- Email: [email protected]
Individualization of Narcotic Analgesic Therapy
Symposium on Individualization of Drug Therapy
Individualization of Narcotic Analgesic Therapy Ben F. Rusy, M.D.*
The individualization of narcotic analgesic drug therapy is based upon a consideration of the ways in which the effects of narcotics are altered by disease states and by interaction with other drugs. Disease states alter the effects of narcotics by changing organ sensitivity to these drugs and by affecting the rates of their metabolism and excretion. Of these two effects of disease, the first is probably the more important. The major side effects of narcotic analgesics which one aims to minimize are respiratory and cardiovascular depression.
FACTORS ALTERING ORGAN SENSITIVITY Pulmonary Disease Respiratory depressant effects of narcotics are especially marked in patients with decreased respiratory reserve and accompanying respiratory acidosis. Figure 1 illustrates the ventilatory response to carbon dioxide observed under various conditions. The curve for a normal subject CC) is shifted to the right, as shown, by 10 mg of morphine sulfate. An equianalgesic dose of any other potent narcotic analgesic would have approximately the same effect. The normal arterial Pco Peo 2 is 40 mm Hg. This will increase approximately 5 mm Hg after the administration of 10 mg of morphine, assuming spontaneous respiration. The respiratory depressant effect of an ordinary therapeutic dose of morphine in a person with normal ventilatory function is probably of little physiological consequence, especially when one considers that similar changes in the arterial Pco sleep.99 In the Peo 2 and in the respiratory response to CO 2 occur in normal sleep. person with moderate to severe respiratory insufficiency the situation is different. For example, it has been shown 77 that arterial oxygen tensions of less than 60 mm Hg, and CO 2 tensions of more than 70 mm Hg are not uncommon in emphysematous patients. The ventilatory response to CO 2 ':'Professor "'Professor of Pharmacology and Anesthesiology, Temple University School of Medicine, Philadelphia, Pennsylvania
Vol. 58, No. 5, September 1974 Medical Clinics of North America- Vo!.
1137
1138
BEN
F.
RUSY
30
25
,....--.......
=
20
E
"".....
'-'"
15
Ci)
~
0 o
:> ::-
10
Ci)
=
=
~
5
t
40
Arterial
50
60
70
80
P cO 2 Peo 2 Figure 1.
in these individuals is markedly depressed. If ordinary doses of narcotic analgesics are administered under these circumstances the result may be a severely uncompensated respiratory acidosis. 22 This is illustrated by the extreme right hand curves of Figure 1. Cardiovascular Disease Circulatory depression and hypotension from ordinary doses of narcotic analgesics usually occur only under special circumstances. In normal supine man, little circulatory depression is seen even with large doses of morphine (up to 2 mg/kg) if respirations are supported so that '4 The hemodynamic factors respiratory acidosis and hypoxia are avoided. 14 responsible for the control of arterial blood pressure are diagrammatically illustrated in Figure 2. Ordinary doses of potent narcotic analgesic drugs may cause postural hypotension even in normal persons. This is because these drugs inhibit the reflex changes in vascular tone (especially venous, capacitance vessel tone) which ordinarily accompany changes in body position and which aid in maintaining venous return and systemic peripheral resistance. If these reflex changes are already inadequate, as they may be in cardiovascular disease, cardiovascular depression and hypotension after the administration of narcotics may be pronounced. This will also be the case when blood volume is decreased, as in hemorrhagic shock.
1139
INDIVIDUALIZATION OF NARCOTIC ANALGESIC THERAPY
CONTROLING BLOOD PRESSURE FACTORS CONTROLlNG
BP
SV ~
/
/
BLOOD VOLUME
""
x
T PR
~
~SYMPATHETIC HR --SYMPATHETIC
" // - ""'" VENOUS VENOUS RETURN
'"
..fQ CO
= =
--
//
CONTROL CONTROL
CONTRACTlLlTY CONTR7CTlLlTY
CAPACITANCE VESSEL VOL UME VOl Figure 2.
