Br. J. clin. Pharmac. (1992), 34, 431-433
Plasma morphine-3-glucuronide, morphine-6-glucuronide and morphine concentrations in patients receiving long-term epidural morphine J. J. SCHNEIDER', P. J. RAVENSCROFT', J. D. CAVENAGH2, A. M. BROWN' & J. P. BRADLEY3 'Department of Clinical Pharmacology, Princess Alexandra Hospital, Woolloongabba, Brisbane, QLD 4102, 2HospiceHome Care Unit, Mt. Olivet Hospital, Kangaroo Point, Brisbane, QLD 4169 and 3Pain Clinic, Princess Alexandra Hospital, Woolloongabba, Brisbane, QLD 4102, Australia
Plasma morphine concentrations were measured in five cancer patients receiving longterm epidural morphine administration. Peak concentrations were observed within 1 h of dosage and concentrations then declined biexponentially. Plasma morphine-3glucuronide (M3G) and morphine-6-glucuronide (M6G) concentrations were measured in two patients and plasma M3G concentrations were observed to be much higher than plasma M6G and morphine concentrations. Peak plasma M6G concentrations occurred within 1.0 h of dosing and plasma M6G concentrations then remained higher than plasma morphine concentrations.
Keywords
morphine
morphine-6-glucuronide
morphine-3-glucuronide
epidural
Introduction Following epidural administration, some morphine penetrates the dura to reach the cerebrospinal fluid (CSF) and act on opioid receptors in the spinal cord. Max et al. (1985) found less than 1% of a single epidural dose of morphine in the CSF. In the absence of any local metabolism all of the dose will eventually reach the systemic circulation. The major metabolites of morphine are morphine-3glucuronide (M3G) and morphine-6-glucuronide (M6G). While M6G has been shown to have analgesic activity (Osborne et al., 1988), animal studies suggest that M3G has no analgesic effect (Shimomura et al., 1971) and may antagonise the analgesic effect of M6G and morphine (Smith et al., 1990). The aim of this study was to document the plasma M3G, M6G and morphine concentrations achieved in patients receiving long-term epidural morphine.
prior to the day of study. All patients had serum creatinine concentrations in the reference range (0.06-0.11 mmol l-1). Written, informed consent was obtained from the patients prior to the study which was approved by the Princess Alexandra Hospital Ethics Committee. Dosage regimens and sample collection
Patients 1, 2 and 5 were studied on two occasions and patients 3 and 4 on one occasion. Patient 1 received 10 mg morphine sulphate twice daily on the first study day and 25 mg twice daily on the second study day. Patient 2 received 30 mg twice daily on the first study day and 45 mg twice daily on the second study day and patient 5 received 10 mg four times a day on the first study day and 30 mg four times a day on the second study day. Patient 3 received 15 mg twice daily and patient 4 received 45 mg three times daily. Time between study days for patients 1, 2 and 5 were 5, 16 and 2 weeks respectively. Blood samples (5 ml) were collected pre-dose, then at 5, 10, 20, 30, 60 min, 2, 4, 6 and 8 h after the dose. Eight hour samples were not collected from patients 1 and 2 receiving 25 mg twice a day and 45 mg twice a day, respectively, since patient 1 required the next dose to be administered earlier because of breakthrough pain and patient 2 was scheduled for surgery prior to the end of sampling. Blood samples were collected up to 6 h in patient 5 since this patient was receiving a four times a
Method Patients
Five male cancer patients requiring opioid analgesia for relief of chronic severe pain were studied. They received morphine sulphate through an epidural catheter. No other opioid analgesics were administered and patients were maintained on the dosage regimen for 3 to 4 days Correspondence: Dr J. J. Schneider, Department of Clinical Pharmacology, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, QLD 4102, Australia
431
432
J. J. Schneider et al.
day dosing regimen. Patient 4 had a dosing regimen of three times a day but the intervals between doses were not equal and this patient was studied during a 6 h interval. Blood was collected through a cannula inserted in a forearm vein. Samples were centrifuged (2000 rev min-1, 10 min) after collection and the plasma was stored at -20° C until assay.
a 2000
1500
10009 500
Analytical method 0
Samples from patients 1, 2 and 3 were assayed for morphine using an h.p.l.c.-fluorescence detection method (Schneider & Ravenscroft, 1989). Samples obtained from patients 4 and 5 were assayed for M3G, M6G and morphine using a modification of a previously published h.p.l.c. method (Joel et al., 1988). Minimum quantifiable concentrations of M3G, M6G and morphine were 40, 10 and 5 ng ml-' respectively. Between and within day coefficients of variation at these concentrations were less than 10%.
