Br.J. Anaesth. (1975), 47, 1265
MORPHINE CONCENTRATIONS IN PLASMA AFTER INTRAMUSCULAR ADMINISTRATION L. LAITINEN, J. KANTO, M. VAPAAVUORI AND M. K. VILJANEN
SUMMARY
As a result of the development of a radioimmunoassay technique accurate measurements of the plasma concentrations of morphine have been made following its administration in clinical dosages (Spector and Parker, 1970). Despite the widespread use of morphine, its pharmacokinetics have not been studied intensively. The aim of this work was to investigate the pharmacokinetics of the drug following intramuscular administration and to compare plasma concentrations of morphine with the degree of analgesia. PATIENTS AND METHODS
Morphine hydrochloride 0.2 mg/kg body weight and hyoscine bromide 0.006 mg/kg body weight (Scopomorphin, Orion) were given i.m. as a preoperative medication to three groups of patients. Group I consisted of 11 healthy patients (mean age 23 yr (SD 5), mean weight 61 kg (SD 8)) who were scheduled for therapeutic abortion by hysterotomy. Plasma morphine concentration was measured at 25-140 min after the administration of the drug immediately before the induction of general anaesthesia. In Group II there were 31 healthy patients (mean age 25 yr (SD 5), mean weight 61 kg (SD 6)) scheduled for therapeutic abortion by dilatation and curettage. There were 13 women who were pregnant for the first time and 18 women who had 1-3 previous pregnancies. Plasma morphine concentrations were LEENA LAITINEN, M.SC, JUSSI KANTO, M.D., Department of
Pharmacology; MATTI VAPAAVUORI, M.D., Department of Anaesthesiology; MATTI K. VILJANEN, M.D., Department of
Medical Microbiology, Turku University, Turku, Finland. Correspondence to L. L.
measured at 20-105 min after the drug injection immediately before dilatation of the cervix in order to insert the laminaria into the cervical canal one day before uterine curettage (always following a Hegar No. 7 dilatator). The plasma concentration was compared with the degree of pain relief. Analgesia was assessed by means of a simple scoring system: 3—the patient did not move or complain; 2— the patient moved or complained; 1—the patient moved and complained when dilatation was performed. Group III consisted of five healthy patients (mean age 27 yr (SD 7), mean weight 58 kg (SD 5)) who were scheduled for therapeutic abortion. Plasma morphine concentrations were measured for 24 hr (fig. 2) after the administration of the drug during the application of the laminaria one day before uterine curettage. No drugs other than hyoscine were used in addition. Plasma morphine concentrations were determined by the Abuscreen-TM radioimmunoassay for morphine (3H) (Chemical Research Department, Hoffmann-LaRoche Inc.) (using 7,8-3H-dihydromorphine with a specific activity of 2.5 mCi/mg). The limit of the method in plasma is 10 ng/ml and it measures both free and glucuronide-conjugated morphine. The reproducibility of the method is + 10%. RESULTS
Individual plasma morphine concentrations for patients in groups I and II are shown in figure 1. The highest plasma concentrations were found about 1 hr after the i.m. administration of morphine. At this time the plasma concentrations varied over a
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 12, 2015
Plasma morphine concentrations were measured by a radioimmunoassay technique following the intramuscular administration of morphine 0.2 mg/kg body weight as a preoperative medication. The highest plasma concentrations were obtained about one hour after the administration of the drug and there was a sevenfold variation in these concentrations between individuals. For 24 hr following a single intramuscular injection, there were measurable quantities of morphine or its metabolites in the plasma. In healthy patients who were undergoing a therapeutic abortion, there was no correlation between pain relief and the plasma concentration of morphine.
