Vol. 19 No. 5 May 2000 Journal of Pain and Symptom Management 393 Clinical Note Prolonged Oral Morphine Therapy for Severe Angina Pectoris Meir Mouallem, MD, Eli Schwartz, MD, and Zvi Farfel, MD Department of Medicine E, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Hashomer, Israel Abstract Patients with intractable angina pectoris despite optimal drug therapy, who are not candidates for revascularization procedures, pose a very difficult problem. We evaluated the role of chronic opioid therapy in four such patients. The patients (mean age 79.5 years) were treated by low doses (mean 40 mg/day) of controlled-release oral morphine () for 1 to 5 years. The treatment was followed by a marked decline in the rate of admissions and hospitalization periods. The number of admissions decreased from a mean of 6 during the year prior to therapy to 1.5 the following year. The duration of hospitalization for angina pectoris during these periods decreased from a mean of 42 35 days to 6 10 days (p 0.05). Side effects were negligible and consisted mainly of lactulose-responsive constipation. We suggest that prolonged oral morphine therapy may be administered with good efficacy and no significant side effects in selected patients with intractable angina pectoris. J Pain Symptom Manage 2000;19:393 397. U.S. Cancer Pain Relief Committee 2000. Key Words Intractable angina pectoris, oral morphine Address reprint requests to: Meir Mouallem, MD, Department of Medicine E, Sheba Medical Center, Tel Hashomer 52621, Israel. Accepted for publication: June 17, 1999 Introduction Angina pectoris is a frequent cause of hospital admissions. In most patients, it can be adequately treated by drug therapy or revascularization procedures, such as percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG). In a small minority of patients, pharmacological therapy is insufficient and revascularization procedures are not feasible. These patients with intractable angina pectoris may be admitted repeatedly to the hospital. Various treatment modalities have been proposed for these patients, such as spinal cord stimulation. 1,2 We describe a series of such patients who were treated successfully with oral controlled-release morphine sulphate() for prolonged periods of time. Patients Four patients with severe anginal syndrome that could not be adequately treated medically or surgically were identified (Tables 1 and 2). Patient 1 The patient was 84 years old at the time treatment with started. He had hypertension with mild renal failure (serum creatinine 177 mol/l) and was a past smoker but did not suffer from lung disease. One year earlier, U.S. Cancer Pain Relief Committee, 2000 0885-3924/00/$ see front matter Published by Elsevier, New York, New York PII S0885-3924(00)00139-1
394 Mouallem et al. Vol. 19 No. 5 May 2000 Patient Number/ Gender Age at Angina Onset Age at Initiation of 1/M 83 84 Non Q ant. wall 2/M 51 71 Inf. wall (16 years). Ant. wall Table 1 Patient Characteristics and Manifestation of Coronary Disease MI (years treatment) CABG Angio Arrhythmia CHF Treatment 0 3VCD Lt main. Normal LV function 15 years Occluded grafts. Native LAD RCA occluded. Cx open and supplies the posterior wall. VPBs Aspirin, Nitrates, Nifedipine, / Heparin CAF Aspirin, Nitrates, / Heparin, Amiodarone then Digoxin, Furosemide Thiazides 3/F 72 81 0 0 N.D. 0 0 Aspirin, Nitrates, Diltiazem 4/F 78 82 Non Q ant. wall 4 years 3VCD. PTCA to RCA Cx CAVB induced by blockers Aspirin, Nitrates, Ca blockers Angio coronary angiography; Ant anterior; CABG coronary artery bypass graft; CAF chronic atrial fibrillation; CAVB complete atrio ventricular block; CHF congestive heart failure; Cx circumflex artery; F female; Inf Inferior; LAD left anterior descending artery; LIMA left internal mammary artery; LV left ventricle; M male; MI myocardial infarction; N.D. not done; PTCA percutaneous coronary angioplasty; RCA right coronary artery; VPBS ventricular premature beats; 3VCD three vessel coronary artery disease. he had a non-q wave anterior wall myocardial infarction (MI), and since then he had severe anginal syndrome with recurrent admissions to the hospital. He was treated by aspirin, nitrates, calcium blockers, and occasionally by heparin. Coronary angiography demonstrated three vessel coronary artery disease with involvement of the left main coronary artery. There was no option for PTCA and surgery was declined mainly because of his age. The patient was treated by 30 mg/day (10 mg in the morning and 20 mg at bedtime) and had marked improvement, without side effects. During the first year of treatment, the patient was admitted twice because of episodes of non-q wave anterior wall MI that were not masked by the morphine treatment. During that year, he was admitted once more, and, during the following year, there was another admission. The patient continued treatment until his death at the age of 89. Patient 2 The patient was 71 years old when was started. This patient had symptoms of ischemic heart disease since the age of 51. He also had Parkinson s disease and mild renal failure (creatinine 141 mol/l). At the age of 55, the patient had an inferior wall MI