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CLINICAL TOXICOLOGY 11(5), pp. 517-529 (1977)
Actions and Metabolism of Codeine (Methylmorphine)Administration by Continuous Intravenous Infusion to Humans*
NORMAN NOMOF, M.D. Solano Institute for Medical and Pharmacologic Research Vacaville, California 95688 HENRY W. ELLIOTT, M.D., Ph.D.t Department of Medical Pharmacology & Therapeutics College of Medicine University of California Irvine, California 92717 KENNETH D. PARKER, M., Crim. Hine Laboratories San Francisco, California 94120
INTRODUCTION Miosis occurs within minutes following injection of morphine, heroin, meperidine, and methadone; antagonism of this drug-induced pupillary constriction by nalorphine can be demonstrated immediately. *Aided by Contract No. PH-43-64-931 from the National Institute of Health, Bethesda. +Deceased. 517 Copyright 0 1978 hy Marcel Dekker, Inc. All Rights Reserved. Neither this work nor any part may be reproduced o r transmitted in any form or by any means. electronic or mechanlcal. including photocopying. microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher.
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518
NOMOF, ELLIOTT, AND PARKER
Administration of codeine a l s o is followed promptly by development of miosis, but nalorphine will not r e v e r s e codeine-induced miosis until 120-mg doses have been taken every 6 h r f o r 2 to 3 days [4]. However, in an experiment in which codeine was infused at a constant rate of 30 mg/hr, nalorphine a t 9 h r r e v e r s e d miosis to varying deg r e e s i n t h r e e of four subjects in whom miosis was the only detectable drug effect [4]. In the constant infusion experiment we a l s o noted that the rate of excretion of codeine and its principle metabolite codeine glucuronide reached a maximum at about 4 h r and then did not change during the duration of infusion. Since 30 mg/hr of codeine produced no a d v e r s e o r behavioral effects, we felt that 60 mg/hr could be administered safely and would provide m o r e information regarding (a) the paradoxical codeine-nalorphine interactions on the pupil, ( b ) the possibility of a ceiling effect (less than expected effect with increasing dose) f o r o r development of acute tolerance to codeine, and ( c ) the maximal r a t e of metabolism of codeine by humans, which to o u r knowledge has not be determined. In this rep o r t we compare the pupillary and behavioral effects and the r a t e of metabolism of codeine when infused i.v. into humans a t r a t e s of 30 and 60 mg/hr. METHODS The subjects were eight fully informed healthy male volunteers with established histories of narcotic u s e but no narcotic intake during the p r i o r s i x months. They were divided into two groups of four subjects each. Group I was given codeine phosphate intravenously in 5% dextrose-0.9% saline a t the r a t e of 0.5 mg/ml.min. Group II was administered 1 mg/ml.min. Subjects of Group I ranged in age from 2645 y e a r s (mean 33) and weighed 140-175 l b (mean 154 lb). In Group I1 age range was 34-45 y e a r s (mean 37) and weight was 142-193 lb (mean 157 lb). No. 18 Medicut cannulas w e r e inserted in a r m veins f o r the i.v. infusion and no. 16 Foley catheters w e r e placed in the bladders f o r urine collection. In Group I, infusion was continued f o r 11 h r in two subjects and for 16 h r in the other two subjects. In Group II infusion was continued for 11 h r in each of the four subjects. The bladder was emptied and urine collected a t 0.5-hr intervals for 2 h r , and then a t hourly intervals from the second to the 24th hour. Final Group I collection was made at the 28th hour. In Group II, specimens w e r e collected from the 24th to the 32nd and 32nd to 40th hours. All urine and blood specimens drawn from each of the subjects in Group II at the 11th hour were analyzed for the presence of free and conjugated codeine, morphine, and norcodeine by methods previously described ["I.
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METABOLISM O F CODEINE
519
Nalorphine was administered i. m. and pupillary size determined from photographs as described in a previous publication [6]. Using standard lighting conditions, we measured the pupil di am et ers of all subjects p r i o r to starting the codeine infusion and seri al l y thereafter. In Group I (30 mg/hr infusion) all subjects were challenged with nalorphine at the ninth hour. In Group XI two subjects were challenged at the fourth and two at the sixth hour of infusion. A l l subjects were observed continuously for signs of drug action and were asked to report any subjective effects immediately. RESULTS In Group I no subjective effects were experienced during o r aft er infusion f o r 11 o r 16 hr. In Group II definite subjective effects were experienced by each of the participants. These were relatively mild fo r narcotics despite the l ar ge quantity of codeine administered. Two hours after onset of infusion (120 mg total dose) two subjects w ere anorexic. After 4 h r these subjects were drowsy. Three subjects vomited during o r following their evening meals, 7 . 5 h r aft er onset of infusion. No increase o r decrease in severity of nausea o r degree of sedation occurred during the l at t er half of the infusion. At 22 hr, 1 1 h r a f te r completion of codeine infusion, three subjects complained of nausea, two vomited, and two complained of headache. Administration of nalorphine, 3 mg i.m., produced no discernible effects in any of the eight subjects, except on pupil diameter. PuDilla r v E f f e c t s
Group I.
A s shown in Table 1, two of four subjects showed minimal m i osi s a t 3 h r following start of infusion, but a t 9.5 h r definite miosis was present in three subjects. Nalorphine challenge (i ncrease in pupil size) was positive in three subjects a t 9.5 h r and caused no change in pupil size in one subject. Group 11. As shown in Table 2, t hr ee subjects showed miosis 2 h r following the s t a r t of infusion but in one subject miosis was delayed until the sixth hour. Nalorphine challenge a t 4 h r was positive i n the miotic subject and negative in the subject whose pupil s i z e was unchanged. Nalorphine challenge a t 6 h r was positive in one and equivocal in another subject even though both subjects were miotic.