1
2
3
4
5
1
2
3
4
5
1
2
6
b
E
0 C cJ 0 0 CU
ECl
350 r 300 250 200 150 100 50 A -dl
-A
v
0
CU
6
c
Results
Plasma morphine concentrations in the five patients are shown in Figure 1 and 2. Peak concentrations occurred 160 F
a
140 120 100 80 60 40 20
1400 1200 1000 800 600 400 200 nI
LI .F
0
rM u'
1
0
2
3
4
5
7
6
4 3 5 6 Time (h) Figure 2 Plasma M3G (0), M6G (A) and morphine (A) concentration plots for a) patient 4 receiving 45 mg morphine sulphate three times daily, b) patient 5 receiving 10 mg morphine sulphate four times daily and c) patient 5 receiving 30 mg morphine sulphate four times daily.
8
b
E
250
within 1 h of dosage and the concentrations then declined biexponentially in all patients. Peak plasma morphine concentrations observed in these patients ranged from 72 to 474 ng ml-'. When the dose of morphine was increased from 10 to 25 mg in patient 1, an increase in plasma morphine concentrations was observed. The area under the curve of plasma morphine concentration vs time from 0 to 6 h for this patient, calculated using the linear trapezoidal rule, increased from 113 to 191 ng ml-1 h. In patient 2, an increase in dose did not result in an increase in plasma morphine concentrations. Plasma M3G, M6G and morphine concentrations observed in patients 4 and 5 are shown in Figure 2. Plasma M3G concentrations were much higher than plasma M6G and morphine concentrations. Peak plasma
CF c
200
0
150 Q)
0
100
C cL
0 0
ECl
co
50 04a 250
1
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4
5
6
7
8
c
200
150 100
50 2
3
4
5
6
7
8
Time (h)
Figure 1 Plasma morphine concentratio in a) patient 1 receiving 10 mg morphine sulphate twice daily (-) and 25 mg twice daily (V), b) patient 2 receiving 30Img morphine sulphate twice daily (A) and 45 mg twice d aily (m) and c) patient 3 receiving 15 mg morphine sulphate twicce daily (O). ins
M3G and M6G concentrations were achieved within 1 h after morphine administration. Plasma M3G and M6G concentrations then remained higher than plasma morphine concentrations. Molar ratios of the area under the curve up to the last sampling time (AUC) for
M3G:M6G, M3G:morphine and M6G:morphine for these two patients ranged from 6.4 to 11.6, 7.6 to 12.1 and 1.2 to 1.6, respectively. Peak plasma morphine, M3G and M6G concentrations and the AUC for morphine
and metabolites (AUC) all increased in patient 5 when
Short report the dose of morphine sulphate was increased from 10 to 30 mg. The AUC for morphine, M3G and M6G increased from 74 to 358 ng ml-' h, 184 to 822 ng ml-' h and from 1364 to 4886 ng ml-' h, respectively.
Discussion In this study, peak plasma morphine concentrations after epidural administration of doses ranging from 10 to 45 mg were, in most cases, higher than the reported peak plasma morphine concentrations (range: 11.5 to 118 ng ml-') observed by Sawe et al. (1983) in cancer patients receiving 20 to 40 mg of oral morphine every 4-6 h. These data indicate that in cancer patients receiving epidural morphine, systemically absorbed morphine may contribute to analgesia. The rapid time to peak plasma morphine concentration observed in these patients is consistent with observations after single epidural doses (Max et al., 1985; Weddel et al., 1981). In the three patients whose doses were changed, two (patients 1 and 5) showed an increase in plasma morphine
433
concentrations when the dose was increased while one (patient 2) showed little change. Patient 2 was studied on two occasions 16 weeks apart and there may have been some catheter blockage or fibrosis at the site of needle placement. The AUC molar ratios of M3G:morphine (range: 7.6 to 12.1) and M6G:morphine (range: 1.2 to 1.6) were in most cases lower than those observed by Sawe (1986) in patients receiving oral morphine chronically (M3G: morphine, range: 9.0 to 43.0; M6G:morphine, range: 1.0 to 6.1). This confirms that epidural administration avoids to some extent the extensive first-pass metabolism of oral morphine. Nevertheless, the plasma concentrations of M3G and M6G were considerably higher than those of morphine itself. These metabolites may play an important role since the presence of high systemic concentrations of M3G may antagonise the analgesic effect of morphine and M6G (Smith et al., 1990) and, on the other hand, high plasma M6G concentrations may contribute to analgesic effect. This work was supported by a grant from the Queensland Cancer Fund.
