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STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA IX: MORPHINE WITH TACRINE
Brit. J. Anaesth. (1965), 37, 779
STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA IX: MORPHINE WITH TACRINE BY
RICHARD S. J. CLARKE AND JOHN W. DUNDEE
Department of Anaesthetics, The Queen's University of Belfast, Northern Ireland SUMMARY
Tacrine (tetrahydroaminacrine, THA, Romotal), an anticholinesterase, has been used principally for prolonging the neuromuscular blocking action of suxamethonium (McCaul and Robinson, 1962; Barrow and Smethurst, 1963). However, it was originally introduced as an antagonist to some of the undesirable actions of morphine such as drowsiness and respiratory depression (Stone, Moon and Shaw, 1961; Simpson, et al., 1962). A mixture of equal parts of morphine and tacrine has been marketed (as Mortha No. 1) as a useful analgesic with reduced side effects. When morphine 10 mg is used as premedication for short operations its principal toxic effect is vomiting and nausea, though, unlike pethidine, this occurs mainly postoperatively (Clarke, Dundee and Love, 1965). This vomiting, which lasts for 6 hours or more after operation, makes morphine alone quite unsuitable as a premedication and although its incidence is reduced by atropine (Riding, 1960) it would be of interest to know whether it is affected by tacrine. It is important to know whether the dose of tacrine contained in the commercially available mixtures would affect the action of a subsequently administered dose of suxamethonium, should the mixture be used (either purposely or inadvertently) as premedication. The influence of the anticholinesterase on the incidence and severity of muscle pains following suxamethonium also needs to be studied.
To date there has been no direct controlled comparison of the effects of morphine and morphine with tacrine as pre-anaesthetic medication. This paper reports a study in which the effects of morphine 10 mg are compared with those of a mixture of morphine 10 mg and tacrine 10 mg. It includes their pre-operative effects, effects on the course of methohexitone anaesthesia, emetic sequelae, and effect on the respiratory depression from sequelae of suxamethonium. It was intended later to study further doses of both drugs particularly using a larger dose of tacrine, but in view of the disappointing findings with the 10 mg dose, this was not done. METHOD
Patients. These were all healthy women scheduled for minor gynaecological operations. Premedication. This consisted of either morphine 10 mg, morphine 10 mg with tacrine 10 mg or morphine 10 mg with atropine 0.6 mg. Pre-operative observations. All of the patients who had morphine with tacrine and half of those who had morphine alone were seen 20, 40, 60 and 90 minutes after administration of the drugs, and the desired and toxic effects were assessed according to the
Downloaded from http://bja.oxfordjournals.org/ at University of Saskatchewan on March 18, 2015
Morphine and morphine with tacrine (tetrahydroaminacrine) have been compared when given intramuscularly as premedication, with regard to the pre-operative state of the patient, course of anaesthesia, sequelae, and effects on reactions to suxamethonium. Tacrine appeared to increase the pre-operative toxic effects of morphine, namely dizziness and nausea. During anaesthesia, hypotension was less common and postoperative recovery more rapid. However, vomiting and nausea during the first 6 hours after anaesthesia were more frequent. The neuromuscular blocking action of suxamethonium was prolonged and postoperative muscle pains were more common in the morphine-with-tacrine group, contrary to the findings of previous workers.
BRITISH JOURNAL OF ANAESTHESIA
780
respiration (apnoea time) and to return of full respiration (duration of respiratory depression) were both noted as described by Clarke, Dundee and Daw (1964). Sequelae. Patients were seen 1 hour and again at 6 hours after the end of the operation and the presence or absence of vomiting (including retching) and nausea were noted. The severity of symptoms was graded according to the scheme described by Dundee, Nicholl and Moore (1962). Patients were also visited on the first and second post-
TABLE
I
Details of patients and dosage of drugs used. Average Average dose of duration of suxaanaes- methonium thesia Total (mg/kg)
Average dose of methohexitone (mg/kg)
No. of cases
Age (yr)
Wt. (kg)
Initial
Morphine 10 mg + tacrine 10 mg (all studies)
50
30.4
59.4
1.57±0.01
1.77±0.01
0.44 ±0.01 7.72 ±0.35
Morphine 10 mg •Detailed premedication studies
50
32.9
60.9
100
33.7
59.7
1.56 ±0.01
2.01 ±0.06
7.43 ±0.39
50
33.1
58.8
1.57 ±0.01
1.63 ±0.02
Index studies and anaesthesia Morphine 10 mg + atropine 0.6 mg •Smtflmrrhoninm
studies only