NOMOF, ELLIOTT, AND PARKER
52 0
TABLE 1. Change in Pupil Diametera during Continuous Intravenous Infusion of Codeine, 30 mg/hr, and a t the Time of Nalorphine Challenge Hour during codeine infusion Subject
Hour of nalorphine challenge during codeine infusion
3
9. 5
9.5
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~~
1
-0.3
-0.6
2
+o. 3
0
+o. 5 +o. 2
3
0
-2.0
+l. 1
4
-0.1
-0.6
0
-0.8
Mean
0 +O. 4 5
aIn millimeters.
TABLE 2. Change in Pupil Mametera during Continuous Intravenous Infusion of Codeine, 60 mg/hr and a t the Time of Nalorphine Challenge Hour during codeine infusion
Hour of nalorphine challenge during codeine infusion
Subject
2
4
6
4
1
-0.5
-1.0
-0.6
+l. 6
2
0
+o. 2
-0.8
-0.6
6
3
-1.0
-1.4
-1.7
-0.2
4
-1.3
-1.2
-2.5
+o. 4
Mean
-0.7
-0.8
-1.4
a
In millimeters.
U r i n a r y E x c r e t i o n of C o d e i n e a n d I t s M e t a b o l i t e s Group I. Two subjects received 330 mg of codeine in 11 hr. The other two received 480 mg in 16 hr. Urine output was above average with a mean 28-hr volume of 3304 * 649 ml and a mean rate of excretion of 119 *
METABOLISM O F CODEINE
52 1
24 ml/hr. A s shown in Table 3, all subjects excreted varying amounts of free and conjugated codeine, morphine, and norcodeine, with recoveries a t 28 h r ranging from 56 to 88% of the administered dose. Codeine was excreted mainly free o r conjugated by these subjects accounting for 82% of recovered metabolites while morphine and norcodeine accounted for 9 and 8%, respectively.
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Group 11. Each of four subjects received 660 m g of codeine in 11 hr. Urine output of these subjects was remarkably constant with a mean 40-hr volume of 2847 300 ml and a mean rate of excretion of 71 f 10 ml/hr. Creatinine clearance rates determined at the eleventh hour were within normal limits as shown in Table 4. Urinary pH ranged between 7.4 and 4.8 over a 24-hr period with a mean of 5.6. Spontaneous changes in urinary pH amount to 0.5 pH units did not produce discernible changes in the rate of excretion of codeine. A s shown in Table 4 all subjects excreted varying amounts of free and conjugated codeine, morphine, and norcodeine with recoveries a t 40 h r ranging from 23.4 to 44.5% of the administered dose. Even though urine was collected for 40 hr, the percent of the administered dose recovered was lower than that for the subjects of Group I whose urine was collected for 28 h r i.e., 31 vs. 68%. Of the amount excreted by the subjects of Group 11, free and conjugated codeine accounted for 88% of recovered metabolites while morphine and norcodeine each accounted f o r 6%. Conjugated codeine was detected in urine 15 min after the infusion was begun; morphine was first detected a t 1.5 h r and norcodeine a t 3.0 hr. Following completion of infusion, excretion of free codeine was minimal after 3-4 hr, and the excretion of metabolites decreased to very low rates after 12 hr. At 32 h r urine specimens contained detectable concentrations of morphine but not of norcodeine. Since over 80% of codeine recovered in the urine is in either the unchanged o r conjugated form, we plotted the cumulative excretion of unchanged plus conjugated codeine to determine rates of metabolism and excretion of codeine under the conditions of o u r experiments. The average cumulative excretion of codeine according to dose and duration of infusion is presented in Fig. 1. By the fourth hour the maximal rate of excretion was approached by each of the groups. The slopes of these curves are virtually identical throughout the duration of infusion. The maximal rates of excretion by the subjects given 30 mg/hr of codeine were 13.5, 10, 15, and 19 mg/hr (mean = 14.4 mg/hr), and f o r the subjects given 60 mg/hr the rates were 21.5, 11.5, 10.5, and 11.5 mg/hr (mean 13.8 mg/hr). The rate of codeine excretion by the subjects given 30 mg/hr for 11 o r 16 h r decreased immediately following termination of infusion of codeine but the decrease was more apparent when the infusion was stopped a t 11 hr. The subjects given 60 mg/hr of codeine continued to exc r e t e codeine at their maximal rates for 3-5 hr.
*
330
480
480
2
3
4
160 139 268 412
11
11 16 16 56.0
78.0
56.0
42.0
48.5
Codeine Hours administered m g %a
22
35
24
21
mg
6.4
4.5
7.2
7.4
6.5
%
Morphine
Percentages expressed on the basis of total codeine administered.
a
Mean
330
~-
1
Subject
Codeine administered, mg
24
30
20
11
mg
5.6
5.0
6.2
6.1
3.3
%
Norcodeine
Excreted in urine
458
333
183
192
mg
68
88
69
56
58
%
All three
TABLE 3. Twenty-Eight Hour Excretion of Total (free plus conjugated) Codeine, Morphine, and Norcodeine during and following Administration of Codeine a t a rate of 30 mg/hr for 11 and 16 h r
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v
U
zi
c3
e
E: 0
m
.!!
a
w
2
40.6
268
130
150
175
181
1
2
3
4
Mean
1.9
2.6
0.5
2.0
2.6
10.8
13.5
10.5
11.0
8.2
a Percentages expressed on the basis of total codeine administered.
