REGIONAL ANESTHESIA AND PAINMANAGEMENT Section Editor Phillip 0. Bridenbaugh
Use of Patient-Controlled Analgesia to Compare the Efficacy of Epidural to Intravenous Fentanyl Administration P. S. A. Glass, MB, BCh, P. Estok, MD, B. Ginsberg, MB, and R. N.Sladen, MB BCh, MRB(UK), FRCP(C)
BCh,
J. S. Goldberg, MD,
Department of Anesthesiology, Duke University Medical Center, and Anesthesiology Service, Veterans' Affairs Medical Center, Durham, North Carolina
Fentanyl, unlike morphine, is highly lipophilic and rapidly diffusesout of the epidural space. Respiratory depression is, therefore, unlikely when fentanyl is given epidurally. However, much of fentanyl's analgesic effect is mediated by systemic rather than spinal receptor binding. To test this hypothesis, we performed a prospective, double-blind, cross-over study comparing epidural and intravenous (IV) administration of fentanyl in 16 patients for the first 12 h after lower abdominal or lower extremity surgery. To allow direct comparison of these two routes of administration, patient-controlled analgesia was used so patients could self-titrate their analgesia. Patients were randomized to receive fentanyl initially by an epidural ( p u p A, n = 8) or IV (group B, n = 8) catheter for 6 h, after which they were crossed-over to the alternate route by means of a hidden three-way stopcock. The degree of analgesia was subjectively
0
piate analgesics are commonly used to alleviate acute postoperative pain. Isolation of spinal opiate receptors (1)and subsequent demonstration of the efficacy of epidural opiate administration resulted in increasing popularity of this route of opiate administration for pain management (2). The initial studies of epidural opiate administration demonstrated that relatively small doses of morphine provided dramatic analgesia of long duration (3), persisting long after morphine plasma concentrations decreased below accepted analgesic levels. Although morphine has a direct spinal action, its slow onset of action is secondary to its poor lipophiliaty. This results in the slow transfer of morphine across the dura into the cerebrospinal fluid, where a large depot is created that provides for a prolonged spinal analgesic effect (4). However, this depot results in Accepted for publication October 29, 1991. Address correspondence to h.Glass,Department of Anesthe siology, Box 3094, Duke University Medical Center, Durham, NC 27710. 01992 by the International Anesthesia Research Society cm3-mm.00
evaluated by a visual analogue scale, and by an observer rating patient's comfort and sedation. Cumulative dosage of fentanyl was recorded, and plasma kntanyl concentrations were measured. The onset of analgesia and increase in plasma fentanyl concentrations were more rapid with intravenous fentanyl. However, after 60 min, analgesia (visual analogue scale 2-4 an)or plasma fentanyl concentrations (0.3-0.7 ng/mL) did not differ between the two routes of administration. There were also no sigruficant differencesin the cumulative dosage of fentanyl within each group (epidural vs IV)or between the groups. Thus, the analgesic effects of epidural fentanyl appear largely mediated by systemic absorption. Intravenous fentanyl achieves a similar degree of analgesia and a more rapid onset of effect without the need for epidural catheterization. (Anesth Analg 1992;7434551)
rostral spread of morphine to the brainstem with possible pruritus, nausea, vomiting, and late respiratory depression (5). In contrast, a more lipophilic agent will have a more rapid onset of action and will also be absorbed rapidly from the cerebrospinal fluid with less risk of rostral spread. Fentanyl and sufentanil are potent opiates that are highly lipophilic (blood: oil partition coeffiaent 813 and 1778, respectively) and rapidly cross the dura. However, they may also rapidly diffuse into epidural vessels and have a primarily systemic effect. Therefore, it is important to establish if epidural administration of the more lipophilic opiates really provides an advantage over direct systemic administration. Patient-controlled analgesia (PCA) enables patients to self-titrate bolus doses of analgesic agents to their desired level of pain relief by using a programmable infusion pump. This individualizes the dose required to maintain adequate analgesia according to the patient's needs and provides a means of comparing the subjective analgesic effects of different drugs Anesth Analg 1992;74-1
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REGIONAL ANESTHESIA AND PAIN MANAGEMENT EPIDURAL VERSUS INTRAVENOUS PCA FENTANYL
GLASS ET AL.
and/or routes of administration in a heterogeneous population. This prospective, double-blind, randomized crossover study was designed to establish whether there is a difference in the dose requirements for fentanyl or in its plasma concentration when it is administered epidurally or intravenously by means of a PCA device.
Methods The study was approved by the Human Investigation Review Board of the Durham Veterans’ Affairs Medical Center. Each patient signed a written informed consent form. ASA physical status 1-111 patients admitted for lower extremity or abdominal surgical procedures that would require a potent analgesic for postoperative pain management were included. The night before surgery, patients were instructed how to use a PCA device (Abbott Life Care-Abbott Laboratories, Chicago, Ill.) and to describe pain on a visual analogue scale (VAS)-a 10-cm straight line marked with “no pain” at 0 cm and “worst imaginable pain” at 10 cm. Patients were encouraged to use the PCA to maintain a satisfactory level of pain relief. Patients were premedicated with diazepam, 10 mg orally, 1-1.5 h before surgery. Two intravenous (IV) catheters were placed, one in the antecubital fossa of the arm opposite that through which fentanyl would be administered. Before induction of anesthesia, a lumbar epidural catheter was placed at the L3-4 or L4-5 interspace. Correct position of the catheter within the epidural space was confirmed by the establishment of neural blockade after the injection of 10 mL of 1.5% lidocaine. General anesthesia was then induced with an IV induction agent and maintained with a potent volatile anesthetic. No opiate was given during the preoperative or intraoperative period. When the patients were awake enough to follow instructions after the completion of surgery, the use of the PCA device and VAS was explained again. Each PCA device was loaded with fentanyl diluted to 10 pg/mL. Patients were then randomly assigned to receive fentanyl via the PCA for the next 6 h either epidurally (group A) or intravenously (group B). The PCA device was connected to both the IV catheter and the epidural catheter by means of a hidden three-way stopcock. At the end of 6 h, the stop cock was rotated by a person not involved in the evaluation of the patient, and the treatments were crossed-over. Thus, fentanyl administration was switched from the epidural to the IV route in group A patients and from the IV to the epidural route in group B patients for the second 6 h. The patients and the evaluating nurse were blinded to the route of fentanyl administration. When patients first complained of pain, an initial
ANESTH ANALG 1992;7434551
dose of fentanyl, 1 pgkg, was administered via the PCA device either epidurally or intravenously according to the randomization schedule. All subsequent doses of fentanyl were self-administered by the patient. The maintenance dose was set at 20 pg (i.e., 2 mL) fentanyl with a lockout interval of 6 min. The cumulative fentanyl dose was recorded during the 12 h of the study. Pain relief was scored subjectively by the patient by means of the VAS before fentanyl administration and then at 1,3, 5,15,30,60, 120,240, 360, 420, 480, 600, and 720 min. At the same time intervals, the recovery room nurse independently estimated the patient’s level of observed comfort and assigned it a score as follows: 0 = none, 1 = fair, 2 = good, 3 = excellent. The level of sedation was simultaneously assessed on a four-point scale: 0 = none, 1 = drowsy, 2 = somnolent but easily arousable, 3 = asleep or somnolent and difficult to arouse. Blood samples for plasma fentanyl content were obtained from the antecubital venous catheter at 1,3, 5,15,30, 60, 120, 240, 360,420,480, 600, and 720 min after the initial dose was given. These samples were drawn into heparinized containers and placed in ice. Plasma was separated by cold centrifugation and stored at -70°C. Fentanyl concentrations were measured using a radioimmunoassay technique. The sensitivity of the assay was 0.1 ng/mL, and the coefficient of variation ranged between 5% and 9% at concentrations of 0.1 and 8.0 ng/mL, respectively. Patients were maintained in the postanesthesia care unit for the entire study duration. Multivariate tests of VAS, comfort and sedation score, cumulative fentanyl dose, and fentanyl plasma concentration were performed to assess the effectiveness and dosing of analgesia between the routes of administration. Probabilities were obtained associated with the effects of group (A or B), hour of study, and cross-over (first 6 h and second 6 h). Because data were collected hourly, a repeated measures analysis of variance, multivariate in the sequential data and with the order of the two routes of drug administration included as an independent effect, was used. Order of cross-over itself was a repeated element for each patient, so the univariate model was also set up as a repeated measures design with appropriate blocking of patients as one of the independent elements. Pearson correlation coefficients were derived to describe the relationship between VAS and plasma fentanyl concentration. A P value of less than 0.05 was considered significant.
