There have been controversies concerning the relative merits of epidural opioid and local anesthetics given alone or in combination (1–4) and whether fentanyl is appropriate for epidural use if, as some have maintained, its primary mechanism of analgesia occurs through systemic absorption (4–9). Two recent studies in nonsurgical obstetric patients using a fixed dose of IV or epidural fentanyl along with a variable dose of epidural bupivacaine demonstrated that epidural fentanyl is responsible for a local anesthetic sparing effect when compared to IV fentanyl and concluded, therefore, that epidural fentanyl acts by a primary spinal mechanism (10,11).
We tested the hypotheses that epidural fentanyl in postsurgical obstetric patients also acts primarily by a spinal mechanism and that the opioid sparing effect that we have seen (3,12) when very small dose local anesthetic plus epinephrine is administered epidurally together with fentanyl requires an interaction of these drugs at the spinal level. We compared the use of fentanyl administered by patient-controlled analgesia (PCA) epidurally or IV with or without bupivacaine and epinephrine infused at a constant rate into the epidural space. In addition, we compared the effects of these treatments on neurobehavioral scores of breast-fed neonates and determined plasma and colostrum fentanyl concentrations in a subset of patients from each group.
Materials and Methods
This study was approved by the IRB of UMDNJ-Robert Wood Johnson Medical School and written informed consent was obtained from each patient. We studied 100 ASA physical status I–II parturients at term who were scheduled to undergo elective cesarean delivery under epidural anesthesia. This sample size was determined from a power analysis designed to detect a 30% or larger difference in total fentanyl dose used during the 48-h study period between the groups receiving epidural versus IV opioid. Patients with a history of known dependence on opioids, allergy to local anesthetics, or accidental dural puncture were excluded from the study.
After the patients received an IV infusion of 1.5–2 L of lactated Ringer’s solution, continuous lumbar epidural anesthesia to achieve a T4–6 sensory level was established by injecting 3 mL followed by 18 mL of lidocaine 2%, fentanyl 5 μg/mL, and epinephrine 5 μg/mL via a closed end Braun 19-gauge catheter (B. Braun Medical Inc., Bethlehem, PA) placed at the L3–4 interspace. The catheter was directed cephalad 5 cm into the epidural space. All patients had a urethral catheter placed. During surgery, the patients were maintained supine with left uterine displacement and monitored continuously with an automated blood pressure cuff, electrocardiogram, and pulse oximeter. Oxygen was supplied by face mask at 6 L/min until the baby was delivered. No additional opioids were administered before the delivery of the baby. After delivery, oxytocin 0.02 U/mL was infused for a duration of 6–8 h.
On arrival in the postanesthesia care unit (PACU), patients were randomly allocated in a double-blinded fashion to four equal groups according to a previously generated table of random numbers. Groups I-BeFe (epidural bupivacaine and epidural fentanyl) and II-BeFi (epidural bupivacaine and intravenous fentanyl) received a continuous 12 mL/h epidural infusion of bupivacaine (0.015%) with epinephrine (1 μg/mL) for 48 h. Groups III-SeFi (epidural saline and intravenous fentanyl) and IV-SeFe (epidural saline and epidural fentanyl) received a 12 mL/h epidural saline infusion for 48 h. Fentanyl (20 μg/mL) was administered via a portable PCA-device (Abbott Pain Management Provider; Abbott Laboratories, North Chicago, IL) either into the epidural infusion (Groups I-BeFe and IV-SeFe) or IV (Groups II-BeFi and III-SeFi). The epidural bupivacaine and saline solutions were prepared in 800-mL coded bags and the fentanyl solutions were prepared in 100-mL bags. The fentanyl-PCA device was connected to both the IV catheter and the epidural catheter by means of a hidden three-way stopcock. Neither the investigator involved in the management and assessment of the patient nor the patient was aware of which epidural infusion solution was being given or the route of administration of the fentanyl solution. Each patient received an initial fentanyl infusion of 2 mL/h (20 μg/mL) and was allowed self-administered PCA boluses of 1 mL (20 μg/mL) with a 10-min lockout time; 6 boluses were allowed in 1 h.