12.8
17.2
26.5 27.4
3.5
13.2
17.2
1.7
2.1
1.6
1.7
1.2
205
206
164
154
294
mg
31.0
31.2
24.9
23.4
44.5
% ~
%
mg
%
mg
All three
Norcodeine
Morphine
22.8
19.7
%a
mg
Subject
Codeine
TABLE 4. Forty Hour Urinary Excretion of Total ( f r e e plus conjugated) Codeine, Morphine, and Norcodeine during and following Administration of 660 mg of Codeine a t a rate of 60 mg/hr for 1 1 h r
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N W
cn
3
U
E
2
0
z
tj
W
4
*
z m
NOMOF, ELLIOTT, AND PARKER
524
300
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250
200 rn
I Lz 4
P
150
-I
4
I
100
50
TIME
IN
HOURS
FIG. 1. Cumulative excretion of total codeine (free plus conjugated) by subjects given codeine by continuous i.v. infusion. 0 --a , average f o r two subjects given 30 mg/hr for 11 hr, &--A, average for two subjects given 30 mg/hr for 16 hr. x---x , average for four subjects given 60 mg/hr for 11 hr. Arrows indicate end of infusion of codeine.
B l o o d C o n c e n t r a t i o n s of C o d e i n e Blood drawn a t the eleventh hour from each subject of Group II contained detectable quantities of free codeine as shown in Table 5. The mean concentration was 1.1 pg/ml. No conjugated codeine was detected as indicated by no increase in the codeine concentration after acid hydrolysis. Morphine and norcodeine were not detected by the methods used (limits of detectability of morphine 0.1 pg/ml; of norcodeine 0.4 pg/ml).
METABOLISM O F CODEINE
52 5
TABLE 5. Blood Codeine Concentration of Subjects following Continuous Intravenous Infusion of Codeine for 11 hra
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Blood codeine concentration, pg/ml Subject
Free
1
1.11
1.08
2
0.82
0.89
3
0.51
0.49
4
1.94
2.00
Mean
1.10
1.12
Totalb
a
Total dose received was 660 mg. bTotal refers to all codeine measurable after acid hydrolysis.
TABLE 6. Codeine Clearance Subject
Creatinine clearance, ml/min
Codeine clearance, ml/min
1
114
133
2
177
65
3
17 5
286
4
129
288
~~
The renal clearance of codeine was calculated from the eleventh hour blood concentration. It was assumed that the codeine concentration had been constant from the tenth to the eleventh hours. Codeine clearance results are recorded in Table 6. Three of the four subjects appeared to c l e a r codeine a t a rate greater than creatinine clearance, suggesting that codeine is excreted by the kidney by both glomerular filtration and tubular secretion. DISCUSSION Previous studies in animals and humans have shown generally s i m i l a r metabolic and excretory pathways for codeine [ 121. Although the type and percentage of metabolites varies among species (e.g., morphine is not a metabolite in the dog) [4], in most of those studied
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52 6
NOMOF, ELLIOTT, AND PARKER
codeine i s largely excreted as a water-soluble conjugate, which has been identified a s the glucuronide in dog urine [14] and as conjugates of morphine and norcodeine [ 121. The pattern of urinary excretion appears independent of dose, route of administration, o r degree of tolerance o r addiction [12]. In our study total recovery of codeine metabolites agrees with the findings of Adler et al. [ l ] who determined the urinary excretion of codeine metabolites i n humans following acute administration of l 4 Clabeled codeine. In both studies percent of administered dose recovered was greater after small doses, and morphine and norcodeine were excreted in significant but l e s s e r quantities than free and conjugated codeine. To our knowledge the present study is the first attempt to demonstrate development of acute tolerance to and the maximal rate of excretion of codeine in humans. The failure of four subjects to report any subjective effects from 30 m g / h r of codeine infused for as long as 16 h r indicates efficient mechanisms for the metabolism and excretion of codeine in humans. Since this dosage induced miosis it was adequate to produce CNS effects if not psychic effects, but the falloff in rate of excretion of metabolites immediately after termination of infusion indicates no build-up of codeine o r active metabolites such as morphine o r norcodeine a t this rate of administration (30 mg/hr). The fact that total codeine excretion proceeded at the same rate after 60 mg/hr a s after 30 mg/hr, suggests that in humans the maximal rate of metabolism and elimination of codeine is about 30 mg/hr. It i s possible that infusion of 60 mg/hr for longer than 11 h r might lead to cumulation since excretion proceeded at the maximal rate for 4 to 5 h r after termination of infusion. However, the lack of progression of CNS depressant effects in the fact of an increasing body burden of codeine favors the concept of a ceiling effect for codeine. There was a striking lack of severe narcotic effects in the four subjects given 60 mg/hr of codeine/hr. Only mild sedation (drowsiness), nausea, and emesis were observed with no evidence of excitation, respiratory depression, confusion, o r other effects on the CNS. There was no reversal of behavioral changes during t h e final hours of infusion to suggest development of acute tolerance to codeine a s was noted for morphine i n dogs given i.v. infusions of morphine for 8 h r [8]. In addition, no withdrawal symptoms followed nalorphine challenge at 9 h r in Group I and at 4 and 6 h r in Group 11. It is notable in view of the relatively mild narcotic effects observed that the mean blood codeine concentration of 1.1 pg/ml after 11 h r of infusion of codeine at the rate of 60 mg/hr was about ten times the peak concentrations reported by Brunson and Nash [2] after a single oral 60-mg dose of codeine (0.107 pg/ml) and by Waife et al. [ l l ] after 60 mg of codeine every 6 h r for four days (0.12 pg/ml). Thus, our values a r e an order of magnitude above the therapeutic range and approach the low end of the fatal range of 1.4-5.6 pg/ml
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METABOLEM O F CODEINE
52 7