Results Demographic data from all 16 patients are presented in Table 1. In group A, six patients had lower limb
REGIONAL ANESTHFSIA AND PAIN MANAGEMENT GLASS ET AL. EPIDURAL VERSUS INTRAVENOUS PCA FENTANYL
ANESTH ANALG 1992;7434551
Table 1. Demographic Data of Patients Studied Age (yr) Weight (kg) Height (cm) Values are mean
Group A
Group B
57.6 f 4.6 70.8 f 1.7 171.2 f 2.4
60.6 2.0 74.3 2 3.8 168.72 2.2
*
? SEM.
orthopedic procedures and two patients lower abdominal surgery. In group B, four patients had lower extremity orthopedic procedures and four patients lower abdominal procedures. The onset of analgesia was more rapid with IV than epidural fentanyl. This is illustrated by a significantly lower VAS score in group B patients at 15 min (Figure 1).Thereafter there was no significant difference in analgesia between the two routes of administration. After 2 h, patients in both groups tended to titrate their analgesia to a VAS of 2 4 cm (mild pain). Sedation and comfort scores were similar between both groups (Figures 2 and 3). There were no statistically sigruficant differences between groups A and B with respect to the cumulative hourly dose of fentanyl, the 12-h cumulative dose of fentanyl, or the cumulative doses of fentanyl during epidural or IV administration (Table 2). Within groups A and B there were no sigruficant difference between fentanyl usage in the first 6 h and second 6 h (Table 2), i.e., before and after cross-over. There were no significant differences in plasma fentanyl concentration whether it was administered epidurally or intravenously. Although fentanyl plasma concentrations were numerically higher in the first 30 min in group B (IV 6rst) than group A (epidural fust), they were not significantly different. Thereafter, plasma concentrations stabilized at 0.5 ng/mL in both groups (Figure 4). There were no signhcant differences in plasma fentanyl concentrations at equivalent time periods between the first and second 6 h. There was a high inverse correlation between VAS and plasma fentanyl concentration (i.e., VAS decreased as plasma fentanyl increased) during epidural administration (r = -0.63, P = c 0.01), but the correlation during IV administration was negligible (r = -0.03, P = 0.91).
Discussion It is almost impossible to objectively measure the quality of analgesia, making it very difficult to establish the true relative efficacy of different analgesic drugs or routes of administration. The PCA pump enables patients to self-titrate analgesia to their de-
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sired pain relief and then to maintain it at that level. In other words, PCA provides a closed-loop system that maintains a fairly constant level of analgesia for an individual patient (6). This enables effective equianalgesic comparisons to be made between different drugs and different routes of drug administration (7,8) and negates the effect of pharmacokinetic, pharmacodynamic, and psychologic variability (9). There was no difference in this study in the analgesic efficacy of epidural versus IV administration of fentanyl when patients were allowed to self-titrate their analgesic requirements using a PCA device. This was evaluated by a subjective criterion (VAS), patient observation (comfort score, sedation score), and pharmacologic data (cumulative fentanyl dose, fentanyl plasma concentration). Although the size of the groups was relatively small, retrospective power analysis estimated that this sample size, with the degree of variability obtained, would have a power of 87% in detecting a within-group difference of 125 pg in the 6-h cumulative dose of fentanyl and an 82% power of detecting a within-group 0.125-ng/mL difference in the average fentanyl plasma concentration. The patients showed no difference in baseline and subsequent VAS pain scores. This indicates that both groups started off with similar amounts of pain and that fentanyl PCA via either the epidural or IV route allowed the patients to achieve and maintain equivalent levels of analgesia. Patients in both groups were able to titrate their analgesia to a VAS of 2 4 cm (i.e., mild pain) after the first 2 h and then maintain it at this level for the remainder of the study. This degree of analgesia is consistent with the levels of analgesia that are routinely achieved with PCA (7,8). After the first hour, the analgesic efficacy of fentanyl by PCA was similar with epidural or IV administration, as were the cumulative fentanyl doses and measured plasma fentanyl concentrations. Welchew (10) reported that a single dose of 100 pg (2 mL) of epidural fentanyl resulted in sigruficant systemic concentrations of fentanyl that were within its accepted analgesic range. This is in contrast to the study by Gourlay et al. (11) in which they were unable to measure fentanyl concentrations above 0.1 ng/mL after a single epidural dose of fentanyl, 1 pgkg. Sufentanil (another highly lipid soluble opiate) given as a single dose (150 pg) either epidurally or intravenously resulted in systemic concentrations, after 15 min, that were similar irrespective of the route of administration (12). In another study, 30 pg of epidural sufentanil also provided similar plasma concentrations to those resulting from the same dose given intravenously. The epidural dose also did not provide any opioid-sparing for postoperative analgesia (13). Several studies have also compared the continuous infusion of fentanyl given either epidurally or intra-
348
REGIONAL ANESTHESIA AND PAIN MANAGEMENT EPIDURAL VERSUS INTRAVENOUS PCA FENTANYL
GLASS ET AL.
