Morphine is used widely for epidural analgesia primarily because it has a relatively long duration of analgesic action after a single bolus dose However, delayed respiratory depression can occur after epidural morphine, and this remains a serious concern with the use of hydrophilic opioids for epidral analgesia (1). Sufentanil, a highly lipophilic opioid with a high affinity for p-opioid receptors (2), is five seven times more potent as an analgesic than fentanyl when intravenous bolus doses are compared (3). Clinical studies have shown that sufentanil produces analgesia rapidly (5-10 min) after epidural bolus dosing (4-6). Theoretically, the high lipophilicity of sufentanil should limit the amount of drug available for rostral spread within the cerebral spinal fluid (CSF) and thereby decrease the risk of respiratory depression (7). These considerations suggest that sufentanil could be a safer agent for epidural analgesia than morphine.
Sufentanil has a relatively short duration of action after epidural bolus dosing (6), probably because of the drug's high lipophilicity, which favors diffusion into the epidural venous plexus, rapid entry into spinal tissue and CSF and removal from sites of action by venous drainage of the spinal cord. This potential limitation might be nullified by use of a continuous epidural infusion if sufentanil does not spread rostrally. However, clinically significant respiratory depression within 60 min of injection has resulted from bolus epidural injection of sufentanil (6,8,9). It has been assumed that this is due to systemic drug redistribution. but the pharmacologic basis of this observed respiratory depression is not clear from these clinical studies.
Previous studies have characterized the CSF pharmacokinetics of epidurally administered morphine, meperidine, fentanyl, and other opioids (10,11). However, CSF and systemic pharmacokinetics have not been described adequately for sufentanil administered epidurally. The purpose of this study was to characterize the pharmacokinetics of sufentanil in the lumbar and cisternal CSF and in plasma after a single large epidural bolus dose in dogs.
With approval from the institutional animal review board at the Uniformed Services University, we studied six female mongrel dogs (weight 22-26 kg). For catheter placement and the duration of the experiment, general anesthesia was induced with intravenous thiopental, 10 mg/kg; the dog's trachea was intubated with a 9.0-mm endotracheal tube; and anesthesia was maintained via mechanical ventilation of the lungs with 0.5-1.0% halothane and 70% N20 in O2. The catheters were placed, and the experiments were completed on the same day with the dogs remaining in lateral decubitus position.
Under fluoroscopic guidance, two 17-G Tuohy needles were inserted percutaneously into the subarachnoid space at the atlanto-occipital interspace. For CSF sampling, radio-opaque 20-G catheters were inserted via the Tuohy needles. One catheter was advanced 2 cm cephalad into the cisterna magna; the second catheter was advanced caudad to the level of the second lumbar vertebral body. A third 17-G Tuohy needle was placed percutaneously in the epidural space at L6-7, using the loss of resistance to air technique to identify the epidural space. Again, using fluoroscopic guidance, a radio-opaque 20-G catheter was inserted through this needle and advanced to the body of the second lumbar vertebra. Finally, an 18-G catheter was inserted percutaneously into a femoral artery for blood pressure monitoring and blood sampling.
Each animal received 50 μg of sufentanil via the epidural catheter (diluted to a total volume of 5 mL with 0.9% NaCI) at time zero. Samples from the three compartments: blood, cisternal CSF (C-CSF), and lumbar CSF (L-CSF), were drawn before and at 1, 5, 15, 30, 60, 90, 120, and 180 min after sufentanil injection. Blood volume withdrawn (10 mL/sample) was replaced with Ringer's lactate at a 3:1 ratio. The initial 0.2 mL of CSF withdrawn for each sample (catheter dead-space) was discarded. CSF withdrawn (0.5 mL/sample) was replaced with 0.9% NaC1 1:1. Blood samples were centrifuged at 3,000 rpm for 10 min to separate cells from plasma. The plasma and CSF samples were frozen and stored at -70°C until assay.
Sufentanil concentrations in plasma and CSF were measured (by R. Schaffer) using gas chromatographymass spectrometry following specific extraction of the drug (and added alfentanil as an internal standard) from the samples by the general methods reported by Weldon et al. (12) and Timmerman et al. (13). Betweenday coefficients of variation of the assay averaged 6.3% for sufentanil concentrations of 0.05-5 ng/mL. The detection limit with this analytical method for sufentanil was 0.02 ng/mL of extracted plasma or CSF.