reported by Wright et al. [13]. Taken with the behavioral effects observed, these blood levels a r e compatible with t h e concept of a ceiling effect for codeine which, however, has been described by Eddy et al. [3] a s controversial, at least as related to analgesia. Both our earlier [4] and present findings that miosis induced by codeine cannot be reversed by nalorphine until codeine h a s been given intermittantly for 2-3 d a y s o r infused at a constant rate for several hours can be explained by the fact that the affinity of nalorphine f o r the opiate receptor is much greater than that of codeine. This has been shown in both rat brain homogenate and guinea pig ileum preparations [lo]. Thus, even though high levels of codeine i n the brain a r e rapidly attained after parenteral administration [9], the agonist actions of nalorphine, including miosis, predominate when this partial agonist of the morphine type is given following acute administration of codeine. However, after prolonged o r continuous administration, enough codeine is present i n the brain to overcome the greater affinity of nalorphine for the opiate receptor. Under these conditions enough receptors a r e occupied by the pure agonist codeine to permit the appearance of the antagonist actions of nalorphine, namely reversal of narcotic effects including miosis. This hypothesis is consistant with the finding that naloxone, a pure narcotic antagonist, can reverse miosis induced by single doses (60-90 mg) of codeine [5]. Thus, i t appears that the apparently complex interactions of codeine and nalorphine on pupil diameter i n vivo can be analyzed with the aid of information derived from in vitro opiate receptor studies. SUMMARY Miosis produced by codeine is not antagonized by nalorphine until large oral doses a r e administered for several days. The present experiment was conducted in o r d e r to further study this characteristic of the codeine effect. Eight healthy male volunteers, who were former drug users, were divided into two groups. Subjects in the first group were given a continuous infusion of codeine, 30 mg/hr for 11-16 hr. N o subjective effects were reported by the volunteers. In three of the individuals definite miosis antagonized by nalorphine was observed a t 9.5 h r . The dose of codeine for the second group was 60 mg/hr for 11 h r . Mild but definite subjective effects were experienced by each of the participants in this group. Miosis appeared between 2 and 6 hr. Challenges at 4 and 6 h r were positive in two subjects and negative o r equivocal in the other two. Codeine was excreted i n the urine as free and conjugated codeine, morphine, and norcodeine. Maximum rates of excretion were similar
528
NOMOF, ELLIOTT, AND PARKER
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for both groups, suggesting that the maximum amount of codeine that can be metabolized is equal o r less than 30 mg/hr. Also codeine clearance, being greater than creatinine clearance, suggests that codeine might be excreted by glomerular filtration and tubular s e c r e tion. Blood levels of codeine in the 60 mg/hr group were about 10 times those reported as therapeutic. However, morphine o r norcodeine were not detectable by the methods used. REFERENCES T. K. Adler, J. M. F’ujimoto, E. L. Way, and E. M. Baker, The metabolic fate of codeine in man, J. Pharmacol. Exptl. Therap., 114. 251 (1955). M. K. Brunson’and J. F. Nash, Gas chromatographic measurement of codeine and norcodeine in human plasma, Clin. Chem., 21. 1956 (1975). K’B. Eddy, H.’Friebel, K. J. Hahn, and H. Halbach, Codeine and alternates for pain and cough relief, Bull. World Health Org.,2,673 (1968). H. W. Elliott, N. Nomof, and K. D. Parker, Correlation of the nalorphine test with concentration of metabolites of codeine in the urine after single doses and continuous administration of codeine, Clin. Pharmacol. and Therap., _8, 78 (1967). H. W. Elliott, N. Nomof, and K. D. Parker, The use of naloxone in the pupil test for the detection of narcotic abuse, Proc. Fourth Nat. Conf. on Methadone Treatment, NAPAN, New York, 1972, p. 135. H. W. Elliott, N. Nomof, K. D. Parker, M. L. Dewey, and E. L. Way, Comparison of the nalorphine test and urinary analysis in the detection of narcotic use, Clin. Pharmacol. and Therap., -5, 405 (1964). H. W. Elliott, K. D, Parker, J. A. Wright, and N. Nomof, Actions and metabolism of heroin administered by continuous intravenous infusion to man, Clin. Pharmacol. a n d Therap., 806 (1971). W. R. Martin and C. G. Eades, Demonstration of tolerance and physical dependence in the dog following a short-term infusion of morphine, J. Pharmacol. Exptl. Therap., 133,262 (1961). J. W. Miller and H. W. Elliott, Rat tissue levels of carbon-14 labeled analgetics as related to pharmacological activity, J. Pharmacol. Exptl. Therap., 113,283 (1955). S. H. Snyder and S. Matthysse, Opiate Receptor Mechanisms, The M.I.T. Press, Cambridge, Mass., 1975. _ I
12,
METABOLISM O F CODEINE
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[ll] S. 0.Waife, C. M. Gruber, Jr., B. E. Rodda, and J. F. Nash, Problems and solutions to single dose testing of analgesics: Comparison of propoxyphene, codeine and fenoproben, Intern. J. Clin. Pharmacol., 301 (1975). r121 E. L. Wav and J. T. Adler. The biological disposition of morphine and" its. surrogates, Bull. WorldHealth Org., 2, 51 ( 1962). I131 J. A. Wright, R. C. Baselt, and C. H. Hine, Blood codeine conc e n t r a t i o i s in fatalities associated with codeine, Clin. Toxicol., 8. 457 f 1975). Y. Yeh and L. A. Woods, Isolation and characterization of r141 codeine- 6-glucuronide from dog urine, J. Pharmacol. Exptl. Therap., 173,21 (1970). I
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CLINICAL TOXICOLOGY 11(5), pp. 517-529 (1977)
Actions and Metabolism of Codeine (Methylmorphine)Administration by Continuous Intravenous Infusion to Humans*
NORMAN NOMOF, M.D. Solano Institute for Medical and Pharmacologic Research Vacaville, California 95688 HENRY W. ELLIOTT, M.D., Ph.D.t Department of Medical Pharmacology & Therapeutics College of Medicine University of California Irvine, California 92717 KENNETH D. PARKER, M., Crim. Hine Laboratories San Francisco, California 94120
INTRODUCTION Miosis occurs within minutes following injection of morphine, heroin, meperidine, and methadone; antagonism of this drug-induced pupillary constriction by nalorphine can be demonstrated immediately. *Aided by Contract No. PH-43-64-931 from the National Institute of Health, Bethesda. +Deceased. 517 Copyright 0 1978 hy Marcel Dekker, Inc. All Rights Reserved. Neither this work nor any part may be reproduced o r transmitted in any form or by any means. electronic or mechanlcal. including photocopying. microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher.
