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Anesth Analg 2003;97:1446-1451
© 2003 International Anesthesia Research Society

PAIN MEDICINE

Spinal Mechanisms Contribute to Analgesia Produced by Epidural Sufentanil Combined with Bupivacaine for Postoperative Analgesia

Jean L. Joris, MD PhD*, Eric A. Jacob, MD*, Daniel I. Sessler, MD{dagger}, Jean-François J. Deleuse, MD*, Abdourahamane Kaba, MD*, and Maurice L. Lamy, MD*

*Department of Anesthesia and Intensive Care Medicine and {dagger}the Outcomes Research® Institute and Department of Anesthesiology, University of Louisville, Louisville, Kentucky

Address correspondence to Jean L. Joris, MD, PhD, Department of Anesthesia and Intensive Care Medicine, CHU de Liège, Domaine du Sart-Tilman, B-4000 Liège, Belgium. Address e-mail to Jean. Joris{at}chu.ulg.ac.be Reprints will not be available from the author.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
When used alone, lipid-soluble epidural opioids are thought to produce analgesia supraspinally via systemic absorption. However, spinal opioids and local anesthetics have been shown to act synergistically at the spinal level in animal studies. We, therefore, tested the hypothesis that sufentanil requirements will be less when given epidurally than IV in patients simultaneously given epidural bupivacaine after major abdominal surgery. Forty patients were anesthetized with isoflurane and epidural bupivacaine for major abdominal surgery. After surgery, each was given a continuous epidural infusion of bupivacaine at a rate of 5 mg/h and sufentanil patient-controlled analgesia (PCA). In a randomized, double-blinded fashion, the sufentanil was given either epidurally or IV. PCA settings were the same in each group. For 60 hrs after surgery, the following variables were measured: pain scores at rest, during mobilization, and during coughing; extension of sensory block; side effects; and sufentanil consumption. Pain scores, extension of sensory block, and the incidence of side effects did not differ between the two groups. Consumption of sufentanil in the epidural group was half that of the IV group (48 h after surgery: 107 ± 57 µg versus 207 ± 100 µg for the epidural and IV groups, respectively; P < 0.05). We conclude that spinal mechanisms contribute to the analgesia produced by epidural sufentanil in combination with a local anesthetic.

IMPLICATIONS: When combined with epidural bupivacaine, the sufentanil requirement was 50% less when given epidurally than IV. Epidural sufentanil thus appears to have a spinal mechanism of action.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Sufentanil, a lipophilic opioid, is often given epidurally for postoperative (1,2) and labor (3) analgesia. Lipophilic opioids such as fentanyl and sufentanil are used instead of hydrophilics such as morphine because it is thought that their lipophilicity allows them to act segmentally on opioid receptors in the dorsal horn of the spinal cord, thus minimizing supraspinal side effects. However, whether epidurally administered sufentanil acts spinally or supraspinally via systemic absorption remains controversial. For example, epidural boluses of sufentanil exceeding 10 µg produce analgesia via a spinal mechanism (4–6). In contrast, analgesia from a continuous infusion of small-dose sufentanil appears to result primarily from systemic absorption of the opioid with subsequent recirculation to supraspinal centers (7–9). In one study, even more epidural than IV sufentanil was required to provide comparable postoperative pain relief, apparently because the drug was sequestered in fat tissue surrounding the epidural space (10).

Epidural opioids are often combined with small doses of local anesthetic because these combinations might improve postoperative outcome (11) and provide better analgesia during mobilization than opioid alone (12). Furthermore, the addition of opioid to local anesthetic allows a reduction in the dose of each; consequently, the risk of side effects from either drug is reduced (13).

Animal studies suggest that small doses of a local anesthetic and an opioid such as morphine (14,15) or sufentanil (16) interact synergistically at the spinal level when both are given spinally or epidurally. These data suggest that, when combined with local anesthesia, epidural sufentanil administration will be more effective than IV administration—although sufentanil is otherwise of roughly comparable efficacy via each route. Studies of epidural bupivacaine and fentanyl also suggest synergy in obstetric patients (17–19). However, obstetric pain is particularly sensitive to spinal lipophilic opioids. Indeed, relatively small doses of these opioids given intrathecally are as effective as small doses of local anesthetics (20,21), whereas spinal morphine is poorly analgesic (22,23). We, therefore, tested the hypothesis that sufentanil requirements will be less when given epidurally than IV in patients simultaneously given epidural bupivacaine during recovery from major abdominal surgery.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
With approval of the Institution Ethics Committee at Centre Hospitalier Universitaire de Liège and informed consent, we enrolled 40 ASA physical status I–III patients who were scheduled for elective major abdominal surgery.

