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MANDRAX AND ITS CONSTITUENTS IN PRE-ANAESTHETIC MEDICATION
Brit. J. Anaesth. (1969), 41, 874
MANDRAX AND ITS CONSTITUENTS IN MEDICATION
PRE-ANAESTHETIC
BY W. NORRIS AND A. B. M. TELFER SUMMARY
Interest in the oral route for the administration of pre-anaesthetic medication continues. Following earlier studies with heptabarbitone (Norris and Nisbet, 1964) and the enthusiastic report by Jolly (1965), a trial of oral Mandrax (Roussel) as a pre-operative sedative was reported (Norris and Nisbet, 1966). The sedative effects of this drug were found to be comparable to that produced in a previous series with papaveretum 20 mg and hyoscine 0.4 mg, changes in heart rate and blood pressure being minimal, and nausea and vomiting absent pre-operatively and rare postoperatively. Mandrax is a combination of methaqualone 250 mg with diphenhydramine hydrochloride 25 mg and this study reports a comparison of Mandrax with each of its individual constituents and a placebo.
TABLE I
Mean ages, weights and time from administration of tablets until readings were taken.
Mean age
Drug Mandrax Methaqualone Diphenhydramine Placebo
(yr) 36.6 33.8 36.2 35.3
Mean weight (lb.) 135.2 134.2 134.5 128.7
Mean time from administration of drug to test (min) 141.0 153.1 153.0 148.2
The allocation was made from random tables, the code being kept in a sealed envelope in the unit but unopened until after the trial was completed. Each patient was given the unknown tablet with a small sip of water at 8 a.m., the theatre operating list being due to commence at 9 a.m. Combined subjective and objective estimates METHOD were made of the degree of sedation present. The method of study was that described in a Changes in heart rate and blood pressure from previous communication (Nisbet and Norris, the previous day's reading were recorded in the 1963) and more recently by Norris and Telfer anaesthetic room. Points were given for patients (1968a, b). All measurements were made on who appeared drowsy or relaxed in the anaesotherwise healthy patients undergoing minor thetic room and who showed either a slight fall gynaecological procedures. The patients were in blood pressure or heart rate or at least no rise divided into groups of 50, comparable in age and in these measures. Further points were awarded weight (see table I) and were given one of four when the patients did not react to a specific tablets. Group 1 were given a tablet of Mandrax, stimulus in the anaesthetic room. Points were Group 2 a tablet containing methaqualone 250 lost when the patient appeared apprehensive or mg, Group 3 a tablet containing diphenhydramine hydrochloride 25 mg, and Group 4 a tablet of a placebo. Allocation of the patients to WALTER NORRIS, M.D., F.F.A.R.C.S.; A. B. M. TELFER, F.F.A.R.C.S.; University Department of Anaesa treatment group was in a double-blind fashion. M.B., thetics, Royal Infirmary, Glasgow, Scotland.
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 7, 2015
The sedative effects of Mandrax, a combination of methaqualone 250 mg with diphenhydramine 25 mg, have been compared with the results produced by each of these constituents on its own, and with a placebo. Two hundred otherwise healthy gynaecological patients undergoing minor operations were studied using the scoring system previously described. Significantly better sedation was produced by Mandrax than by methaqualone or the placebo. Changes in heart rate and blood pressure were minimal after each of the drugs and postoperative nausea and vomiting rare.
875
MANDRAX IN PRE-ANAESTHETIC MEDICATION showed a rise in blood pressure or heart rate on arrival in the anaesthetic room or after application of the stimulus. Atropine was withheld from the premedication and given only with the injection of thiopentone used to induce anaesthesia. In over half the patients total forearm blood flow was measured using the technique described by Norris and Telfer (1968a). RESULTS
Side effects. Table III shows the effects of the drugs on the blood pressure and heart rate. The changes in blood pressure and heart rate from the reading taken on the day before operation to the reading taken immediately pre-operatively are small in each case and, as there is a wide variation and therefore a large standard deviation, none of the changes in blood pressure produced with each of the drugs is significantly different from any other. Changes in heart rate are similarly not significant. Postoperative sequelae. Postoperative sequelae were studied from the period when the patient returned to the ward until the change of nursing staff at 9 p.m., i.e.
