van den Nieuwenhuyzen, Marjolein C. O. MD; Stienstra, Rudolf MD, PhD; Burm, Anton G. L. MSc, PhD; Vletter, Arie A. BSc; van Kleef, Jack W. MD, PhD
Section Editor: Denise J. Wedel.
Epidural administration of combinations of local anesthetics and opioids is an attractive and widely used treatment modality for the relief of postoperative pain. Although there is abundant evidence that neuraxial opioid administration provides effective analgesia in a variety of perioperative settings, the search continues to identify the optimal choice of opioid, as well as the usefulness of adjunctive drugs for improving analgesic efficacy and reducing side effects.
Several studies have attempted to determine whether the analgesic effect of epidurally administered fentanyl congeners is primarily spinally or supraspinally mediated [1,2]. The contribution of supraspinal effects secondary to the systemic absorption of such epidurally administered lipophilic opioids is controversial.
The slow initial absorption rate of alfentanil from the epidural space  may make this drug superior to fentanyl and sufentanil for epidural administration when systemic side effects are to be avoided, such as when it is used for postoperative pain relief. In a previous study , we were not able to show an advantage of epidural administration over IV administration of alfentanil when used alone. In that study, the administered dose was chosen so that the resulting plasma concentrations were similar and subanalgesic with both routes of administration. Because the combination of epidural opioids with local anesthetics is known to provide superior analgesia in the postoperative period, we wanted to compare the efficacy of such a combination with that of epidural administration of the same local anesthetic solution in combination with IV administration of the same opioid, resulting in similar and subanalgesic plasma concentrations in both groups. In the present study, epidural and IV infusions of alfentanil were combined with epidural bupivacaine. In this study, we intended to investigate the efficacy and the mechanism of action (i.e., binding to spinal or supraspinal opioid receptors) of epidurally administered alfentanil when combined with small-dose bupivacaine. Both regimens were chosen so that subanalgesic plasma concentrations would be obtained. If epidurally administered alfentanil combined with small-dose bupivacaine acts primarily by binding to spinal rather than supraspinal receptors, the quality of analgesia would be expected to be better in the epidural group under these conditions.
After obtaining medical ethics committee approval and informed consent, we studied 32 patients, ASA physical status I or II, aged 18-65 yr, scheduled for gynecologic laparotomies. Patients were randomly assigned to one of the two study groups. In addition, the study design was double-blind. Patients with a history of cardiovascular, pulmonary, hepatic, or renal disease were excluded from the study. Also excluded were patients who had taken opioids in the preceding month and patients with known contraindications to epidural catheter placement. Before surgery, each patient was instructed on the use of the patientcontrolled analgesia (PCA) system, as well as on the use of the visual analog scale (VAS) for pain scoring.
Premedication was with oral temazepam, 10-30 mg, 1 h before surgery. On the patient's arrival in the operating room, electrocardiogram electrodes were attached and blood pressure was measured. An IV cannula was inserted in a large forearm vein. Before lumbar puncture, a preload of 500 mL of NaCl 0.9% was given. Patients were placed in the sitting position, and the epidural puncture was performed at the L2-3 vertebral interspace with a 16-gauge Tuohy needle using a paramedian approach and a loss of resistance to saline technique for identification of the epidural space. An 18-gauge epidural catheter was inserted and advanced 5 cm cephalad into the epidural space. After the administration of a test dose of 2 mL of bupivacaine 0.5% with epinephrine 1:200,000 to exclude an inadvertent subarachnoid or intravascular location of the epidural catheter, a loading dose of 10 mL of bupivacaine 0.5% without epinephrine was administered.
Immediately after the bolus injection, the patients in the epidural group (EPI) received an epidural infusion of bupivacaine 0.125% plus alfentanil 45 [micro sign]g/mL and an IV infusion of saline, both at the rate of 8 mL/h. The patients in the IV group (IV) received an epidural infusion of bupivacaine 0.125% at a rate of 8 mL/h and an IV infusion of alfentanil 45 [micro sign]g/mL at a rate of 8 mL/h. The infusions were continued for 24 h. The dose regimen was chosen to maintain equivalent and subanalgesic plasma concentrations of alfentanil in both groups . The predicted steady-state plasma concentrations based on disposition data according to Maitre et al.  and absorption kinetic data according to Burm et al.  were <20 ng/mL, whereas the median effective analgesic concentration of alfentanil on the day of surgery for elective orthopedic surgery was approximately 50 ng/mL .