The patients fasted at least 6 h and were then orally premedicated with 50 mg of hydroxyzine and 0.5 mg of alprazolam 2 h before surgery. In the operating theater, an epidural catheter was inserted at the T8-9 or T9-10 interspace. After an epidural test dose (4 mL of 1% lidocaine with 1:200,000 epinephrine), 0.1 mL/kg of 0.5% bupivacaine was injected, and a continuous epidural infusion of 0.25% bupivacaine (0.1 mL · kg-1 · h-1) was started. General anesthesia was induced with propofol (2 mg/kg), sufentanil (0.25 µg/kg), and atracurium (0.5 mg/kg); anesthesia was subsequently maintained with isoflurane in a 50% oxygen/air mixture. When necessary, IV boluses of sufentanil 5 µg were given during surgery, but no epidural sufentanil was administered.

Lactated Ringer’s solution was given at 10 mL · kg-1 · h-1 throughout surgery. Intraoperative blood loss was replaced with crystalloid at a 3:1 ratio or allogeneic blood at a 1:1 ratio. Propacetamol 2 g (a precursor of paracetamol; Pro-Dafalgan®; UPSA Medica, Belgium; 2 g of propacetamol = 1 g of paracetamol or acetaminophen in the United States) was given IV 30 min before the end of surgery and at 6-h intervals throughout hospitalization.

General anesthesia was discontinued at the end of surgery. A continuous epidural infusion of 0.1% bupivacaine (5 mL/h) replaced the infusion of 0.25% bupivacaine that was used during surgery. Patients were then randomly allocated in a double-blinded manner to 2 groups (n = 20 each). Randomization was based on computer-generated codes that were maintained in sequentially numbered opaque envelopes until immediately before use. In the first group, sufentanil was given epidurally with a patient-controlled analgesia (PCA) pump; sufentanil was given IV to the remaining patients by using the same PCA pump (Pain Management Provider; Abbott, Chicago, IL).

Each PCA device was loaded with sufentanil diluted to 2.5 µg/mL, and PCA settings were identical in the 2 groups: bolus dose, 2.5 µg; lockout interval, 10 min; no basal infusion. When analgesia was considered unsatisfactory by the patient, a bolus of 5 µg was given through the pump by an anesthesiologist who was not otherwise involved in the study. Patients and observers were fully blinded to group assignment by means of a hidden three-way stopcock (24).

Pain and motor block were evaluated 4 h after surgery and at 8:00 AM, 1:00 PM, and 6:00 PM on the first and second postoperative days. Pain was scored on a 100-mm visual analog scale at rest, during mobilization (while changing from the supine to the sitting position), and when coughing (0 mm = no pain; 100 mm = worst imaginable pain). Sufentanil consumption was recorded at 4-h intervals. Motor block was evaluated with the Bromage scale (1 = no motor block, 2 = knee blocked and mobility of ankle preserved, 3 = mobility of ankle difficult, and 4 = knee and ankle blocked). The sensory block level was evaluated by response to cutaneous cold.

Respiratory rate was monitored by ward nurses every 4 h; respiratory depression was defined by a respiratory rate of <12 breaths/min. Sedation scores were also evaluated at 4-h intervals (0 = awake, 1 = drowsy, 2 = asleep, and 3 = unconscious). Episodes of nausea, vomiting, pruritus, and dysphoria were recorded. Urinary retention was not evaluated because all patients had an indwelling bladder catheter during the initial postoperative period.

Our sample-size estimate was based on anticipated epidural sufentanil consumption. A previous study1 indicated that mean epidural PCA sufentanil use over 48 h would be 100 µg with an SD of 40 µg. Fourteen patients per group would thus provide a 90% power for detecting a 50% difference between the groups at an {alpha} level of 0.05. The study size was thus prospectively set to 40 patients, with 20 assigned to each treatment group.