Anaesthesia. Patients were anaesthetized with methohexitone 1.6 mg/kg, and anaesthesia was maintained with 75 per cent nitrous oxide in oxygen, and further doses of methohexitone to suppress reflex activity. The complications were noted and anaesthesia graded according to the scheme of Dundee, Moore and Nicholl (1962b). In all the cases given tacrine, suxamethonium 25 mg and atropine 0.3 mg was given about 1 minute after the methohexitone. The patients who had morphine and atropine as premedication were given suxamethonium 25 mg without further atropine. The delay of 1 minute gave time to assess induction characteristics of the barbiturate. Ventilation was manually controlled or assisted as necessary and the time from the end of the injection to return of first spontaneous
0.44 ±0.01
operative days and the presence and severity of muscle pains or stiffness noted. These were also graded as described by Clarke, Dundee and Daw (1964). RESULTS
When compared 60-90 minutes after premedication (table H) there was a significantly greater degree of sleepiness after morphine rhnn after morphine with tacrine (y2 = 7.89: n = 3; P<0.05). The incidence of apprehension and restlessness did not differ significantly between the premedication groups. There was, however, a significantly greater incidence of dizziness (^ 3 =3.86; n = l ; P<0.05) and of vomiting and nausea ( y 2 = 12.49; n = l; P<0.001) after morphine with tacrine than after morphine alone. The difference in the
Downloaded from http://bja.oxfordjournals.org/ at University of Saskatchewan on March 18, 2015
scheme described by Dundee, Moore and Nicholl (1962a) and Dundee, Moore and Clarke (1964). These are referred to as "detailed observations" in contrast to the remaining fifty morphine patients who were only seen once between 60 and 90 minutes after giving the premedication. The pre-operative observations on the morphine with atropine series are not included in the present study. Details of patients in each group and dosage of drugs used are shown in table I, from which it can be seen that the groups are broadly comparable.
STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA—IX incidence of tachycardia between the two groups was not significant; although it was less common after morphine with tacrine. The detailed studies (fig. 1) add little to the above except that the high incidence of nausea after the morphine-tacrine mixture occurred very early, there being a threefold difference after 20 minutes.
Anaesthesia did not differ significantly with the two premedications (table HI) except with regard to hypotension which was more marked with morphine alone fy! = 10.89; n = l ; P<0.0005). The hypotension index, calculated as described by Dundee (1963), demonstrates the greater safety of morphine with tacrine. The percentage of patients awake 2 minutes
MORPHINE-T.H.A
lOOi
DROWSINESS
APPREHENSION
DIZZINESS 2O-
EMETIC EFFECTS
IO
o4O-
HEART RATE MINUTES AFTER INJECTION
2O
4O
6O
9O
2O
4O
6O
9O
FIG. 1 Comparison of morphine and morphine with tacrine at 20> 40, 60 and 90 minutes after injection.
Drowsiness Apprehension Dizziness Emetic effects Heart rate
Solid column Good or fair Moderate or marked Marked Vomiting 120+ b.p.m.
Hatched column Slight SUght Slight Nausea 100-120 b.p.m.
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MORPHINE
EFFECT
781
BRITISH JOURNAL OF ANAESTHESIA
782 after the end of anaesthesia was significantly higher after morphine and tacrine (-/2=8.64; n = 2; P<0.025) than after morphine alone. Postoperative emetic sequelae were more frequent after the mixture than after morphine alone,
TABLE III
The influence of premedication with morphine 10 mg and morphine 10 mg+tacrine 10 mg on methohexitone anaesthesia and recovery. Morphine Morphine
TABLE II
The desired and toxic effects of morphine 10 mg and morphine 10 mg + tacrine 10 mg, 60-90 minutes after intramuscular administration. Morphine Drowsiness Good Fair Slight Apprehension Slight Marked Excitement or restlessness Pain at injection site Dizziness Slight Marked Emetic symptoms Nausea Vomiting Tachycardia 100-120 120 + Hypotension 20 mm Hg + Efficacy score
tacrine
38 38 19
30 32 22
17 6 3 5
14 6 2 4
31 3
48 8
7 3 19 2 4
32 6 10 2 2
1 2 3 4 5
4 11 19 32 34
4 10 32 28 26
Mean Toxic score
3.81
3.62
47 33 16 3 1
28 28 30 12 2
1 2 3 4 5
Mean Net mean score
1.78 + 2.03
tacrine
10 33
4 32
11 2 17.9
6 0 7.1
50 43 7 0
62 38 0 0
62 23 15
68 28 4
although the difference between the two series was not significant at the 5 per cent level. The response to suxamethonium 25 mg was compared in patients who had received morphine with atropine as premedication and those who had received morphine with tacrine (table V). In the latter group the time from giving the premedication to induction of anaesthesia varied from 60 to 138 minutes (average 102 minutes), but within this range there was no consistent relationship between time after premedication and duration of apnoea or respiratory depression. The percentage of patients apnoeic, the average duration of apnoea, and the average duration of respiratory depression, were all much greater after morphine with tacrine than after morphine with atropine. Postoperative muscle pains were also more frequent and of greater severity in patients premedicated with the mixture ( 7 a =7.11; n = 2 ; P<0.005).
