 10032, USA (ZS, JM); and Mailman School of Public Health, New York, NY, USA (ZS) 1
Philpott A, Knerr W, Maher D. Promoting protection and pleasure: amplifying the effectiveness of barriers against sexually transmitted infections and pregnancy. Lancet 2006; 368: 2028–31.
Human papillomavirus vaccine policy Your Editorial on human papillomavirus (HPV) vaccination (Oct 7, p 1212)1 is disastrous for public health. Your message—that the EU is misguidedly dragging its feet over compulsory vaccination—is what the manufacturers want us to believe. But it is wrong. You say we must eradicate HPV infection, irrespective of cost or collateral damage. This is rubbish, our aim must be to reduce illness caused by HPV infection, and the prime ill effect is cervical cancer. Countries with high mortality and no screening can achieve major gain from vaccination. But rushed introduction in Europe will worsen HPV-related illness by undermining existing screening and leaving women less protected than now. In November, 2005, a meeting in London, UK, brought experts from all fields to consider the needs of National Health Service (NHS) research and policy. The conclusions were: women are well served by the NHS screening programme, which meets exacting standards2 and is averting 80% of deaths;3 if and when we have vaccine evidence on long-term disease
The printed journal includes an image merely for illustration
367
Science Photo Library
USA, 30–60 mg/day is an infrequently prescribed dose, whereas doses over 100 mg/day are now the norm. It is with consternation that we acknowledge the escalation of dosing standards as our best explanation for the increase in morbidity and mortality among methadone-treated patients. Indeed, these very concerns regarding high-dose methadone are expressed by the manufacturer in a just-released black box warning label.3
were regular smokers at the beginning of the study.3 Therefore, it is not likely that smoking status had any effect on the observations as a whole. Owing to the low numbers, subgroup analyses by smoking are not rational. Two-thirds of the DPS participants were middle-aged women, among whom smoking is relatively uncommon.4 A low prevalence of smoking might be a marker of health-consciousness among the volunteers willing to participate in the DPS. In future programmes for the prevention of chronic diseases, the focus of lifestyle interventions might need to be adjusted according to smoking status. Additionally, because atherosclerotic vascular diseases are the most common cause of death among people with different degrees of glucose abnormality, stopping smoking should always be one of the main goals in prevention strategies dealing with these high-risk groups. We declare that we have no conflict of interest.
*Jaana Lindström, Pirjo Ilanne-Parikka, Markku Peltonen, Matti Uusitupa, Jaakko Tuomilehto jaana.lindstrom@ktl.fi Diabetes Unit, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Mannerheimintie 166, 00300 Helsinki, Finland (JL, MP, JT); The Diabetes Centre, Finnish Diabetes Association, Tampere, Finland (PI-P); and Department of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland (MU) 1
2
3
4
366
Tuomilehto J. Primary prevention of type 2 diabetes: lifestyle intervention works and saves money, but what should be done with smokers? Ann Intern Med 2005; 142: 381–83. Davey Smith G, Bracha Y, Svendsen KH, Neaton JD, Haffner SM, Kuller LH. Incidence of type 2 diabetes in the randomized multiple risk factor intervention trial. Ann Intern Med 2005; 142: 313–22. Lindström J, Louheranta A, Mannelin M, et al. The Finnish Diabetes Prevention Study (DPS): Lifestyle intervention and 3-year results on diet and physical activity. Diabetes Care 2003; 26: 3230–36. Dobson AJ, Kuulasmaa K, Moltchanov V, et al. Changes in cigarette smoking among adults in 35 populations in the mid-1980s. WHO MONICA Project. Tob Control 1998; 7: 14–21.