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Figure 2. Mean (? SEM) sedation scores after patient-controlled administration (PCA) of fentanyl either epidurally or intravenously. No difference was found between the two routes of administration on the level of sedation as measured on the fourpoint scale: (0 = no sedation, 1= drowsy, 2 = somnolent but easily arousable, 3 = asleep or somnolent and difficult to arouse).
venously (14-16). Loper et al. (14) found equivalent analgesia after knee surgery with either continuous epidural or IV infusion of fentanyl, with similar mean plasma fentanyl concentrations (1.8 ? 0.4 and 1.7 0.4 ng/mL, respectively). In postthoracotomy patients, a continuous infusion of fentanyl at 1.0 pg.kg-l.min-' via either a lumbar epidural or IV catheter resulted in equivalent plasma concentrations of fentanyl (1-2 ng/mL) (15). After cesarean section, the infusion rate of fentanyl required to produce adequate analgesia was similar whether given intravenously or epidurally (16). All three of
*
0
80 120 180 240 300 360 420 480 540 600 660 720 780 840
nnu (Mln Figure 3. Mean (? SEM) comfort scores after patient-controlled administration (PCA) of fentanyl either epidurally or intravenously. No difference was found between the two methods of administration in the level of comfort (0 = none, 1 = fair, 2 = good, 3 = excellent).
these studies demonstrated sustained plasma concentrations of fentanyl that exceeded 1 ng/mL after both epidural and IV administration. Additional analgesia was given for breakthrough pain in these studies but no adjustments were made to minimize the infusion rate of fentanyl. As the dose was not titrated, a relative overdose of fentanyl may have been administered via the epidural route, resulting in higher systemic concentrations than were found in our study. However, these studies support the premise that an important component of the analgesia after the epidural administration of fentanyl may be provided by its systemic absorption.
REGIONAL ANESTHESIA AND PAIN MANAGEMENT GLASS ET AL. EPIDURAL VERSUS INTRAVENOUS PCA FENTANYL
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Table 2. Dose of Fentanyl During Self-Administration via Either the Intravenous or Epidural Route Time (h) 1
2 4 6 7 8 10 12 Mean hourly cumulative dose Total epidural use Total intravenous use
Group A 157.0 213.3 309.4 389.6
f 32 f 44.3
i 69.5 f 95.8 419.6 t 89.5 462.1 t 97.5 538.9 f 122
619.6 2 151.6 56.6 f 45.1
Group B
Combined
104.6 t 32.6 152.1 f. 69.4 209.6 ? 78.6 285.9 t 148.6
130.8 f 41.4 182.7 f 64.5 259.5 f 88.3 337.8 t 132.1 372.1 f. 139.9 414.3 f 167.2 508.2 2 250.8 574.8 f 291.6 52.1 f 46.2
324.6 366.4 472.5 530.0
f 169.6 f 212.5 f 343.1
f 393
47.7 f 47.2
389.6 f 95.8
244.1
* 257.7
316.9 f 194.4
230.0 f 68.7
285.9 f 148.6
258.0 f 115.8
A
0
10
20
30
40
50
60
TIME (Yln)
Cumulativefentanyl use in micropm (? SD). The figures in bold depict the period that the patients self-administeredfentanyl via the epiduralroute.
Using the epidural route, the concentration and volume (10)of the fentanyl dose as well as the site of the epidural catheter in relation to the site of surgery is important in providing optimal analgesia with the smallest dose. We used a concentration of 10 pg/mL with a volume of 2 mL as a maintenance dose. This concentration has previously been shown to be optimal for fentanyl via the epidural route (10).To ensure the epidural catheter site was appropriate, it was inserted at the L3-4 or L45 interspace and all operations were restricted to those involving the lower extremity or lower abdomen. The use of PCA for fentanyl administration in the present study ensured that the minimal effective dose was given, so that any discrepancy in analgesic requirements between the different routes would have been evident. Under these conditions, there were no differences in fentanyl plasma concentrations between epidural and IV administration when patients self-titrated their fentanyl requirements, and analgesia was achieved at much lower plasma fentanyl concentrations than in studies in which a continuous infusion was used (14-16). Similarly, in another study, the plasma hydromorphone levels after epidural PCA were lower than those achieved by a fixed-rate continuous hydromorphone infusion that obtained the same degree of analgesia (17). Gourlay et al. (18) defined the minimal effective analgesic concentration for IV fentanyl in patients having either upper or lower abdominal surgery as 0.63 0.25 ng/mL, with an average hourly consumption of 55.8 22 pg/h (18). In the present study, whether fentanyl was given epidurally or intravenously, the hourly fentanyl consumption and resultant fentanyl plasma concentrations were similar to those reported by Gourlay et al.
*
*
B
0 60 120 180 240 300 360420 480 540 600 680 720 780 840 TINE (Ih)
Figure 4. Mean (f SEM) plasma fentanyl concentrations after patientcontrolled administration (PCA) of fentanyl either epidurally or intravenously. The plasma concentrations of fentanyl did not differ statisticallybetween the two groups during the first hour (A) or during the remaining 11 h of the study (B).
Welchew and Breen (19) have also recently compared the use of epidural fentanyl to N PCA in patients admitted for abdominal surgery. They found that both routes of fentanyl administration resulted in equally satisfactory analgesia. In their study, however, the patients receiving IV PCA fentanyl selfadministered twice the cumulative dose over 24 h of the group self-titratingtheir fentanyl via the epidural route. The patients in the two groups received different amounts of fentanyl with each request. The maintenance doses were 20 pg fentanyl in the IV group and 5 pg fentanyl in the epidural group. The cumulative or total dose for IV PCA is sigruficantly altered by the size of the maintenance dose (20,21).In Welchew and Breeds study (19),the IV maintenance dose was four times greater than the epidural maintenance dose, and this may have accounted for the differences in the cumulative dose that resulted between the two routes of fentanyl administration. In contrast to fentanyl, the epidural PCA administration of morphine or meperidine is associated with a dramatically decreased dose requirement compared
350
REGIONAL ANESTHESIA AND PAIN MANAGEMENT EPIDURAL VERSUS INTRAVENOUS PCA FENTANYL
GLASS ET AL.