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518
NOMOF, ELLIOTT, AND PARKER
Administration of codeine a l s o is followed promptly by development of miosis, but nalorphine will not r e v e r s e codeine-induced miosis until 120-mg doses have been taken every 6 h r f o r 2 to 3 days [4]. However, in an experiment in which codeine was infused at a constant rate of 30 mg/hr, nalorphine a t 9 h r r e v e r s e d miosis to varying deg r e e s i n t h r e e of four subjects in whom miosis was the only detectable drug effect [4]. In the constant infusion experiment we a l s o noted that the rate of excretion of codeine and its principle metabolite codeine glucuronide reached a maximum at about 4 h r and then did not change during the duration of infusion. Since 30 mg/hr of codeine produced no a d v e r s e o r behavioral effects, we felt that 60 mg/hr could be administered safely and would provide m o r e information regarding (a) the paradoxical codeine-nalorphine interactions on the pupil, ( b ) the possibility of a ceiling effect (less than expected effect with increasing dose) f o r o r development of acute tolerance to codeine, and ( c ) the maximal r a t e of metabolism of codeine by humans, which to o u r knowledge has not be determined. In this rep o r t we compare the pupillary and behavioral effects and the r a t e of metabolism of codeine when infused i.v. into humans a t r a t e s of 30 and 60 mg/hr. METHODS The subjects were eight fully informed healthy male volunteers with established histories of narcotic u s e but no narcotic intake during the p r i o r s i x months. They were divided into two groups of four subjects each. Group I was given codeine phosphate intravenously in 5% dextrose-0.9% saline a t the r a t e of 0.5 mg/ml.min. Group II was administered 1 mg/ml.min. Subjects of Group I ranged in age from 2645 y e a r s (mean 33) and weighed 140-175 l b (mean 154 lb). In Group I1 age range was 34-45 y e a r s (mean 37) and weight was 142-193 lb (mean 157 lb). No. 18 Medicut cannulas w e r e inserted in a r m veins f o r the i.v. infusion and no. 16 Foley catheters w e r e placed in the bladders f o r urine collection. In Group I, infusion was continued f o r 11 h r in two subjects and for 16 h r in the other two subjects. In Group II infusion was continued for 11 h r in each of the four subjects. The bladder was emptied and urine collected a t 0.5-hr intervals for 2 h r , and then a t hourly intervals from the second to the 24th hour. Final Group I collection was made at the 28th hour. In Group II, specimens w e r e collected from the 24th to the 32nd and 32nd to 40th hours. All urine and blood specimens drawn from each of the subjects in Group II at the 11th hour were analyzed for the presence of free and conjugated codeine, morphine, and norcodeine by methods previously described ["I.
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METABOLISM O F CODEINE
519
Nalorphine was administered i. m. and pupillary size determined from photographs as described in a previous publication [6]. Using standard lighting conditions, we measured the pupil di am et ers of all subjects p r i o r to starting the codeine infusion and seri al l y thereafter. In Group I (30 mg/hr infusion) all subjects were challenged with nalorphine at the ninth hour. In Group XI two subjects were challenged at the fourth and two at the sixth hour of infusion. A l l subjects were observed continuously for signs of drug action and were asked to report any subjective effects immediately. RESULTS In Group I no subjective effects were experienced during o r aft er infusion f o r 11 o r 16 hr. In Group II definite subjective effects were experienced by each of the participants. These were relatively mild fo r narcotics despite the l ar ge quantity of codeine administered. Two hours after onset of infusion (120 mg total dose) two subjects w ere anorexic. After 4 h r these subjects were drowsy. Three subjects vomited during o r following their evening meals, 7 . 5 h r aft er onset of infusion. No increase o r decrease in severity of nausea o r degree of sedation occurred during the l at t er half of the infusion. At 22 hr, 1 1 h r a f te r completion of codeine infusion, three subjects complained of nausea, two vomited, and two complained of headache. Administration of nalorphine, 3 mg i.m., produced no discernible effects in any of the eight subjects, except on pupil diameter. PuDilla r v E f f e c t s
Group I.
A s shown in Table 1, two of four subjects showed minimal m i osi s a t 3 h r following start of infusion, but a t 9.5 h r definite miosis was present in three subjects. Nalorphine challenge (i ncrease in pupil size) was positive in three subjects a t 9.5 h r and caused no change in pupil size in one subject. Group 11. As shown in Table 2, t hr ee subjects showed miosis 2 h r following the s t a r t of infusion but in one subject miosis was delayed until the sixth hour. Nalorphine challenge a t 4 h r was positive i n the miotic subject and negative in the subject whose pupil s i z e was unchanged. Nalorphine challenge a t 6 h r was positive in one and equivocal in another subject even though both subjects were miotic.