Drug Mandrax Methaqualone Diphenhydramine Placebo Mandrax v. Placebo Methaqualone Mandrax v. Placebo Methaqualone
Mean score
Good (7-10)
6.90 + 2.11 6.08 + 2.09 6.28 + 2.14 5.62 ±2.45
33 22 24 18
Fair Poor (5,6) (0-4) 8 9 16 12 9 17 14 18
Mean scores Mean scores
t =2.81 t =1.95
P<0.01 P<0.06
"Goods" "Goods"
x-
P<0.01 P<0.05
x-
=7.843 =4.040
TABLE III
Changes in blood pressure and heart rate from day before operation to immediate pre-operative reading.
Drug Mandrax Methaqualone Diphenhydramine Placebo
Mean changes in blood pressure (mm Hg) Systolic Diastolic -3 -6 -8 -8
-5 -3 -3 -6
Mean changes in heart (beats/min)
+2 -2 -2 -2
TABLE IV
Postoperative sequelae within the first 9-12 hours. Drug
Emetic sequelae
Resdessness
Mandrax Methaqualone Diphenhydramine Placebo
16% 24%
22% 26% 18% 22%
20% 24%
over a period of 9-12 hours. The results are recorded in table IV. It can be seen that there is no significant difference in emetic sequelae or restlessness between any of the four combinations. Total forearm blood flow. The results of the total forearm blood flow measurements are neither recorded nor discussed in this paper since they will be reported in a subsequent publication. The performance of this test had no statistically significant effect on the sedation scores.
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 7, 2015
Sedation. The results of the trial are shown in table II. The mean score with Mandrax was significantly higher than that obtained after either methaqualone alone or after the placebo. Similarly, a higher percentage of patients showed good sedation after Mandrax than after methaqualone or the placebo. Although both the mean score and the number of patients showing good sedation was higher after Mandrax than after diphenhydramine, the differences were not statistically significant. Similarly, it was impossible to distinguish between methaqualone and diphenhydramine or the results produced by the placebo. The patients were studied during a period of 4-5 hours after administration of the tablet, the mean time between administration of the tablet and the study in the anaesthetic room being similar with each drug. As previously reported (Norris and Nisbet, 1966) adequate sedation appeared to be provided with each drug up to 5 hours after administration.
TABLE II
Sedation scores from each drug.
BRITISH JOURNAL OF ANAESTHESIA
876 DISCUSSION
It appears, therefore, that diphenhydramine potentiates the sedative properties of methaqualone when the drugs are given together without producing any of the cardiovascular side effects often associated with these antihistamine drugs.
MANDRAX ET SES CONSTITUANTS EN MEDICATION PREANESTHESIQUE SOMMAIRE
Les effets sedatifs de Mandrax, une association de methaqualone 250 mg et diphenhydramine 25 mg, ont ete compares avec les resultats obtenus a l'aide des deux constituants individuellement, et d'un placebo. Deux cent patientes gynecologiques, autrement saines, et subissant des operations mineures, ont ete etudiees en utilisant !e systeme de scores, decrit anterieurement. La sedation obtenue avec Mandrax fut significativement meilleure que celle par methaqualone ou placebo. Les modifications de la frequence cardiaque et de la pression sanguine furet minimales apres chacun de ces medicaments, et la nausee et le vomissement postoperatoires rares. MANDRAX UND SEINE KOMPONENTEN IN DER NARKOSE-PRAMEDIKATION ZUSAMMENFASSUNG
REFERENCES
Becker, B. A., and Hayes, E. E. (1958). Prolongation and potentiation of oral codeine analgesia in the rat. Proc. Soc. exp. Biol. (N.Y.), 99, 17. Cass, L. J., and Fredrik, W. S. (1958). The clinical investigation of a codeine resin complex; a long acting analgesic for oral administration. New Engl. J. Med., 259, 1108. Jolly, C. (1965). Oral premedication for operations. Lancet, 1, 42. Lear, E., Pollin, I. M., Chiron, A. E., Rousseau, L., and Aochi, O. (1958). Comparative studies of tranquillisers in anesthesia. J. Amer. med. Ass., 166, 1438.
