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Narcotic analgesics in heart disease
Appraisal and reappraisalofcardiactherapy
Narcotic
analgesics
in heart
disease
Walter Modell, M.D.* New York, N. Y.
T
he acute pain of ischemic heart disease and the much less common chronic pain of aortitis represent the major pain problems in heart disease. For the most part, these are severe and beyond the scope of mild analgesics. In addition to the need to relieve the suffering of the patient, it is important to control this symptom because of the further noxious effect of pain on cardiovascular responses. The potent narcotic analgesics remain the only drugs adequate for the treatment of cardiac pain, despite side effects which can cause serious problems in the cardiac patient. When given in therapeutic dosage, these drugs may variously produce respiratory depression, nausea and vomiting, constipation gall-bladder colic, dysuria, bronchospasm, tachycardia and arrhythmia, tolerance and addiction. Some of these adverse effects are produced by morphine and its congeners, others by meperidine and its congeners, and some by both, although chemically very different. Methadone produces side effects similar to the morphine group. The derivative drugs within each group are not qualitatively different from the parent drugs, so that morphine and meperidine can still serve as prototypes for discussion. Respiratory depression. Excessive respiratory depression due to a direct effect on the respiratory center is the most serious complication of these drugs. Although some Received for publication Feb. *Department of Pharmacology, York 21, N. Y.
709
1, 1963. Cornell
University
respiratory depression is helpful in the with hyperventilation or pulpatient monary edema, a greater degree in a patient with circulatory or pulmonary insufficiency can be a life-threatening complication. In normal man there is measurable respiratory depression after as little as 5 mg. of morphine. In patients with cardiac pain, however, considerably larger doses are tolerated without respiratory depression. Some late depression may be due to a change in the state of the patient as the pain is relieved. Often, however, such late depression is due to the cumulative effect of the drug, as the physician prescribes frequent and increased doses to control severe pain, losing sight of the delay in effect after even intravenous administration and of its increasing effect over several hours. Therefore, it is safer in situations of refractory pain to attempt to diminish pain to the point of acceptability rather than to eliminate it. Meperidine is not so potent a respiratory depressant as is morphine, but the significant effect of meperidine and its congeners on respiration provide a real hazard. Nausea and vomiting. Nausea and vomiting commonly occur after narcotic analgesics and are due to stimulation of the central nervous system. None of the drugs now available is free of this effect, nor is there evidence that any one is preferable to the others in this regard, despite claims to the contrary. The tendency toMedical
College.
New
York,
N. Y. Address:
1300
York
Ave.,
New
710
Am. Heart J. May, 1963
Model1
ward emesis is an individual idiosyncrasy with these drugs. There is no predictable pattern in the responses of patients susceptible to the various agents. Certainly a patient should not receive the drug which has caused emesis previously, and other agents should be used with caution in such patients because of the likelihood of similar response. Narcotic-induced emesis can usually be relieved by chlorpromazine, but the routine prophylactic use of chlorpromazine is not recommended because of the special danger of its hypotensive effect in the cardiac patient, as well as its other toxic manifestations. Effects on smooth muscle. Constipation, dysuria, gall-bladder colic, and bronchospasm are due to a direct effect of morphine on smooth muscle tone. Meperidine has no significant effect on smooth muscle tone in the gastrointestinal tract. Morphine may also produce bronchospasm by releasing histamine, making its use especially hazardous in the asthmatic patient. In this respect, meperidine has an advantage over morphine. If anything, it exerts a feeble spasmolytic effect on the bronchial musculature. Meperidine, however, produces cardiac acceleration through a vagolytic action.
Morphine tends to slow the heart through central vagal action. Cardiac arrhythmia is also seen after meperidine. In these two aspects, its value may be inferior to that of morphine in the cardiac patient. Tolerance and addiction. Tolerance and addiction are infrequent complications of these drugs when used for acute myocardial infarction, and occur only in former addicts or in the very unstable individuals with a high addiction liability. Addiction is common when the drug is used for more than 2 weeks, however. Despite various claims, there is no substantial difference in the addiction liability of any of these drugs. Phenazocine, which was thought a few years ago to be different in this regard, has been shown to have no advantage over morphine. Meperidine causes many more cases of accidental addiction because it is used with much less caution than morphine by the medical profession. Derivatives of morphine and wzeperidine. Within the morphine group (see Table I), differences are primarily in dosage. In some, smaller doses are used, but in maximum safe doses, none will relieve more severe pain than morphine. Some have a slightly more rapid onset of action than
Table I Drug Group Generic Morphine
and congeners
name
Proprietary
name
Approximate equianalgesic dose (mg.) subcutaneous
Morphine Codeine Dihydrocodeine Dihydrocodeinone Dihydromorphinone Levorphanol Oxymorphone Pantopium Phenazocine
Paracodin Hycodan Dilaudid Levo-Dromoran Numorphan Pantopon Prinadol
10 60 30 1.5 2 2 1 20 2.5 10 10
Methadone
and congeners
Methadone Dipipanone
Dolophine Pipadone
Meperidine
and congeners
Meperidine Alphaprodine Anileridine Piminodine
Demerol Nisentil Leritine Alvodine
100 50 40 10
Volume Number
65
5
does morphine, but with no practical advantage. Because of rapid destruction by the liver, none is very effective by mouth. Methadone differs from morphine only in fairly good oral activity. The current popularity of meperidine and its congeners cannot be accounted for by any proved virtue. They are highly addictive, cause respiratory depression,
Narcotic
analgesics in heart disease
711
induce nausea and vomiting, and are not so potent as morphine. Regardless of dose, they cannot relieve some severe pain that responds readily to morphine. Given by mouth, they produce inconstant effects. When assurance of activity is necessary, they must be given parenterall y.