2.32 + 1.30
TABLE IV
The influence of premedication with morphine 10 mg and morphine 10 mg+tacrine 10 mg on emetic sequelae of methohexitone anaesthesia. First 6 hours
Premedication
V
N
V
N
V
N
Nil
Average score
Average score, sick patients only
Morphine Morphine + tacrine
24 26
18 4
33 44
17 12
45 56
15 10
40 34
3.03 3.84
5.05 5.82
1-6 hrs.
0-1 hrs.
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Morphine
Excitatory effects Hiccough Hypotension 20-40 mm Hg 40+ mm Hg Hypotension index Grade of anaesthesia 1 2a 2b 3 Recovery Awake Safe Unsafe
STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA—IX
783
TABLE V
The incidence and duration of apnoea, respiratory depression and muscle pains in patients who had received suxamethonium 25 mg after methohexitone anaesthesia, using morphine and atropine or morphine and tacrine premedication.
Morphine + atropine Morphine + tacrine
Percentage of patients apnoeic
Apnoeic cases only
All cases
Average duration of respiratory depression (sec)
68 94
107 237
75 223
144 376
Average duration of apnoea (sec)
It was shown by Shaw and Bentley (1949) that tacrine antagonized the depression of consciousness in the dog following morphine administration. Since then several workers have commented on this action in man with a view to relieving pain with less depression of consciousness (Stone, Moon and Shaw, 1961; Simpson et al., 1962). The lesser degree of hypnosis after morphine and tacrine was confirmed by the present study, but this effect cannot be considered advantageous for preanaesthetic medication. The difference in the incidence of toxic effects was not expected because dizziness had not been mentioned elsewhere and previous workers had commented on the infrequency of vomiting (Stone, Moon and Shaw, 1961; Simpson et al., 1962). Only McCaul and Robinson (1962) mentioned a high incidence of "emergent" sickness. In this series pre-operative nausea was much commoner and postoperative emetic sequelae appeared slightly more frequent after morphine with tacrine. In general, it has been found that when quicker recovery occurs after anaesthesia there is more early vomiting, but a high incidence of late vomiting is more difficult to explain. It might be suggested that the patients who had received tacrine were more alert and therefore had more vomiting due to moving about. The influence of pre-operative tacrine on the action of suxamethonium is of interest but in general our findings do not suggest any benefits from its use. If tacrine had been given intravenously before anaesthesia then the effects on prolongation of apnoea and respiratory depression would not have been unexpected. It was
Severe Moderate 6 8 10 24
Mild
Nil
32 20
54 46
surprising, however, to find that these still occurred to a clinically significant degree when the tacrine was given by intramuscular injection about 100 minutes previously. The potentiation of suxamethonium means that in general it would be possible to intubate with smaller doses of the relaxant but there appears to be no real advantage in this. Contrary to the impressions of previous users of the suxamethonium-tacrine combination (Gordh and WShlin, 1961; McCaul and Robinson, 1962; Barrow and Smethurst, 1963; Kenton, 1963; Thomas, 1964), there was an increase rather than the expected reduction in muscle pains. However, no other comparative series has been reported and in view of the wide variation in the incidence of muscle pains from unit to unit, it seems possible that the apparently lower incidence found by other workers after tacrine is attributable to other factors. The earlier recovery after the tacrine mixture may have led to more movement (as suggested above) resulting in a higher incidence of pains. ACKNOWLEDGMENTS
Our thanks are again due to the nursing, theatre and gynaecological staff of Musgrave Park Hospital, Balmoral, without whose co-operation this study would not have been possible, and to Ward Blenkinsop & Co. Ltd. for supplies of Mortha No. 1. REFERENCES
Barrow, M. E. H., and Smethurst, J. R. (1963). Suxamethonium modified by tetrahydroaminacrine. Brit. J. Anaesth., 35, 465. Clarke, R. S. J., Dundee, J. W., and Daw, R. H. (1964). Clinical studies of induction agents. XI: The influence of some intravenous anaesthetics on the respiratory effects and sequelae of suxamethonium. Brit. J. Anaesth., 36, 307. Love, W. J. (1965). Studies of drugs given before anaesthesia. VIII: Morphine 10 mg alone and with atropine or hyoscine. Brit. J. Anaesth., 37, 772.
