P&7, 45 (1991) 11-15 ‘i 1991 Elsevier Science Publishers A DONIS 0304395991000976
11 B.V. 0304-3959/91/$03.50
PAIN 01771
CSF and blood pharmacokinetics of hydromorphone and morphine following lumbar epidural administration William G. Brose ‘, Darrell L. Tanelian ‘, Jay B. Brodsky a, James B.D. Mark ’ and Michael J. Cousins ‘IDepartment ofAnesthesia,and ’ Department of Surgev, Stanford University School of Medicine, Stanford, CA 94305 (U.S.A.), and h Deparimeni
o/Anaesthesia (Received
b
and Intensive Care, Flinders Medical Centre, Adelarde, SA 5042 (Australia)
2 July 1990. revision received and accepted
5 October
1990)
S”lllllliU-y
Sixteen consenting patients scheduled for elective thoracotomy were enrolled into a randomized trial of epidural morphine and hydromorphone. Each patient had a lumbar epidural catheter placed preoperatively for the purpose of post-thoracotomy analgesia. Shortly before the end of the operative procedure each patient received 5 mg of morphine and 0.75 mg of hydromorphone via the epidural catheter. Blood was sampled at regular intervals following the opiate administration and patients were randomized to 1 of 7 cervical CSF sampling times. Blood and C’SF samples were assayed for morphine and hydromorphone concentration to determine blood and CSF pharmacokinetic profiles. A maximum blood morphine concentration of 60 k 25 ng/ml (mean + S.D.) was obtained at 11 k 6 min (mean + S.D.). The blood hydromorphone peak of 14 & 13 ng/ml (mean + S.D.) occurred 8 &-6 min (mean f SD.). The mean peak CSF opioid concentrations of 1581 ng/ml for morphine and 309 ng/ml for hydromorphone occurred 60 min after epidural administration. The blood and CSF pharmacokinetic profiles for morphine and hvdromorphone are presented. These profiles are similar for the two drugs after lumbar epidural administration. Key words: Morphine;
Hydromorphone;
Pharmacokinetics;
Introduction The lumbar epidural space is commonly used to administer spinal opiates for pain control. Ease of catheter placement and low risk of direct trauma to the spinal cord are considered advantages of this technique. Opiates delivered via this route may be absorbed into local tissues, traverse the dura and gain access to the cerebrospinal fluid (CSF), or be absorbed into the systemic circulation. Opiate which enters the spinal cord binds with endogenous opiate receptors in the dorsal horn producing analgesia. The unbound opiate will either move to non-active tissues or bind opiate receptors at a more distant site, e.g., the brain. Rostra1 migration of opioids in CSF has been propc)sed as the cause of delayed respiratory depression seen with this therapy [3]. Other undesirable side effects (pruritus, urinary retention, nausea, and vomiting) asso-
Correspondence to: William G. Brose, Department of Anesthesia. Stanford University School of Medicine, Stanford, CA 94305, U.S.A.
Spinal
opioids;
Epidural
opioids
ciated with spinal opiate therapy may also be caused by migration to distant sites [5]. However, distribution of opiates throughout the CSF can have beneficial effects by binding with receptors in the dorsal horn at multiple levels providing widespread analgesia. The physiochemical characteristics of each drug administered into the epidural space likely confers a unique profile of analgesia and side effects. Lumbar epidural morphine produces excellent analgesia for patients following surgery [1,2]. It has also been shown to be effective in managing pain from multiple sites as reported by patients suffering from metastatic cancer [16]. The cephalad migration of morphine in the CSF has been previously reported [8]. Morphine migrates from lumbar epidural sites to the low cervical region over l-6 h. Morphine which moves through the CSF in this fashion can exert an analgesic effect over a large area of the spinal cord. Hydromorphone has also been reported to provide excellent analgesia following lumbar epidural administration [4.11]. In addition, some reports would suggest that hydromorphone has a shorter latency to effect and reduced inci-
dence of spinal opiate-related side effects [17]. If confirmed, these differences would confer a clinical advantage to hydromorphone over morphine. Pharmacokinetic studies evaluating the CSF and blood absorption of this drug have not yet been conducted.
I‘ABLE
I
-____ (’
Morphme Hydromorphonr
111.1,
(%/W
-1,,, ,*
(fnln)
Mean + S.D.
Range
Mean i_ S D.