with IV PCA (22). Plasma concentrations of morphine and meperidine are well below minimal effective analgesic concentration. This difference is more prominent with morphine, the less lipophilic opiate, than with meperidine because the rate and degree of systemic absorption after epidural administration of an opiate is related to its lipophilicity (23). The epidural administration of fentanyl, a highly lipophilic opiate, should result in plasma concentrations similar to those of an equal dose given intravenously. Therefore, the similar plasma fentanyl concentrations we obtained after repeated dosing, either epidurally or intravenously, are explained by the high lipophilicity of fentanyl. In addition, the EDso of intrathecal fentanyl in rats exceeds the concentration required for epidural use (24). The authors attribute the analgesia obtained from the epidural administration of fentanyl primarily to its systemic absorption and not to its effect on the pain receptors in the dorsal horn of the spinal cord. In view of the significant systemic absorption of fentanyl from the epidural space and the equal dosage requirements between epidural and systemic administration for equivalent analgesia, the value of epidural fentanyl as a sole analgesic agent is uncertain. The onset of analgesia was slower in the patients initially receiving epidural fentanyl. There are two possible explanations for this. The peak effect of IV fentanyl occurs 2-5 min after IV bolus administration (25), whereas the onset of effect after epidural administration is delayed for 10-20 min (26). This delay may be explained by the time taken for fentanyl to traverse the dura and cerebrospinal fluid and bind to opiate receptors in the neuraxis of the spinal cord. An alternative explanation may be that the analgesic effect of epidural fentanyl is mediated systemically rather than in the neuraxis, and the delay is caused by the time for systemic absorption; in our study, adequate analgesia was obtained by epidural administration once there was an adequate plasma concentration of fentanyl. We found a significant correlation between plasma fentanyl concentration and VAS pain score during epidural but not during IV fentanyl PCA administration. Blood samples were taken at fixed time intervals and independent of the time of fentanyl administration. Fentanyl displays hysteresis of its concentration-effect relationship (25), with the difference being greatest just after a bolus dose is administered. The poor correlation between fentanyl plasma concentration and VAS scores, when fentanyl was administered by intermittent IV doses via the PCA pump, may be explained by a continuously changing relationship between plasma concentration and effect. However, the administration of fentanyl by bolus dose into the epidural space results in a slower
ANESTH ANALG 1992;7434551
increase and decline in the systemic concentration (i.e., more closely resembling the plasma profile of an IV infusion), thus maintaining a more constant relationship between plasma concentration and effect. The significant correlation between plasma fentanyl concentration and VAS scores with epidural PCA would thus further support the premise that systemic absorption is responsible for a major portion of the efficacy of epidural fentanyl. In conclusion, a PCA pump was used to establish the efficacy of epidural versus IV administration of fentanyl. The onset of adequate analgesia was slower via the epidural route. However, once equieffective analgesia was obtained, both fentanyl utilization and plasma concentrations were similar between the two routes of administration. Fentanyl's high lipid solubility leads to rapid systemic absorption from the epidural space so that, unlike other less lipid soluble opiates, there is little advantage to its administration by the epidural route. Indeed, N administration of fentanyl may be preferable because the onset of action is faster and the problems of epidural catheterization are avoided.
References 1. Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science 1973;179:947-9. 2. Rawal N, Arner S, Gustafsson LL, Alvin R. Present state of epidural and intrathecal opiate analgesia-a nationwide follow I& survey in Sweden. Br j Anaest61987;59:791-9. 3. Gustafsson LL, Fridberg-Niekson S, Garle M, et al. Extradural and parenteral morphine: kinetics and effects in post operative pain. A controlled clinical study. Br J Anaesth 1982;54:1167-73. 4. Nordberg G, Hedner T, Mellstrand T, Dahlstrom B. Pharmacokinetic aspects of epidural morphine analgesia. Anesthesiology 1983;58545-51. 5. Gourlay GK, Cherry DA, Cousins MJ. Cephalad migration of morphine in CSF following lumbar epidural administration in patients with cancer pain. Pain 1985;23:317-26. 6. Tamsen A, Hartvig P, Fagerland C. Patient controlled analgesia. Part 2: Individual analgesic demands and analgesic plasma concentration of pethidine in post operative pain. Clin Pharmacokinet 1985;7:164-75. 7. Hamson DM, Sinartra R, Morgese L, Chung JH. Epidural narcotic and patient-controlled analgesia for post-cesarean section pain relief. Anesthesiology 1988;68:454-7. 8. Eisenach JC, Grice SC, Dewan DM. Patient-controlled analgesia following cesarean section: a comparison with epidural and intramuscular narcotics. Anesthesiology 1988;68:444-8. 9. Gil KM, Ginsberg B, Muir M, Sykes D, Williams DA. Patient controlled analgesia in post operative pain: the relationship of psychological factors to pain and analgesic use. Clin J Pain 1990;6:1374. 10. Welchew EA. The optimum concentration for epidural fentanyl. A double-blind comparison with and without 1:200,000 adrenaline. Anaesthesia 1983;38:103741. 11. Gourlay GK, Murphy TM, Plummer JM, Kowalski SR, Cherry DA, Cousins MJ. Pharmacokinetics of fentanyl in lumbar and cervical CSF following lumbar epidural and intravenous administration. Pain 1989;38:253-9. 12. Ionescu TI, Taverne RHT, Houweliig PL, Drost RH, Nuijten S, Van Rossum J. Pharmacokinetic study of extradural and in-
ANESTH ANALG 1992;7434551
13. 14. 15. 16. 17. 18.
19.
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trathecal sufentanil anaesthesia for major surgery. Br J Anaesth 1991;66458-64. Cohen SE, Tan S, White PF. Sufentanil analgesia following cesarian section: epidural versus intravenous administration. Anesthesiology 1988;68:129-34. Loper KA, Ready BL, Downey M, et al. Epidural and intravenous fentanyl infusions are clinically equivalent after knee surgery. Anesth Analg 1990;7072-5. Panos L, Sandler AN, Stringer DG, et al. Epidural vs intravenous fentanyl infusions in post thoracotomy patient: analgesic and pharmacokinetic effects. Anesthesiology 1990;73:A831. Ellis DJ, h4illar WL, Reisner LS. Comparison of epidural and intravenous fentanyl infusions after cesarean section. Anesthesiology 1990;72:981-6. Marlowe S, Engstrom R, White PF. Epidural patient controlled analgesia (PCA): an alternative to continuous epidural infusions. Pain 1989;3797-101. Gourlay GK, Kowalski SR, Plummer JL, Cousins MJ, Armstrong PJ. Fentanyl blood concentration-analgesic response relationship on post operative pain. Anesth Analg 1988;67:32937. Welchew EA, Breen DP. Patient controlled on demand epidural fentanyl. A comparison of patient-controlled on demand
20. 21. 22. 23. 24. 25. 26.
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fentanyl delivered epidurally or intravenously. Anaesthesia 1991;46:438-41. Owen H, Plummer JL, Armstrong I, Mather LE, Cousins MJ. Variables of patient controlled analgesia 1: bolus size. Anaesthesia 1989;44.7-10. Owen H, Huger MT, Plummer JL. Variables of patient controlled analgesia 4 the relevance of bolus dose size to supplement a background infusion. Anaesthesia 1990;45:619-22. Sjostrom S, Hartvig D, Tamsen A. Patient-controlledanalgesia with extradural morphine and pethidine. Br J Anaesth 1989; 60:35848. Bromage PR, Camporesi E, Chestnut D. Epidural narcotics for post operative analgesia. Anesth Analg 1982;59:473-80. Plummer JL, Cmielewski PL, Reynolds GD, Gourlay GK, Cherry DA. Influence of polarity on dose-response relationships of intrathecal opioids in rats. Pain 1990;40:33947. Shafer SL, Varvel JR. Pharmacokinetics, pharmacodynamics and rational opioid selection. Anesthesiology 1991;74:53-63. Rostaing S, Bonnet F, Levron JC, Vodinh J, Pluskwa F, Saada M. Effect of epidural donidine on analgesia and pharmacokinetics of epidural fentanyl in postoperative patients. Anesthesiology 1991;75:42&5.