FACTORS ALTERING BIOTRANSFORMATION AND EXCRETION
Hepatic Disease Biotransformation of narcotic analgesics occurs in the liver. The major mechanism for detoxication is conjugation; glucuronide conN-dealkylation jugates predominate. N -dealkylation and O-dealkylation are also important for some narcotics, as are hydrolysis and oxidation. The liver also plays a small role in the excretion of narcotics and their metabolic products through the bile. It has been stated that "biotransformation is the chief factor limiting the intensity of response and duration of effect of morphine and its surrogates"13 and that "when there is evidence of hepatic insufficiency from whatever cause, one may expect duration of action to be prolonged and accumulative effects should be anticipated."4 Although decreased tolerance to narcotics has been described in patients with severe liver dysfunction 33 little is known about the effect of liver disease on metabolism of these drugs. Sherlock33 believes that the intolerance of severe cirrhotics to morphine is due to an increased brain sensitivity to morphine rather than to any appreciable change in the metabolism of the drug. Effect of Age on Biotransformation Decreased rates of biotransformation are observed in the newborn. Oxidative enzymes appear in the first week of birth and reach normal levels of activity by eight weeks. Glucuronide conjugation pathways do not become fully developed until three months.'3 months.3 Respiratory distress is not uncommon in the newborn when the mother has received a narcotic analgesic prior to delivery. This is very likely due, in part, to impaired hepatic biotransformation. It has been shown that the metabolism of 10 meperidine (Demerol) is impaired in the newborn. 1O
1140
BEN
F.
RUSY
Renal Disease Drugs and their metabolic products may accumulate in the body dur12 Wade!" ing renal failure. Wade states that since pethidine (meperidine) is largely metabolized in the liver whereas 50 per cent of morphine is excreted unchanged, it is safer to use meperidine in renal failure. ReidenbergB8 states that although there are few data to suggest modification of berg dosage of either morphine or meperidine in uremics, some uremics are very sensitive to the depressant effects of narcotics. For this reason "initial doses of narcotics should be low until the individual patient's sensitivity to the drug has been determined."
INTERACTION WITH OTHER DRUGS The depressant effects of narcotic analgesics summate with other classes of depressants. For example, it has been shown that fetal distress can be caused by 50 mg of meperidine plus a barbiturate given to the mother prior to delivery. 11 delivery.ll Phenothiazines and antidepressant drugs potentiate the actions of narcotics, their effects being supra-additive. Deaths from ordinary doses of meperidine given to patients who have also received phenelzine (an MAO inhibitor) have been reported. reported.!1 Both MAO inhibitor and tricyclic antidepressants cause a supra-additive effect. Phenothiazines have been used to potentiate the analgesic effect of narcotics. However, the sedative and respiratory depressant effects of narcotics are also potentiated to a similar degree,5 and these drug combinations therefore have little therapeutic advantage. One of the phenothiazines (promethazine [Phenergan]) actually has an antianalgesic effect. 66
REFERENCES 1. Albert, A.: Patterns of metabolic disposition of drugs in man and other species. In Wolstenholm, G., and Porter, R. (eds.): Drug Response in Man. Boston, Little, Brown, 1967, pp. 55-63. 2. Eckenhoff, J. E., and Oech, S. R.: The effects of narcotics and antagonists upon respiration and circulation in man. A review. Clin. Pharmacol. Ther., 1:483-524, 1 :483-524, 1960. 3. Gillette, J. R.: Individually different responses to drugs according to age, sex, and functional or pathological state. In Wolstenholm, G., and Porter, R. (eds.): Drug Response in Man. Boston, Little, Brown, 1967, Discussion, p. 49. 4. Jaffee, J. H.: Narcotic analgesics. In Goodman, L. S., and Gilman, A. (eds.): The Pharmacological Basis of Therapeutics. 4th ed. New York, Macmillan, 1970. 5. Lambersten, C. J., Wendel, H., and Longenhagen, J. B.: The separate and combined respiratory effects of chlorpromazine and meperidine in normal man controlled at 46 mm Hg Peo,. J. Pharmacol., 131 131:381-393, alveolar PeG:!. :381-393, 1961. 6. Moore, J., and Dundee, J. W.: Alterations in response to somatic pain associated with anaesthesia. VII. The effect of phenothiazine derivatives. Brit. J. Anaesth., 33:422-431, 1961. J., and Westlake, E. K.: The respiratory response to CO CO,2 in emphysema. Clin. 7. Prime, E. J., 13:321-332, 1954. Sei., 13:321-332,1954. ScL, 8. Reidenberg, M. M.: Renal Function and Drug Action. Philadelphia, W. B. Saunders Co., 1971. 9. Robin, E. D., Whaley, R. D., Crump, C. H., and Travis, D. M.: Alveolar gas tensions, pulmo-
INDIVIDUALIZATION OF NARCOTIC ANALGESIC THERAPY
10.