hot 75 14*13
244117 ?~_ 49
11 s
Ranpc
!h f fr
4 20 I Ii
Methods Putients Sixteen patients with diagnosed pulmonary pathology scheduled for thoracotomy provided informed consent for involvement in the study which was approved by the institutional review board. All patients received a standardized anesthetic technique. Spinal opiates were administered to all patients during the surgical procedure. Anesthetic management All patients had a lumbar epidural catheter placed at the Lz,i interspace prior to operation. Location of the catheter was confirmed by documenting segmental anesthesia after administration of 15 ml of 1.5% lidoCaine with epinephrine (5 pg/ml). General anesthesia was induced and maintained with thiopental, isoflurane and oxygen. Muscle relaxation was initiated with succinylcholine and maintained with pancuronium. Opiate administration Morphine (5 mg) and hydromorphone (0.75 mg) were co-administered via a lumbar epidural catheter prior to the end of surgery. The opiates were diluted in a total volume of 10 ml with preservative-free normal saline. and delivered as a bolus over 2 min. Time zero was taken to be the time that the opiate administration was completed. Blood sampling Blood was sampled from an indwelling radial arterial cannula at times 0, 1, 2, 3. 4, 5, 10, 15. 20, 30. 45, 60, 90, 120, 150, 180, and 240 min following epidural opiate administration. Samples were immediately frozen and stored at 0°C until the time of assay. C’SF sumpling Patients recovered from anesthesia throughout the immediate postoperative period in a semirecumbent position. During CSF sampling, patients were positioned in a lateral decubitus position with the neck flexed. A 26-gauge spinal needle was inserted into the subarachnoid space at the C7-Tl interspace. A single 3 ml sample of CSF was withdrawn at one of the following sampling times determined by random assignment: 10. 30, 60, 120, 180, 240 min following opiate administration. CSF samples were immediately frozen and stored at -4°C until the time of assay.
Opiate ussq Whole blood and CSF concentrations of morphine and hydromorphone were measured by gas chromatography using a nitrogen-phosphorous detector as previously described [8]. Standard curves constructed for each assay were linear and passed through the origin. The lower limit of sensitivity for the morphine and hydromorphone assays was 1 ng/ml.
Results One minute following the epidural administration ot study drug, morphine and hydromorphone could be detected in the patient’s blood. The concentration of hydromorphone in the systemic circulation increased progressively and achieved a maximum of 14 ng/ml + 13 ng/ml (mean + S.D.) after 4 min (Table I). The peak blood morphine concentration, 60 ng/ml + 25 ng/ml (mean + S.D.), was measured after 15 min as shown in Table I. Cervical cerebrospinal fluid samples contained detectable opiate even at the earliest sampling time of 10 min. Both morphine and hydromorphone concentrations in the CSF peaked at 60 min. By the 240 min sampling period no hydromorphone was detectable in
loo00
4 /’
lOOO? Id
*---____
CSF Morphine -0-_
I/’
-.. --__ J
9
\
d’ 100
\
\
\
\
\
\
\
\
\
\
\ ‘0
10 -
Blcad Morphme
.1-I 0
60
120
Time
180
1 240
(min)
Fig. 1. Blood (s&d circles) and (‘SF (open circles) morphine concentrations versus time after lumbar epidural administration of 5 mg of morphine sulfate combined wth 0.75 mg hydromorphonc.
13
1
\
\
I
.I
\
Q
!
1
0
60
I20 Tilnc
180
(min)
Blood (solid circles) and CSF (open circles) hydromorphone concentrations versus time after lumbar epidural administration of 0.75 mg hydromorphone combined with 5 mg of morphine sulfate.
the cervical CSF and there was a more than IO-fold decrease in measurable morphine. These data are summarized in Figs. 1 and 2. The points plotted are mean values of 2-4 measurements at each collection time. The mean peak CSF opiate concentrations measured were 1581 ng/ml for morphine and 309 ng/ml for hydromorphone. The opiate concentrations dropped slowly over the next 2 h, and then more quickly in the fourth hour. Fig. 1 illustrates the arterial blood and cervical CSF morphine concentra-
2000 = _g
E
P,
’ ‘\
E ._
:
5
:
‘\ ,,
‘l‘imc
240
FMorphine
(min)
Fig. 4. Log of the morphine/hydromorphone concentration ratio in CSF as a function of time after administration (solid line). The interrupted line represents the fixed ratio of morphine (5 mg)/hydromorphone (0.75 mg) which was administered into the lumbar epidural space at time zero.
tions as a function of time following lumbar epidural administration. In order to deliver equianalgesic doses of both opioids evaluated in this study, markedly different doses of morphine and hydromorphone were selected. On a mg to mg basis, 6.67 times more morphine was administered than hydromorphone. This potency ratio was chosen based on extensive clinical eperience with epidural hydromorphone and morphine in our hospital. Using this ratio it would be predicted that the two drugs would appear in the CSF in proportional amounts if the physiochemical characteristics were similar. Comparison of the two CSF absorption profiles illustrated in Fig. 3 shows a similar pattern of drug appearance in the cervical CSF. Both hydromorphone and morphine peak 1 h following lumbar epidural administration in this group of patients. Fig. 4 presents these data in a different way. By taking the ratio of morphine to hydromorphone in the cervical CSF at any sampling time one can look for differences in CSF absorption and distribution by comparing this to the fixed ratio that was administered in the lumbar epidural space.
Discussion
0
60
120
180
210
Time (min) Fig. 3. Graphic representation of cervical CSF concentration of morphine and hydromorphone as a function of time after the lumbar epidural administration of 5 mg morphine and 0.75 mg hydromorphone.