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DISCUSSION
Percentage incidence muscle pains
784
BRITISH JOURNAL OF ANAESTHESIA ETUDE DES DROGUES DONNEES AVANT L'ANESTHESIE IX: MORPHINE-TACRINE SOMMAIRE
On a compare la morphine et la morphine avec tacrine tetrahydroaminacrine) donnees comme premedication en injection intra-musculaire, en ce qui concerne l'etat pre-operatoire du malade, Involution de l'anesthesie, les sequelles et les effets sur les reactions au suxamcthonium. La tacrine a sembl£ augmenter les effets toxiques pre-operatoires de la morphine, c*est-adire les vertiges et nausees. Pendant l'anesth&ie, l'hypotension a ete moins frequente et la guerison post-operatoire plus rapide. Pourtant, vomissements et nausees pendant les six premieres heures apres l'anesthesie etaient plus frequentes. L'action de blocage neuro-musculaire du suxamethonium a ete prolongee et les myalgies post-operatoires etaient plus frequentes dans le groupe morphine-tacrine, contrairement aux resultats des precedents chercheurs.
UNTERSUCHUNG VON MEDIKAMENTEN ZUR VORBEHANDLUNG BEI NARKOSE IX: MORPHIN-TACRIN ZUSAMMENFASSUNG
Morphin und Morphin mit Tacrin (Tetrahydroaminoacrin), intramuskular als Praemedikation verabreicht, wurden hinsichtlich des praeoperativen Befinden des Patienten, des Verlaufs der Narkose, ihren Folgeerscheinungen und des Effektes auf die Wirkungen von Suxamethonium verglichen. Tacrin schien die praeoperativen toxischen Wirkungen des Morphins, namlich Schwindelgefuhl und Ubelkeit, zu verstarken. Wahrend der Narkose war Hypotonie weniger ha'ufiK, und nach der Narkose trat die Erholung schneller ein. Erbrechen und Ubelkeit wahrend der ersten sechs Stunden nach der Narkose traten jedoch haufiger auf. Die neuromuskular blockierende Wirkung war in der mit Morphin-Tacrin behandelten Gruppe verlangert, und postoperative Muskelschmerzen waren haufiger, im Gegensatz zu den Ergebnissen friiherer Autoren.
YORKSHIRE SOQETY OF ANAESTHETISTS A meeting will be held in The Littlewood Hall, The General Infirmary, Leeds, at 8 p.m. on WEDNESDAY, DECEMBER 1 (Provisional) Speakers: Dr. Whitwam and Dr. Kinnel, "Anaesthesia in U.S.A." Dr. Kelman, "Computers in Anaesthesia"
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Dundee, J. W. (1963). minimi studies of induction agents. VIII: A comparison of eight intravenous anaesthetics as main agents for a standard operation. Brit. J. Anaesth., 35, 784. Moore, J., and Clarke, R. S. J. (1964). Studies of drugs given bifore anaesthesia. VI: Pethidine 100 mg alone and with atropine or hyoscine. Brit. J. Anaesth., 36, 703. Nicholl, R. M. (1962a). Studies of drugs given before anaesthesia. I : A method of preoperative assessment. Brit. J. Anaesth., 34, 458. (1962b). Studies of drugs given before anaesthesia. I I : A method for the assessment of their influence on the course of anaesthesia. Brit. J. Anaesth., 34, 523. Nicholl, R. M., and Moore, J. (1962). Studies of drugs given before anaesthesia. I l l : A method for the studying of their effects on postoperative vomiting and nausea. Brit. J. Anaesth., 34, 527. Gordh, T., and Wahlin, A. (1961). Potentiation of the neuromuscular effect of succinylcholine by tetrahydroamino-acridine. Ada anaesth. scand., 5, 55. Kenton, B. (1963). Suxamethonium modified by tetrahydroaminacrine. Brit. J. Anaesth., 35, 825. McCaul, K., and Robinson, G. D. (1962). Suxamethonium "extension" by tetrahydroaminacrine. Brit. J. Anaesth., 34, 536. Riding, J. E. (1960). Postoperative vomiting. Proc. roy. Soc. Med., 53, 671. Shaw, F. H., and Bentley, G. (1949). Some aspects of the pharmacology of morphine with special reference to its antagonism by 5-amino-acridine and other chemically related compounds. Med. J. Aust., 2, 868. Simpson, B. R., Seelye, E., Oayton, J. I., and Parkhouse, J. (1962). Morphine combined with tetrahydroaminacrine for postoperative pain. Brit. J. Anaesth., 34, 95. Stone, V., Moon, W., and Shaw, E. H. (1961). Treatment of intractable pain with morphine and tetrahydroaminacrine. Brit. med. J., 1, 471. Thomas, K. B. (1964). Reduction of suxamethonium muscle pains. Brit. med. J., 1, 1639.
STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA IX: MORPHINE WITH TACRINE BY
RICHARD S. J. CLARKE AND JOHN W. DUNDEE
Department of Anaesthetics, The Queen's University of Belfast, Northern Ireland SUMMARY
Tacrine (tetrahydroaminacrine, THA, Romotal), an anticholinesterase, has been used principally for prolonging the neuromuscular blocking action of suxamethonium (McCaul and Robinson, 1962; Barrow and Smethurst, 1963). However, it was originally introduced as an antagonist to some of the undesirable actions of morphine such as drowsiness and respiratory depression (Stone, Moon and Shaw, 1961; Simpson, et al., 1962). A mixture of equal parts of morphine and tacrine has been marketed (as Mortha No. 1) as a useful analgesic with reduced side effects. When morphine 10 mg is used as premedication for short operations its principal toxic effect is vomiting and nausea, though, unlike pethidine, this occurs mainly postoperatively (Clarke, Dundee and Love, 1965). This vomiting, which lasts for 6 hours or more after operation, makes morphine alone quite unsuitable as a premedication and although its incidence is reduced by atropine (Riding, 1960) it would be of interest to know whether it is affected by tacrine. It is important to know whether the dose of tacrine contained in the commercially available mixtures would affect the action of a subsequently administered dose of suxamethonium, should the mixture be used (either purposely or inadvertently) as premedication. The influence of the anticholinesterase on the incidence and severity of muscle pains following suxamethonium also needs to be studied.
To date there has been no direct controlled comparison of the effects of morphine and morphine with tacrine as pre-anaesthetic medication. This paper reports a study in which the effects of morphine 10 mg are compared with those of a mixture of morphine 10 mg and tacrine 10 mg. It includes their pre-operative effects, effects on the course of methohexitone anaesthesia, emetic sequelae, and effect on the respiratory depression from sequelae of suxamethonium. It was intended later to study further doses of both drugs particularly using a larger dose of tacrine, but in view of the disappointing findings with the 10 mg dose, this was not done. METHOD
Patients. These were all healthy women scheduled for minor gynaecological operations. Premedication. This consisted of either morphine 10 mg, morphine 10 mg with tacrine 10 mg or morphine 10 mg with atropine 0.6 mg. Pre-operative observations. All of the patients who had morphine with tacrine and half of those who had morphine alone were seen 20, 40, 60 and 90 minutes after administration of the drugs, and the desired and toxic effects were assessed according to the
Downloaded from http://bja.oxfordjournals.org/ at University of Saskatchewan on March 18, 2015
Morphine and morphine with tacrine (tetrahydroaminacrine) have been compared when given intramuscularly as premedication, with regard to the pre-operative state of the patient, course of anaesthesia, sequelae, and effects on reactions to suxamethonium. Tacrine appeared to increase the pre-operative toxic effects of morphine, namely dizziness and nausea. During anaesthesia, hypotension was less common and postoperative recovery more rapid. However, vomiting and nausea during the first 6 hours after anaesthesia were more frequent. The neuromuscular blocking action of suxamethonium was prolonged and postoperative muscle pains were more common in the morphine-with-tacrine group, contrary to the findings of previous workers.
BRITISH JOURNAL OF ANAESTHESIA
780
respiration (apnoea time) and to return of full respiration (duration of respiratory depression) were both noted as described by Clarke, Dundee and Daw (1964). Sequelae. Patients were seen 1 hour and again at 6 hours after the end of the operation and the presence or absence of vomiting (including retching) and nausea were noted. The severity of symptoms was graded according to the scheme described by Dundee, Nicholl and Moore (1962). Patients were also visited on the first and second post-
TABLE
I
Details of patients and dosage of drugs used. Average Average dose of duration of suxaanaes- methonium thesia Total (mg/kg)
Average dose of methohexitone (mg/kg)
No. of cases
Age (yr)
Wt. (kg)
Initial
Morphine 10 mg + tacrine 10 mg (all studies)
50
30.4
59.4
1.57±0.01
1.77±0.01
0.44 ±0.01 7.72 ±0.35
Morphine 10 mg •Detailed premedication studies
50
32.9
60.9
100
33.7
59.7
1.56 ±0.01
2.01 ±0.06
7.43 ±0.39
50
33.1
58.8
1.57 ±0.01
1.63 ±0.02
Index studies and anaesthesia Morphine 10 mg + atropine 0.6 mg •Smtflmrrhoninm
studies only