Die sedativen Wirkungen von Mandrax — einer Kombination von 250 mg Methaqualon mit 25 mg Diphenhydramin — sind mit den Wirkungen von jedem dieser Bestandteile allein und denen eines Placebos verglichen worden. Zweihundert, anderweitig gesunde, gynakologische Patientinnen, die sich kleineren chirurgischen Eingriffen zu unterziehen hatten, wurden unter Anwendung des vorher beschriebenen Bewertungssystems untersucht. Durch Mandrax wurde eine erheblich bessere Sedierung erzielt als durch Methaqualon oder das Placebo. Veranderungen in der Herzfrequenz und dem Blutdruck waren nach jeder der verabreichten Wirkstoffe minimal, postoperative Nausea und Erbrechen traten nur selten auf.
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 7, 2015
It is not the purpose of this paper to discuss the merits or demerits of oral premedication. These have been considered in the papers previously referred to and are further dealt with in the study by Murray, Bechtold and Berman (1968). The advantage of methaqualone as opposed to other hypnotics is that it has been shown experimentally to potentiate the analgesic effect of codeine in animals (Becker and Hayes, 1958) and in man (Cass and Fredrik, 1958). Diphenhydramine, an antihistamine, has been used by Lear and his colleagues (1958) and found to be a satisfactory premedicant agent. The results of the present study suggest that when the two drugs are combined in the tablet Mandrax better sedation is produced in a higher number of patients than when methaqualone is administered alone. This improvement is obtained without producing any significant difference in blood pressure or heart rate changes following administration of the tablet. The incidence of emetic sequelae and restlessness postoperatively is similar whether the drug is given combined or when the constituents are used individually.
Murray, W. J., Bechtold, A. A., and Berman, L. (1968). Efficacy of oral psychosedative drugs for preanesthetic medication. J. Amer. med. Ass., 203, 327. Nisbet, H. I. A., and Norris, W. (1963). The objective measurement of sedation. I I : A simple scoring system. Brit. J. Anaesth., 35, 618. Norris, W., and Nisbet, H. I. A. (1964). Heptabarbitone as a pre-operative sedative. Brit. J. Anaesth., 36, 46. (1966). Oral premedication: a study of the sedative effects of Mandrax. Brit. J. Anaesth., 38, 886. Telfer, A. B. M. (1968a). The sedative properties of pentazocine (Fortral). Brit. J. Anaesth., 40, 341. (1968b). Thalamonal as a pre-operative sedative. Brit. J. Anaesth., 40, 517.
MANDRAX AND ITS CONSTITUENTS IN MEDICATION
PRE-ANAESTHETIC
BY W. NORRIS AND A. B. M. TELFER SUMMARY
Interest in the oral route for the administration of pre-anaesthetic medication continues. Following earlier studies with heptabarbitone (Norris and Nisbet, 1964) and the enthusiastic report by Jolly (1965), a trial of oral Mandrax (Roussel) as a pre-operative sedative was reported (Norris and Nisbet, 1966). The sedative effects of this drug were found to be comparable to that produced in a previous series with papaveretum 20 mg and hyoscine 0.4 mg, changes in heart rate and blood pressure being minimal, and nausea and vomiting absent pre-operatively and rare postoperatively. Mandrax is a combination of methaqualone 250 mg with diphenhydramine hydrochloride 25 mg and this study reports a comparison of Mandrax with each of its individual constituents and a placebo.
TABLE I
Mean ages, weights and time from administration of tablets until readings were taken.
Mean age
Drug Mandrax Methaqualone Diphenhydramine Placebo
(yr) 36.6 33.8 36.2 35.3
Mean weight (lb.) 135.2 134.2 134.5 128.7
Mean time from administration of drug to test (min) 141.0 153.1 153.0 148.2
The allocation was made from random tables, the code being kept in a sealed envelope in the unit but unopened until after the trial was completed. Each patient was given the unknown tablet with a small sip of water at 8 a.m., the theatre operating list being due to commence at 9 a.m. Combined subjective and objective estimates METHOD were made of the degree of sedation present. The method of study was that described in a Changes in heart rate and blood pressure from previous communication (Nisbet and Norris, the previous day's reading were recorded in the 1963) and more recently by Norris and Telfer anaesthetic room. Points were given for patients (1968a, b). All measurements were made on who appeared drowsy or relaxed in the anaesotherwise healthy patients undergoing minor thetic room and who showed either a slight fall gynaecological procedures. The patients were in blood pressure or heart rate or at least no rise divided into groups of 50, comparable in age and in these measures. Further points were awarded weight (see table I) and were given one of four when the patients did not react to a specific tablets. Group 1 were given a tablet of Mandrax, stimulus in the anaesthetic room. Points were Group 2 a tablet containing methaqualone 250 lost when the patient appeared apprehensive or mg, Group 3 a tablet containing diphenhydramine hydrochloride 25 mg, and Group 4 a tablet of a placebo. Allocation of the patients to WALTER NORRIS, M.D., F.F.A.R.C.S.; A. B. M. TELFER, F.F.A.R.C.S.; University Department of Anaesa treatment group was in a double-blind fashion. M.B., thetics, Royal Infirmary, Glasgow, Scotland.