The analgesia produced by epidural opioids depends directly on their availability to bind spinal opiate receptors. A pharmacokinetic model for epidural morphine has been previously presented [6]. This model includes drug administration into the epidural space, deposition in epidural fat, uptake into epidural blood vessels, diffusion through the dura into the CSF, and migration of drug via bulk flow within the CSF. Drug which is
delivered to the spinal cord is assumed to arrive via passive diffusion through the CSF or via local circulation. Nordberg suggested that epidural opiate distribution in the spinal cord is dependent on passage across the dura into the CSF [14]. Uptake of drug into the vascular system has been demonstrated as the major route of distribution of extradural opioids [7.18.19]. This systemic absorption may be responsible for some component of early analgesia mediated via central opiate receptors [5]. However. the prolonged analgesia reported with epidural opiates is thought to be mediated primarily via spinal cord receptors. The proximity of spinal opiate administration site to the segment of the dorsal horn receiving noxious information may have clinical importance. Pharmacokinetic support for the selective spinal analgesic effect of epidural morphine has been convincing [8,18]. Sjiistriim et al. reported peak lumbar CSF morphine concentrations of 1290 ng/ml occurring at 60-90 min following the lumbar epidural administration of 3 mg. Extrapolating these data linearly to a 5 mg dose one would anticipate a lumbar CSF morphine concentration of 2150 ng/ml. Using a similar study design comparing the cephalad migration of lumbar epidural morphine and meperidine (pethidine), with sampling at C7-Tl, Gourlay et al. reported a peak CSF morphine concentration of 1025 ng/ml 2 h after administration. The morphine data presented in the current study are in general agreement with previous studies using cervical (C7- -Tl) CSF sampling techniques. This study reports a peak cervical CSF morphine concentration of 1500 ng/ml at 60 min. When compared with SjiistrBm’s data for lumbar CSF sampling, and normalized to a 5 mg dose. it appears that there is a concentration gradient of morphine within the CSF following lumbar epidural administration, such that the lumbar concentration is higher than the cervical concentration [18]. Nordberg introduced evidence of such a CSF concentration gradient for epidural morphine in the CNS [14]. A CSF concentration gradient for continuously administered lumbar and thoracic intrathecal morphine was also reported by Moulin et al. [13]. Assuming that the CSF is the biophase for spinal opiate analgesia, confirmation of a concentration gradient for epidural morphine predicts that delivery of opiate at the appropriate spinal cord level would play some role in determining the dose required to achieve analgesia in any given patient. The proximity of the epidural administration site and dorsal horn effector site may not only affect the dose required. but likely also play some role in determining the latency of selective spinal analgesia. Opioid physiochemical characteristics including lipid solubility have also been associated with latency of analgesia. Drug polarity is thought to be an important variable in controlling absorption into and removal from CSF. (iourlay et al., comparing morphine and meperidine.
pointed out that the more rapid xcumulation OI meperidine (lipophilic. less polar) than morphine (h!drophilic, more polar) in the CSF following lumbar epidural administration [9]. Sjiistriim et i11. reported the mean elimination half-life of morphine from (‘SF to he 90 min while meperidine was eliminated with ;I half-life of 68 min [1X,20]. Max et al. correlated the: CSF elimination half-lives of methadone. morphine and beta-endorphin with their respective lipid solubilitlcs [12]. These findings have lead to the suggestion that clearance of drugs from the CSF occurs by uptake into the lipid-rich spinal cord and subsequent removal \ia the blood. These data provide pharmacokinetic support for the clinical observation of a shorter latency 01 analgesia following epidural meperidinc as compared to epidural morphine [7]. This may also explain why ep~dural meperidine has a shorter duration of analgesia (4- 6 h) than morphine (12 18 11). Clinical experience with hydromorphone in our Institution has established this opioid as an excellent analgesic when delivered to the epidural space. Epidural hydromorphone is reported to have an analgesic latency similar to meperidine. but the duration of action i\, much longer. similar to morphine [5]. Hydromorphone has also been reported to provide excellent poatthoracotomy analgesia following lumbar administration [ 171. The short latency and long duration of analgesia in spinal cord regions far distant to the site of hydromorphone injection are desirable characteristics. While previous reports of lipid solubility have suggested that hydromorphone is more lipid soluble than morphine. Plummer et al. recently reported very similar octanol-pH 7.4 buffer distribution coefficients for the twc> drugs 1151. The data presented in Table I and Figs. 1 and 7 suggest that the two drugs have similar CSF and blood kinetic profiles. While the actual concentrations of hydromorphone in the C‘SF are less than morphine at an> time. the time course of hydromorphone absorption into the CSF is very similar to morphine over the 4 h stud) period (Fig. 3). Allowing for a 6-7-fold adjustment for equipotency, the relative blood and CSF concentrations of morphine were very close to hydromorphone. This is illustrated in the plot of CSF morphine/hydromorphone ratio ~5. time (Fig. 4). The short latency reported following epidural hydromorphone is not explained by the data above. Based on the similarity between the CSF profiles of morphine and hydromorphone one would expect a similar time course for spinal analgesia. The faster onset of pain relief with hydromorphone may relate to an initial supraspinal effect rather than selective spinal analgesia. The clinical success reported with hydromorphone may indicate that this drug has the appropriate kinetics I’OI blood and CSF to permit initial supraspinal analgesia which persists until the spinal opiate analgesia ha> taken effect. Alternatively. other factors which involve
15
spinal cord opiate receptor kinetics including receptor binding affinities and molecular shape may explain this clinical difference. In conclusion, these data provide pharmacokinetic support for the use of lumbar epidural hydromorphone for the treatment of pain at distant sites. From a kinetic point of view hydromorphone appears very similar to morphine and would appear to be an acceptable alternative. Further controlled study of the clinical advantages and disadvantages of each of these drugs should provide useful information.