BRITISH JOURNAL OF ANAESTHESIA
1266
variations in the plasma concentrations of diazepam, lignocaine and digoxin have been observed after i.m. administration (Ryden and Werko, 1971; Kanto et al., 1974; Steiness, Svendsen and Rasmussen, 1974). In 300 the present study a similar wide variation in plasma drug concentrations was found in different individuals. 250 x •• One hour after an i.m. injection, the plasma morphine 200 .• * concentrations varied sevenfold. Variations in the .XXX 150 muscular circulation, the locus of injection, and the pH of the site of injection may have affected the rate 100 * •• * of absorption of morphine. 50 Following the peak plasma concentrations obtained at 0.5-2 hr in group III, the values decreased rela2 hours 3 tively rapidly up to 6£-8 hr. Twenty four hours after FIG. 1. Individual plasma morphine concentrations after the injection only small amounts of morphine or its the i.m. injection of morphine hydrochloride 0.2 mg/kg metabolites were detectable. However, toxicity resand hyoscine 0.006 mg/kg body weight. * = Group I, results suiting from accumulation of these compounds in 25-140 min after the drug administration. • = Group II, blood may occur with repeated injections of morphine results 20-105 min after the drug administration. (Spector and Vesell, 1971). Morphine is metabolized mainly by conjugation as sevenfold range. The plasma morphine concentra- glucuronide. N-demethylation is only a minor route tions for patients in group III are shown in figure 2. of metabolism (Brunk and Delle, 1974). Our method The peak plasma concentrations were found at measures both free and conjugated morphine and 0.5-2 hr. Thereafter the concentrations decreased probably the N-demethylated metabolites also. Morrapidly. At 24 hr only small or unmeasurable phine and hyoscine have synergistic hypnotic and amounts of morphine were present in the plasma. narcotic actions. For these reasons it is understandFor both the primiparous and multiparous patients able that no relationship was observed between plasma in group II, there was no correlation between morphine concentration and pain relief in this study. plasma morphine concentration and pain relief during A better correlation may be possible between the cervical dilatation (regression analysis: b = 0.000348 plasma free morphine concentration and the analgesic activity in man since, following a single dose, the and 0.000325 respectively). plasma free morphine concentration may reflect better the drug concentration in the brain (Way, 1968; Brunk and Delle, 1974). In animal studies a morphine ng/ml plasma close relationship has been observed between the 200concentration of morphine in the brain and the degree of analgesia (Paalzow and Paalzow, 1971). Our data suggest that for intramuscular medication before operation, morphine should be given about one hour before the induction of general anaesthesia. morphine ng/ml plasma • 350
hours REFERENCES
FIG. 2. Individual plasma morphine concentrations in five patients in Group III. Morphine 0.2 mg/kg and hyoscine 0.006 mg/kg body weight.
DISCUSSION
The rate of absorption of a drug from an intramuscular site of injection varies considerably. Large
Brunk, S. F., and Delle, M. (1974). Morphine metabolism in man. Clin. Pharmacol. Ther., 16, 51. Kanto, J., Kangas, L., Sellman, R., and Syvalahti, E. (1974). Tensopamin ja sen metaboliittien pitoisuus plasmassa erilaisten annosten ja antotapojen jalkeen. Ladkeuutiset, 1, 17. Paalzow, L., and Paalzow, G. (1971). Blood and brain concentrations of morphine and its relation to the analgesic activity in mice. Acta Pharm. Suec, 8, 329.
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 12, 2015
8
PLASMA MORPHINE CONCENTRATIONS Ryden, L., and Werko, L. (1971). Arytmi som dodsursak vid akut hjartinfarktprofylaktiska atgarder. Ldkartidningen, 68 (Suppl. II), 53. Spector, S.j and Parker, C. W. (1970). Morphine: radioimmunoassay. Science, 168, 1347. Spector, S., Vesell, E. S. (1971). Disposition of morphine in man. Science, VIA, 421. Steiness, E.3 Svendsen, O., and Rasmussen, F. (1974). Plasma digoxin after parenteral administration. Local reaction after intramuscular injection. Clin. Pharmacol. Ther. 16, 430. Way, E. L. (1968). Distribution and metabolism of morphine and its surrogates. Res. Publ. Assoc. Res. Nerv. Mem. Dis., 46, 13.
RESUME
On a mesure les concentrations de morphine par une technique de radio-immunologie apres administration intramusculaire de morphine—a raison de 0,2 mg/kg de poids du corps—comme medication preoperatoire. Les plus fortes concentrations de plasma ont ete obtenues environ une heure apres radministration de la drogue et on a constate des variations dans ces concentrations se multipliant jusqu'a sept fois suivant les individus. Pendant 24 h, apres une seule injection intramusculaire, il y a eu des quantity measurables de morphine ou de ses metabolites dans le plasma. Sur des operees en bonne sante, qui 6taient la pour subir un avortement therapeutique, il n'y a eu aucune correlation entre le soulagement de la souffrance et la concentration de morphine dans le plasma.