References Joel, S. P., Osborne, R. J. & Slevin, M. L. (1988). An improved method for the simultaneous determination of morphine and its principal glucuronide metabolites. J. Chromatogr., 430, 394-399. Max, M. B., Inturrisi, C. E., Kaiko, R. F., Grabinski, P. Y., Li, C. H. & Foley, K. M. (1985). Epidural and intrathecal opiates: cerebrospinal fluid and plasma profiles in patients with chronic cancer pain. Clin. Pharmac. Ther., 38, 631641. Osborne, R., Joel, S., Trew, D. & Slevin, M. (1988). Analgesic activity of morphine-6-glucuronide. Lancet, i, 828. Sawe, J. (1986). Morphine and its 3- and 6-glucuronides in plasma and urine during chronic oral administration in cancer patients. In Advances in Pain Research and Therapy, eds Foley K. M. & Inturrisi C. E., pp. 45-55. Vol 8. New York: Raven Press. Sawe, J., Dahlstrom, B. & Rane, A. (1983). Steady-state kinetic and analgesic effect of oral morphine in cancer
patients. Eur. J. clin. Pharmac., 24, 537-542. Schneider, J. J. & Ravenscroft, P. J. (1989). Determination of morphine in plasma by high performance liquid chromatography with fluorescence detection. J. Chromatogr., 497, 326-329. Shimomura, K., Kamata, O., Ueki, S., Ida, S., Oguri, K., Yoshimura, H. & Tsukamoto, H. (1971). Analgesic effects of morphine-glucuronides. Tohoku J. exp. Med., 105, 4552. Smith, M. T., Watt, J. A. & Cramond, T. (1990). Morphine3-glucuronide-a potent antagonist of morphine analgesia. Life Sci., 47, 579-585. Weddel, S. J. & Ritter, R. R. (1981). Serum levels following epidural administration of morphine and correlation with relief of postsurgical pain. Anesthesiol., 54, 210-214.
(Received 28 February 1992, accepted 3 June 1992)
Plasma morphine-3-glucuronide, morphine-6-glucuronide and morphine concentrations in patients receiving long-term epidural morphine J. J. SCHNEIDER', P. J. RAVENSCROFT', J. D. CAVENAGH2, A. M. BROWN' & J. P. BRADLEY3 'Department of Clinical Pharmacology, Princess Alexandra Hospital, Woolloongabba, Brisbane, QLD 4102, 2HospiceHome Care Unit, Mt. Olivet Hospital, Kangaroo Point, Brisbane, QLD 4169 and 3Pain Clinic, Princess Alexandra Hospital, Woolloongabba, Brisbane, QLD 4102, Australia
Plasma morphine concentrations were measured in five cancer patients receiving longterm epidural morphine administration. Peak concentrations were observed within 1 h of dosage and concentrations then declined biexponentially. Plasma morphine-3glucuronide (M3G) and morphine-6-glucuronide (M6G) concentrations were measured in two patients and plasma M3G concentrations were observed to be much higher than plasma M6G and morphine concentrations. Peak plasma M6G concentrations occurred within 1.0 h of dosing and plasma M6G concentrations then remained higher than plasma morphine concentrations.
Keywords
morphine
morphine-6-glucuronide
morphine-3-glucuronide
epidural
Introduction Following epidural administration, some morphine penetrates the dura to reach the cerebrospinal fluid (CSF) and act on opioid receptors in the spinal cord. Max et al. (1985) found less than 1% of a single epidural dose of morphine in the CSF. In the absence of any local metabolism all of the dose will eventually reach the systemic circulation. The major metabolites of morphine are morphine-3glucuronide (M3G) and morphine-6-glucuronide (M6G). While M6G has been shown to have analgesic activity (Osborne et al., 1988), animal studies suggest that M3G has no analgesic effect (Shimomura et al., 1971) and may antagonise the analgesic effect of M6G and morphine (Smith et al., 1990). The aim of this study was to document the plasma M3G, M6G and morphine concentrations achieved in patients receiving long-term epidural morphine.