References Barron, D.W. and Strong, J.E., Postoperative analgesia in major orthopedic surgery. Epidural and intrathecal opiates, Anaesthesia, 36 (1981) 937. Bromage, P.R., Camporesi, E. and Chestnut, D., Epidural narcotics for postoperative analgesia, Anesth. Analg., 59 (1980) 473. Bromage, P.R., Camporesi, E.M., Durant. P.A.C. and Nielsen, C.H., Rostra1 spread of epidural morphine, Anesthesiology, 56 (1982) 431. Chestnut, D.H., Choi, W.W. and Isbell. T.J.. Epidural hydromorphone for postcesarean analgesia, Obstet. Gynecol., 68 (1986) 65-69. Cousins, M.J., Cherry, D.A. and Gourlay. G., Acute and chronic pain: use of spinal opioids. In: M.J. Cousins and P.O. Bridenbaugh (Eds.). Neural Blockade in Clinical Anesthesia and Management of Pain, Lippincott, Philadelphia, PA, 1988, pp. 955-1030. 6 Cousins, M.J. and Mather, L.E., Intrathecal and epidural administration of opioids, Anesthesiology, 61 (1984) 276-310. 7 Glynn, C.J., Mather, L.E., Cousins, M.J., Graham, J.R. and Wilson. P.R.. Peridural meperidine in humans: analgetic response, pharmacokinetics and transmission into the CSF, Anesthesiology, 55 (1981) 520. 8 Gourlay. G., Cherry, D.A. and Cousins, M.J., Cephalad migration of morphine in CSF following lumbar epidural administration in patients with cancer pain, Pain, 23 (1985) 317-326.
G., Cherry. D.A., Plummer, J.L., Armstrong, P.J. and 9 Gourlay, Cousins. M.J., The influence of drug polarity on the absorption of opioid drugs into the CSF and subsequent cephalad migration following lumbar epidural administration: application to morphine and pethidine, Pain, 31 (1987) 297-305. 10 Gourlay, G.K., McLean, C.F., Murphy, G.A. and Badcock, N.R., A rapid method for the determination of blood morphine concentration suitable for use in studies involving acute and chronic pain. J. Pharmacol. Meth., 13 (1985) 317-324. 11 Horan, C.T.. Beeby, D.G., Brodsky, J.B. and Oberhelman, H.A., Segmental effect of lumbar epidural hydromorphone: a case report, Anesthesiology, 62 (1985) 84-85. 12 Max, M.B.. Inturssi, C.E.. Kaiko, R.F., Grabinski, P.Y., Li, C.H. and Foley, K.M., Epidural and intrathecal opiates: cerebrospinal fluid and plasma profiles in patients with chronic cancer pain, Clin. Pharmacol. Ther., 38 (1985) 631-641. 13 Moulin. D.E.. Inturrisi, C.E. and Foley, K.M., Cerebrospinal fluid pharmacokinetics of intrathecal morphine sulfate and D-Ala-DLeu-enkephalin, Ann. Neural.. 20 (1986) 218-222. 14 Nordberg, G., Hansdottir, V.. Kvist, L., Mellstrand, T. and Hedner, T., Pharmacokinetics of different epidural sites of morphine administration. Eur. J. Clin. Pharmacol.. 33 (1987) 499-504. 15 Plummer, J.L., Cmielewski, P.L., Reynolds, G.D.. Gourlay, G. and Cherry. D.A.. Influence of polarity on dose response relationships of intrathecal opioids in rats. Pain, 40 (1990) 339-347. 16 Samuelsson. H., Nordberg. G., Hedner, T. and Lindqvist, J., CSF and plasma morphine concentrations in cancer patients during chronic epidural morphine therapy and its relation to pain relief, Pain, 30 (1987) 303-310. 17 Shulman. MS.. Wakerlin, G.. Yamaguchi, L. and Brodsky, J.B., Experience with epidural hydromorphone for post-thoracotomy pain relief, Anesth. Analg., 66 (1987) 1331-1333. 18 SjostrBm. S., Hartvig. P., Persson, M.P. and Tamsen, A., Pharmacokinetics of epidural morphine and meperidine in humans, Anesthesiology, 67 (1987) 877-888. 19 Sjostriim, S.. Hartvig, P. and Tamsen, A., Patient-controlled analgesia with epidural morphine and pethidine, Br. J. Anaesth., 60 (1988) 358-366. 20 Sjiistrom. S., Tamsen, A., Persson. M.P. and Hartvig, P., Pharmacokinetics of intrathecal morphine and meperidine in humans, Anesthesiology, 67 (1987) 889-895.