Use of Patient-Controlled Analgesia to Compare the Efficacy of Epidural to Intravenous Fentanyl Administration P. S. A. Glass, MB, BCh, P. Estok, MD, B. Ginsberg, MB, and R. N.Sladen, MB BCh, MRB(UK), FRCP(C)
BCh,
J. S. Goldberg, MD,
Department of Anesthesiology, Duke University Medical Center, and Anesthesiology Service, Veterans' Affairs Medical Center, Durham, North Carolina
Fentanyl, unlike morphine, is highly lipophilic and rapidly diffusesout of the epidural space. Respiratory depression is, therefore, unlikely when fentanyl is given epidurally. However, much of fentanyl's analgesic effect is mediated by systemic rather than spinal receptor binding. To test this hypothesis, we performed a prospective, double-blind, cross-over study comparing epidural and intravenous (IV) administration of fentanyl in 16 patients for the first 12 h after lower abdominal or lower extremity surgery. To allow direct comparison of these two routes of administration, patient-controlled analgesia was used so patients could self-titrate their analgesia. Patients were randomized to receive fentanyl initially by an epidural ( p u p A, n = 8) or IV (group B, n = 8) catheter for 6 h, after which they were crossed-over to the alternate route by means of a hidden three-way stopcock. The degree of analgesia was subjectively
0
piate analgesics are commonly used to alleviate acute postoperative pain. Isolation of spinal opiate receptors (1)and subsequent demonstration of the efficacy of epidural opiate administration resulted in increasing popularity of this route of opiate administration for pain management (2). The initial studies of epidural opiate administration demonstrated that relatively small doses of morphine provided dramatic analgesia of long duration (3), persisting long after morphine plasma concentrations decreased below accepted analgesic levels. Although morphine has a direct spinal action, its slow onset of action is secondary to its poor lipophiliaty. This results in the slow transfer of morphine across the dura into the cerebrospinal fluid, where a large depot is created that provides for a prolonged spinal analgesic effect (4). However, this depot results in Accepted for publication October 29, 1991. Address correspondence to h.Glass,Department of Anesthe siology, Box 3094, Duke University Medical Center, Durham, NC 27710. 01992 by the International Anesthesia Research Society cm3-mm.00
evaluated by a visual analogue scale, and by an observer rating patient's comfort and sedation. Cumulative dosage of fentanyl was recorded, and plasma kntanyl concentrations were measured. The onset of analgesia and increase in plasma fentanyl concentrations were more rapid with intravenous fentanyl. However, after 60 min, analgesia (visual analogue scale 2-4 an)or plasma fentanyl concentrations (0.3-0.7 ng/mL) did not differ between the two routes of administration. There were also no sigruficant differencesin the cumulative dosage of fentanyl within each group (epidural vs IV)or between the groups. Thus, the analgesic effects of epidural fentanyl appear largely mediated by systemic absorption. Intravenous fentanyl achieves a similar degree of analgesia and a more rapid onset of effect without the need for epidural catheterization. (Anesth Analg 1992;7434551)
rostral spread of morphine to the brainstem with possible pruritus, nausea, vomiting, and late respiratory depression (5). In contrast, a more lipophilic agent will have a more rapid onset of action and will also be absorbed rapidly from the cerebrospinal fluid with less risk of rostral spread. Fentanyl and sufentanil are potent opiates that are highly lipophilic (blood: oil partition coeffiaent 813 and 1778, respectively) and rapidly cross the dura. However, they may also rapidly diffuse into epidural vessels and have a primarily systemic effect. Therefore, it is important to establish if epidural administration of the more lipophilic opiates really provides an advantage over direct systemic administration. Patient-controlled analgesia (PCA) enables patients to self-titrate bolus doses of analgesic agents to their desired level of pain relief by using a programmable infusion pump. This individualizes the dose required to maintain adequate analgesia according to the patient's needs and provides a means of comparing the subjective analgesic effects of different drugs Anesth Analg 1992;74-1
395
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and/or routes of administration in a heterogeneous population. This prospective, double-blind, randomized crossover study was designed to establish whether there is a difference in the dose requirements for fentanyl or in its plasma concentration when it is administered epidurally or intravenously by means of a PCA device.
Methods The study was approved by the Human Investigation Review Board of the Durham Veterans’ Affairs Medical Center. Each patient signed a written informed consent form. ASA physical status 1-111 patients admitted for lower extremity or abdominal surgical procedures that would require a potent analgesic for postoperative pain management were included. The night before surgery, patients were instructed how to use a PCA device (Abbott Life Care-Abbott Laboratories, Chicago, Ill.) and to describe pain on a visual analogue scale (VAS)-a 10-cm straight line marked with “no pain” at 0 cm and “worst imaginable pain” at 10 cm. Patients were encouraged to use the PCA to maintain a satisfactory level of pain relief. Patients were premedicated with diazepam, 10 mg orally, 1-1.5 h before surgery. Two intravenous (IV) catheters were placed, one in the antecubital fossa of the arm opposite that through which fentanyl would be administered. Before induction of anesthesia, a lumbar epidural catheter was placed at the L3-4 or L4-5 interspace. Correct position of the catheter within the epidural space was confirmed by the establishment of neural blockade after the injection of 10 mL of 1.5% lidocaine. General anesthesia was then induced with an IV induction agent and maintained with a potent volatile anesthetic. No opiate was given during the preoperative or intraoperative period. When the patients were awake enough to follow instructions after the completion of surgery, the use of the PCA device and VAS was explained again. Each PCA device was loaded with fentanyl diluted to 10 pg/mL. Patients were then randomly assigned to receive fentanyl via the PCA for the next 6 h either epidurally (group A) or intravenously (group B). The PCA device was connected to both the IV catheter and the epidural catheter by means of a hidden three-way stopcock. At the end of 6 h, the stop cock was rotated by a person not involved in the evaluation of the patient, and the treatments were crossed-over. Thus, fentanyl administration was switched from the epidural to the IV route in group A patients and from the IV to the epidural route in group B patients for the second 6 h. The patients and the evaluating nurse were blinded to the route of fentanyl administration. When patients first complained of pain, an initial
ANESTH ANALG 1992;7434551
dose of fentanyl, 1 pgkg, was administered via the PCA device either epidurally or intravenously according to the randomization schedule. All subsequent doses of fentanyl were self-administered by the patient. The maintenance dose was set at 20 pg (i.e., 2 mL) fentanyl with a lockout interval of 6 min. The cumulative fentanyl dose was recorded during the 12 h of the study. Pain relief was scored subjectively by the patient by means of the VAS before fentanyl administration and then at 1,3, 5,15,30,60, 120,240, 360, 420, 480, 600, and 720 min. At the same time intervals, the recovery room nurse independently estimated the patient’s level of observed comfort and assigned it a score as follows: 0 = none, 1 = fair, 2 = good, 3 = excellent. The level of sedation was simultaneously assessed on a four-point scale: 0 = none, 1 = drowsy, 2 = somnolent but easily arousable, 3 = asleep or somnolent and difficult to arouse. Blood samples for plasma fentanyl content were obtained from the antecubital venous catheter at 1,3, 5,15,30, 60, 120, 240, 360,420,480, 600, and 720 min after the initial dose was given. These samples were drawn into heparinized containers and placed in ice. Plasma was separated by cold centrifugation and stored at -70°C. Fentanyl concentrations were measured using a radioimmunoassay technique. The sensitivity of the assay was 0.1 ng/mL, and the coefficient of variation ranged between 5% and 9% at concentrations of 0.1 and 8.0 ng/mL, respectively. Patients were maintained in the postanesthesia care unit for the entire study duration. Multivariate tests of VAS, comfort and sedation score, cumulative fentanyl dose, and fentanyl plasma concentration were performed to assess the effectiveness and dosing of analgesia between the routes of administration. Probabilities were obtained associated with the effects of group (A or B), hour of study, and cross-over (first 6 h and second 6 h). Because data were collected hourly, a repeated measures analysis of variance, multivariate in the sequential data and with the order of the two routes of drug administration included as an independent effect, was used. Order of cross-over itself was a repeated element for each patient, so the univariate model was also set up as a repeated measures design with appropriate blocking of patients as one of the independent elements. Pearson correlation coefficients were derived to describe the relationship between VAS and plasma fentanyl concentration. A P value of less than 0.05 was considered significant.