To describe the absorption of drug from the epidural space, redistribution to plasma or CSF, and elimination of drug from each “compartment,” sufentanil concentration-time data from each dog was fitted to a tri-exponential curve by least squares method with weighting of 1/(measured concentration)2 for each compartment (14). We chose the best fit in each case based on the smallest sum of squared residuals with adjustment for the number of parameters used according to Akaike (15). We used coefficients of the fitted tri-exponential (C(t) = Pe-πλ + Ae-αλ + Be-βλ) to calculate distributional half-lives, maximum predicted plasma or CSF sufentanil concentration in nanograms per milliliter (Cmax), and postinjection time to reach Cmax (Tmax) for individual animals. Areas under the sufentanil concentration-time curves (AUC) were calculated by trapezoidal summation from 0 to 180 min and addition of the quotient of the last measured concentration/β. Data are presented in means ± SEM. Paired t-test was used to test for significant differences. Statistical significance was set at P < 0.05.
After epidural administration, sufentanil concentrations in lumbar CSF were significantly greater than in plasma or cisternal CSF at each sampling time (see Figure 1). Mean cisternal CSF concentrations were also greater than mean plasma concentrations after 5 min, but these differences were statistically significant only at 30 and 60 min after epidural administration. A rapid absorption phase followed by bi-exponential decline (redistribution, followed by elimination) of sufentanil concentration was observed in all three “compartments” (plasma, lumbar CSF, and cisternal CSF). Sufentanil appeared rapidly in lumbar CSF, reaching a calculated Cmax of 57 ng/mL at 6.5 min (Tmax) (see Table 1). In cisternal CSF, the sufentanil Cmax (1.2 ng/mL) was calculated to be reached 21 min after injection. Sufentanil also redistributed rapidly to plasma (Tmax = 6 min), but Cmax in plasma was lower (0.35 ng/mL) than for either lumbar or cisternal CSF, although this difference was not significant for cisternal CSF versus plasma.
Table 2 provides a basis for comparison of AUC ratios after epidural sufentanil administration. From the ratios of AUC's for each sampling compartment, one can see that the amount of sufentanil reaching the lumbar CSF is about 140 times that reaching plasma. Similarly, the amount of sufentanil reaching cisternal CSF is about six times that reaching plasma. The sufentanil reaching cisternal CSF is only 5% of that reaching lumbar CSF. These differences are all significant.
Within 1 min after epidural administration, we found high lumbar CSF sufentanil concentrations, reaching peak concentrations by 6.5 min. These high lumbar CSF sufentanil concentrations were maintained for at least 3 h after injection. In contrast to initial expectations, we found measurable cisternal CSF sufentanil concentrations within 1 min after a 50-μg dose of sufentanil injected into the lumbar epidural space. Although the mass of sufentanil reaching cisternal CSF during the 3-h period was only about 5% of that reaching the lumbar epidural space, peak concentrations (Cmax) were 1.2 ng/mL. Because plasma sufentanil concentrations were equal to, or lower than cisternal concentrations after the first 5 min, systemic redistribution of epidurally administered sufentanil is inadequate to completely explain the appreciable concentration of sufentanil in cisternal CSF that was observed. High lumbar CSF sufentanil concentrations would strongly favor redistribution within the subarachnoid space by mass diffusion and could explain rostral spread of sufentanil to cisternal CSF. Evidence of spread within the spinal axis also comes from comparison of AUC values, which are six times as great in cisternal CSF as in plasma. These data provide evidence that early rostral spread (i.e., within 30 min) of sufentanil within the subarachnoid space can occur in this canine model after a large lumbar epidural bolus dose.
We used a large dose of sufentanil so that concentrations several hours after injection would be measurable in all compartments, which is important for calculation of AUC and elimination half-life. This dose was about 2 μg/kg for our dogs, which is about two to six times the dose reported in human studies (6,8,9). The applicability of our data to clinical situations would then depend upon whether sufentanil absorption from the epidural space is dose-linear and whether opioid absorption from the epidural space differs between man and dog (see below). We used a total diluent volume of 5 mL, since clinically lipidsoluble opioids are often diluted to 10-15 mL total volume for lumbar epidural injection. From previous experience, we know that epidural injection of 5 mL of radio-contrast material (Isovue 300, E.R. Squibb & Sons, Princeton, NJ) at L6-7 in dogs of 22-26 kg of range will reliably spread to the mid-thoracic region, but not to the cervical epidural space (R. Stevens, R. Petty, unpublished observations). Although radio contrast material is more viscous than 0.9% NaCl, based on our epidurography experience, we do not believe that a diluent volume of 5 mL resulted in excessive rostral spread of the sufentanil in our canine model.