11 B.V. 0304-3959/91/$03.50
PAIN 01771
CSF and blood pharmacokinetics of hydromorphone and morphine following lumbar epidural administration William G. Brose ‘, Darrell L. Tanelian ‘, Jay B. Brodsky a, James B.D. Mark ’ and Michael J. Cousins ‘IDepartment ofAnesthesia,and ’ Department of Surgev, Stanford University School of Medicine, Stanford, CA 94305 (U.S.A.), and h Deparimeni
o/Anaesthesia (Received
b
and Intensive Care, Flinders Medical Centre, Adelarde, SA 5042 (Australia)
2 July 1990. revision received and accepted
5 October
1990)
S”lllllliU-y
Sixteen consenting patients scheduled for elective thoracotomy were enrolled into a randomized trial of epidural morphine and hydromorphone. Each patient had a lumbar epidural catheter placed preoperatively for the purpose of post-thoracotomy analgesia. Shortly before the end of the operative procedure each patient received 5 mg of morphine and 0.75 mg of hydromorphone via the epidural catheter. Blood was sampled at regular intervals following the opiate administration and patients were randomized to 1 of 7 cervical CSF sampling times. Blood and C’SF samples were assayed for morphine and hydromorphone concentration to determine blood and CSF pharmacokinetic profiles. A maximum blood morphine concentration of 60 k 25 ng/ml (mean + S.D.) was obtained at 11 k 6 min (mean + S.D.). The blood hydromorphone peak of 14 & 13 ng/ml (mean + S.D.) occurred 8 &-6 min (mean f SD.). The mean peak CSF opioid concentrations of 1581 ng/ml for morphine and 309 ng/ml for hydromorphone occurred 60 min after epidural administration. The blood and CSF pharmacokinetic profiles for morphine and hvdromorphone are presented. These profiles are similar for the two drugs after lumbar epidural administration. Key words: Morphine;
Hydromorphone;
Pharmacokinetics;
Introduction The lumbar epidural space is commonly used to administer spinal opiates for pain control. Ease of catheter placement and low risk of direct trauma to the spinal cord are considered advantages of this technique. Opiates delivered via this route may be absorbed into local tissues, traverse the dura and gain access to the cerebrospinal fluid (CSF), or be absorbed into the systemic circulation. Opiate which enters the spinal cord binds with endogenous opiate receptors in the dorsal horn producing analgesia. The unbound opiate will either move to non-active tissues or bind opiate receptors at a more distant site, e.g., the brain. Rostra1 migration of opioids in CSF has been propc)sed as the cause of delayed respiratory depression seen with this therapy [3]. Other undesirable side effects (pruritus, urinary retention, nausea, and vomiting) asso-
Correspondence to: William G. Brose, Department of Anesthesia. Stanford University School of Medicine, Stanford, CA 94305, U.S.A.
Spinal
opioids;
Epidural
opioids
ciated with spinal opiate therapy may also be caused by migration to distant sites [5]. However, distribution of opiates throughout the CSF can have beneficial effects by binding with receptors in the dorsal horn at multiple levels providing widespread analgesia. The physiochemical characteristics of each drug administered into the epidural space likely confers a unique profile of analgesia and side effects. Lumbar epidural morphine produces excellent analgesia for patients following surgery [1,2]. It has also been shown to be effective in managing pain from multiple sites as reported by patients suffering from metastatic cancer [16]. The cephalad migration of morphine in the CSF has been previously reported [8]. Morphine migrates from lumbar epidural sites to the low cervical region over l-6 h. Morphine which moves through the CSF in this fashion can exert an analgesic effect over a large area of the spinal cord. Hydromorphone has also been reported to provide excellent analgesia following lumbar epidural administration [4.11]. In addition, some reports would suggest that hydromorphone has a shorter latency to effect and reduced inci-
dence of spinal opiate-related side effects [17]. If confirmed, these differences would confer a clinical advantage to hydromorphone over morphine. Pharmacokinetic studies evaluating the CSF and blood absorption of this drug have not yet been conducted.
I‘ABLE
I
-____ (’
Morphme Hydromorphonr
111.1,
(%/W
-1,,, ,*
(fnln)
Mean + S.D.
Range
Mean i_ S D.