Every 4 h, or sooner if requested, an investigator evaluated the patient for side effects, complications, and quality of analgesia. Pain intensity at rest was assessed by using a 10-point linear visual analog scale (VAS; 0 = no pain, 10 = the worst pain imaginable). If necessary to provide satisfactory analgesia, the investigator increased the infusion rate of fentanyl by 0.5 mL/h and administered additional 1–3 mL boluses in an attempt to achieve a pain score of <3. A decision to decrease the hourly dose was made jointly by the patient and the investigator. If no PCA requests had been made and no rescue doses had been needed during the preceding 4-h interval, the investigator offered to reduce the infusion rate by 0.5 mL/h. If the patient refused, the hourly dose was not reduced. The patients were assessed for incidence of any pruritus, facial pruritus (as indication of rostral opioid spread), sedation, nausea, vomiting, backache, urinary retention, and uncomfortable uterine cramping. The severity of pruritus and sedation was assessed using a 10-point scale (0 = none, 10 = worst imaginable). At the patient’s request, severe pruritus or severe sedation was treated by administering increments of IV naloxone 0.04 mg until relief was achieved. Nausea and vomiting were treated by administering IV metoclopramide 10 mg. Time to resume a liquid diet, as well as the time to pass flatus, duration of urethral catheterization, and duration of hospitalization were recorded. The incidence of side effects indicates the number of patients in whom the side effect occurred regardless of duration or the number of time intervals during which it occurred. Motor block was assessed using a score modified from that described by Bromage (13), (1 = complete block, unable to move feet or knees; 6 = able to perform partial knee bend while standing).
Patients received no additional systemic opioids, nonsteroidal analgesics or sedatives during treatment. Each patient had IV access throughout. Blood pressure, pulse, respiratory rate and adequacy of respiration were monitored every 1–2 h by a nurse during the treatment. Twelve hours after surgery, if patients demonstrated normal leg strength (Modified Bromage score at least 5), an attempt was made to let the patient ambulate. Heart rate and blood pressure were measured by nurses before and 2 min after the start of each ambulation to assess orthostatic hypotension, defined as a decrease in systolic blood pressure 20% from baseline, and bradycardia, defined as a heart rate less than 60 bpm. Symptoms of dizziness, nausea, or vomiting were also recorded. Nurses were instructed not to allow any patient with evidence of hypotension, bradycardia, or dizziness to ambulate. Overall satisfaction with treatment was assessed at the termination of treatment by using a 10-point VAS (0 = no satisfaction, 10 = best satisfaction). Breast-fed neonates were assessed at 1 h and 48 h of life by a pediatric nurse practitioner blinded to the solution administered, using the Neurologic and Adaptive Capacity Score (14).
Concentration of fentanyl was measured in samples of blood and/or colostrum obtained from patients arbitrarily selected from each group. Blood was drawn from an antecubital vein of the arm contralateral to the one with an IV line at 0, 24, and 48 h of the epidural infusion. Colostrum samples were collected at 24 and 48 h of the epidural infusion and shortly before discharge from the hospital. Colostrum samples and (after centrifuging blood) plasma samples were stored at −20°C until analysis. Plasma and colostrum concentrations of fentanyl were determined using a radioimmunoassay kit (Diagnostic Products Corporation, Los Angeles, CA) for both plasma and colostrum. The assay has a limit of detection of 0.1 ng/mL and intra- and interassay coefficients of variation were 3.3%–4.0% and 4.9%–6.7% respectively.
Data are presented as mean ± sd except for side effects, which are expressed as incidence. Data measured over time were analyzed by repeated-measures analysis of variance and overall differences between groups were assessed by contrasts. Data expressed as an average or sum of all values obtained during the 48 h of the study were analyzed by analysis of variance with a Bonferroni/Dunn post hoc test. Categorical variables were analyzed by using Fisher’s exact test or χ2 as appropriate. Data from the few patients who did not complete the study were excluded from analyses that required summation of data over time, but were otherwise included throughout their period of participation. Data that were not normally distributed were log transformed before analysis. A P value of <0.05 was considered significant.
The groups did not differ in age or parity. Weight and height of Group III-SeFi were slightly less than those of Group I-BeFe (P < 0.05). Ninety-two patients completed the study. The treatment was discontinued because of lightheadedness from IV fentanyl in four patients (two in Group II-BeFi and two in Group III-SeFi) and because of a dislodged epidural catheter in four patients in Group IV-SeFe. At 24 h, there were 25, 25, 25, and 24 patients in Groups I-BeFe, II-BeFi, III-SeFi, and IV-SeFe respectively, and at 48 h, there were 25, 23, 23, and 21 patients in the respective groups.