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 7, 2015
The sedative effects of Mandrax, a combination of methaqualone 250 mg with diphenhydramine 25 mg, have been compared with the results produced by each of these constituents on its own, and with a placebo. Two hundred otherwise healthy gynaecological patients undergoing minor operations were studied using the scoring system previously described. Significantly better sedation was produced by Mandrax than by methaqualone or the placebo. Changes in heart rate and blood pressure were minimal after each of the drugs and postoperative nausea and vomiting rare.
875
MANDRAX IN PRE-ANAESTHETIC MEDICATION showed a rise in blood pressure or heart rate on arrival in the anaesthetic room or after application of the stimulus. Atropine was withheld from the premedication and given only with the injection of thiopentone used to induce anaesthesia. In over half the patients total forearm blood flow was measured using the technique described by Norris and Telfer (1968a). RESULTS
Side effects. Table III shows the effects of the drugs on the blood pressure and heart rate. The changes in blood pressure and heart rate from the reading taken on the day before operation to the reading taken immediately pre-operatively are small in each case and, as there is a wide variation and therefore a large standard deviation, none of the changes in blood pressure produced with each of the drugs is significantly different from any other. Changes in heart rate are similarly not significant. Postoperative sequelae. Postoperative sequelae were studied from the period when the patient returned to the ward until the change of nursing staff at 9 p.m., i.e.
Drug Mandrax Methaqualone Diphenhydramine Placebo Mandrax v. Placebo Methaqualone Mandrax v. Placebo Methaqualone
Mean score
Good (7-10)
6.90 + 2.11 6.08 + 2.09 6.28 + 2.14 5.62 ±2.45
33 22 24 18
Fair Poor (5,6) (0-4) 8 9 16 12 9 17 14 18
Mean scores Mean scores
t =2.81 t =1.95
P<0.01 P<0.06
"Goods" "Goods"
x-
P<0.01 P<0.05
x-
=7.843 =4.040
TABLE III
Changes in blood pressure and heart rate from day before operation to immediate pre-operative reading.
Drug Mandrax Methaqualone Diphenhydramine Placebo
Mean changes in blood pressure (mm Hg) Systolic Diastolic -3 -6 -8 -8
-5 -3 -3 -6
Mean changes in heart (beats/min)
+2 -2 -2 -2
TABLE IV
Postoperative sequelae within the first 9-12 hours. Drug
Emetic sequelae
Resdessness
Mandrax Methaqualone Diphenhydramine Placebo
16% 24%
22% 26% 18% 22%
20% 24%
over a period of 9-12 hours. The results are recorded in table IV. It can be seen that there is no significant difference in emetic sequelae or restlessness between any of the four combinations. Total forearm blood flow. The results of the total forearm blood flow measurements are neither recorded nor discussed in this paper since they will be reported in a subsequent publication. The performance of this test had no statistically significant effect on the sedation scores.
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 7, 2015
Sedation. The results of the trial are shown in table II. The mean score with Mandrax was significantly higher than that obtained after either methaqualone alone or after the placebo. Similarly, a higher percentage of patients showed good sedation after Mandrax than after methaqualone or the placebo. Although both the mean score and the number of patients showing good sedation was higher after Mandrax than after diphenhydramine, the differences were not statistically significant. Similarly, it was impossible to distinguish between methaqualone and diphenhydramine or the results produced by the placebo. The patients were studied during a period of 4-5 hours after administration of the tablet, the mean time between administration of the tablet and the study in the anaesthetic room being similar with each drug. As previously reported (Norris and Nisbet, 1966) adequate sedation appeared to be provided with each drug up to 5 hours after administration.
TABLE II
Sedation scores from each drug.