hot 75 14*13
244117 ?~_ 49
11 s
Ranpc
!h f fr
4 20 I Ii
Methods Putients Sixteen patients with diagnosed pulmonary pathology scheduled for thoracotomy provided informed consent for involvement in the study which was approved by the institutional review board. All patients received a standardized anesthetic technique. Spinal opiates were administered to all patients during the surgical procedure. Anesthetic management All patients had a lumbar epidural catheter placed at the Lz,i interspace prior to operation. Location of the catheter was confirmed by documenting segmental anesthesia after administration of 15 ml of 1.5% lidoCaine with epinephrine (5 pg/ml). General anesthesia was induced and maintained with thiopental, isoflurane and oxygen. Muscle relaxation was initiated with succinylcholine and maintained with pancuronium. Opiate administration Morphine (5 mg) and hydromorphone (0.75 mg) were co-administered via a lumbar epidural catheter prior to the end of surgery. The opiates were diluted in a total volume of 10 ml with preservative-free normal saline. and delivered as a bolus over 2 min. Time zero was taken to be the time that the opiate administration was completed. Blood sampling Blood was sampled from an indwelling radial arterial cannula at times 0, 1, 2, 3. 4, 5, 10, 15. 20, 30. 45, 60, 90, 120, 150, 180, and 240 min following epidural opiate administration. Samples were immediately frozen and stored at 0°C until the time of assay. C’SF sumpling Patients recovered from anesthesia throughout the immediate postoperative period in a semirecumbent position. During CSF sampling, patients were positioned in a lateral decubitus position with the neck flexed. A 26-gauge spinal needle was inserted into the subarachnoid space at the C7-Tl interspace. A single 3 ml sample of CSF was withdrawn at one of the following sampling times determined by random assignment: 10. 30, 60, 120, 180, 240 min following opiate administration. CSF samples were immediately frozen and stored at -4°C until the time of assay.
Opiate ussq Whole blood and CSF concentrations of morphine and hydromorphone were measured by gas chromatography using a nitrogen-phosphorous detector as previously described [8]. Standard curves constructed for each assay were linear and passed through the origin. The lower limit of sensitivity for the morphine and hydromorphone assays was 1 ng/ml.
Results One minute following the epidural administration ot study drug, morphine and hydromorphone could be detected in the patient’s blood. The concentration of hydromorphone in the systemic circulation increased progressively and achieved a maximum of 14 ng/ml + 13 ng/ml (mean + S.D.) after 4 min (Table I). The peak blood morphine concentration, 60 ng/ml + 25 ng/ml (mean + S.D.), was measured after 15 min as shown in Table I. Cervical cerebrospinal fluid samples contained detectable opiate even at the earliest sampling time of 10 min. Both morphine and hydromorphone concentrations in the CSF peaked at 60 min. By the 240 min sampling period no hydromorphone was detectable in
loo00
4 /’
lOOO? Id
*---____
CSF Morphine -0-_
I/’
-.. --__ J
9
\
d’ 100
\
\
\
\
\
\
\
\
\
\
\ ‘0
10 -
Blcad Morphme
.1-I 0
60
120
Time
180
1 240
(min)
Fig. 1. Blood (s&d circles) and (‘SF (open circles) morphine concentrations versus time after lumbar epidural administration of 5 mg of morphine sulfate combined wth 0.75 mg hydromorphonc.
13
1
\
\
I
.I
\
Q
!
1
0
60
I20 Tilnc
180
(min)
Blood (solid circles) and CSF (open circles) hydromorphone concentrations versus time after lumbar epidural administration of 0.75 mg hydromorphone combined with 5 mg of morphine sulfate.
the cervical CSF and there was a more than IO-fold decrease in measurable morphine. These data are summarized in Figs. 1 and 2. The points plotted are mean values of 2-4 measurements at each collection time. The mean peak CSF opiate concentrations measured were 1581 ng/ml for morphine and 309 ng/ml for hydromorphone. The opiate concentrations dropped slowly over the next 2 h, and then more quickly in the fourth hour. Fig. 1 illustrates the arterial blood and cervical CSF morphine concentra-
2000 = _g
E
P,
’ ‘\
E ._
:
5
:
‘\ ,,
‘l‘imc
240
FMorphine
(min)
Fig. 4. Log of the morphine/hydromorphone concentration ratio in CSF as a function of time after administration (solid line). The interrupted line represents the fixed ratio of morphine (5 mg)/hydromorphone (0.75 mg) which was administered into the lumbar epidural space at time zero.
tions as a function of time following lumbar epidural administration. In order to deliver equianalgesic doses of both opioids evaluated in this study, markedly different doses of morphine and hydromorphone were selected. On a mg to mg basis, 6.67 times more morphine was administered than hydromorphone. This potency ratio was chosen based on extensive clinical eperience with epidural hydromorphone and morphine in our hospital. Using this ratio it would be predicted that the two drugs would appear in the CSF in proportional amounts if the physiochemical characteristics were similar. Comparison of the two CSF absorption profiles illustrated in Fig. 3 shows a similar pattern of drug appearance in the cervical CSF. Both hydromorphone and morphine peak 1 h following lumbar epidural administration in this group of patients. Fig. 4 presents these data in a different way. By taking the ratio of morphine to hydromorphone in the cervical CSF at any sampling time one can look for differences in CSF absorption and distribution by comparing this to the fixed ratio that was administered in the lumbar epidural space.
Discussion
0
60
120
180
210
Time (min) Fig. 3. Graphic representation of cervical CSF concentration of morphine and hydromorphone as a function of time after the lumbar epidural administration of 5 mg morphine and 0.75 mg hydromorphone.