NOMOF, ELLIOTT, AND PARKER
52 0
TABLE 1. Change in Pupil Diametera during Continuous Intravenous Infusion of Codeine, 30 mg/hr, and a t the Time of Nalorphine Challenge Hour during codeine infusion Subject
Hour of nalorphine challenge during codeine infusion
3
9. 5
9.5
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~~
1
-0.3
-0.6
2
+o. 3
0
+o. 5 +o. 2
3
0
-2.0
+l. 1
4
-0.1
-0.6
0
-0.8
Mean
0 +O. 4 5
aIn millimeters.
TABLE 2. Change in Pupil Mametera during Continuous Intravenous Infusion of Codeine, 60 mg/hr and a t the Time of Nalorphine Challenge Hour during codeine infusion
Hour of nalorphine challenge during codeine infusion
Subject
2
4
6
4
1
-0.5
-1.0
-0.6
+l. 6
2
0
+o. 2
-0.8
-0.6
6
3
-1.0
-1.4
-1.7
-0.2
4
-1.3
-1.2
-2.5
+o. 4
Mean
-0.7
-0.8
-1.4
a
In millimeters.
U r i n a r y E x c r e t i o n of C o d e i n e a n d I t s M e t a b o l i t e s Group I. Two subjects received 330 mg of codeine in 11 hr. The other two received 480 mg in 16 hr. Urine output was above average with a mean 28-hr volume of 3304 * 649 ml and a mean rate of excretion of 119 *
METABOLISM O F CODEINE
52 1
24 ml/hr. A s shown in Table 3, all subjects excreted varying amounts of free and conjugated codeine, morphine, and norcodeine, with recoveries a t 28 h r ranging from 56 to 88% of the administered dose. Codeine was excreted mainly free o r conjugated by these subjects accounting for 82% of recovered metabolites while morphine and norcodeine accounted for 9 and 8%, respectively.
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Group 11. Each of four subjects received 660 m g of codeine in 11 hr. Urine output of these subjects was remarkably constant with a mean 40-hr volume of 2847 300 ml and a mean rate of excretion of 71 f 10 ml/hr. Creatinine clearance rates determined at the eleventh hour were within normal limits as shown in Table 4. Urinary pH ranged between 7.4 and 4.8 over a 24-hr period with a mean of 5.6. Spontaneous changes in urinary pH amount to 0.5 pH units did not produce discernible changes in the rate of excretion of codeine. A s shown in Table 4 all subjects excreted varying amounts of free and conjugated codeine, morphine, and norcodeine with recoveries a t 40 h r ranging from 23.4 to 44.5% of the administered dose. Even though urine was collected for 40 hr, the percent of the administered dose recovered was lower than that for the subjects of Group I whose urine was collected for 28 h r i.e., 31 vs. 68%. Of the amount excreted by the subjects of Group 11, free and conjugated codeine accounted for 88% of recovered metabolites while morphine and norcodeine each accounted f o r 6%. Conjugated codeine was detected in urine 15 min after the infusion was begun; morphine was first detected a t 1.5 h r and norcodeine a t 3.0 hr. Following completion of infusion, excretion of free codeine was minimal after 3-4 hr, and the excretion of metabolites decreased to very low rates after 12 hr. At 32 h r urine specimens contained detectable concentrations of morphine but not of norcodeine. Since over 80% of codeine recovered in the urine is in either the unchanged o r conjugated form, we plotted the cumulative excretion of unchanged plus conjugated codeine to determine rates of metabolism and excretion of codeine under the conditions of o u r experiments. The average cumulative excretion of codeine according to dose and duration of infusion is presented in Fig. 1. By the fourth hour the maximal rate of excretion was approached by each of the groups. The slopes of these curves are virtually identical throughout the duration of infusion. The maximal rates of excretion by the subjects given 30 mg/hr of codeine were 13.5, 10, 15, and 19 mg/hr (mean = 14.4 mg/hr), and f o r the subjects given 60 mg/hr the rates were 21.5, 11.5, 10.5, and 11.5 mg/hr (mean 13.8 mg/hr). The rate of codeine excretion by the subjects given 30 mg/hr for 11 o r 16 h r decreased immediately following termination of infusion of codeine but the decrease was more apparent when the infusion was stopped a t 11 hr. The subjects given 60 mg/hr of codeine continued to exc r e t e codeine at their maximal rates for 3-5 hr.
*
330
480
480
2
3
4
160 139 268 412
11
11 16 16 56.0
78.0
56.0
42.0
48.5
Codeine Hours administered m g %a
22
35
24
21
mg
6.4
4.5
7.2
7.4
6.5
%
Morphine
Percentages expressed on the basis of total codeine administered.
a
Mean
330
~-
1
Subject
Codeine administered, mg
24
30
20
11
mg
5.6
5.0
6.2
6.1
3.3
%
Norcodeine
Excreted in urine
458
333
183
192
mg
68
88
69
56
58
%
All three
TABLE 3. Twenty-Eight Hour Excretion of Total (free plus conjugated) Codeine, Morphine, and Norcodeine during and following Administration of Codeine a t a rate of 30 mg/hr for 11 and 16 h r
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v
U
zi
c3
e
E: 0
m
.!!
a
w
2
40.6
268
130
150
175
181
1
2
3
4
Mean
1.9
2.6
0.5
2.0
2.6
10.8
13.5
10.5
11.0
8.2
a Percentages expressed on the basis of total codeine administered.