MORPHIUMKONZENTRATIONEN IN PLASMA NACH INTRAMUSKULARER VERABREICHUNG ZUSAMMENFASSUNG
Plasma-Morphiumkonzentrationen wurden durch eine Radioimmunitats-Prufmethode gemessen, und zwar nach intramuskularer Verabreichung von Morphium 0,2 mg/kg Kdrpergewicht. Die hochsten Plasmakonzentrationen von Morphium ergaben sich etwa 1 Stunde nach Verabreichung der Droge, und zwischen verschiedenen Individuen ergaben sich in diesen Konzentrationen siebenfache Veranderungen. Vierundzwanzig Stunden lang nach einer einzigen intramuskularen Injektion waren messbare Mengen von Morphium oder dessen Metaboliten im Plasma vorhenden. Bei gesunden Patientinnen, die sich einer therapeutischen Schwangerschaftsunterbrechung unterzogen, gab es keine Korrelation zwischen Schmerzlinderung und Plasma-Morphiumkonzentrationen. CONCENTRACIONES DE MORFINA EN EL PLASMA, DESPUES DE ADMINISTRACION INTRAMUSCULAR SUMARIO
Se midieron las concentraciones de morfina en plasma siguiendo una tecnica de ensayo de minimization radial despues de la administration intramuscular de morfina 0,2 mg/kg peso del cuerpo coma una medication preoperativa. Se obtuvieron las maximas concentraciones de plasma una hora aproximadamente despues de la administration de la droga y hubo una variacion de siete divisiones entre individuos en dichas concentraciones. Durante las 24 horas que siguieron a una inyeccion intramuscular simple, hubo cantidades de morfina o sus rendimientos en la plasma. En pacientes sanos que estaban sufriendo un arborto terapeutico, no hubo correlacidn entre el alivio del dolor y la concentration de plasma de morfina.
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 12, 2015
CONCENTRATIONS DE MORPHINE DANS LE PLASMA APRES ADMINISTRATION INTRAMUSCULAIRE
1267
MORPHINE CONCENTRATIONS IN PLASMA AFTER INTRAMUSCULAR ADMINISTRATION L. LAITINEN, J. KANTO, M. VAPAAVUORI AND M. K. VILJANEN
SUMMARY
As a result of the development of a radioimmunoassay technique accurate measurements of the plasma concentrations of morphine have been made following its administration in clinical dosages (Spector and Parker, 1970). Despite the widespread use of morphine, its pharmacokinetics have not been studied intensively. The aim of this work was to investigate the pharmacokinetics of the drug following intramuscular administration and to compare plasma concentrations of morphine with the degree of analgesia. PATIENTS AND METHODS
Morphine hydrochloride 0.2 mg/kg body weight and hyoscine bromide 0.006 mg/kg body weight (Scopomorphin, Orion) were given i.m. as a preoperative medication to three groups of patients. Group I consisted of 11 healthy patients (mean age 23 yr (SD 5), mean weight 61 kg (SD 8)) who were scheduled for therapeutic abortion by hysterotomy. Plasma morphine concentration was measured at 25-140 min after the administration of the drug immediately before the induction of general anaesthesia. In Group II there were 31 healthy patients (mean age 25 yr (SD 5), mean weight 61 kg (SD 6)) scheduled for therapeutic abortion by dilatation and curettage. There were 13 women who were pregnant for the first time and 18 women who had 1-3 previous pregnancies. Plasma morphine concentrations were LEENA LAITINEN, M.SC, JUSSI KANTO, M.D., Department of
Pharmacology; MATTI VAPAAVUORI, M.D., Department of Anaesthesiology; MATTI K. VILJANEN, M.D., Department of
Medical Microbiology, Turku University, Turku, Finland. Correspondence to L. L.