Narcotic
analgesics
in heart
disease
Walter Modell, M.D.* New York, N. Y.
T
he acute pain of ischemic heart disease and the much less common chronic pain of aortitis represent the major pain problems in heart disease. For the most part, these are severe and beyond the scope of mild analgesics. In addition to the need to relieve the suffering of the patient, it is important to control this symptom because of the further noxious effect of pain on cardiovascular responses. The potent narcotic analgesics remain the only drugs adequate for the treatment of cardiac pain, despite side effects which can cause serious problems in the cardiac patient. When given in therapeutic dosage, these drugs may variously produce respiratory depression, nausea and vomiting, constipation gall-bladder colic, dysuria, bronchospasm, tachycardia and arrhythmia, tolerance and addiction. Some of these adverse effects are produced by morphine and its congeners, others by meperidine and its congeners, and some by both, although chemically very different. Methadone produces side effects similar to the morphine group. The derivative drugs within each group are not qualitatively different from the parent drugs, so that morphine and meperidine can still serve as prototypes for discussion. Respiratory depression. Excessive respiratory depression due to a direct effect on the respiratory center is the most serious complication of these drugs. Although some Received for publication Feb. *Department of Pharmacology, York 21, N. Y.
709
1, 1963. Cornell
University
respiratory depression is helpful in the with hyperventilation or pulpatient monary edema, a greater degree in a patient with circulatory or pulmonary insufficiency can be a life-threatening complication. In normal man there is measurable respiratory depression after as little as 5 mg. of morphine. In patients with cardiac pain, however, considerably larger doses are tolerated without respiratory depression. Some late depression may be due to a change in the state of the patient as the pain is relieved. Often, however, such late depression is due to the cumulative effect of the drug, as the physician prescribes frequent and increased doses to control severe pain, losing sight of the delay in effect after even intravenous administration and of its increasing effect over several hours. Therefore, it is safer in situations of refractory pain to attempt to diminish pain to the point of acceptability rather than to eliminate it. Meperidine is not so potent a respiratory depressant as is morphine, but the significant effect of meperidine and its congeners on respiration provide a real hazard. Nausea and vomiting. Nausea and vomiting commonly occur after narcotic analgesics and are due to stimulation of the central nervous system. None of the drugs now available is free of this effect, nor is there evidence that any one is preferable to the others in this regard, despite claims to the contrary. The tendency toMedical
College.
New
York,
N. Y. Address:
1300
York
Ave.,
New
710
Am. Heart J. May, 1963
Model1
ward emesis is an individual idiosyncrasy with these drugs. There is no predictable pattern in the responses of patients susceptible to the various agents. Certainly a patient should not receive the drug which has caused emesis previously, and other agents should be used with caution in such patients because of the likelihood of similar response. Narcotic-induced emesis can usually be relieved by chlorpromazine, but the routine prophylactic use of chlorpromazine is not recommended because of the special danger of its hypotensive effect in the cardiac patient, as well as its other toxic manifestations. Effects on smooth muscle. Constipation, dysuria, gall-bladder colic, and bronchospasm are due to a direct effect of morphine on smooth muscle tone. Meperidine has no significant effect on smooth muscle tone in the gastrointestinal tract. Morphine may also produce bronchospasm by releasing histamine, making its use especially hazardous in the asthmatic patient. In this respect, meperidine has an advantage over morphine. If anything, it exerts a feeble spasmolytic effect on the bronchial musculature. Meperidine, however, produces cardiac acceleration through a vagolytic action.
Morphine tends to slow the heart through central vagal action. Cardiac arrhythmia is also seen after meperidine. In these two aspects, its value may be inferior to that of morphine in the cardiac patient. Tolerance and addiction. Tolerance and addiction are infrequent complications of these drugs when used for acute myocardial infarction, and occur only in former addicts or in the very unstable individuals with a high addiction liability. Addiction is common when the drug is used for more than 2 weeks, however. Despite various claims, there is no substantial difference in the addiction liability of any of these drugs. Phenazocine, which was thought a few years ago to be different in this regard, has been shown to have no advantage over morphine. Meperidine causes many more cases of accidental addiction because it is used with much less caution than morphine by the medical profession. Derivatives of morphine and wzeperidine. Within the morphine group (see Table I), differences are primarily in dosage. In some, smaller doses are used, but in maximum safe doses, none will relieve more severe pain than morphine. Some have a slightly more rapid onset of action than
Table I Drug Group Generic Morphine
and congeners
name
Proprietary
name
Approximate equianalgesic dose (mg.) subcutaneous
Morphine Codeine Dihydrocodeine Dihydrocodeinone Dihydromorphinone Levorphanol Oxymorphone Pantopium Phenazocine
Paracodin Hycodan Dilaudid Levo-Dromoran Numorphan Pantopon Prinadol
10 60 30 1.5 2 2 1 20 2.5 10 10
Methadone
and congeners
Methadone Dipipanone
Dolophine Pipadone
Meperidine
and congeners
Meperidine Alphaprodine Anileridine Piminodine
Demerol Nisentil Leritine Alvodine
100 50 40 10
Volume Number
65
5
does morphine, but with no practical advantage. Because of rapid destruction by the liver, none is very effective by mouth. Methadone differs from morphine only in fairly good oral activity. The current popularity of meperidine and its congeners cannot be accounted for by any proved virtue. They are highly addictive, cause respiratory depression,
Narcotic
analgesics in heart disease
711
induce nausea and vomiting, and are not so potent as morphine. Regardless of dose, they cannot relieve some severe pain that responds readily to morphine. Given by mouth, they produce inconstant effects. When assurance of activity is necessary, they must be given parenterall y.