Anaesthesia. Patients were anaesthetized with methohexitone 1.6 mg/kg, and anaesthesia was maintained with 75 per cent nitrous oxide in oxygen, and further doses of methohexitone to suppress reflex activity. The complications were noted and anaesthesia graded according to the scheme of Dundee, Moore and Nicholl (1962b). In all the cases given tacrine, suxamethonium 25 mg and atropine 0.3 mg was given about 1 minute after the methohexitone. The patients who had morphine and atropine as premedication were given suxamethonium 25 mg without further atropine. The delay of 1 minute gave time to assess induction characteristics of the barbiturate. Ventilation was manually controlled or assisted as necessary and the time from the end of the injection to return of first spontaneous
0.44 ±0.01
operative days and the presence and severity of muscle pains or stiffness noted. These were also graded as described by Clarke, Dundee and Daw (1964). RESULTS
When compared 60-90 minutes after premedication (table H) there was a significantly greater degree of sleepiness after morphine rhnn after morphine with tacrine (y2 = 7.89: n = 3; P<0.05). The incidence of apprehension and restlessness did not differ significantly between the premedication groups. There was, however, a significantly greater incidence of dizziness (^ 3 =3.86; n = l ; P<0.05) and of vomiting and nausea ( y 2 = 12.49; n = l; P<0.001) after morphine with tacrine than after morphine alone. The difference in the
Downloaded from http://bja.oxfordjournals.org/ at University of Saskatchewan on March 18, 2015
scheme described by Dundee, Moore and Nicholl (1962a) and Dundee, Moore and Clarke (1964). These are referred to as "detailed observations" in contrast to the remaining fifty morphine patients who were only seen once between 60 and 90 minutes after giving the premedication. The pre-operative observations on the morphine with atropine series are not included in the present study. Details of patients in each group and dosage of drugs used are shown in table I, from which it can be seen that the groups are broadly comparable.
STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA—IX incidence of tachycardia between the two groups was not significant; although it was less common after morphine with tacrine. The detailed studies (fig. 1) add little to the above except that the high incidence of nausea after the morphine-tacrine mixture occurred very early, there being a threefold difference after 20 minutes.
Anaesthesia did not differ significantly with the two premedications (table HI) except with regard to hypotension which was more marked with morphine alone fy! = 10.89; n = l ; P<0.0005). The hypotension index, calculated as described by Dundee (1963), demonstrates the greater safety of morphine with tacrine. The percentage of patients awake 2 minutes
MORPHINE-T.H.A
lOOi
DROWSINESS
APPREHENSION
DIZZINESS 2O-
EMETIC EFFECTS
IO
o4O-
HEART RATE MINUTES AFTER INJECTION
2O
4O
6O
9O
2O
4O
6O
9O
FIG. 1 Comparison of morphine and morphine with tacrine at 20> 40, 60 and 90 minutes after injection.
Drowsiness Apprehension Dizziness Emetic effects Heart rate
Solid column Good or fair Moderate or marked Marked Vomiting 120+ b.p.m.
Hatched column Slight SUght Slight Nausea 100-120 b.p.m.
Downloaded from http://bja.oxfordjournals.org/ at University of Saskatchewan on March 18, 2015
MORPHINE
EFFECT
781
BRITISH JOURNAL OF ANAESTHESIA
782 after the end of anaesthesia was significantly higher after morphine and tacrine (-/2=8.64; n = 2; P<0.025) than after morphine alone. Postoperative emetic sequelae were more frequent after the mixture than after morphine alone,
TABLE III
The influence of premedication with morphine 10 mg and morphine 10 mg+tacrine 10 mg on methohexitone anaesthesia and recovery. Morphine Morphine
TABLE II
The desired and toxic effects of morphine 10 mg and morphine 10 mg + tacrine 10 mg, 60-90 minutes after intramuscular administration. Morphine Drowsiness Good Fair Slight Apprehension Slight Marked Excitement or restlessness Pain at injection site Dizziness Slight Marked Emetic symptoms Nausea Vomiting Tachycardia 100-120 120 + Hypotension 20 mm Hg + Efficacy score
tacrine
38 38 19
30 32 22
17 6 3 5
14 6 2 4
31 3
48 8
7 3 19 2 4
32 6 10 2 2
1 2 3 4 5
4 11 19 32 34
4 10 32 28 26
Mean Toxic score
3.81
3.62
47 33 16 3 1
28 28 30 12 2
1 2 3 4 5
Mean Net mean score
1.78 + 2.03
tacrine
10 33
4 32
11 2 17.9
6 0 7.1
50 43 7 0
62 38 0 0
62 23 15
68 28 4
although the difference between the two series was not significant at the 5 per cent level. The response to suxamethonium 25 mg was compared in patients who had received morphine with atropine as premedication and those who had received morphine with tacrine (table V). In the latter group the time from giving the premedication to induction of anaesthesia varied from 60 to 138 minutes (average 102 minutes), but within this range there was no consistent relationship between time after premedication and duration of apnoea or respiratory depression. The percentage of patients apnoeic, the average duration of apnoea, and the average duration of respiratory depression, were all much greater after morphine with tacrine than after morphine with atropine. Postoperative muscle pains were also more frequent and of greater severity in patients premedicated with the mixture ( 7 a =7.11; n = 2 ; P<0.005).