measured at 20-105 min after the drug injection immediately before dilatation of the cervix in order to insert the laminaria into the cervical canal one day before uterine curettage (always following a Hegar No. 7 dilatator). The plasma concentration was compared with the degree of pain relief. Analgesia was assessed by means of a simple scoring system: 3—the patient did not move or complain; 2— the patient moved or complained; 1—the patient moved and complained when dilatation was performed. Group III consisted of five healthy patients (mean age 27 yr (SD 7), mean weight 58 kg (SD 5)) who were scheduled for therapeutic abortion. Plasma morphine concentrations were measured for 24 hr (fig. 2) after the administration of the drug during the application of the laminaria one day before uterine curettage. No drugs other than hyoscine were used in addition. Plasma morphine concentrations were determined by the Abuscreen-TM radioimmunoassay for morphine (3H) (Chemical Research Department, Hoffmann-LaRoche Inc.) (using 7,8-3H-dihydromorphine with a specific activity of 2.5 mCi/mg). The limit of the method in plasma is 10 ng/ml and it measures both free and glucuronide-conjugated morphine. The reproducibility of the method is + 10%. RESULTS
Individual plasma morphine concentrations for patients in groups I and II are shown in figure 1. The highest plasma concentrations were found about 1 hr after the i.m. administration of morphine. At this time the plasma concentrations varied over a
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 12, 2015
Plasma morphine concentrations were measured by a radioimmunoassay technique following the intramuscular administration of morphine 0.2 mg/kg body weight as a preoperative medication. The highest plasma concentrations were obtained about one hour after the administration of the drug and there was a sevenfold variation in these concentrations between individuals. For 24 hr following a single intramuscular injection, there were measurable quantities of morphine or its metabolites in the plasma. In healthy patients who were undergoing a therapeutic abortion, there was no correlation between pain relief and the plasma concentration of morphine.
BRITISH JOURNAL OF ANAESTHESIA
1266
variations in the plasma concentrations of diazepam, lignocaine and digoxin have been observed after i.m. administration (Ryden and Werko, 1971; Kanto et al., 1974; Steiness, Svendsen and Rasmussen, 1974). In 300 the present study a similar wide variation in plasma drug concentrations was found in different individuals. 250 x •• One hour after an i.m. injection, the plasma morphine 200 .• * concentrations varied sevenfold. Variations in the .XXX 150 muscular circulation, the locus of injection, and the pH of the site of injection may have affected the rate 100 * •• * of absorption of morphine. 50 Following the peak plasma concentrations obtained at 0.5-2 hr in group III, the values decreased rela2 hours 3 tively rapidly up to 6£-8 hr. Twenty four hours after FIG. 1. Individual plasma morphine concentrations after the injection only small amounts of morphine or its the i.m. injection of morphine hydrochloride 0.2 mg/kg metabolites were detectable. However, toxicity resand hyoscine 0.006 mg/kg body weight. * = Group I, results suiting from accumulation of these compounds in 25-140 min after the drug administration. • = Group II, blood may occur with repeated injections of morphine results 20-105 min after the drug administration. (Spector and Vesell, 1971). Morphine is metabolized mainly by conjugation as sevenfold range. The plasma morphine concentra- glucuronide. N-demethylation is only a minor route tions for patients in group III are shown in figure 2. of metabolism (Brunk and Delle, 1974). Our method The peak plasma concentrations were found at measures both free and conjugated morphine and 0.5-2 hr. Thereafter the concentrations decreased probably the N-demethylated metabolites also. Morrapidly. At 24 hr only small or unmeasurable phine and hyoscine have synergistic hypnotic and amounts of morphine were present in the plasma. narcotic actions. For these reasons it is understandFor both the primiparous and multiparous patients able that no relationship was observed between plasma in group II, there was no correlation between morphine concentration and pain relief in this study. plasma morphine concentration and pain relief during A better correlation may be possible between the cervical dilatation (regression analysis: b = 0.000348 plasma free morphine concentration and the analgesic activity in man since, following a single dose, the and 0.000325 respectively). plasma free morphine concentration may reflect better the drug concentration in the brain (Way, 1968; Brunk and Delle, 1974). In animal studies a morphine ng/ml plasma close relationship has been observed between the 200concentration of morphine in the brain and the degree of analgesia (Paalzow and Paalzow, 1971). Our data suggest that for intramuscular medication before operation, morphine should be given about one hour before the induction of general anaesthesia. morphine ng/ml plasma • 350
hours REFERENCES
FIG. 2. Individual plasma morphine concentrations in five patients in Group III. Morphine 0.2 mg/kg and hyoscine 0.006 mg/kg body weight.