11. 12. 13. 14.
1141
nary ventilation, and blood pH during physiologic sleep in normal subjects. subjects . J. .T. Clin. Invest., 37:981-989, 1958. Rudofsky, S., and Crawford, J. S.: Some alterations in the pattern of drug metabolism associated with pregnancy, oral contraceptives, and the newly born. Pharmacologist, 8:181,1966. Shnider, S. M., and Maya, F.: Effects of meperidine on the newborn infant. Amer. J. Obstet. Gynec., 89:1009-1015,1964. 89:1009-1015, 1964. Wade, O. L.: Adverse Reactions to Drugs. London, Heinemann, 1970, p. 28. Way, E. L., and Adler, T. K.: The pharmacologic implications of the fate of morphine and its surrogates. Pharmacol. Rev., 12:383-446,1960. 12:383-446, 1960. Wong, K. C., Martin, W. E., Hornbein, T. F., et al.: The cardiovascular effects of morphine sulfate with oxygen and with nitrous oxide in man. Anesthesiology, 38:542-549,1973. 38:542-549, 1973.
Departments of Pharmacology and Anesthesiology Temple University School of Medicine Philadelphia, Pennsylvania 19140
Individualization of Narcotic Analgesic Therapy Ben F. Rusy, M.D.*
The individualization of narcotic analgesic drug therapy is based upon a consideration of the ways in which the effects of narcotics are altered by disease states and by interaction with other drugs. Disease states alter the effects of narcotics by changing organ sensitivity to these drugs and by affecting the rates of their metabolism and excretion. Of these two effects of disease, the first is probably the more important. The major side effects of narcotic analgesics which one aims to minimize are respiratory and cardiovascular depression.
FACTORS ALTERING ORGAN SENSITIVITY Pulmonary Disease Respiratory depressant effects of narcotics are especially marked in patients with decreased respiratory reserve and accompanying respiratory acidosis. Figure 1 illustrates the ventilatory response to carbon dioxide observed under various conditions. The curve for a normal subject CC) is shifted to the right, as shown, by 10 mg of morphine sulfate. An equianalgesic dose of any other potent narcotic analgesic would have approximately the same effect. The normal arterial Pco Peo 2 is 40 mm Hg. This will increase approximately 5 mm Hg after the administration of 10 mg of morphine, assuming spontaneous respiration. The respiratory depressant effect of an ordinary therapeutic dose of morphine in a person with normal ventilatory function is probably of little physiological consequence, especially when one considers that similar changes in the arterial Pco sleep.99 In the Peo 2 and in the respiratory response to CO 2 occur in normal sleep. person with moderate to severe respiratory insufficiency the situation is different. For example, it has been shown 77 that arterial oxygen tensions of less than 60 mm Hg, and CO 2 tensions of more than 70 mm Hg are not uncommon in emphysematous patients. The ventilatory response to CO 2 ':'Professor "'Professor of Pharmacology and Anesthesiology, Temple University School of Medicine, Philadelphia, Pennsylvania
Vol. 58, No. 5, September 1974 Medical Clinics of North America- Vo!.
1137
1138
BEN
F.
RUSY
30
25
,....--.......