prior to the day of study. All patients had serum creatinine concentrations in the reference range (0.06-0.11 mmol l-1). Written, informed consent was obtained from the patients prior to the study which was approved by the Princess Alexandra Hospital Ethics Committee. Dosage regimens and sample collection
Patients 1, 2 and 5 were studied on two occasions and patients 3 and 4 on one occasion. Patient 1 received 10 mg morphine sulphate twice daily on the first study day and 25 mg twice daily on the second study day. Patient 2 received 30 mg twice daily on the first study day and 45 mg twice daily on the second study day and patient 5 received 10 mg four times a day on the first study day and 30 mg four times a day on the second study day. Patient 3 received 15 mg twice daily and patient 4 received 45 mg three times daily. Time between study days for patients 1, 2 and 5 were 5, 16 and 2 weeks respectively. Blood samples (5 ml) were collected pre-dose, then at 5, 10, 20, 30, 60 min, 2, 4, 6 and 8 h after the dose. Eight hour samples were not collected from patients 1 and 2 receiving 25 mg twice a day and 45 mg twice a day, respectively, since patient 1 required the next dose to be administered earlier because of breakthrough pain and patient 2 was scheduled for surgery prior to the end of sampling. Blood samples were collected up to 6 h in patient 5 since this patient was receiving a four times a
Method Patients
Five male cancer patients requiring opioid analgesia for relief of chronic severe pain were studied. They received morphine sulphate through an epidural catheter. No other opioid analgesics were administered and patients were maintained on the dosage regimen for 3 to 4 days Correspondence: Dr J. J. Schneider, Department of Clinical Pharmacology, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, QLD 4102, Australia
431
432
J. J. Schneider et al.
day dosing regimen. Patient 4 had a dosing regimen of three times a day but the intervals between doses were not equal and this patient was studied during a 6 h interval. Blood was collected through a cannula inserted in a forearm vein. Samples were centrifuged (2000 rev min-1, 10 min) after collection and the plasma was stored at -20° C until assay.
a 2000
1500
10009 500
Analytical method 0
Samples from patients 1, 2 and 3 were assayed for morphine using an h.p.l.c.-fluorescence detection method (Schneider & Ravenscroft, 1989). Samples obtained from patients 4 and 5 were assayed for M3G, M6G and morphine using a modification of a previously published h.p.l.c. method (Joel et al., 1988). Minimum quantifiable concentrations of M3G, M6G and morphine were 40, 10 and 5 ng ml-' respectively. Between and within day coefficients of variation at these concentrations were less than 10%.
1
2
3
4
5
1
2
3
4
5
1
2
6
b
E
0 C cJ 0 0 CU
ECl
350 r 300 250 200 150 100 50 A -dl
-A
v
0
CU
6
c
Results
Plasma morphine concentrations in the five patients are shown in Figure 1 and 2. Peak concentrations occurred 160 F
a
140 120 100 80 60 40 20
1400 1200 1000 800 600 400 200 nI
LI .F
0
rM u'
1
0
2
3
4
5
7
6
4 3 5 6 Time (h) Figure 2 Plasma M3G (0), M6G (A) and morphine (A) concentration plots for a) patient 4 receiving 45 mg morphine sulphate three times daily, b) patient 5 receiving 10 mg morphine sulphate four times daily and c) patient 5 receiving 30 mg morphine sulphate four times daily.
8
b
E
250
within 1 h of dosage and the concentrations then declined biexponentially in all patients. Peak plasma morphine concentrations observed in these patients ranged from 72 to 474 ng ml-'. When the dose of morphine was increased from 10 to 25 mg in patient 1, an increase in plasma morphine concentrations was observed. The area under the curve of plasma morphine concentration vs time from 0 to 6 h for this patient, calculated using the linear trapezoidal rule, increased from 113 to 191 ng ml-1 h. In patient 2, an increase in dose did not result in an increase in plasma morphine concentrations. Plasma M3G, M6G and morphine concentrations observed in patients 4 and 5 are shown in Figure 2. Plasma M3G concentrations were much higher than plasma M6G and morphine concentrations. Peak plasma
CF c
200
0
150 Q)
0
100
C cL
0 0
ECl
co
50 04a 250
1
2
3
4
5
6
7
8
c
200
150 100
50 2
3
4
5
6
7
8
Time (h)
Figure 1 Plasma morphine concentratio in a) patient 1 receiving 10 mg morphine sulphate twice daily (-) and 25 mg twice daily (V), b) patient 2 receiving 30Img morphine sulphate twice daily (A) and 45 mg twice d aily (m) and c) patient 3 receiving 15 mg morphine sulphate twicce daily (O). ins
M3G and M6G concentrations were achieved within 1 h after morphine administration. Plasma M3G and M6G concentrations then remained higher than plasma morphine concentrations. Molar ratios of the area under the curve up to the last sampling time (AUC) for
M3G:M6G, M3G:morphine and M6G:morphine for these two patients ranged from 6.4 to 11.6, 7.6 to 12.1 and 1.2 to 1.6, respectively. Peak plasma morphine, M3G and M6G concentrations and the AUC for morphine
and metabolites (AUC) all increased in patient 5 when
Short report the dose of morphine sulphate was increased from 10 to 30 mg. The AUC for morphine, M3G and M6G increased from 74 to 358 ng ml-' h, 184 to 822 ng ml-' h and from 1364 to 4886 ng ml-' h, respectively.