The mean fentanyl infusion rate during successive intervals of the 48-h study was less among patients in Group I-BeFe (Fig. 1, P < 0.001) than among patients in the other three groups and less among patients in Group IV-SeFe compared with those in Group II-BeFi and Group III-SeFi (P < 0.001). The mean infused dose and total dose of fentanyl during the 48 h of the study were less among patients in Group I-BeFe (Table 1, P < 0.02) compared with all other patients and were more among patients in Groups II-BeFi and III-SeFi than among those in Group IV-SeFe (Table 1, P < 0.05). Total PCA attempts during the 48 h study were more among patients in Group III-SeFi than Groups I-BeFe and II-BeFi (Table 1, P < 0.05). However, actual doses delivered from the PCA device did not differ among the groups.
Groups in which patients received fentanyl IV (II-BeFi and III-SeFi) had greater mean pain scores than those in which patients received epidural fentanyl (I-BeFe and IV-SeFe) (P < 0.001, Fig. 2). Overall, satisfaction scores were high (9.7 ± 0.5, 8.8 ± 1.3, 8.6 ± 1.3, and 8.9 ± 1.4 for Groups I to IV, respectively) but that of Group III-SeFi was significantly (P < 0.05) less than that of Group I-BeFe. No patient had fewer than 12 respirations/min during the study. Clinically significant motor block (modified Bromage score <6), hypotension at rest, orthostatic hypotension or bradycardia on ambulation, did not develop in any patient. Time to removal of the urethral catheter ranged from 13 to 17 h. No patient developed urinary retention after the removal of the urethral catheter. No patient complained of severe backache or back pressure during this treatment. No patient dropped out because of inadequate pain control.
Table 2 shows the incidence of side effects and complications. Patients in Group II-BeFi made significantly (P < 0.01) fewer requests for treatment of pruritus than the other groups. No patient complained of facial pruritus. Groups in which patients received fentanyl epidurally (I-BeFe and IV-SeFe) had a less frequent incidence of excessive sedation (score >3) than did groups in which patients received IV fentanyl (II-BeFi and III-SeFi, P < 0.01). There was an increased incidence of nausea in groups in which patients received IV fentanyl (II-BeFi and III-SeFi) than in those in which patients received fentanyl epidurally (I-BeFe and IV-SeFe, P < 0.04). There was also a more frequent incidence of vomiting among patients in Groups II-BeFi and III-SeFi than those in Group I-BeFe and Group IV-SeFe (P < 0.05). Patients in Group I-BeFe reported a less frequent incidence of uterine cramping (P < 0.05) than did patients in Group IV-SeFe. Groups in which patients received fentanyl IV (Group II-BeFi and Group III-SeFi) required a longer time to resume a liquid diet than those in which patients received fentanyl epidurally (I-BeFe and IV-SeFe, P < 0.05), and patients in Group III-SeFi also required a longer time to passage of flatus than those in Groups I-BeFe and IV-SeFe (P < 0.05). The mean hospital stay, which did not differ among the groups, was 4.4 ± 0.7, 3.9 ± 0.8, 4.2 ± 1.0, and 3.9 ± 1.2 days for Groups I to IV, respectively.
We performed an additional analysis comparing all patients receiving epidural fentanyl (Groups I-BeFe and IV-SeFe) with all patients receiving IV fentanyl (Groups II-BeFi and III-SeFi). Patients receiving epidural fentanyl had a slower average infusion rate (2.8 ± 1.0 mL/h versus 4.8 ± 1.3 mL/h, P < 0.0001), required less total opioid 3584 ± 1252 μg versus 5952 ± 1719 μg, P < 0.0001), and had a less frequent incidence (P < 0.01) of nausea (8% versus 34%), sedation (68% versus 96%) and vomiting (6% versus 24%) than those receiving IV fentanyl.
For breast-fed babies, there were no differences among treatment groups with respect to mean neonatal adaptive or neurologic capacity or cumulative scores at either 1 or 48 h of life. The cumulative scores at 1 and 48 h were 37.3 ± 2.3 and 39.2 ± 0.8, 38.2 ± 1.5, and 39.4 ± 1.4, 37.6 ± 1.8 and 39.5 ± 0.8, 37.8 ± 1.7, and 38.8 ± 1.5 for Group I (n = 9), II (n = 8), III (n = 13), and IV (n = 11) respectively.