The analgesia produced by epidural opioids depends directly on their availability to bind spinal opiate receptors. A pharmacokinetic model for epidural morphine has been previously presented [6]. This model includes drug administration into the epidural space, deposition in epidural fat, uptake into epidural blood vessels, diffusion through the dura into the CSF, and migration of drug via bulk flow within the CSF. Drug which is
delivered to the spinal cord is assumed to arrive via passive diffusion through the CSF or via local circulation. Nordberg suggested that epidural opiate distribution in the spinal cord is dependent on passage across the dura into the CSF [14]. Uptake of drug into the vascular system has been demonstrated as the major route of distribution of extradural opioids [7.18.19]. This systemic absorption may be responsible for some component of early analgesia mediated via central opiate receptors [5]. However. the prolonged analgesia reported with epidural opiates is thought to be mediated primarily via spinal cord receptors. The proximity of spinal opiate administration site to the segment of the dorsal horn receiving noxious information may have clinical importance. Pharmacokinetic support for the selective spinal analgesic effect of epidural morphine has been convincing [8,18]. Sjiistriim et al. reported peak lumbar CSF morphine concentrations of 1290 ng/ml occurring at 60-90 min following the lumbar epidural administration of 3 mg. Extrapolating these data linearly to a 5 mg dose one would anticipate a lumbar CSF morphine concentration of 2150 ng/ml. Using a similar study design comparing the cephalad migration of lumbar epidural morphine and meperidine (pethidine), with sampling at C7-Tl, Gourlay et al. reported a peak CSF morphine concentration of 1025 ng/ml 2 h after administration. The morphine data presented in the current study are in general agreement with previous studies using cervical (C7- -Tl) CSF sampling techniques. This study reports a peak cervical CSF morphine concentration of 1500 ng/ml at 60 min. When compared with SjiistrBm’s data for lumbar CSF sampling, and normalized to a 5 mg dose. it appears that there is a concentration gradient of morphine within the CSF following lumbar epidural administration, such that the lumbar concentration is higher than the cervical concentration [18]. Nordberg introduced evidence of such a CSF concentration gradient for epidural morphine in the CNS [14]. A CSF concentration gradient for continuously administered lumbar and thoracic intrathecal morphine was also reported by Moulin et al. [13]. Assuming that the CSF is the biophase for spinal opiate analgesia, confirmation of a concentration gradient for epidural morphine predicts that delivery of opiate at the appropriate spinal cord level would play some role in determining the dose required to achieve analgesia in any given patient. The proximity of the epidural administration site and dorsal horn effector site may not only affect the dose required. but likely also play some role in determining the latency of selective spinal analgesia. Opioid physiochemical characteristics including lipid solubility have also been associated with latency of analgesia. Drug polarity is thought to be an important variable in controlling absorption into and removal from CSF. (iourlay et al., comparing morphine and meperidine.
pointed out that the more rapid xcumulation OI meperidine (lipophilic. less polar) than morphine (h!drophilic, more polar) in the CSF following lumbar epidural administration [9]. Sjiistriim et i11. reported the mean elimination half-life of morphine from (‘SF to he 90 min while meperidine was eliminated with ;I half-life of 68 min [1X,20]. Max et al. correlated the: CSF elimination half-lives of methadone. morphine and beta-endorphin with their respective lipid solubilitlcs [12]. These findings have lead to the suggestion that clearance of drugs from the CSF occurs by uptake into the lipid-rich spinal cord and subsequent removal \ia the blood. These data provide pharmacokinetic support for the clinical observation of a shorter latency 01 analgesia following epidural meperidinc as compared to epidural morphine [7]. This may also explain why ep~dural meperidine has a shorter duration of analgesia (4- 6 h) than morphine (12 18 11). Clinical experience with hydromorphone in our Institution has established this opioid as an excellent analgesic when delivered to the epidural space. Epidural hydromorphone is reported to have an analgesic latency similar to meperidine. but the duration of action i\, much longer. similar to morphine [5]. Hydromorphone has also been reported to provide excellent poatthoracotomy analgesia following lumbar administration [ 171. The short latency and long duration of analgesia in spinal cord regions far distant to the site of hydromorphone injection are desirable characteristics. While previous reports of lipid solubility have suggested that hydromorphone is more lipid soluble than morphine. Plummer et al. recently reported very similar octanol-pH 7.4 buffer distribution coefficients for the twc> drugs 1151. The data presented in Table I and Figs. 1 and 7 suggest that the two drugs have similar CSF and blood kinetic profiles. While the actual concentrations of hydromorphone in the C‘SF are less than morphine at an> time. the time course of hydromorphone absorption into the CSF is very similar to morphine over the 4 h stud) period (Fig. 3). Allowing for a 6-7-fold adjustment for equipotency, the relative blood and CSF concentrations of morphine were very close to hydromorphone. This is illustrated in the plot of CSF morphine/hydromorphone ratio ~5. time (Fig. 4). The short latency reported following epidural hydromorphone is not explained by the data above. Based on the similarity between the CSF profiles of morphine and hydromorphone one would expect a similar time course for spinal analgesia. The faster onset of pain relief with hydromorphone may relate to an initial supraspinal effect rather than selective spinal analgesia. The clinical success reported with hydromorphone may indicate that this drug has the appropriate kinetics I’OI blood and CSF to permit initial supraspinal analgesia which persists until the spinal opiate analgesia ha> taken effect. Alternatively. other factors which involve
15
spinal cord opiate receptor kinetics including receptor binding affinities and molecular shape may explain this clinical difference. In conclusion, these data provide pharmacokinetic support for the use of lumbar epidural hydromorphone for the treatment of pain at distant sites. From a kinetic point of view hydromorphone appears very similar to morphine and would appear to be an acceptable alternative. Further controlled study of the clinical advantages and disadvantages of each of these drugs should provide useful information.