There are several other factors which could influence the clinical applicability of our data. What effect halothane/N2O anesthesia has on the absorption and redistribution of sufentanil from the epidural space is unknown. It appears that the spinal meninges may be a more significant barrier in the dog, at least to morphine, than in the human, and that elimination of morphine from the CSF may be slower in the human than the dog (16). Because of these differences, caution should be used in applying the observations of the present study to the clinical situation.
Durant and Yaksh used a canine model very similar to our experimental model to examine the pharmacokinetics of epidural morphine (16). They also found epidural morphine to undergo bi-exponential elimination following an initial absorption phase of drug from the epidural space into the CSF. Comparing Durant and Yaksh's data to ours for sufentanil, morphine was slower to cross the spinal meninges (Tmax 5-60 min), had a slower re-distribution phase (mean: 15 min; range: 63-180 min) and a similar terminal excretion phase (mean: 106 min; range: 63-180 min). Given higher lipid solubility of sufentanil, the faster uptake and re-distribution observed in our experiments was expected.
Sjostrom et al. sampling lumbar CSF in patients after epidural administration of morphine or meperidine, also used a tri-exponential equation to described the absorption-distribution-elimination curve for CSF opioid concentration versus time (10). They found a rapid CSF peak (Tmax) for meperidine (15-30 min), but slower for the less lipid soluble morphine (60-90 min). The average CSF half-lives for meperidine and morphine were 68 ± 5 min and 90 ± 40 min, respectively. This compares to 110 ± 22 min for sufentanil in lumbar CSF in the present study. Lipid solubility does not appear to play a determining role in elimination halflife from CSF, based on this data.
It is commonly believed that lipid solubility is an important determinant of the fraction of the dose of an opioid that diffuses across the spinal meninges (10). Absorption and deposition of opioid into epidural fat may also affect the fraction of drug available to cross the spinal meninges and reach the spinal cord, particularly for the highly lipid-soluble sufentanil (17). Lipid solubility of drugs also has been proposed as the primary determinant of spinal cord uptake of an opioid from CSF. However, other results indicate that lipid solubility may not be the major determinant of spinal cord opioid concentration after epidural dosing. Molecular weight, maximum molecular radius, charge distribution (18), or other yet undefined factors (19), e.g., pKa of the opioid may be more important than lipid solubility. Some of these factors potentially could explain the difference in rate of dural penetration between morphine and sufentanil.
Judging from results of the present study, highly lipid-soluble sufentanil appeared to spread readily from the site of administration (lumbar epidural space) to cisternal CSF. Our results contradict the usual supposition that lipophilic opioids will remain localized to spinal tissues near the site of action (10,20,21). Rapid cephalad spread of meperidine (a moderately lipid-soluble opioid) reaching cervical spinal CSF within 10 min after lumbar epidural injection also has been reported in humans (22). Therefore, the supposition that lipophilic opioids do not spread rostrally in the CSF after lumbar epidural injection is probably incorrect, and our data do not support the position that sufentanil is a priori safer for epidural analgesia than morphine.
In our canine model, we calculated that peak lumbar CSF sufentanil concentrations are reached within 6.5 min after epidural injection. Concentrations of sufentanil reach a peak in the cisterna magna within 21 min after lumbar epidural injection. This is consistent with reports of early respiratory depression in postoperative patients receiving large epidural bolus doses (>40 μg) of sufentanil (6,8,9). Presumably, respiratory depression would depend on brain drug levels at the medullary respiratory center. Durant and Yaksh (16) have shown that morphine concentration in the Azygos vein was relatively high after lumbar epidural administration. The drug concentrations in the vasculature of the epidural venous plexus (seen by spinal and supraspinal structures) may not be reflected accurately by arterial drug concentrations. Therefore, we can not conclude from our data that physiologic effects (respiratory depression) of epidural sufentanil necessarily result from rostral spread within the CSF.
High doses of sufentanil given into the lumbar epidural space result in very high peak lumbar CSF concentrations, probably far in excess of what is needed to achieve analgesia. If resultant lumbar CSF concentrations are dose-linear, smaller unit doses of sufentanil may produce less rostral spread than large doses because the Cmax in lumbar CSF and the CSF diffusion gradient would be decreased. This hypothesis warrants further testing in animal models. Because transit of sufentanil across the spinal meninges is quite rapid, small patient-controlled doses of epidural sufentanil may be the ideal way to administer this drug in clinical situations, if this hypothesis proves to be correct.
We dedicate this article to the memory of our co-author, teacher, and friend, Harlan F. Hill, PhD The authors also wish to thank Tony L. Yaksh, PhD, for his kind review of our manuscript.
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