The anesthetic technique was standardized. After an appropriate (above T10) dermatomal anesthetic sensory level was obtained, patients were preoxygenated, and anesthesia was induced with alfentanil 1 mg IV and propofol 2-2.5 mg/kg until the patient had lost consciousness. After the administration of vecuronium 0.1 mg/kg, the trachea was intubated. A urinary catheter was inserted. Anesthesia in both groups was maintained with propofol, and vecuronium when indicated. Patients were ventilated with oxygen in air (fraction of inspired oxygen [FIO2] 0.33). A bolus dose of 1 mg of alfentanil was administered if signs of inadequate anesthesia developed.
After surgery, residual neuromuscular block was reversed with neostigmine after the administration of atropine. On arrival in the recovery room, all patients received the PCA device (Graseby Medical, Watford, UK).
The patient was instructed to report the onset of pain to one of the investigators. At that moment, the dermatomal anesthetic sensory level was tested and, when appropriate (above T10), the patient's pain was scored using a 10-cm VAS, and the degree of sedation was scored using the 6-point scale described by Ramsay et al. .
If the sedation score was <or=to3, the PCA system was activated by the investigator and programmed to deliver 2.5 mg of morphine. After 10 min, the patient's sedation and pain scores were again assessed, and when the patient indicated a need for additional analgesia and the sedation score was <or=to3, another 2.5 mg of morphine was delivered by the PCA pump. This was repeated at 10-min intervals until the patient, while oriented (sedation score <or=to3), indicated no need for additional analgesia and had a VAS score of <or=to3.0 for 30 min. When these criteria had been met, the loading period was ended, the PCA bolus dose was reduced to 1 mg, the lockout time was set to 5 min, and the PCA device was handed to the patient. Patients did not receive a loading dose of morphine when they reported the onset of pain after more than 2 h postoperatively.
Every 10 min during the first 2 h postoperatively and hourly during the remaining observation period, the VAS score, requests for additional analgesia, sedation score, and vital signs were documented. No VAS scores were obtained when the patient was asleep; VAS scores were then considered to be <or=to3.0. Peripheral oxygen saturation (SpO2), respiratory rate (MR10 Graseby Medical), and heart rate were continuously registered. Respiratory depression was defined as a respiration rate <8 bpm and/or SpO2 <90%.
PCA data were collected continuously. The amount of postoperatively administered morphine and the number of rewarded and unrewarded (during the lockout interval) demands were recorded. If respiratory depression developed, the continuous infusion of alfentanil and the PCA device were discontinued. Side effects observed during the postoperative period were registered. After 24 h, the epidural and IV infusions were stopped, and the study was ended. The study was discontinued when the dermatomal anesthetic sensory level was inappropriate (T10 or lower) when tested on the patient's arrival at the recovery room. At the end of the study, the epidural catheter was removed, and patients were asked whether they were satisfied with their postoperative analgesia. PCA was continued for at least 24 h after the study.
In 10 patients (5 in the EPI group, 5 in the IV group), arterial blood samples were collected before the start of the continuous infusion of alfentanil and at 5, 15, 30, 45, 60, and 90 min, as well as at 2, 3, 4, 6, 8, 12, 16, 20, and 24 h after the start of the infusion. Plasma was obtained by centrifugation and stored at -20[degree sign]C until analysis. A capillary gas chromatographic technique  was used to determine the plasma concentrations of alfentanil. The detection limit was 0.1 ng/mL plasma. The coefficient of variation in the concentration range (>1 ng/mL) encountered in this study was <7%.
Times to onset of postoperative analgesia and total morphine consumption were used as parameters to compare the efficacy of the two analgesic regimens. Power analysis based on previous observations, in which a 40% variability in morphine consumption was observed , showed that a sample size of 15 patients per group would be associated with an approximately 80% probability of detecting a 50% reduction in morphine consumption. Data were examined for normality using the Shapiro-Wilk test and are presented as mean +/- SD, mean +/- SEM, or as median and range, as appropriate. Parameters describing the efficacy of the two treatments were compared by using the two-sample t-test or the Mann-Whitney U-test, as appropriate. Demographic data were compared by using the two-sample t-test. Adverse reactions were reported as the frequency of occurrence and compared between the groups using Fisher's exact test. For each patient, the total time with pain scores >3.0 was calculated. To achieve this, the time intervals from the moment that VAS score >3.0 until the moment that either the VAS score was <or=to3.0 while the patient was awake or the patient was asleep were calculated and then compared between the two groups with the Mann-Whitney U-test. The areas under the plasma concentration of alfentanil versus time curves were determined for each patient with the linear trapezoidal rule and compared between the groups by using the two-sample t-test. A value of P < 0.05 was regarded as the minimal level of statistical significance.