Results Demographic data from all 16 patients are presented in Table 1. In group A, six patients had lower limb
REGIONAL ANESTHFSIA AND PAIN MANAGEMENT GLASS ET AL. EPIDURAL VERSUS INTRAVENOUS PCA FENTANYL
ANESTH ANALG 1992;7434551
Table 1. Demographic Data of Patients Studied Age (yr) Weight (kg) Height (cm) Values are mean
Group A
Group B
57.6 f 4.6 70.8 f 1.7 171.2 f 2.4
60.6 2.0 74.3 2 3.8 168.72 2.2
*
? SEM.
orthopedic procedures and two patients lower abdominal surgery. In group B, four patients had lower extremity orthopedic procedures and four patients lower abdominal procedures. The onset of analgesia was more rapid with IV than epidural fentanyl. This is illustrated by a significantly lower VAS score in group B patients at 15 min (Figure 1).Thereafter there was no significant difference in analgesia between the two routes of administration. After 2 h, patients in both groups tended to titrate their analgesia to a VAS of 2 4 cm (mild pain). Sedation and comfort scores were similar between both groups (Figures 2 and 3). There were no statistically sigruficant differences between groups A and B with respect to the cumulative hourly dose of fentanyl, the 12-h cumulative dose of fentanyl, or the cumulative doses of fentanyl during epidural or IV administration (Table 2). Within groups A and B there were no sigruficant difference between fentanyl usage in the first 6 h and second 6 h (Table 2), i.e., before and after cross-over. There were no significant differences in plasma fentanyl concentration whether it was administered epidurally or intravenously. Although fentanyl plasma concentrations were numerically higher in the first 30 min in group B (IV 6rst) than group A (epidural fust), they were not significantly different. Thereafter, plasma concentrations stabilized at 0.5 ng/mL in both groups (Figure 4). There were no signhcant differences in plasma fentanyl concentrations at equivalent time periods between the first and second 6 h. There was a high inverse correlation between VAS and plasma fentanyl concentration (i.e., VAS decreased as plasma fentanyl increased) during epidural administration (r = -0.63, P = c 0.01), but the correlation during IV administration was negligible (r = -0.03, P = 0.91).
Discussion It is almost impossible to objectively measure the quality of analgesia, making it very difficult to establish the true relative efficacy of different analgesic drugs or routes of administration. The PCA pump enables patients to self-titrate analgesia to their de-
347
sired pain relief and then to maintain it at that level. In other words, PCA provides a closed-loop system that maintains a fairly constant level of analgesia for an individual patient (6). This enables effective equianalgesic comparisons to be made between different drugs and different routes of drug administration (7,8) and negates the effect of pharmacokinetic, pharmacodynamic, and psychologic variability (9). There was no difference in this study in the analgesic efficacy of epidural versus IV administration of fentanyl when patients were allowed to self-titrate their analgesic requirements using a PCA device. This was evaluated by a subjective criterion (VAS), patient observation (comfort score, sedation score), and pharmacologic data (cumulative fentanyl dose, fentanyl plasma concentration). Although the size of the groups was relatively small, retrospective power analysis estimated that this sample size, with the degree of variability obtained, would have a power of 87% in detecting a within-group difference of 125 pg in the 6-h cumulative dose of fentanyl and an 82% power of detecting a within-group 0.125-ng/mL difference in the average fentanyl plasma concentration. The patients showed no difference in baseline and subsequent VAS pain scores. This indicates that both groups started off with similar amounts of pain and that fentanyl PCA via either the epidural or IV route allowed the patients to achieve and maintain equivalent levels of analgesia. Patients in both groups were able to titrate their analgesia to a VAS of 2 4 cm (i.e., mild pain) after the first 2 h and then maintain it at this level for the remainder of the study. This degree of analgesia is consistent with the levels of analgesia that are routinely achieved with PCA (7,8). After the first hour, the analgesic efficacy of fentanyl by PCA was similar with epidural or IV administration, as were the cumulative fentanyl doses and measured plasma fentanyl concentrations. Welchew (10) reported that a single dose of 100 pg (2 mL) of epidural fentanyl resulted in sigruficant systemic concentrations of fentanyl that were within its accepted analgesic range. This is in contrast to the study by Gourlay et al. (11) in which they were unable to measure fentanyl concentrations above 0.1 ng/mL after a single epidural dose of fentanyl, 1 pgkg. Sufentanil (another highly lipid soluble opiate) given as a single dose (150 pg) either epidurally or intravenously resulted in systemic concentrations, after 15 min, that were similar irrespective of the route of administration (12). In another study, 30 pg of epidural sufentanil also provided similar plasma concentrations to those resulting from the same dose given intravenously. The epidural dose also did not provide any opioid-sparing for postoperative analgesia (13). Several studies have also compared the continuous infusion of fentanyl given either epidurally or intra-
348
REGIONAL ANESTHESIA AND PAIN MANAGEMENT EPIDURAL VERSUS INTRAVENOUS PCA FENTANYL
GLASS ET AL.