Discussion In this study, peak plasma morphine concentrations after epidural administration of doses ranging from 10 to 45 mg were, in most cases, higher than the reported peak plasma morphine concentrations (range: 11.5 to 118 ng ml-') observed by Sawe et al. (1983) in cancer patients receiving 20 to 40 mg of oral morphine every 4-6 h. These data indicate that in cancer patients receiving epidural morphine, systemically absorbed morphine may contribute to analgesia. The rapid time to peak plasma morphine concentration observed in these patients is consistent with observations after single epidural doses (Max et al., 1985; Weddel et al., 1981). In the three patients whose doses were changed, two (patients 1 and 5) showed an increase in plasma morphine
433
concentrations when the dose was increased while one (patient 2) showed little change. Patient 2 was studied on two occasions 16 weeks apart and there may have been some catheter blockage or fibrosis at the site of needle placement. The AUC molar ratios of M3G:morphine (range: 7.6 to 12.1) and M6G:morphine (range: 1.2 to 1.6) were in most cases lower than those observed by Sawe (1986) in patients receiving oral morphine chronically (M3G: morphine, range: 9.0 to 43.0; M6G:morphine, range: 1.0 to 6.1). This confirms that epidural administration avoids to some extent the extensive first-pass metabolism of oral morphine. Nevertheless, the plasma concentrations of M3G and M6G were considerably higher than those of morphine itself. These metabolites may play an important role since the presence of high systemic concentrations of M3G may antagonise the analgesic effect of morphine and M6G (Smith et al., 1990) and, on the other hand, high plasma M6G concentrations may contribute to analgesic effect. This work was supported by a grant from the Queensland Cancer Fund.
References Joel, S. P., Osborne, R. J. & Slevin, M. L. (1988). An improved method for the simultaneous determination of morphine and its principal glucuronide metabolites. J. Chromatogr., 430, 394-399. Max, M. B., Inturrisi, C. E., Kaiko, R. F., Grabinski, P. Y., Li, C. H. & Foley, K. M. (1985). Epidural and intrathecal opiates: cerebrospinal fluid and plasma profiles in patients with chronic cancer pain. Clin. Pharmac. Ther., 38, 631641. Osborne, R., Joel, S., Trew, D. & Slevin, M. (1988). Analgesic activity of morphine-6-glucuronide. Lancet, i, 828. Sawe, J. (1986). Morphine and its 3- and 6-glucuronides in plasma and urine during chronic oral administration in cancer patients. In Advances in Pain Research and Therapy, eds Foley K. M. & Inturrisi C. E., pp. 45-55. Vol 8. New York: Raven Press. Sawe, J., Dahlstrom, B. & Rane, A. (1983). Steady-state kinetic and analgesic effect of oral morphine in cancer
patients. Eur. J. clin. Pharmac., 24, 537-542. Schneider, J. J. & Ravenscroft, P. J. (1989). Determination of morphine in plasma by high performance liquid chromatography with fluorescence detection. J. Chromatogr., 497, 326-329. Shimomura, K., Kamata, O., Ueki, S., Ida, S., Oguri, K., Yoshimura, H. & Tsukamoto, H. (1971). Analgesic effects of morphine-glucuronides. Tohoku J. exp. Med., 105, 4552. Smith, M. T., Watt, J. A. & Cramond, T. (1990). Morphine3-glucuronide-a potent antagonist of morphine analgesia. Life Sci., 47, 579-585. Weddel, S. J. & Ritter, R. R. (1981). Serum levels following epidural administration of morphine and correlation with relief of postsurgical pain. Anesthesiol., 54, 210-214.
(Received 28 February 1992, accepted 3 June 1992)