12.8
17.2
26.5 27.4
3.5
13.2
17.2
1.7
2.1
1.6
1.7
1.2
205
206
164
154
294
mg
31.0
31.2
24.9
23.4
44.5
% ~
%
mg
%
mg
All three
Norcodeine
Morphine
22.8
19.7
%a
mg
Subject
Codeine
TABLE 4. Forty Hour Urinary Excretion of Total ( f r e e plus conjugated) Codeine, Morphine, and Norcodeine during and following Administration of 660 mg of Codeine a t a rate of 60 mg/hr for 1 1 h r
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N W
cn
3
U
E
2
0
z
tj
W
4
*
z m
NOMOF, ELLIOTT, AND PARKER
524
300
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250
200 rn
I Lz 4
P
150
-I
4
I
100
50
TIME
IN
HOURS
FIG. 1. Cumulative excretion of total codeine (free plus conjugated) by subjects given codeine by continuous i.v. infusion. 0 --a , average f o r two subjects given 30 mg/hr for 11 hr, &--A, average for two subjects given 30 mg/hr for 16 hr. x---x , average for four subjects given 60 mg/hr for 11 hr. Arrows indicate end of infusion of codeine.
B l o o d C o n c e n t r a t i o n s of C o d e i n e Blood drawn a t the eleventh hour from each subject of Group II contained detectable quantities of free codeine as shown in Table 5. The mean concentration was 1.1 pg/ml. No conjugated codeine was detected as indicated by no increase in the codeine concentration after acid hydrolysis. Morphine and norcodeine were not detected by the methods used (limits of detectability of morphine 0.1 pg/ml; of norcodeine 0.4 pg/ml).
METABOLISM O F CODEINE
52 5
TABLE 5. Blood Codeine Concentration of Subjects following Continuous Intravenous Infusion of Codeine for 11 hra
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Blood codeine concentration, pg/ml Subject
Free
1
1.11
1.08
2
0.82
0.89
3
0.51
0.49
4
1.94
2.00
Mean
1.10
1.12
Totalb
a
Total dose received was 660 mg. bTotal refers to all codeine measurable after acid hydrolysis.
TABLE 6. Codeine Clearance Subject
Creatinine clearance, ml/min
Codeine clearance, ml/min
1
114
133
2
177
65
3
17 5
286
4
129
288
~~
The renal clearance of codeine was calculated from the eleventh hour blood concentration. It was assumed that the codeine concentration had been constant from the tenth to the eleventh hours. Codeine clearance results are recorded in Table 6. Three of the four subjects appeared to c l e a r codeine a t a rate greater than creatinine clearance, suggesting that codeine is excreted by the kidney by both glomerular filtration and tubular secretion. DISCUSSION Previous studies in animals and humans have shown generally s i m i l a r metabolic and excretory pathways for codeine [ 121. Although the type and percentage of metabolites varies among species (e.g., morphine is not a metabolite in the dog) [4], in most of those studied
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52 6
NOMOF, ELLIOTT, AND PARKER
codeine i s largely excreted as a water-soluble conjugate, which has been identified a s the glucuronide in dog urine [14] and as conjugates of morphine and norcodeine [ 121. The pattern of urinary excretion appears independent of dose, route of administration, o r degree of tolerance o r addiction [12]. In our study total recovery of codeine metabolites agrees with the findings of Adler et al. [ l ] who determined the urinary excretion of codeine metabolites i n humans following acute administration of l 4 Clabeled codeine. In both studies percent of administered dose recovered was greater after small doses, and morphine and norcodeine were excreted in significant but l e s s e r quantities than free and conjugated codeine. To our knowledge the present study is the first attempt to demonstrate development of acute tolerance to and the maximal rate of excretion of codeine in humans. The failure of four subjects to report any subjective effects from 30 m g / h r of codeine infused for as long as 16 h r indicates efficient mechanisms for the metabolism and excretion of codeine in humans. Since this dosage induced miosis it was adequate to produce CNS effects if not psychic effects, but the falloff in rate of excretion of metabolites immediately after termination of infusion indicates no build-up of codeine o r active metabolites such as morphine o r norcodeine a t this rate of administration (30 mg/hr). The fact that total codeine excretion proceeded at the same rate after 60 mg/hr a s after 30 mg/hr, suggests that in humans the maximal rate of metabolism and elimination of codeine is about 30 mg/hr. It i s possible that infusion of 60 mg/hr for longer than 11 h r might lead to cumulation since excretion proceeded at the maximal rate for 4 to 5 h r after termination of infusion. However, the lack of progression of CNS depressant effects in the fact of an increasing body burden of codeine favors the concept of a ceiling effect for codeine. There was a striking lack of severe narcotic effects in the four subjects given 60 mg/hr of codeine/hr. Only mild sedation (drowsiness), nausea, and emesis were observed with no evidence of excitation, respiratory depression, confusion, o r other effects on the CNS. There was no reversal of behavioral changes during t h e final hours of infusion to suggest development of acute tolerance to codeine a s was noted for morphine i n dogs given i.v. infusions of morphine for 8 h r [8]. In addition, no withdrawal symptoms followed nalorphine challenge at 9 h r in Group I and at 4 and 6 h r in Group 11. It is notable in view of the relatively mild narcotic effects observed that the mean blood codeine concentration of 1.1 pg/ml after 11 h r of infusion of codeine at the rate of 60 mg/hr was about ten times the peak concentrations reported by Brunson and Nash [2] after a single oral 60-mg dose of codeine (0.107 pg/ml) and by Waife et al. [ l l ] after 60 mg of codeine every 6 h r for four days (0.12 pg/ml). Thus, our values a r e an order of magnitude above the therapeutic range and approach the low end of the fatal range of 1.4-5.6 pg/ml