We studied 32 patients, 15 in the EPI group and 17 in the IV group. In two patients in the IV group, the study was ended prematurely without breaking the codes and two other patients were substituted. In one patient the dermatomal anesthetic sensory level had regressed below T10 at arrival in the PACU. The other patient developed a temperature of >39[degree sign]C 2 h postoperatively, and the epidural catheter was removed. We excluded these two patients from the data analysis. The demographic data ([mean +/- SD age: EPI 41 +/- 8 yr, IV 47 +/- 9 yr; weight: EPI 63 +/- 6 kg, IV 67 +/- 11 kg), the duration of anesthesia (EPI 114 +/- 44 min, IV 120 +/- 49 min), and the intraoperative alfentanil consumption (EPI 1.2 +/- 0.4 mg, IV 1.3 +/- 0.7 mg) for the 30 remaining patients enrolled in the study did not differ between the groups. No patient required naloxone to restore adequate ventilation after anesthesia. All patients were breathing spontaneously on arrival at the recovery room.
There were no statistically significant differences between the two groups regarding onset of postoperative pain (EPI median 600 min, range 100-1425 min; IV median 360 min, range 30-1560 min; P > 0.2). Three patients in each group did not require morphine postoperatively. Morphine consumption in the remaining patients is shown in Table 1. Total morphine consumption over all patients (EPI median 11 mg, range 0-78 mg; IV median 10 mg, range 0-68.5 mg) did not differ between the groups (P > 0.2).
The number of rewarded (EPI median 13, range 0-126; IV median 12, range 0-119) and unrewarded (EPI median 1, range 0-48; IV median 0, range 0-78) PCA demands were similar in both groups (P > 0.2), as were times with VAS scores > 3.0 (EPI median 60 min, range 0-420 min; IV median 120 min, range 0-600 min; P > 0.2).
The measured plasma concentration of alfentanil versus time curves is shown in Figure 1. Measured plasma concentrations of alfentanil corresponded with the predicted plasma concentrations and were similar in both groups. Mean steady-state plasma concentrations (averaged samples 480-1440 min) varied from 8.5 to 18.4 ng/mL in the EPI group and from 6.7 to 14.8 ng/mL in the IV group. Areas under the plasma concentration of alfentanil versus time curves also did not differ between the EPI and IV groups.
When the patients were not asleep, sedation scores were always <3 in both groups. Respiratory rate and postoperative SpO2 were always within the clinically acceptable range. No patient developed hypotension, defined as a decrease in blood pressure of more than 15% from preoperative control values. The incidence of nausea (11 patients in the EPI group versus 12 in the IV group) and vomiting (6 patients in the EPI group and 4 patients in the IV group) did not differ between the groups. Despite these side effects, all patients were satisfied with the analgesic regimen. Median morphine consumption in the 24 h after the study period was 43 mg (range 0-72 mg) in the EPI group and 27 mg (0-51 mg) in the IV group.
Opioids are often combined with local anesthetics for postoperative epidural analgesia. Despite the widely held impression that the combination of epidural administration of local anesthetics and opioids provides superior analgesia with less untoward effects compared with epidural local anesthetics alone, the mechanism of action of epidurally administered opioids is still not clear. For lipophilic drugs, such as alfentanil, fentanyl, and sufentanil, there is no conclusive evidence demonstrating a spinal mechanism of action [1,2,4]. Almost all studies examining epidural infusions of fentanyl or sufentanil as the sole agent have demonstrated the development of effective analgesic plasma concentrations of the opioids, indicating rapid absorption of fentanyl and sufentanil from the epidural space .