=
20
E
"".....
'-'"
15
Ci)
~
0 o
:> ::-
10
Ci)
=
=
~
5
t
40
Arterial
50
60
70
80
P cO 2 Peo 2 Figure 1.
in these individuals is markedly depressed. If ordinary doses of narcotic analgesics are administered under these circumstances the result may be a severely uncompensated respiratory acidosis. 22 This is illustrated by the extreme right hand curves of Figure 1. Cardiovascular Disease Circulatory depression and hypotension from ordinary doses of narcotic analgesics usually occur only under special circumstances. In normal supine man, little circulatory depression is seen even with large doses of morphine (up to 2 mg/kg) if respirations are supported so that '4 The hemodynamic factors respiratory acidosis and hypoxia are avoided. 14 responsible for the control of arterial blood pressure are diagrammatically illustrated in Figure 2. Ordinary doses of potent narcotic analgesic drugs may cause postural hypotension even in normal persons. This is because these drugs inhibit the reflex changes in vascular tone (especially venous, capacitance vessel tone) which ordinarily accompany changes in body position and which aid in maintaining venous return and systemic peripheral resistance. If these reflex changes are already inadequate, as they may be in cardiovascular disease, cardiovascular depression and hypotension after the administration of narcotics may be pronounced. This will also be the case when blood volume is decreased, as in hemorrhagic shock.
1139
INDIVIDUALIZATION OF NARCOTIC ANALGESIC THERAPY
CONTROLING BLOOD PRESSURE FACTORS CONTROLlNG
BP
SV ~
/
/
BLOOD VOLUME
""
x
T PR
~
~SYMPATHETIC HR --SYMPATHETIC
" // - ""'" VENOUS VENOUS RETURN
'"
..fQ CO
= =
--
//
CONTROL CONTROL
CONTRACTlLlTY CONTR7CTlLlTY
CAPACITANCE VESSEL VOL UME VOl Figure 2.
FACTORS ALTERING BIOTRANSFORMATION AND EXCRETION
Hepatic Disease Biotransformation of narcotic analgesics occurs in the liver. The major mechanism for detoxication is conjugation; glucuronide conN-dealkylation jugates predominate. N -dealkylation and O-dealkylation are also important for some narcotics, as are hydrolysis and oxidation. The liver also plays a small role in the excretion of narcotics and their metabolic products through the bile. It has been stated that "biotransformation is the chief factor limiting the intensity of response and duration of effect of morphine and its surrogates"13 and that "when there is evidence of hepatic insufficiency from whatever cause, one may expect duration of action to be prolonged and accumulative effects should be anticipated."4 Although decreased tolerance to narcotics has been described in patients with severe liver dysfunction 33 little is known about the effect of liver disease on metabolism of these drugs. Sherlock33 believes that the intolerance of severe cirrhotics to morphine is due to an increased brain sensitivity to morphine rather than to any appreciable change in the metabolism of the drug. Effect of Age on Biotransformation Decreased rates of biotransformation are observed in the newborn. Oxidative enzymes appear in the first week of birth and reach normal levels of activity by eight weeks. Glucuronide conjugation pathways do not become fully developed until three months.'3 months.3 Respiratory distress is not uncommon in the newborn when the mother has received a narcotic analgesic prior to delivery. This is very likely due, in part, to impaired hepatic biotransformation. It has been shown that the metabolism of 10 meperidine (Demerol) is impaired in the newborn. 1O
1140
BEN
F.
RUSY
Renal Disease Drugs and their metabolic products may accumulate in the body dur12 Wade!" ing renal failure. Wade states that since pethidine (meperidine) is largely metabolized in the liver whereas 50 per cent of morphine is excreted unchanged, it is safer to use meperidine in renal failure. ReidenbergB8 states that although there are few data to suggest modification of berg dosage of either morphine or meperidine in uremics, some uremics are very sensitive to the depressant effects of narcotics. For this reason "initial doses of narcotics should be low until the individual patient's sensitivity to the drug has been determined."