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METABOLEM O F CODEINE
52 7
reported by Wright et al. [13]. Taken with the behavioral effects observed, these blood levels a r e compatible with t h e concept of a ceiling effect for codeine which, however, has been described by Eddy et al. [3] a s controversial, at least as related to analgesia. Both our earlier [4] and present findings that miosis induced by codeine cannot be reversed by nalorphine until codeine h a s been given intermittantly for 2-3 d a y s o r infused at a constant rate for several hours can be explained by the fact that the affinity of nalorphine f o r the opiate receptor is much greater than that of codeine. This has been shown in both rat brain homogenate and guinea pig ileum preparations [lo]. Thus, even though high levels of codeine i n the brain a r e rapidly attained after parenteral administration [9], the agonist actions of nalorphine, including miosis, predominate when this partial agonist of the morphine type is given following acute administration of codeine. However, after prolonged o r continuous administration, enough codeine is present i n the brain to overcome the greater affinity of nalorphine for the opiate receptor. Under these conditions enough receptors a r e occupied by the pure agonist codeine to permit the appearance of the antagonist actions of nalorphine, namely reversal of narcotic effects including miosis. This hypothesis is consistant with the finding that naloxone, a pure narcotic antagonist, can reverse miosis induced by single doses (60-90 mg) of codeine [5]. Thus, i t appears that the apparently complex interactions of codeine and nalorphine on pupil diameter i n vivo can be analyzed with the aid of information derived from in vitro opiate receptor studies. SUMMARY Miosis produced by codeine is not antagonized by nalorphine until large oral doses a r e administered for several days. The present experiment was conducted in o r d e r to further study this characteristic of the codeine effect. Eight healthy male volunteers, who were former drug users, were divided into two groups. Subjects in the first group were given a continuous infusion of codeine, 30 mg/hr for 11-16 hr. N o subjective effects were reported by the volunteers. In three of the individuals definite miosis antagonized by nalorphine was observed a t 9.5 h r . The dose of codeine for the second group was 60 mg/hr for 11 h r . Mild but definite subjective effects were experienced by each of the participants in this group. Miosis appeared between 2 and 6 hr. Challenges at 4 and 6 h r were positive in two subjects and negative o r equivocal in the other two. Codeine was excreted i n the urine as free and conjugated codeine, morphine, and norcodeine. Maximum rates of excretion were similar
528
NOMOF, ELLIOTT, AND PARKER
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for both groups, suggesting that the maximum amount of codeine that can be metabolized is equal o r less than 30 mg/hr. Also codeine clearance, being greater than creatinine clearance, suggests that codeine might be excreted by glomerular filtration and tubular s e c r e tion. Blood levels of codeine in the 60 mg/hr group were about 10 times those reported as therapeutic. However, morphine o r norcodeine were not detectable by the methods used. REFERENCES T. K. Adler, J. M. F’ujimoto, E. L. Way, and E. M. Baker, The metabolic fate of codeine in man, J. Pharmacol. Exptl. Therap., 114. 251 (1955). M. K. Brunson’and J. F. Nash, Gas chromatographic measurement of codeine and norcodeine in human plasma, Clin. Chem., 21. 1956 (1975). K’B. Eddy, H.’Friebel, K. J. Hahn, and H. Halbach, Codeine and alternates for pain and cough relief, Bull. World Health Org.,2,673 (1968). H. W. Elliott, N. Nomof, and K. D. Parker, Correlation of the nalorphine test with concentration of metabolites of codeine in the urine after single doses and continuous administration of codeine, Clin. Pharmacol. and Therap., _8, 78 (1967). H. W. Elliott, N. Nomof, and K. D. Parker, The use of naloxone in the pupil test for the detection of narcotic abuse, Proc. Fourth Nat. Conf. on Methadone Treatment, NAPAN, New York, 1972, p. 135. H. W. Elliott, N. Nomof, K. D. Parker, M. L. Dewey, and E. L. Way, Comparison of the nalorphine test and urinary analysis in the detection of narcotic use, Clin. Pharmacol. and Therap., -5, 405 (1964). H. W. Elliott, K. D, Parker, J. A. Wright, and N. Nomof, Actions and metabolism of heroin administered by continuous intravenous infusion to man, Clin. Pharmacol. a n d Therap., 806 (1971). W. R. Martin and C. G. Eades, Demonstration of tolerance and physical dependence in the dog following a short-term infusion of morphine, J. Pharmacol. Exptl. Therap., 133,262 (1961). J. W. Miller and H. W. Elliott, Rat tissue levels of carbon-14 labeled analgetics as related to pharmacological activity, J. Pharmacol. Exptl. Therap., 113,283 (1955). S. H. Snyder and S. Matthysse, Opiate Receptor Mechanisms, The M.I.T. Press, Cambridge, Mass., 1975. _ I
12,
METABOLISM O F CODEINE
529
[ll] S. 0.Waife, C. M. Gruber, Jr., B. E. Rodda, and J. F. Nash, Problems and solutions to single dose testing of analgesics: Comparison of propoxyphene, codeine and fenoproben, Intern. J. Clin. Pharmacol., 301 (1975). r121 E. L. Wav and J. T. Adler. The biological disposition of morphine and" its. surrogates, Bull. WorldHealth Org., 2, 51 ( 1962). I131 J. A. Wright, R. C. Baselt, and C. H. Hine, Blood codeine conc e n t r a t i o i s in fatalities associated with codeine, Clin. Toxicol., 8. 457 f 1975). Y. Yeh and L. A. Woods, Isolation and characterization of r141 codeine- 6-glucuronide from dog urine, J. Pharmacol. Exptl. Therap., 173,21 (1970). I
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