References Barron, D.W. and Strong, J.E., Postoperative analgesia in major orthopedic surgery. Epidural and intrathecal opiates, Anaesthesia, 36 (1981) 937. Bromage, P.R., Camporesi, E. and Chestnut, D., Epidural narcotics for postoperative analgesia, Anesth. Analg., 59 (1980) 473. Bromage, P.R., Camporesi, E.M., Durant. P.A.C. and Nielsen, C.H., Rostra1 spread of epidural morphine, Anesthesiology, 56 (1982) 431. Chestnut, D.H., Choi, W.W. and Isbell. T.J.. Epidural hydromorphone for postcesarean analgesia, Obstet. Gynecol., 68 (1986) 65-69. Cousins, M.J., Cherry, D.A. and Gourlay. G., Acute and chronic pain: use of spinal opioids. In: M.J. Cousins and P.O. Bridenbaugh (Eds.). Neural Blockade in Clinical Anesthesia and Management of Pain, Lippincott, Philadelphia, PA, 1988, pp. 955-1030. 6 Cousins, M.J. and Mather, L.E., Intrathecal and epidural administration of opioids, Anesthesiology, 61 (1984) 276-310. 7 Glynn, C.J., Mather, L.E., Cousins, M.J., Graham, J.R. and Wilson. P.R.. Peridural meperidine in humans: analgetic response, pharmacokinetics and transmission into the CSF, Anesthesiology, 55 (1981) 520. 8 Gourlay. G., Cherry, D.A. and Cousins, M.J., Cephalad migration of morphine in CSF following lumbar epidural administration in patients with cancer pain, Pain, 23 (1985) 317-326.
G., Cherry. D.A., Plummer, J.L., Armstrong, P.J. and 9 Gourlay, Cousins. M.J., The influence of drug polarity on the absorption of opioid drugs into the CSF and subsequent cephalad migration following lumbar epidural administration: application to morphine and pethidine, Pain, 31 (1987) 297-305. 10 Gourlay, G.K., McLean, C.F., Murphy, G.A. and Badcock, N.R., A rapid method for the determination of blood morphine concentration suitable for use in studies involving acute and chronic pain. J. Pharmacol. Meth., 13 (1985) 317-324. 11 Horan, C.T.. Beeby, D.G., Brodsky, J.B. and Oberhelman, H.A., Segmental effect of lumbar epidural hydromorphone: a case report, Anesthesiology, 62 (1985) 84-85. 12 Max, M.B.. Inturssi, C.E.. Kaiko, R.F., Grabinski, P.Y., Li, C.H. and Foley, K.M., Epidural and intrathecal opiates: cerebrospinal fluid and plasma profiles in patients with chronic cancer pain, Clin. Pharmacol. Ther., 38 (1985) 631-641. 13 Moulin. D.E.. Inturrisi, C.E. and Foley, K.M., Cerebrospinal fluid pharmacokinetics of intrathecal morphine sulfate and D-Ala-DLeu-enkephalin, Ann. Neural.. 20 (1986) 218-222. 14 Nordberg, G., Hansdottir, V.. Kvist, L., Mellstrand, T. and Hedner, T., Pharmacokinetics of different epidural sites of morphine administration. Eur. J. Clin. Pharmacol.. 33 (1987) 499-504. 15 Plummer, J.L., Cmielewski, P.L., Reynolds, G.D.. Gourlay, G. and Cherry. D.A.. Influence of polarity on dose response relationships of intrathecal opioids in rats. Pain, 40 (1990) 339-347. 16 Samuelsson. H., Nordberg. G., Hedner, T. and Lindqvist, J., CSF and plasma morphine concentrations in cancer patients during chronic epidural morphine therapy and its relation to pain relief, Pain, 30 (1987) 303-310. 17 Shulman. MS.. Wakerlin, G.. Yamaguchi, L. and Brodsky, J.B., Experience with epidural hydromorphone for post-thoracotomy pain relief, Anesth. Analg., 66 (1987) 1331-1333. 18 SjostrBm. S., Hartvig. P., Persson, M.P. and Tamsen, A., Pharmacokinetics of epidural morphine and meperidine in humans, Anesthesiology, 67 (1987) 877-888. 19 Sjostriim, S.. Hartvig, P. and Tamsen, A., Patient-controlled analgesia with epidural morphine and pethidine, Br. J. Anaesth., 60 (1988) 358-366. 20 Sjiistrom. S., Tamsen, A., Persson. M.P. and Hartvig, P., Pharmacokinetics of intrathecal morphine and meperidine in humans, Anesthesiology, 67 (1987) 889-895.
