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Morpheus, God of Sleep or God of Death?
Editorial
Morpheus, God of Sleep or God of Death? Freek W.A. Verheugt, MD Nijmegen, The Netherlands
See related article on page 1043.
Morphine is a highly effective drug for the relief of pain, dyspnea, and agony. Therefore, it seems to be the drug of choice in the first line treatment of patients with acute myocardial infarction (MI). Besides its effect on the central nervous system, it also lowers blood pressure, which may be of additional value in the treatment of acute left ventricular failure. Finally, morphine is used in the palliative treatment of patients with end-stage diseases such as the terminal phase of either congestive heart failure or acute MI without change of surviving. Morphine has also some untoward effects such as nausea and unintended lowering of blood pressure. Therefore, parasympathicolytic drugs such as atropine or antiemetics like droperidol are sometimes necessary to suppress nausea, and pressor agents to counteract low blood pressure. Both atropine and pressor drugs increase heart rate and may eventually infarct size. The safety of opioids in the early management of acute MI has never been systematically evaluated in trials large enough to be conclusive. In this issue of Journal, the Duke Clinical Research Institute (Durham, NC) presents a post hoc analysis on the use of morphine in the well-known CRUSADE registry including patients with non–ST-segment elevation acute coronary syndromes. They find an increased mortality in patients who were given morphine in the first 24 hours after hospital admission. This increase of nearly 50% was found in all subgroups and seems to be independent of the use of intravenous nitroglycerin. Because morphine is widely used for the above reasons in patients with acute myocardial ischemia and infarction, these data are disturbing but raise more questions than they answer. First, the large group of patients receiving morphine (about one third of the total
From the 540 Cardiology, Heart Center, University Medical Center St Radboud, Nijmegen, The Netherlands. Submitted February 17, 2005; accepted February 20, 2005. Reprint requests: Freek WA Verheugt, MD, 540 Cardiology, Heart Center, University Medical Center St Radboud, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands. E-mail: [email protected] Am Heart J 2005;149:945-6. 0002-8703/$ - see front matter n 2005, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2005.02.035
population) was 5 years younger than the patients who did not receive it. In addition, more patients with ST-segment depression, transient ST-segment elevation, and positive markers were given morphine, but interestingly, not those with signs of heart failure. More morphine patients underwent inhospital procedures such as catheterization and percutaneous coronary intervention, whereas the use of coronary artery bypass graft was not different. Despite the much younger age (65 years for morphine vs 70 for no morphine), adjusted analysis showed 34% more postadmission MI, 71% more cardiogenic shock, 27% more congestive failure, and 48% more mortality (5.5% for morphine administration vs 4.7% without morphine). The patients receiving morphine are clearly a specific group with a higher risk that cannot be easily corrected for by the classical risk factors, for example, age, which is the strongest predictor of death in this syndrome.1 The authors suggest that the concomitant use of morphine with nitroglycerin may lead to a lower dosing of nitroglycerin to compensate for the effects on blood pressure. A lower dose of nitroglycerin may be less effective than regular doses. However, in the megatrials on full-dose nitroglycerin or mononitrate intervention in acute MI, there was only a minute effect with regard to 35 days mortality,2,3 which cannot account for the nearly 50% increased mortality in the morphine patients in CRUSADE. One would think that morphine was given more to patients with congestive heart failure than to those without, and that heart failure may be the mechanism of increased mortality. However, the patients in heart failure at baseline did not receive more morphine and those without. Therefore, the authors compared the patients who got intravenous nitroglycerin alone to those who got intravenous morphine alone. Again, they found the same increase of complications such as death, postadmission MI, and cardiogenic shock in the patients who received intravenous morphine only, whereas the development of congestive heart failure in both groups was quite similar when adjusted for the classical risk factors. So, again, it is unlikely that a lower dose of nitroglycerin by itself is responsible for the increased death in the patients treated with intravenous morphine. These observations suggest that morphine has an unknown harmful effect on the natural cause of patients with non–ST-segment elevation acute coronary syndromes. A definite harm of morphine can only be studied in a randomized trial, in which morphine must
American Heart Journal June 2005
946 Verheugt