Methadone and QTc prolongation Mori Krantz and Philip Mehler (Aug 12, p 556)1 write about preventable cardiac risks of methadone treatment. They state: “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”.2 We have re-read this reference (one of us, BS, was co-author) and find no reference to unexplained deaths in methadone patients. Of more importance, however, is that the patients in the methadone group were all using several other drugs in addition to heroin for at least 3 days before the cardiography. There was no group in that study that was only using methadone. The frequency of QTc prolongation was 18% in those using heroin versus 34% in those misusing several drugs while on methadone maintenance. We could find no other series of unexplained deaths of addicts in treatment at that time, nor in the decades since. After widespread use throughout the world, often under close medical supervision, it is hard to accept that a serious side-effect would be entirely overlooked. Most of the small number of reported torsades cases have involved other risk factors or doses averaging nearly 400 mg daily for pain management3—ie, more than four times the average used in addiction treatment. Krantz and Mehler’s implication that high doses of methadone should be avoided could paradoxically lead to more cocaine use and other highrisk behaviour, far outweighing any possible cardiac side-effect.4 It seems more reasonable to monitor the changes in QT intervals when the need for high doses arises, especially in circumstances where multiple drugs are needed to control pain, depression, or other complex disorders. We declare that we have no conflict of interest.
*Andrew Byrne, Barry Stimmel [email protected] 75 Redfern Street, Redfern, New South Wales 2016, Australia (AB); and Mount Sinai Medical Center, 5th Avenue, New York City, NY, USA. 1
2
3
4
Krantz MJ, Mehler PS. QTc prolongation: methadone’s efficacy-safety paradox. Lancet 2006; 368: 556–57. 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. Borg L, Broe DM, Ho A, Kreek MJ. Cocaine abuse sharply reduced in an effective methadone maintenance program. J Addictive Dis 1999; 18: 63–75.
Authors‘ reply We thank Andrew Byrne and Barry Stimmel for their insightful comments. However, we stand by our contention that sudden death is not a rarity among heroin addicts, whether treated with methadone or not. Therefore, we feel this is worthy of further investigation, given a report of rising mortality attributed to methadone.1 Regarding the 1973 study by Lipski and Stimmel,2 we agree that there is a confounding effect of poly-drug abuse on the QTc interval that cannot be adjudicated in a post-hoc review of this study. Nonetheless, the fact that clinically important QTc prolongation was nearly twice as common among patients receiving methadone (proven by urine toxicology) than those who were methadone-naive is uncanny. We concur with Byrne and Stimmel that electrocardiographic monitoring seems most appropriate for patients in whom the methadone dose is being escalated and among those on multiple QTc-prolonging drugs. Moreover, we also wholeheartedly agree that highdose methadone is very effective in reducing illicit drug use. However, we believe that a high-dose methadone strategy has a clear safety trade-off. Our field has moved dramatically towards higher methadone doses over the past decade. In our methadone maintenance treatment practice in Denver, CO, www.thelancet.com Vol 369 February 3, 2007
Correspondence
We declare that we have no conflict of interest.
is another risk factor not cited in their review.5 I declare that I have no conflict of interest.
Daniele Focosi [email protected] Division of Hematology, University of Pisa, via Roma 56, I-56100 Pisa, Italy 1 2
3
*Philip Mehler, Mori Krantz [email protected] Denver Health Medical Center, Denver, CO 80204, USA 1
2
3
Ballesteros MF, Budnitz DS, Sanford CP, Gilchrist J, Agyekum GA, Butts J. Increase in deaths due to methadone in North Carolina. JAMA 2003; 290: 40. Lipski J, Stimmel B, Donoso E. The effect of heroin and multiple drug abuse on the electrocardiogram. Am Heart J 1973; 86: 663–68. Roxane Laboratories Inc. Dolophine hydrochloride. http://www.fda.gov/cder/foi/ label/2006/006134s028lbl.pdf (accessed Jan 15, 2007).