Continuous variables were compared by using repeated-measures analysis of variance (time and treatment) or Student’s t-test, as appropriate. Categorical data were analyzed by using Fisher’s exact tests. Continuous variables are presented as mean ± SD or SEM, as noted, and categorical variables are presented as numbers of patients. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
There were no significant differences between the two groups with regard to demographic and intraoperative data or type of surgery (Tables 1 and 2). Two patients given IV sufentanil required a single supplemental bolus of the drug, and one required two supplemental boluses. Two patients given epidural sufentanil required a single supplemental bolus. All patients except one in the epidural group had a motor block of 1 on the Bromage scale; the remaining patient had a score of 2. The incidence of opioid-related side effects did not differ significantly between the two groups. Five patients in each group experienced postoperative nausea and vomiting. No patient complained of pruritus or dysphoria. No respiratory depression was detected in either group. Seven patients in the IV group and three patients in the epidural group had a daytime sedation score of 2 (P = 0.14).


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  		Table 1. Patient Data
 

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  		Table 2. Type of Surgery
 
Epidural and IV sufentanil provided similar analgesia at rest, during mobilization, and during coughing (Fig. 1). The extension of sensory blockade in the two groups did not differ significantly (Fig. 2); however, sufentanil consumption in the IV group was twice that of the epidural group (P < 0.05; Fig. 3).



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  		Figure 1. Pain scores at rest, during mobilization, and on coughing on a 100-mm visual analog scale (VAS). Results are presented as mean ± SEM. None of the differences was statistically significant.

 


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  		Figure 2. Dermatomal extension of anesthesia as determined by response to cutaneous cold. Filled symbols indicate the upper boundary of sensory block, whereas the lower boundary is shown with open symbols. Results are presented as mean ± SEM.

 


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  		Figure 3. Sufentanil consumption (µg) after surgery. Results are presented as mean ± SEM. The difference between the two groups was statistically significant (P < 0.05) after the fourth postoperative hour.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our results demonstrate that in combination with epidural local anesthetic, sufentanil requirements are less epidurally than IV. These data are in agreement with animal studies suggesting that epidural sufentanil produces analgesia primarily by a spinal mechanism when combined with local anesthetic. This provides a rationale for combining small doses of lipid-soluble opioids with small concentrations of local anesthetic.

Epidural opioids can provide analgesia via three mechanisms: 1) transport to supraspinal receptors by cerebrospinal fluid, 2) blood-borne transport to supraspinal receptors after systemic absorption, and 3) direct stimulation of spinal opioid receptors. Epidural or spinal administration of sufentanil produces concentration gradients within the cerebrospinal fluid, with the largest concentrations being near the drug administration site (5,25–28). There is nonetheless significant cephalad spread to supraspinal opioid receptors after spinal (28) or epidural (25) administration. These studies, though, involved large doses of sufentanil (10–50 µg) given as a bolus—far more than given in this study. In contrast, small doses of lipid-soluble opioids are poorly transmitted to spinal fluid. For example, after epidural administration, the availability of sufentanil to cerebrospinal fluid was calculated to be only 0.4%–0.7% during epidural infusions and only slightly more after a bolus administration (2.7%) (5,26). A supraspinal analgesic effect after rostral cerebrospinal fluid transport thus appears unlikely to have contributed much to the excellent analgesia observed in our patients.

Morphine, a poorly lipid-soluble opioid, produces analgesia by a spinal mechanism whether administered epidurally or intrathecally (29,30). In contrast, highly soluble opioids, including fentanyl (31–33) and sufentanil (7–9), apparently produce analgesia mostly via systemic uptake and redistribution to the brain. Consumption of sufentanil in our patients was reduced by a factor of 2 when the drug was given epidurally rather than IV. Our results thus suggest that sufentanil given epidurally with small concentrations of local anesthetic produces analgesia primarily by a spinal effect rather than systemic absorption.

Menigaux et al. (10) reported that more epidural than IV sufentanil was required to relieve postoperative pain. However, their patients, who were not simultaneously given local anesthetic, required 10 times more epidural sufentanil and 3 times more IV sufentanil than our patients. This enormous difference in opioid requirement presumably results from the synergistic interaction between spinally or epidurally administered opioid and local anesthetic that has been demonstrated in animals (14–16).