INTERACTION WITH OTHER DRUGS The depressant effects of narcotic analgesics summate with other classes of depressants. For example, it has been shown that fetal distress can be caused by 50 mg of meperidine plus a barbiturate given to the mother prior to delivery. 11 delivery.ll Phenothiazines and antidepressant drugs potentiate the actions of narcotics, their effects being supra-additive. Deaths from ordinary doses of meperidine given to patients who have also received phenelzine (an MAO inhibitor) have been reported. reported.!1 Both MAO inhibitor and tricyclic antidepressants cause a supra-additive effect. Phenothiazines have been used to potentiate the analgesic effect of narcotics. However, the sedative and respiratory depressant effects of narcotics are also potentiated to a similar degree,5 and these drug combinations therefore have little therapeutic advantage. One of the phenothiazines (promethazine [Phenergan]) actually has an antianalgesic effect. 66
REFERENCES 1. Albert, A.: Patterns of metabolic disposition of drugs in man and other species. In Wolstenholm, G., and Porter, R. (eds.): Drug Response in Man. Boston, Little, Brown, 1967, pp. 55-63. 2. Eckenhoff, J. E., and Oech, S. R.: The effects of narcotics and antagonists upon respiration and circulation in man. A review. Clin. Pharmacol. Ther., 1:483-524, 1 :483-524, 1960. 3. Gillette, J. R.: Individually different responses to drugs according to age, sex, and functional or pathological state. In Wolstenholm, G., and Porter, R. (eds.): Drug Response in Man. Boston, Little, Brown, 1967, Discussion, p. 49. 4. Jaffee, J. H.: Narcotic analgesics. In Goodman, L. S., and Gilman, A. (eds.): The Pharmacological Basis of Therapeutics. 4th ed. New York, Macmillan, 1970. 5. Lambersten, C. J., Wendel, H., and Longenhagen, J. B.: The separate and combined respiratory effects of chlorpromazine and meperidine in normal man controlled at 46 mm Hg Peo,. J. Pharmacol., 131 131:381-393, alveolar PeG:!. :381-393, 1961. 6. Moore, J., and Dundee, J. W.: Alterations in response to somatic pain associated with anaesthesia. VII. The effect of phenothiazine derivatives. Brit. J. Anaesth., 33:422-431, 1961. J., and Westlake, E. K.: The respiratory response to CO CO,2 in emphysema. Clin. 7. Prime, E. J., 13:321-332, 1954. Sei., 13:321-332,1954. ScL, 8. Reidenberg, M. M.: Renal Function and Drug Action. Philadelphia, W. B. Saunders Co., 1971. 9. Robin, E. D., Whaley, R. D., Crump, C. H., and Travis, D. M.: Alveolar gas tensions, pulmo-
INDIVIDUALIZATION OF NARCOTIC ANALGESIC THERAPY
10.
11. 12. 13. 14.
1141
nary ventilation, and blood pH during physiologic sleep in normal subjects. subjects . J. .T. Clin. Invest., 37:981-989, 1958. Rudofsky, S., and Crawford, J. S.: Some alterations in the pattern of drug metabolism associated with pregnancy, oral contraceptives, and the newly born. Pharmacologist, 8:181,1966. Shnider, S. M., and Maya, F.: Effects of meperidine on the newborn infant. Amer. J. Obstet. Gynec., 89:1009-1015,1964. 89:1009-1015, 1964. Wade, O. L.: Adverse Reactions to Drugs. London, Heinemann, 1970, p. 28. Way, E. L., and Adler, T. K.: The pharmacologic implications of the fate of morphine and its surrogates. Pharmacol. Rev., 12:383-446,1960. 12:383-446, 1960. Wong, K. C., Martin, W. E., Hornbein, T. F., et al.: The cardiovascular effects of morphine sulfate with oxygen and with nitrous oxide in man. Anesthesiology, 38:542-549,1973. 38:542-549, 1973.
Departments of Pharmacology and Anesthesiology Temple University School of Medicine Philadelphia, Pennsylvania 19140