Acute myeloid leukaemia In their review, Elihu Estey and Hartmut Döhner (Nov 25, p 1894)1 cite the 1999 paper by Gundestrup and Storm,2 reporting a 5·1-fold increased incidence of acute myeloid leukaemia in 3000 Danish male cockpit crew, a finding arbitrarily attributed to increased cosmic ray exposure. However, in 2003, Pukkala and colleagues showed in the largest study published to date that the incidence of acute myeloid leukaemia was not significantly higher than that of the general population in a cohort of 10 000 North European airline pilots who had served more than 20 years. The only cancers whose incidence has been found consistently increased in airline crew involve the skin.3 A more proven environmental risk factor for radiation-induced acute myeloid leukaemia is indoor radon exposure;4 cigarette smoking www.thelancet.com Vol 369 February 3, 2007
4
5
Estey E, Döhner H. Acute myeloid leukaemia. Lancet 2006; 368: 1894–907. Gunderstrup M, Storm HH. Radiation-induced acute myeloid leukaemia and other cancers in commercial jet cockpit crews: a populationbased cohort study. Lancet 1999; 354: 2029–31. Pukkala E, Aspholm R, Auvinen A, et al. Cancer incidence among 10,211 airline pilots: a Nordic study. Aviat Space Environ Med 2003; 74: 699–706. Evrard AS, Hemon D, Billon S, et al. Childhood leukemia incidence and exposure to indoor radon, terrestrial and cosmic gamma radiation. Health Phys 2006; 90: 569–79. Chelgoum Y, Danaila C, Belhabri A, et al. Influence of cigarette smoking on the presentation and course of acute myeloid leukemia. Ann Oncol 2002; 13: 1621–27.
Barriers against STDs: what about planned pregnancy? We welcome Anne Philpott and colleagues’ proposal that barriers against sexually transmitted diseases should be designed to promote sexual pleasure (Dec 2, p 2028).1 We agree that the uptake and consistency of use of such barriers, and hence their effectiveness, would be thereby enhanced. This is surely a concern to be kept in mind by those who design physical and chemical barriers. Also, those who aim to dispense them to potential users have to work within the cultural constraints of the society to maximise their pleasurable use. An issue no less fundamental and in need of attention, however, is that for many young women and men, conception is also an integral part of sexual relationships. Fertility is not only desirable but essential to the maintenance of the community. There are many individuals who will accept neither physical barriers such as condoms, nor microbicides that
are contraceptive, even if the risk of infection is reported to be high. Perhaps these concerns seem obvious; nevertheless, Philpott and colleagues’ publication, and we hope ours too, go beyond the laboratory considerations that too often seem to take priority in prevention of HIV. We declare that we have no conflict of interest.
Zena Stein, *Joanne Mantell [email protected] HIV Center for Clinical and Behavioral Studies at the New York State Psychiatric Institute and Columbia University, New York, NY 10032, USA (ZS, JM); and Mailman School of Public Health, New York, NY, USA (ZS) 1
Philpott A, Knerr W, Maher D. Promoting protection and pleasure: amplifying the effectiveness of barriers against sexually transmitted infections and pregnancy. Lancet 2006; 368: 2028–31.
Human papillomavirus vaccine policy Your Editorial on human papillomavirus (HPV) vaccination (Oct 7, p 1212)1 is disastrous for public health. Your message—that the EU is misguidedly dragging its feet over compulsory vaccination—is what the manufacturers want us to believe. But it is wrong. You say we must eradicate HPV infection, irrespective of cost or collateral damage. This is rubbish, our aim must be to reduce illness caused by HPV infection, and the prime ill effect is cervical cancer. Countries with high mortality and no screening can achieve major gain from vaccination. But rushed introduction in Europe will worsen HPV-related illness by undermining existing screening and leaving women less protected than now. In November, 2005, a meeting in London, UK, brought experts from all fields to consider the needs of National Health Service (NHS) research and policy. The conclusions were: women are well served by the NHS screening programme, which meets exacting standards2 and is averting 80% of deaths;3 if and when we have vaccine evidence on long-term disease
The printed journal includes an image merely for illustration
367
Science Photo Library
USA, 30–60 mg/day is an infrequently prescribed dose, whereas doses over 100 mg/day are now the norm. It is with consternation that we acknowledge the escalation of dosing standards as our best explanation for the increase in morbidity and mortality among methadone-treated patients. Indeed, these very concerns regarding high-dose methadone are expressed by the manufacturer in a just-released black box warning label.3