DISCUSSION
The rate of absorption of a drug from an intramuscular site of injection varies considerably. Large
Brunk, S. F., and Delle, M. (1974). Morphine metabolism in man. Clin. Pharmacol. Ther., 16, 51. Kanto, J., Kangas, L., Sellman, R., and Syvalahti, E. (1974). Tensopamin ja sen metaboliittien pitoisuus plasmassa erilaisten annosten ja antotapojen jalkeen. Ladkeuutiset, 1, 17. Paalzow, L., and Paalzow, G. (1971). Blood and brain concentrations of morphine and its relation to the analgesic activity in mice. Acta Pharm. Suec, 8, 329.
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 12, 2015
8
PLASMA MORPHINE CONCENTRATIONS Ryden, L., and Werko, L. (1971). Arytmi som dodsursak vid akut hjartinfarktprofylaktiska atgarder. Ldkartidningen, 68 (Suppl. II), 53. Spector, S.j and Parker, C. W. (1970). Morphine: radioimmunoassay. Science, 168, 1347. Spector, S., Vesell, E. S. (1971). Disposition of morphine in man. Science, VIA, 421. Steiness, E.3 Svendsen, O., and Rasmussen, F. (1974). Plasma digoxin after parenteral administration. Local reaction after intramuscular injection. Clin. Pharmacol. Ther. 16, 430. Way, E. L. (1968). Distribution and metabolism of morphine and its surrogates. Res. Publ. Assoc. Res. Nerv. Mem. Dis., 46, 13.
RESUME
On a mesure les concentrations de morphine par une technique de radio-immunologie apres administration intramusculaire de morphine—a raison de 0,2 mg/kg de poids du corps—comme medication preoperatoire. Les plus fortes concentrations de plasma ont ete obtenues environ une heure apres radministration de la drogue et on a constate des variations dans ces concentrations se multipliant jusqu'a sept fois suivant les individus. Pendant 24 h, apres une seule injection intramusculaire, il y a eu des quantity measurables de morphine ou de ses metabolites dans le plasma. Sur des operees en bonne sante, qui 6taient la pour subir un avortement therapeutique, il n'y a eu aucune correlation entre le soulagement de la souffrance et la concentration de morphine dans le plasma.
MORPHIUMKONZENTRATIONEN IN PLASMA NACH INTRAMUSKULARER VERABREICHUNG ZUSAMMENFASSUNG
Plasma-Morphiumkonzentrationen wurden durch eine Radioimmunitats-Prufmethode gemessen, und zwar nach intramuskularer Verabreichung von Morphium 0,2 mg/kg Kdrpergewicht. Die hochsten Plasmakonzentrationen von Morphium ergaben sich etwa 1 Stunde nach Verabreichung der Droge, und zwischen verschiedenen Individuen ergaben sich in diesen Konzentrationen siebenfache Veranderungen. Vierundzwanzig Stunden lang nach einer einzigen intramuskularen Injektion waren messbare Mengen von Morphium oder dessen Metaboliten im Plasma vorhenden. Bei gesunden Patientinnen, die sich einer therapeutischen Schwangerschaftsunterbrechung unterzogen, gab es keine Korrelation zwischen Schmerzlinderung und Plasma-Morphiumkonzentrationen. CONCENTRACIONES DE MORFINA EN EL PLASMA, DESPUES DE ADMINISTRACION INTRAMUSCULAR SUMARIO
Se midieron las concentraciones de morfina en plasma siguiendo una tecnica de ensayo de minimization radial despues de la administration intramuscular de morfina 0,2 mg/kg peso del cuerpo coma una medication preoperativa. Se obtuvieron las maximas concentraciones de plasma una hora aproximadamente despues de la administration de la droga y hubo una variacion de siete divisiones entre individuos en dichas concentraciones. Durante las 24 horas que siguieron a una inyeccion intramuscular simple, hubo cantidades de morfina o sus rendimientos en la plasma. En pacientes sanos que estaban sufriendo un arborto terapeutico, no hubo correlacidn entre el alivio del dolor y la concentration de plasma de morfina.
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 12, 2015
CONCENTRATIONS DE MORPHINE DANS LE PLASMA APRES ADMINISTRATION INTRAMUSCULAIRE
1267