BRITISH JOURNAL OF ANAESTHESIA
876 DISCUSSION
It appears, therefore, that diphenhydramine potentiates the sedative properties of methaqualone when the drugs are given together without producing any of the cardiovascular side effects often associated with these antihistamine drugs.
MANDRAX ET SES CONSTITUANTS EN MEDICATION PREANESTHESIQUE SOMMAIRE
Les effets sedatifs de Mandrax, une association de methaqualone 250 mg et diphenhydramine 25 mg, ont ete compares avec les resultats obtenus a l'aide des deux constituants individuellement, et d'un placebo. Deux cent patientes gynecologiques, autrement saines, et subissant des operations mineures, ont ete etudiees en utilisant !e systeme de scores, decrit anterieurement. La sedation obtenue avec Mandrax fut significativement meilleure que celle par methaqualone ou placebo. Les modifications de la frequence cardiaque et de la pression sanguine furet minimales apres chacun de ces medicaments, et la nausee et le vomissement postoperatoires rares. MANDRAX UND SEINE KOMPONENTEN IN DER NARKOSE-PRAMEDIKATION ZUSAMMENFASSUNG
REFERENCES
Becker, B. A., and Hayes, E. E. (1958). Prolongation and potentiation of oral codeine analgesia in the rat. Proc. Soc. exp. Biol. (N.Y.), 99, 17. Cass, L. J., and Fredrik, W. S. (1958). The clinical investigation of a codeine resin complex; a long acting analgesic for oral administration. New Engl. J. Med., 259, 1108. Jolly, C. (1965). Oral premedication for operations. Lancet, 1, 42. Lear, E., Pollin, I. M., Chiron, A. E., Rousseau, L., and Aochi, O. (1958). Comparative studies of tranquillisers in anesthesia. J. Amer. med. Ass., 166, 1438.
Die sedativen Wirkungen von Mandrax — einer Kombination von 250 mg Methaqualon mit 25 mg Diphenhydramin — sind mit den Wirkungen von jedem dieser Bestandteile allein und denen eines Placebos verglichen worden. Zweihundert, anderweitig gesunde, gynakologische Patientinnen, die sich kleineren chirurgischen Eingriffen zu unterziehen hatten, wurden unter Anwendung des vorher beschriebenen Bewertungssystems untersucht. Durch Mandrax wurde eine erheblich bessere Sedierung erzielt als durch Methaqualon oder das Placebo. Veranderungen in der Herzfrequenz und dem Blutdruck waren nach jeder der verabreichten Wirkstoffe minimal, postoperative Nausea und Erbrechen traten nur selten auf.
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 7, 2015
It is not the purpose of this paper to discuss the merits or demerits of oral premedication. These have been considered in the papers previously referred to and are further dealt with in the study by Murray, Bechtold and Berman (1968). The advantage of methaqualone as opposed to other hypnotics is that it has been shown experimentally to potentiate the analgesic effect of codeine in animals (Becker and Hayes, 1958) and in man (Cass and Fredrik, 1958). Diphenhydramine, an antihistamine, has been used by Lear and his colleagues (1958) and found to be a satisfactory premedicant agent. The results of the present study suggest that when the two drugs are combined in the tablet Mandrax better sedation is produced in a higher number of patients than when methaqualone is administered alone. This improvement is obtained without producing any significant difference in blood pressure or heart rate changes following administration of the tablet. The incidence of emetic sequelae and restlessness postoperatively is similar whether the drug is given combined or when the constituents are used individually.
Murray, W. J., Bechtold, A. A., and Berman, L. (1968). Efficacy of oral psychosedative drugs for preanesthetic medication. J. Amer. med. Ass., 203, 327. Nisbet, H. I. A., and Norris, W. (1963). The objective measurement of sedation. I I : A simple scoring system. Brit. J. Anaesth., 35, 618. Norris, W., and Nisbet, H. I. A. (1964). Heptabarbitone as a pre-operative sedative. Brit. J. Anaesth., 36, 46. (1966). Oral premedication: a study of the sedative effects of Mandrax. Brit. J. Anaesth., 38, 886. Telfer, A. B. M. (1968a). The sedative properties of pentazocine (Fortral). Brit. J. Anaesth., 40, 341. (1968b). Thalamonal as a pre-operative sedative. Brit. J. Anaesth., 40, 517.