2.32 + 1.30
TABLE IV
The influence of premedication with morphine 10 mg and morphine 10 mg+tacrine 10 mg on emetic sequelae of methohexitone anaesthesia. First 6 hours
Premedication
V
N
V
N
V
N
Nil
Average score
Average score, sick patients only
Morphine Morphine + tacrine
24 26
18 4
33 44
17 12
45 56
15 10
40 34
3.03 3.84
5.05 5.82
1-6 hrs.
0-1 hrs.
Downloaded from http://bja.oxfordjournals.org/ at University of Saskatchewan on March 18, 2015
Morphine
Excitatory effects Hiccough Hypotension 20-40 mm Hg 40+ mm Hg Hypotension index Grade of anaesthesia 1 2a 2b 3 Recovery Awake Safe Unsafe
STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA—IX
783
TABLE V
The incidence and duration of apnoea, respiratory depression and muscle pains in patients who had received suxamethonium 25 mg after methohexitone anaesthesia, using morphine and atropine or morphine and tacrine premedication.
Morphine + atropine Morphine + tacrine
Percentage of patients apnoeic
Apnoeic cases only
All cases
Average duration of respiratory depression (sec)
68 94
107 237
75 223
144 376
Average duration of apnoea (sec)
It was shown by Shaw and Bentley (1949) that tacrine antagonized the depression of consciousness in the dog following morphine administration. Since then several workers have commented on this action in man with a view to relieving pain with less depression of consciousness (Stone, Moon and Shaw, 1961; Simpson et al., 1962). The lesser degree of hypnosis after morphine and tacrine was confirmed by the present study, but this effect cannot be considered advantageous for preanaesthetic medication. The difference in the incidence of toxic effects was not expected because dizziness had not been mentioned elsewhere and previous workers had commented on the infrequency of vomiting (Stone, Moon and Shaw, 1961; Simpson et al., 1962). Only McCaul and Robinson (1962) mentioned a high incidence of "emergent" sickness. In this series pre-operative nausea was much commoner and postoperative emetic sequelae appeared slightly more frequent after morphine with tacrine. In general, it has been found that when quicker recovery occurs after anaesthesia there is more early vomiting, but a high incidence of late vomiting is more difficult to explain. It might be suggested that the patients who had received tacrine were more alert and therefore had more vomiting due to moving about. The influence of pre-operative tacrine on the action of suxamethonium is of interest but in general our findings do not suggest any benefits from its use. If tacrine had been given intravenously before anaesthesia then the effects on prolongation of apnoea and respiratory depression would not have been unexpected. It was
Severe Moderate 6 8 10 24
Mild
Nil
32 20
54 46
surprising, however, to find that these still occurred to a clinically significant degree when the tacrine was given by intramuscular injection about 100 minutes previously. The potentiation of suxamethonium means that in general it would be possible to intubate with smaller doses of the relaxant but there appears to be no real advantage in this. Contrary to the impressions of previous users of the suxamethonium-tacrine combination (Gordh and WShlin, 1961; McCaul and Robinson, 1962; Barrow and Smethurst, 1963; Kenton, 1963; Thomas, 1964), there was an increase rather than the expected reduction in muscle pains. However, no other comparative series has been reported and in view of the wide variation in the incidence of muscle pains from unit to unit, it seems possible that the apparently lower incidence found by other workers after tacrine is attributable to other factors. The earlier recovery after the tacrine mixture may have led to more movement (as suggested above) resulting in a higher incidence of pains. ACKNOWLEDGMENTS
Our thanks are again due to the nursing, theatre and gynaecological staff of Musgrave Park Hospital, Balmoral, without whose co-operation this study would not have been possible, and to Ward Blenkinsop & Co. Ltd. for supplies of Mortha No. 1. REFERENCES
Barrow, M. E. H., and Smethurst, J. R. (1963). Suxamethonium modified by tetrahydroaminacrine. Brit. J. Anaesth., 35, 465. Clarke, R. S. J., Dundee, J. W., and Daw, R. H. (1964). Clinical studies of induction agents. XI: The influence of some intravenous anaesthetics on the respiratory effects and sequelae of suxamethonium. Brit. J. Anaesth., 36, 307. Love, W. J. (1965). Studies of drugs given before anaesthesia. VIII: Morphine 10 mg alone and with atropine or hyoscine. Brit. J. Anaesth., 37, 772.