be compared to another drug relieving pain, dyspnea, and agony. There have been some small but elaborate studies that have compared morphine to other analgesics, the best of which included only 12 patients. In that study, patients with acute MI underwent catheterization and echocardiography after they were randomized to either morphine sulfate, meperidine, or pentazocine.4 In this well-performed study, pentazocine increased left ventricular preload and afterload, and therefore, myocardial oxygen demand, where the others did not. Morphine has also been compared in a randomized study to metoprolol. Acute h-blockade may result in less ischemic burden, and therefore, less chest pain. In the MEMO study, 265 patients with a suspected acute MI were randomized double-blind to receive morphine or metoprolol intravenously.5 The main end point was pain relief, which was better with morphine than with the h-blocker. Mortality at 6 months in this study was low and similar in both groups (4.4% for morphine and 4.7% for metoprolol). Clearly, for a randomized trial to scrutinize morphine in acute MI, a proper alternative as effective in relief of pain, dyspnea, and agony as morphine will be hard to find. Therefore, the question raised by authors why not to perform a randomized study will be almost impossible to answer. Post hoc analysis of nonrandomized variables remains difficult even when a corrected analysis has been performed. In CRUSADE, the patients receiving morphine form a very special group. The only thing we know in fact is that morphine was administered in the first 24 hours, but the reason for which it was given may be variable: pain relief, alleviation of dyspnea, or, which cannot be excluded at all, the relief of agony in the final moments of the patients. If morphine was given to comfort patients dying of non–ST-elevation acute coronary syndrome, the relation with mortality in this registry is very clear. Yet, this cannot be proven. In general, morphine is widely used in the final stages of
not only chronic, but also acute diseases, such as MI complicated with congestive failure, shock, or incessant chest pain. This may be a good explanation for the morphine findings in CRUSADE. In the Greek mythology, Morpheus was the god of sleep and that was the reason to name a specific opioid for insomnia morphine. Because we have much better sleep medications nowadays, morphine is more and more used for other conditions than insomnia. Morpheus would never have anticipated that a drug was called after him, but if so, he and his fellow gods would have been happy to hear that it had been designed for the relief of pain or insomnia. Had they known that the drug is also used for the dying patient, it would have made Morpheus not only the god of sleep, but probably also the god of death. The question remains, whether the Greek theocracy would have been happy with that.
References 1. Antman EM, Cohen M, Bernink PJLM, et al. The TIMI risk score for unstable angina/non–ST elevation MI: a method for prognostication and therapeutic decision making. JAMA 2000;284:835 - 42. 2. Gruppo per lo Studio della Sopravvivenza nell’Infarto Miocardico. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-weeks mortality and ventricular function after acute myocardial infarction. Lancet 1994;343:1115 - 22. 3. Fourth International Study of Infarct Survival Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction. Lancet 1995;345:669 - 85. 4. Lee G, DeMaria AN, Amsterdam EA, et al. Comparative effects of morphine, meperidine and pentazocine on cardiocirculatory dynamics in patients with acute myocardial infarction. Am J Med 1976;60:949 - 55. 5. Everts B, Karlson B, Abdon NJ, et al. A comparison of metoprolol and morphine in the treatment of chest pain in patients with suspected acute myocardial infarction: the MEMO study. J Intern Med 1999;245:133 - 41.
Morpheus, God of Sleep or God of Death? Freek W.A. Verheugt, MD Nijmegen, The Netherlands
See related article on page 1043.
Morphine is a highly effective drug for the relief of pain, dyspnea, and agony. Therefore, it seems to be the drug of choice in the first line treatment of patients with acute myocardial infarction (MI). Besides its effect on the central nervous system, it also lowers blood pressure, which may be of additional value in the treatment of acute left ventricular failure. Finally, morphine is used in the palliative treatment of patients with end-stage diseases such as the terminal phase of either congestive heart failure or acute MI without change of surviving. Morphine has also some untoward effects such as nausea and unintended lowering of blood pressure. Therefore, parasympathicolytic drugs such as atropine or antiemetics like droperidol are sometimes necessary to suppress nausea, and pressor agents to counteract low blood pressure. Both atropine and pressor drugs increase heart rate and may eventually infarct size. The safety of opioids in the early management of acute MI has never been systematically evaluated in trials large enough to be conclusive. In this issue of Journal, the Duke Clinical Research Institute (Durham, NC) presents a post hoc analysis on the use of morphine in the well-known CRUSADE registry including patients with non–ST-segment elevation acute coronary syndromes. They find an increased mortality in patients who were given morphine in the first 24 hours after hospital admission. This increase of nearly 50% was found in all subgroups and seems to be independent of the use of intravenous nitroglycerin. Because morphine is widely used for the above reasons in patients with acute myocardial ischemia and infarction, these data are disturbing but raise more questions than they answer. First, the large group of patients receiving morphine (about one third of the total
From the 540 Cardiology, Heart Center, University Medical Center St Radboud, Nijmegen, The Netherlands. Submitted February 17, 2005; accepted February 20, 2005. Reprint requests: Freek WA Verheugt, MD, 540 Cardiology, Heart Center, University Medical Center St Radboud, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands. E-mail: [email protected] Am Heart J 2005;149:945-6. 0002-8703/$ - see front matter n 2005, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2005.02.035