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60 120 180 240 300 360 420 480 540 600 660 720 780 840 Time (Mln )
Figure 2. Mean (? SEM) sedation scores after patient-controlled administration (PCA) of fentanyl either epidurally or intravenously. No difference was found between the two routes of administration on the level of sedation as measured on the fourpoint scale: (0 = no sedation, 1= drowsy, 2 = somnolent but easily arousable, 3 = asleep or somnolent and difficult to arouse).
venously (14-16). Loper et al. (14) found equivalent analgesia after knee surgery with either continuous epidural or IV infusion of fentanyl, with similar mean plasma fentanyl concentrations (1.8 ? 0.4 and 1.7 0.4 ng/mL, respectively). In postthoracotomy patients, a continuous infusion of fentanyl at 1.0 pg.kg-l.min-' via either a lumbar epidural or IV catheter resulted in equivalent plasma concentrations of fentanyl (1-2 ng/mL) (15). After cesarean section, the infusion rate of fentanyl required to produce adequate analgesia was similar whether given intravenously or epidurally (16). All three of
*
0
80 120 180 240 300 360 420 480 540 600 660 720 780 840
nnu (Mln Figure 3. Mean (? SEM) comfort scores after patient-controlled administration (PCA) of fentanyl either epidurally or intravenously. No difference was found between the two methods of administration in the level of comfort (0 = none, 1 = fair, 2 = good, 3 = excellent).
these studies demonstrated sustained plasma concentrations of fentanyl that exceeded 1 ng/mL after both epidural and IV administration. Additional analgesia was given for breakthrough pain in these studies but no adjustments were made to minimize the infusion rate of fentanyl. As the dose was not titrated, a relative overdose of fentanyl may have been administered via the epidural route, resulting in higher systemic concentrations than were found in our study. However, these studies support the premise that an important component of the analgesia after the epidural administration of fentanyl may be provided by its systemic absorption.
REGIONAL ANESTHESIA AND PAIN MANAGEMENT GLASS ET AL. EPIDURAL VERSUS INTRAVENOUS PCA FENTANYL
ANESTH ANALG ~
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349
Table 2. Dose of Fentanyl During Self-Administration via Either the Intravenous or Epidural Route Time (h) 1
2 4 6 7 8 10 12 Mean hourly cumulative dose Total epidural use Total intravenous use
Group A 157.0 213.3 309.4 389.6
f 32 f 44.3
i 69.5 f 95.8 419.6 t 89.5 462.1 t 97.5 538.9 f 122
619.6 2 151.6 56.6 f 45.1
Group B
Combined
104.6 t 32.6 152.1 f. 69.4 209.6 ? 78.6 285.9 t 148.6
130.8 f 41.4 182.7 f 64.5 259.5 f 88.3 337.8 t 132.1 372.1 f. 139.9 414.3 f 167.2 508.2 2 250.8 574.8 f 291.6 52.1 f 46.2
324.6 366.4 472.5 530.0
f 169.6 f 212.5 f 343.1
f 393
47.7 f 47.2
389.6 f 95.8
244.1
* 257.7
316.9 f 194.4
230.0 f 68.7
285.9 f 148.6
258.0 f 115.8
A
0
10
20
30
40
50
60
TIME (Yln)
Cumulativefentanyl use in micropm (? SD). The figures in bold depict the period that the patients self-administeredfentanyl via the epiduralroute.
Using the epidural route, the concentration and volume (10)of the fentanyl dose as well as the site of the epidural catheter in relation to the site of surgery is important in providing optimal analgesia with the smallest dose. We used a concentration of 10 pg/mL with a volume of 2 mL as a maintenance dose. This concentration has previously been shown to be optimal for fentanyl via the epidural route (10).To ensure the epidural catheter site was appropriate, it was inserted at the L3-4 or L45 interspace and all operations were restricted to those involving the lower extremity or lower abdomen. The use of PCA for fentanyl administration in the present study ensured that the minimal effective dose was given, so that any discrepancy in analgesic requirements between the different routes would have been evident. Under these conditions, there were no differences in fentanyl plasma concentrations between epidural and IV administration when patients self-titrated their fentanyl requirements, and analgesia was achieved at much lower plasma fentanyl concentrations than in studies in which a continuous infusion was used (14-16). Similarly, in another study, the plasma hydromorphone levels after epidural PCA were lower than those achieved by a fixed-rate continuous hydromorphone infusion that obtained the same degree of analgesia (17). Gourlay et al. (18) defined the minimal effective analgesic concentration for IV fentanyl in patients having either upper or lower abdominal surgery as 0.63 0.25 ng/mL, with an average hourly consumption of 55.8 22 pg/h (18). In the present study, whether fentanyl was given epidurally or intravenously, the hourly fentanyl consumption and resultant fentanyl plasma concentrations were similar to those reported by Gourlay et al.
*
*
B
0 60 120 180 240 300 360420 480 540 600 680 720 780 840 TINE (Ih)
Figure 4. Mean (f SEM) plasma fentanyl concentrations after patientcontrolled administration (PCA) of fentanyl either epidurally or intravenously. The plasma concentrations of fentanyl did not differ statisticallybetween the two groups during the first hour (A) or during the remaining 11 h of the study (B).
Welchew and Breen (19) have also recently compared the use of epidural fentanyl to N PCA in patients admitted for abdominal surgery. They found that both routes of fentanyl administration resulted in equally satisfactory analgesia. In their study, however, the patients receiving IV PCA fentanyl selfadministered twice the cumulative dose over 24 h of the group self-titratingtheir fentanyl via the epidural route. The patients in the two groups received different amounts of fentanyl with each request. The maintenance doses were 20 pg fentanyl in the IV group and 5 pg fentanyl in the epidural group. The cumulative or total dose for IV PCA is sigruficantly altered by the size of the maintenance dose (20,21).In Welchew and Breeds study (19),the IV maintenance dose was four times greater than the epidural maintenance dose, and this may have accounted for the differences in the cumulative dose that resulted between the two routes of fentanyl administration. In contrast to fentanyl, the epidural PCA administration of morphine or meperidine is associated with a dramatically decreased dose requirement compared
350
REGIONAL ANESTHESIA AND PAIN MANAGEMENT EPIDURAL VERSUS INTRAVENOUS PCA FENTANYL
GLASS ET AL.