and, one year later, CABG was performed with vein grafts to the three coronary vessels. In the year prior to treatment, he was admitted to the hospital 3 times because of severe anginal syndrome and was found to have atrial fibrillation and congestive heart failure (left ventricular ejection fraction 15%). Coronary angiography demonstrated occluded grafts, only the circumflex artery was patent and supplied the posterior wall. The option for PTCA or operation was rejected because of his general condition. The patient has been on treatment for more than 3 years. During these years, he has been admitted only once, for one day, because of anginal pains. Initially, the dose of was 10 mg twice daily; later, the dose was gradually increased to 50 mg twice daily because of increased intensity of the pain. Side effects included severe constipation that was treated successfully by lactulose. In addition, he was admitted once because of confusion induced by the opioid or by the low cardiac output. The patient recovered spontaneously without dose modification. Patient 3 The patient was 81 years old at the time treatment with started. She had Parkinson s disease with recurrent cerebrovascular accidents. Cerebral angiography demonstrated vertebral artery stenosis. Anginal syndrome appeared 9 years prior to treatment and became more severe in the year preceding its initiation. She was treated by aspirin, nitrates and calcium blockers. Nevertheless, in the year prior to treatment, she was admitted 7
Vol. 19 No. 5 May 2000 Prolonged Oral Morphine Therapy for Severe Angina 395 Table 2 Admission and Hospitalization Days Due to Angina Pectoris, Related to Treatment with Patient Number 1 2 3 4 Admissions in the year prior to 7 (92) 3 (41) 7 (22) 7 (13) treatment (hospitalization days) Admissions in the first year 3 (21) 1 (1) 1 (1) 1 (1) following therapy Admissions in the second year 1 (1) 0 0 Admissions in the third year 0 1 (1) 0 Treatment duration (years) 5 3, currently 3, currently 1, currently (until death) on Dose of (mg per day) 10 20 10 2 raised to 50 2 on on 10 2 10 2 times to the hospital. The ECG demonstrated sinus bradycardia and left anterior hemiblock; chest radiography, echocardiogram, and thallium scan were normal. The type of the pain and her neurologic abnormalities made us consider the pain as angina. Coronary angiography was not performed and she was treated successfully by 10 mg twice a day. Since then, she was admitted only once because of chest pain and for only one day, following discontinuation by her physician. treatment was accompanied by constipation and was treated successfully by lactulose. The patient had also an episode of biliary colic that could be ascribed to the morphine treatment, which has been administered to her for the last 3 years. Patient 4 The patient was 82 years old when treatment by started. She had hypertension and diabetes, and was a heavy smoker without evidence of chronic obstructive pulmonary disease (COPD). At the age of 78, she began to suffer from anginal pain and CABG was performed, but shortly afterwards the anginal syndrome reappeared and she was treated by aspirin, nitrates, calcium blockers and -blockers, which were discontinued after she had complete atrioventricular block and mild heart failure. Two years treatment, coronary angiography was performed and threevessel coronary disease was demonstrated. PTCA to the right coronary artery and to the circumflex artery was performed, but the patient continued to suffer from intractable angina. In the year prior to treatment, she was admitted 7 times to the hospital. She has been treated by 10 mg twice daily, and, in the first year of treatment, she has been admitted only once, due to temporary discontinuation of the medication. She has been tolerating the treatment very well and has had no side effects. Table 1 shows the clinical data regarding the patients coronary artery disease. Table 2 shows the response of the patients to the treatment. It is clear that after initiation of therapy, there was a marked decline in the number and duration of hospitalizations due to angina. The number of hospitalizations decreased from a mean of 6 during the year prior to therapy to a mean of 1.5 the following year. The total duration of hospitalizations during the year prior to decreased from a mean of 42 35 days to a mean of 6 10 days the following year (p 0.05). During this period, the patients were not hospitalized on other wards. Discussion Prolonged treatment of patients with angina pectoris by epidural morphine infusion was first reported by Clemensen et al in 1987. 3 They described 7 patients with intractable angina which lasted for 1 10 years and had failed revascularization procedures. In response to the epidural morphine, which was administered by the patients or by family members, the pain decreased in all patients for a follow-up period of 3 11 months. Two other patients treated by epidural morphine administration