Three human studies conducted in obstetric patients suggested that epidural fentanyl also has a spinal effect when combined with epidural bupivacaine (17–19), but spinal lipophilic opioids are particularly effective at alleviating obstetric pain. This greater sensitivity to lipophilic opioids might explain why studies comparing epidural and IV fentanyl for postoperative pain found no difference in opioid requirements and plasma concentrations (24,31,32), whereas Cohen et al. (19) reported that fentanyl consumption after cesarean delivery was significantly reduced when given epidurally, even in the absence of epidural local anesthetic. However, it should be noted that the use of epidural bupivacaine enhances the difference between epidural and IV fentanyl (19).

The design of our study differed from the previous obstetric studies (17–19) in several important aspects. We used sufentanil instead of fentanyl, and its administration was strictly patient controlled, without a basal infusion. The opioid and the local anesthetic were also given separately and independently. Finally, we demonstrated a reduction in the sufentanil requirement with concomitant epidural local anesthetic, whereas others reported a sparing effect on local anesthetic consumption when fentanyl was given epidurally as compared with IV. Taken together, these results suggest that the spinal effect of lipid-soluble epidural opioids combined with local anesthetic is not restricted to obstetric pain, but is also a dominant mechanism in postoperative patients.

An important aspect of our protocol was insertion of the epidural catheter at the level of the dermatomes involved in the surgery to reduce local anesthetic needs and side effects (hypotension and motor blockade). Insertion of the catheter at the appropriate dermatome is presumably more important with lipophilic than hydrophilic opioids because they are more dermatomally restricted (26,33). Consider, for example, the results of van den Nieuwenhuyzen et al. (34). They used alfentanil as an adjuvant to epidural bupivacaine and were unable to demonstrate a spinal mechanism of action for epidurally administered alfentanil. However, epidural catheters were inserted at the L2-3 level, whereas the surgery (gynecologic laparotomy) involved the dermatomes T9, T10 to T12, and L1. This may have reduced the efficacy of the spinal effect of epidural alfentanil. Furthermore, the dose of alfentanil given was much smaller than that of another study (35). The fact that the dose selected was small is confirmed by the substantial consumption of PCA morphine in many patients—despite the administration of epidural bupivacaine at 12 mg/h. Each of these factors presumably contributes to the discrepancy between van den Nieuwenhuyzen et al.’s study and others (17–19), including our current one.

A natural consequence of dermatomal restriction is that relatively small drug doses are required when lipid-soluble opioids are given at the appropriate dermatomes. The synergistic effects of combining opioids with local anesthetics further reduce required opioid doses. Not surprisingly, the incidence of opioid-related side effects was infrequent and similar in each group, although slightly more sedation was observed with IV sufentanil; this is consistent with a previous report (19).

Although the doses of epidural sufentanil administered by the patients were small (on average <2.5 µg/h), they were, nevertheless, effective because the tachyphylaxis that is usually observed when local anesthetics are used alone was prevented (36,37). Indeed, sensory block remained constant over the observation period (Fig. 2) in both our groups. This is similar to a previous finding that systemic morphine augments sensory block during continuous epidural bupivacaine (38) and, similarly, that IV fentanyl extends the level of sensory block produced by spinal bupivacaine (39,40). All these data support a spinal analgesic effect of systemic opioid when combined with epidural local anesthetic.

In conclusion, combining small-dose lipid-soluble epidural opioids with small-dose epidural bupivacaine produced excellent analgesia and minimal toxicity even after major abdominal surgery. Spinal mechanisms contributed to epidural sufentanil analgesia when combined with local anesthetic. This analgesia was presumably augmented by a synergistic reaction with bupivacaine, as suggested previously in animal studies.


   Acknowledgments
 
Supported in part by National Institutes of Health Grant GM 58273 (Bethesda, MD) and the Commonwealth of Kentucky Research Challenge Trust Fund (Louisville, KY).


   Footnotes
 
None of the authors has any personal financial interest related to this research.

Presented in part at the annual meeting of the European Society of Anaesthesiologists, Barcelona, Spain, April 25–28, 1998.

1 Davin C, Joris J, Schoofs R, Lamy M. Thoracic patient-controlled epidural analgesia using opioid-local anesthetic mixture is safe and efficient for providing pain relief after abdominal surgery. Anesthesiology 1993;(Suppl 3A):A843. Back


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 Discussion
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Accepted for publication June 3, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2003 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press