with IV PCA (22). Plasma concentrations of morphine and meperidine are well below minimal effective analgesic concentration. This difference is more prominent with morphine, the less lipophilic opiate, than with meperidine because the rate and degree of systemic absorption after epidural administration of an opiate is related to its lipophilicity (23). The epidural administration of fentanyl, a highly lipophilic opiate, should result in plasma concentrations similar to those of an equal dose given intravenously. Therefore, the similar plasma fentanyl concentrations we obtained after repeated dosing, either epidurally or intravenously, are explained by the high lipophilicity of fentanyl. In addition, the EDso of intrathecal fentanyl in rats exceeds the concentration required for epidural use (24). The authors attribute the analgesia obtained from the epidural administration of fentanyl primarily to its systemic absorption and not to its effect on the pain receptors in the dorsal horn of the spinal cord. In view of the significant systemic absorption of fentanyl from the epidural space and the equal dosage requirements between epidural and systemic administration for equivalent analgesia, the value of epidural fentanyl as a sole analgesic agent is uncertain. The onset of analgesia was slower in the patients initially receiving epidural fentanyl. There are two possible explanations for this. The peak effect of IV fentanyl occurs 2-5 min after IV bolus administration (25), whereas the onset of effect after epidural administration is delayed for 10-20 min (26). This delay may be explained by the time taken for fentanyl to traverse the dura and cerebrospinal fluid and bind to opiate receptors in the neuraxis of the spinal cord. An alternative explanation may be that the analgesic effect of epidural fentanyl is mediated systemically rather than in the neuraxis, and the delay is caused by the time for systemic absorption; in our study, adequate analgesia was obtained by epidural administration once there was an adequate plasma concentration of fentanyl. We found a significant correlation between plasma fentanyl concentration and VAS pain score during epidural but not during IV fentanyl PCA administration. Blood samples were taken at fixed time intervals and independent of the time of fentanyl administration. Fentanyl displays hysteresis of its concentration-effect relationship (25), with the difference being greatest just after a bolus dose is administered. The poor correlation between fentanyl plasma concentration and VAS scores, when fentanyl was administered by intermittent IV doses via the PCA pump, may be explained by a continuously changing relationship between plasma concentration and effect. However, the administration of fentanyl by bolus dose into the epidural space results in a slower
ANESTH ANALG 1992;7434551
increase and decline in the systemic concentration (i.e., more closely resembling the plasma profile of an IV infusion), thus maintaining a more constant relationship between plasma concentration and effect. The significant correlation between plasma fentanyl concentration and VAS scores with epidural PCA would thus further support the premise that systemic absorption is responsible for a major portion of the efficacy of epidural fentanyl. In conclusion, a PCA pump was used to establish the efficacy of epidural versus IV administration of fentanyl. The onset of adequate analgesia was slower via the epidural route. However, once equieffective analgesia was obtained, both fentanyl utilization and plasma concentrations were similar between the two routes of administration. Fentanyl's high lipid solubility leads to rapid systemic absorption from the epidural space so that, unlike other less lipid soluble opiates, there is little advantage to its administration by the epidural route. Indeed, N administration of fentanyl may be preferable because the onset of action is faster and the problems of epidural catheterization are avoided.
References 1. Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science 1973;179:947-9. 2. Rawal N, Arner S, Gustafsson LL, Alvin R. Present state of epidural and intrathecal opiate analgesia-a nationwide follow I& survey in Sweden. Br j Anaest61987;59:791-9. 3. Gustafsson LL, Fridberg-Niekson S, Garle M, et al. Extradural and parenteral morphine: kinetics and effects in post operative pain. A controlled clinical study. Br J Anaesth 1982;54:1167-73. 4. Nordberg G, Hedner T, Mellstrand T, Dahlstrom B. Pharmacokinetic aspects of epidural morphine analgesia. Anesthesiology 1983;58545-51. 5. Gourlay GK, Cherry DA, Cousins MJ. Cephalad migration of morphine in CSF following lumbar epidural administration in patients with cancer pain. Pain 1985;23:317-26. 6. Tamsen A, Hartvig P, Fagerland C. Patient controlled analgesia. Part 2: Individual analgesic demands and analgesic plasma concentration of pethidine in post operative pain. Clin Pharmacokinet 1985;7:164-75. 7. Hamson DM, Sinartra R, Morgese L, Chung JH. Epidural narcotic and patient-controlled analgesia for post-cesarean section pain relief. Anesthesiology 1988;68:454-7. 8. Eisenach JC, Grice SC, Dewan DM. Patient-controlled analgesia following cesarean section: a comparison with epidural and intramuscular narcotics. Anesthesiology 1988;68:444-8. 9. Gil KM, Ginsberg B, Muir M, Sykes D, Williams DA. Patient controlled analgesia in post operative pain: the relationship of psychological factors to pain and analgesic use. Clin J Pain 1990;6:1374. 10. Welchew EA. The optimum concentration for epidural fentanyl. A double-blind comparison with and without 1:200,000 adrenaline. Anaesthesia 1983;38:103741. 11. Gourlay GK, Murphy TM, Plummer JM, Kowalski SR, Cherry DA, Cousins MJ. Pharmacokinetics of fentanyl in lumbar and cervical CSF following lumbar epidural and intravenous administration. Pain 1989;38:253-9. 12. Ionescu TI, Taverne RHT, Houweliig PL, Drost RH, Nuijten S, Van Rossum J. Pharmacokinetic study of extradural and in-
ANESTH ANALG 1992;7434551
13. 14. 15. 16. 17. 18.
19.
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trathecal sufentanil anaesthesia for major surgery. Br J Anaesth 1991;66458-64. Cohen SE, Tan S, White PF. Sufentanil analgesia following cesarian section: epidural versus intravenous administration. Anesthesiology 1988;68:129-34. Loper KA, Ready BL, Downey M, et al. Epidural and intravenous fentanyl infusions are clinically equivalent after knee surgery. Anesth Analg 1990;7072-5. Panos L, Sandler AN, Stringer DG, et al. Epidural vs intravenous fentanyl infusions in post thoracotomy patient: analgesic and pharmacokinetic effects. Anesthesiology 1990;73:A831. Ellis DJ, h4illar WL, Reisner LS. Comparison of epidural and intravenous fentanyl infusions after cesarean section. Anesthesiology 1990;72:981-6. Marlowe S, Engstrom R, White PF. Epidural patient controlled analgesia (PCA): an alternative to continuous epidural infusions. Pain 1989;3797-101. Gourlay GK, Kowalski SR, Plummer JL, Cousins MJ, Armstrong PJ. Fentanyl blood concentration-analgesic response relationship on post operative pain. Anesth Analg 1988;67:32937. Welchew EA, Breen DP. Patient controlled on demand epidural fentanyl. A comparison of patient-controlled on demand
20. 21. 22. 23. 24. 25. 26.
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fentanyl delivered epidurally or intravenously. Anaesthesia 1991;46:438-41. Owen H, Plummer JL, Armstrong I, Mather LE, Cousins MJ. Variables of patient controlled analgesia 1: bolus size. Anaesthesia 1989;44.7-10. Owen H, Huger MT, Plummer JL. Variables of patient controlled analgesia 4 the relevance of bolus dose size to supplement a background infusion. Anaesthesia 1990;45:619-22. Sjostrom S, Hartvig D, Tamsen A. Patient-controlledanalgesia with extradural morphine and pethidine. Br J Anaesth 1989; 60:35848. Bromage PR, Camporesi E, Chestnut D. Epidural narcotics for post operative analgesia. Anesth Analg 1982;59:473-80. Plummer JL, Cmielewski PL, Reynolds GD, Gourlay GK, Cherry DA. Influence of polarity on dose-response relationships of intrathecal opioids in rats. Pain 1990;40:33947. Shafer SL, Varvel JR. Pharmacokinetics, pharmacodynamics and rational opioid selection. Anesthesiology 1991;74:53-63. Rostaing S, Bonnet F, Levron JC, Vodinh J, Pluskwa F, Saada M. Effect of epidural donidine on analgesia and pharmacokinetics of epidural fentanyl in postoperative patients. Anesthesiology 1991;75:42&5.