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DISCUSSION
Percentage incidence muscle pains
784
BRITISH JOURNAL OF ANAESTHESIA ETUDE DES DROGUES DONNEES AVANT L'ANESTHESIE IX: MORPHINE-TACRINE SOMMAIRE
On a compare la morphine et la morphine avec tacrine tetrahydroaminacrine) donnees comme premedication en injection intra-musculaire, en ce qui concerne l'etat pre-operatoire du malade, Involution de l'anesthesie, les sequelles et les effets sur les reactions au suxamcthonium. La tacrine a sembl£ augmenter les effets toxiques pre-operatoires de la morphine, c*est-adire les vertiges et nausees. Pendant l'anesth&ie, l'hypotension a ete moins frequente et la guerison post-operatoire plus rapide. Pourtant, vomissements et nausees pendant les six premieres heures apres l'anesthesie etaient plus frequentes. L'action de blocage neuro-musculaire du suxamethonium a ete prolongee et les myalgies post-operatoires etaient plus frequentes dans le groupe morphine-tacrine, contrairement aux resultats des precedents chercheurs.
UNTERSUCHUNG VON MEDIKAMENTEN ZUR VORBEHANDLUNG BEI NARKOSE IX: MORPHIN-TACRIN ZUSAMMENFASSUNG
Morphin und Morphin mit Tacrin (Tetrahydroaminoacrin), intramuskular als Praemedikation verabreicht, wurden hinsichtlich des praeoperativen Befinden des Patienten, des Verlaufs der Narkose, ihren Folgeerscheinungen und des Effektes auf die Wirkungen von Suxamethonium verglichen. Tacrin schien die praeoperativen toxischen Wirkungen des Morphins, namlich Schwindelgefuhl und Ubelkeit, zu verstarken. Wahrend der Narkose war Hypotonie weniger ha'ufiK, und nach der Narkose trat die Erholung schneller ein. Erbrechen und Ubelkeit wahrend der ersten sechs Stunden nach der Narkose traten jedoch haufiger auf. Die neuromuskular blockierende Wirkung war in der mit Morphin-Tacrin behandelten Gruppe verlangert, und postoperative Muskelschmerzen waren haufiger, im Gegensatz zu den Ergebnissen friiherer Autoren.
YORKSHIRE SOQETY OF ANAESTHETISTS A meeting will be held in The Littlewood Hall, The General Infirmary, Leeds, at 8 p.m. on WEDNESDAY, DECEMBER 1 (Provisional) Speakers: Dr. Whitwam and Dr. Kinnel, "Anaesthesia in U.S.A." Dr. Kelman, "Computers in Anaesthesia"
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Dundee, J. W. (1963). minimi studies of induction agents. VIII: A comparison of eight intravenous anaesthetics as main agents for a standard operation. Brit. J. Anaesth., 35, 784. Moore, J., and Clarke, R. S. J. (1964). Studies of drugs given bifore anaesthesia. VI: Pethidine 100 mg alone and with atropine or hyoscine. Brit. J. Anaesth., 36, 703. Nicholl, R. M. (1962a). Studies of drugs given before anaesthesia. I : A method of preoperative assessment. Brit. J. Anaesth., 34, 458. (1962b). Studies of drugs given before anaesthesia. I I : A method for the assessment of their influence on the course of anaesthesia. Brit. J. Anaesth., 34, 523. Nicholl, R. M., and Moore, J. (1962). Studies of drugs given before anaesthesia. I l l : A method for the studying of their effects on postoperative vomiting and nausea. Brit. J. Anaesth., 34, 527. Gordh, T., and Wahlin, A. (1961). Potentiation of the neuromuscular effect of succinylcholine by tetrahydroamino-acridine. Ada anaesth. scand., 5, 55. Kenton, B. (1963). Suxamethonium modified by tetrahydroaminacrine. Brit. J. Anaesth., 35, 825. McCaul, K., and Robinson, G. D. (1962). Suxamethonium "extension" by tetrahydroaminacrine. Brit. J. Anaesth., 34, 536. Riding, J. E. (1960). Postoperative vomiting. Proc. roy. Soc. Med., 53, 671. Shaw, F. H., and Bentley, G. (1949). Some aspects of the pharmacology of morphine with special reference to its antagonism by 5-amino-acridine and other chemically related compounds. Med. J. Aust., 2, 868. Simpson, B. R., Seelye, E., Oayton, J. I., and Parkhouse, J. (1962). Morphine combined with tetrahydroaminacrine for postoperative pain. Brit. J. Anaesth., 34, 95. Stone, V., Moon, W., and Shaw, E. H. (1961). Treatment of intractable pain with morphine and tetrahydroaminacrine. Brit. med. J., 1, 471. Thomas, K. B. (1964). Reduction of suxamethonium muscle pains. Brit. med. J., 1, 1639.