396 Mouallem et al. Vol. 19 No. 5 May 2000 or by continuous intrathecal infusion of morphine were described later. 4,5 Since increased use of systemic morphine for nonmalignant conditions has become more prevalent and acceptable, 6,7 we decided to treat patients with intractable angina who were not candidates for revascularization by this modality. Our patients are the first described group with intractable angina treated with oral opioids for a prolonged time. All the patients had severe anginal symptoms and severe coronary artery disease was demonstrated by coronary angiography in three. Two had failed CABG and none was a candidate for a revascularization procedure. One patient (number 3) had a stroke in the past and Parkinson s disease, and invasive procedures were, therefore, not performed. These patients were relatively old. Three were in their eighties and one was 71 years at the beginning of treatment. In contrast to the relatively short duration of epidural morphine therapy described earlier (a few months), 3 our patients were treated for prolonged periods, 1 5 years, with a mean follow up of 3 years. Although this was not a controlled study, it was obvious that treatment with morphine significantly improved the quality of life of the patients. The patients reported a definite decline in the number and intensity of the anginal episodes. The number and duration of hospitalizations decreased dramatically in all the patients. The first patient who was admitted more times than the other patients during the first year of treatment was admitted twice because of non-q wave anterior wall MI. The third and the fourth patients were admitted only once and for only one day during the first year of treatment. The cause of admissions in both patients was discontinuation because their family physicians avoided prescription of. A few issues should be considered regarding prolonged oral opioid therapy in angina pectoris. No patient developed tolerance to the drug, and the low doses of used were usually constant. Dose increase was not observed also in patients who were treated intrathecally or epidurally. 3,5 This differs from patients with malignant disease in whom the intensity of the pain increases over time, with consequent requirement for escalation of the opioid dose. It is conceivable that in patients with anginal syndrome, the intensity of the pain is relatively constant and there is apparently no need to increase the dose of the drug. In only one patient (number 2), the dose of was escalated because of increased pain intensity. Side effects seen in the treatment group were relatively insignificant. As is common in patients treated with opioids, two of the patients had constipation necessitating treatment with lactulose. The second patient had an episode of confusion that could be ascribed to treatment or to the severity of heart failure. It is also possible that abdominal pain and biliary colic that caused hospitalization in the third patient were induced by treatment with morphine. Can therapy mask ischemic episodes? 5,8 Because the group is small, it is difficult to address this issue. However, Patient 1 had two ischemic episodes that were recognized by him and were not masked by the treatment. Moreover, even if ischemic episodes were masked, they did not cause myocardial infarction. Of note is the long survival of these elderly patients. It is obvious that such a nonconventional treatment should be undertaken only after detailed discussion with the patients, their families, and their physicians. Clarification that this kind of therapy can be used although no malignancy is being treated is very important for the success of this unorthodox therapy. From the small series of patients here described, it seems that prolonged oral morphine therapy for intractable angina can be administered with good efficacy and negligible side effects in selected patients. Large series will be required to better define the indication for such therapy and the mechanism of its beneficial effect. References 1. Jessurun GAJ, DeJongste MJL, Blanksma PK. Current views on neurostimulation in the treatment of cardiac ischemic syndromes. Pain 1996;66:109 116. 2. Hautvast RWM, Brouwer J, DeJongste MJL, Lie KI. Effect of spinal cord stimulation on heart rate variability and myocardial ischemia in patients with chronic intractable angina pectoris a prospective ambulatory electrocardiographic study. Clin Cardiol 1998;21:33 38.
Vol. 19 No. 5 May 2000 Prolonged Oral Morphine Therapy for Severe Angina 397 3. Clemensen SF, Thayssen P, Hole P. Epidural morphine for outpatients with severe anginal pain. Br Med J 1987;294:475 476. 4. Cherry DA, Gourlay GK. CT contrast evidence of injectate encapsulation after long-term epidural administration. Pain 1992;49:369 371. 5. Segal R, Murali S, Tipton K. Treatment of chronic unstable angina pectoris: use of a totally implantable programmable device for continuous intrathecal infusion of opiates: case report. Neurosurgery 1996;38:385 388. 6. Portenoy RK. Opioid therapy for chronic nonmalignant pain: a review of the critical issues. J Pain Symptom Manage 1996;11:203 217. 7. Brookoff D, Polomano R. Treating sickle cell pain like cancer pain. Ann Intern Med 1992;116:364 368. 8. Dershwitz M, Sherman EP. Acute myocardial infarction symptoms masked by epidural morphine? J Clin Anesth 1991;3:146 148.