population) was 5 years younger than the patients who did not receive it. In addition, more patients with ST-segment depression, transient ST-segment elevation, and positive markers were given morphine, but interestingly, not those with signs of heart failure. More morphine patients underwent inhospital procedures such as catheterization and percutaneous coronary intervention, whereas the use of coronary artery bypass graft was not different. Despite the much younger age (65 years for morphine vs 70 for no morphine), adjusted analysis showed 34% more postadmission MI, 71% more cardiogenic shock, 27% more congestive failure, and 48% more mortality (5.5% for morphine administration vs 4.7% without morphine). The patients receiving morphine are clearly a specific group with a higher risk that cannot be easily corrected for by the classical risk factors, for example, age, which is the strongest predictor of death in this syndrome.1 The authors suggest that the concomitant use of morphine with nitroglycerin may lead to a lower dosing of nitroglycerin to compensate for the effects on blood pressure. A lower dose of nitroglycerin may be less effective than regular doses. However, in the megatrials on full-dose nitroglycerin or mononitrate intervention in acute MI, there was only a minute effect with regard to 35 days mortality,2,3 which cannot account for the nearly 50% increased mortality in the morphine patients in CRUSADE. One would think that morphine was given more to patients with congestive heart failure than to those without, and that heart failure may be the mechanism of increased mortality. However, the patients in heart failure at baseline did not receive more morphine and those without. Therefore, the authors compared the patients who got intravenous nitroglycerin alone to those who got intravenous morphine alone. Again, they found the same increase of complications such as death, postadmission MI, and cardiogenic shock in the patients who received intravenous morphine only, whereas the development of congestive heart failure in both groups was quite similar when adjusted for the classical risk factors. So, again, it is unlikely that a lower dose of nitroglycerin by itself is responsible for the increased death in the patients treated with intravenous morphine. These observations suggest that morphine has an unknown harmful effect on the natural cause of patients with non–ST-segment elevation acute coronary syndromes. A definite harm of morphine can only be studied in a randomized trial, in which morphine must
American Heart Journal June 2005
946 Verheugt
be compared to another drug relieving pain, dyspnea, and agony. There have been some small but elaborate studies that have compared morphine to other analgesics, the best of which included only 12 patients. In that study, patients with acute MI underwent catheterization and echocardiography after they were randomized to either morphine sulfate, meperidine, or pentazocine.4 In this well-performed study, pentazocine increased left ventricular preload and afterload, and therefore, myocardial oxygen demand, where the others did not. Morphine has also been compared in a randomized study to metoprolol. Acute h-blockade may result in less ischemic burden, and therefore, less chest pain. In the MEMO study, 265 patients with a suspected acute MI were randomized double-blind to receive morphine or metoprolol intravenously.5 The main end point was pain relief, which was better with morphine than with the h-blocker. Mortality at 6 months in this study was low and similar in both groups (4.4% for morphine and 4.7% for metoprolol). Clearly, for a randomized trial to scrutinize morphine in acute MI, a proper alternative as effective in relief of pain, dyspnea, and agony as morphine will be hard to find. Therefore, the question raised by authors why not to perform a randomized study will be almost impossible to answer. Post hoc analysis of nonrandomized variables remains difficult even when a corrected analysis has been performed. In CRUSADE, the patients receiving morphine form a very special group. The only thing we know in fact is that morphine was administered in the first 24 hours, but the reason for which it was given may be variable: pain relief, alleviation of dyspnea, or, which cannot be excluded at all, the relief of agony in the final moments of the patients. If morphine was given to comfort patients dying of non–ST-elevation acute coronary syndrome, the relation with mortality in this registry is very clear. Yet, this cannot be proven. In general, morphine is widely used in the final stages of
not only chronic, but also acute diseases, such as MI complicated with congestive failure, shock, or incessant chest pain. This may be a good explanation for the morphine findings in CRUSADE. In the Greek mythology, Morpheus was the god of sleep and that was the reason to name a specific opioid for insomnia morphine. Because we have much better sleep medications nowadays, morphine is more and more used for other conditions than insomnia. Morpheus would never have anticipated that a drug was called after him, but if so, he and his fellow gods would have been happy to hear that it had been designed for the relief of pain or insomnia. Had they known that the drug is also used for the dying patient, it would have made Morpheus not only the god of sleep, but probably also the god of death. The question remains, whether the Greek theocracy would have been happy with that.
References 1. Antman EM, Cohen M, Bernink PJLM, et al. The TIMI risk score for unstable angina/non–ST elevation MI: a method for prognostication and therapeutic decision making. JAMA 2000;284:835 - 42. 2. Gruppo per lo Studio della Sopravvivenza nell’Infarto Miocardico. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-weeks mortality and ventricular function after acute myocardial infarction. Lancet 1994;343:1115 - 22. 3. Fourth International Study of Infarct Survival Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction. Lancet 1995;345:669 - 85. 4. Lee G, DeMaria AN, Amsterdam EA, et al. Comparative effects of morphine, meperidine and pentazocine on cardiocirculatory dynamics in patients with acute myocardial infarction. Am J Med 1976;60:949 - 55. 5. Everts B, Karlson B, Abdon NJ, et al. A comparison of metoprolol and morphine in the treatment of chest pain in patients with suspected acute myocardial infarction: the MEMO study. J Intern Med 1999;245:133 - 41.