The main objective of this study was to assess the scientific rationale of the epidural administration of alfentanil as an adjuvant to epidural bupivacaine for postoperative analgesia. Bupivacaine 0.125% was selected because it is the smallest concentration often used for postoperative pain relief and because it is generally insufficient for pain relief after laparotomies when given as the sole drug. In a previous study , we were not able to show an advantage of the epidural administration of alfentanil over IV administration when the drug was given alone and the administered doses were such that the resulting plasma concentrations were similar and subanalgesic with both regimens. That study therefore failed to demonstrate a spinal mechanism of action of alfentanil. This does not exclude the possibility that alfentanil may be a useful adjuvant to augment the action of epidurally administered local anesthetics. For example, if alfentanil and bupivacaine interact synergistically at the spinal level, an alfentanil dose that in itself is subtherapeutic could enhance the effect of epidural bupivacaine, thereby producing superior analgesia compared with bupivacaine alone. If this were the case, the present study should have demonstrated a spinal mechanism of action manifested by a reduction of the PCA morphine consumption. However, because morphine consumption was similar in patients receiving alfentanil by the epidural and IV routes, this study also failed to demonstrate a spinal mechanism of action of alfentanil. Thus, a type II error could have occurred in the study. As indicated in Methods, the study had an 80% probability of detecting a 50% reduction in morphine consumption, assuming a 50% variability. However, in this study, the variability was considerably larger. On the other hand, if a synergistic interaction between bupivacaine and alfentanil were present, we would predict a dose reduction greater than 50%.
Although median times to onset of postoperative pain differed considerably in both groups, the ranges are similar, and, consequently, the groups did not differ significantly. This is not unusual if data span wide ranges, in particular when data are skewed, as is the case in this study. Because we administered 60 mg of bupivacaine in the epidural space preoperatively to induce an anesthetic sensory block, we anticipated a pain-free period of at least 4 hours. Patients complained of postoperative pain 6 hours after the end of anesthesia in the IV group and 10 hours after the end of anesthesia in the EPI group. Likewise, morphine consumption in the first 8-hour postoperative period was low.
Although the bolus dose of bupivacaine was expected to provide postoperative analgesia for several hours, we started the infusions of local anesthetic and opioid directly after the bolus dose of bupivacaine 0.5% to ensure similar plasma alfentanil concentrations in both groups during the early postoperative phase. Achievement of steady-state plasma concentrations of alfentanil is expected when continuous epidural opioid infusions are administered for a prolonged time period, approximately three to four half-lives. The pharmacokinetic interaction between bupivacaine and alfentanil and the influence on the steady-state plasma concentration is unknown. Because the measured plasma concentrations of alfentanil for the patients in the EPI group were as predicted, this study showed no influence of epidurally administered bupivacaine on the steady-state plasma concentration of alfentanil.
Despite the ideal characteristics of alfentanil for epidural administration, there are few studies that have investigated the epidural administration of alfentanil for postoperative analgesia. Cooper et al.  compared the efficacy of a continuous infusion of epidural bupivacaine 0.25% with a bupivacaine 0.125%/alfentanil 0.005% mixture for analgesia during labor and found that women receiving the mixture required fewer incremental bolus doses of bupivacaine to prevent residual pain from uterine contractions. Evidence from studies of anesthesia for cesarean section suggest that there is an advantage in mixing local anesthetics with opioids for this application. The original observation leading to the use of fentanyl bupivacaine mixtures concluded that the addition of fentanyl improved bupivacaine analgesia for labor . George et al.  suggested improved analgesia with a fentanyl/bupivacaine mixture, compared with fentanyl alone or bupivacaine alone, in a group of patients who underwent abdominal aortic surgery. Other studies [13,14], however, reported that after abdominal, thoracic, or knee replacement surgery, there was no advantage in using a mixture of bupivacaine with fentanyl compared with fentanyl alone. Yet, the practice of using opioid local anesthetic mixtures for postoperative surgical pain relief has become widespread.
In summary, epidural and IV infusions of alfentanil resulting in equivalent, subanalgesic plasma concentrations of alfentanil, resulted in similar postoperative morphine consumption when combined with an epidural infusion of bupivacaine 0.125%. Under the conditions of the present study, we were therefore not able to demonstrate a spinal mechanism for action of epidurally administered alfentanil. The epidural administration of alfentanil may offer no clinical advantage over the IV route.
We thank the surgical and nursing staff of the department of gynecology, under whose care the patients were admitted, for their willing cooperation. We are grateful to B. J. A. Beuker, L. Meijer, M. Simon, M. Tyink, M. Vogt, and B. E. Zeppenfeldt for their valuable clinical assistance.
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