Plasma concentrations of fentanyl are shown in Table 3. Fentanyl plasma concentrations were larger in patients receiving fentanyl IV (Group II-BeFi and Group III-SeFi) than among patients receiving fentanyl epidurally (Group I-BeFe and Group IV-SeFe, P < 0.001) at 24 and 48 h of the study. It was not possible to analyze statistically the data for concentration of fentanyl in colostrum because parturients were not able to repeatedly express sufficient colostrum for analysis. Fentanyl concentrations in colostrum ranged from not detectable to 5.5 ng/mL. The greatest observed values were as follows: Group I, 1.8 ng/mL; Group II, 4.8 ng/mL; Group III, 5.5 ng/mL; and Group IV, 3.1 ng/mL.
Our data in parturients after cesarean delivery clearly demonstrate that fentanyl administered into the epidural space, with or without bupivacaine and epinephrine, provides superior analgesia with significantly fewer side effects, reduced fentanyl requirements and smaller plasma fentanyl concentrations, than fentanyl administered IV. Pruritus requiring treatment occurred less often among patients receiving IV fentanyl. However, when compared with patients who were treated with epidural opioid, those receiving IV fentanyl had a significantly more frequent incidence of excessive sedation, nausea, and vomiting, and took longer to resume a liquid diet and return to bowel function after surgery. These results convincingly support the hypothesis that epidural fentanyl in these patients acts primarily by a spinal mechanism. Our data are also consistent with evidence in animal studies showing a synergistic interaction between very small dose bupivacaine and opioid when both are given epidurally, which results in a significant opioid-sparing effect and improved analgesia (15–17).
We had anticipated that 20 μg/mL fentanyl administered IV at an initial infusion rate of 40 μg/h and augmented by patient 20 μg PCA dose or investigator 20–60 μg additional administered boluses would provide satisfactory analgesia and still permit us to differentiate the efficacy of analgesia in the four groups. However, this dose was barely satisfactory for the IV fentanyl groups (Groups II-BeFi and III-SeFi). Although the mean pain score for these groups was near our target score of <3, these groups reported scores as high as 5 or 6 during the early hours of the study before adjustments of flow rate were made. Despite this, no patient in any group dropped out of the study because of inadequate pain relief. Increasing the IV fentanyl infusion rate or adding rescue doses did not improve patient satisfaction. Much to the contrary, faster infusion rates were associated with more opioid-related side effects.
A local anesthetic-sparing effect of fentanyl used for labor pain was demonstrated in two recent studies using fentanyl administered as constant amounts epidurally or IV and bupivacaine administered into the epidural space as the variably administered solution (10,11). Both groups of investigators concluded that epidural fentanyl used in a nonsurgical obstetric population acted primarily by a spinal mechanism. Our results extend these conclusions to an obstetric population recovering from cesarean surgery and show that administration of fentanyl and bupivacaine together in the epidural space is associated with an opioid-sparing effect that is not observed in the presence of the same amount of epidural bupivacaine when fentanyl is administered IV. We further show that these effects persist for at least 48 h and are associated with less sedation and lower fentanyl plasma levels.
Although we have limited our conclusions with respect to the primary mechanism of action of epidural fentanyl to the population studied, they may be generally applicable. Studies comparing epidural and IV infusions of fentanyl for postoperative pain in nonobstetric as well as obstetric patients have found no differences between the two routes of administration with regard to serum fentanyl concentrations, side effects, or quality of analgesia and have concluded that the mechanism of epidural fentanyl analgesia was mostly related to its systemic absorption and a supraspinal effect. Some of these studies administered the fentanyl necessary for adequate analgesia using initial epidural infusion rates of 2–7 mL/h (5–7,9). We believe that, in contrast to our study, these studies used diluent volumes of epidural fentanyl that were too small. The epidural efficacy of fentanyl is dependent on the use of an adequate dilutional volume (18,19). We believe that to compensate for inadequate dermatomal spread, these studies used concentrations of fentanyl large enough to result in systemic absorption sufficient to produce analgesia by a supraspinal mechanism. Other studies used adequate diluent volumes but differed from our study in using substantially larger concentrations of fentanyl than we used (4,8). The administration of large amounts of fentanyl epidurally, regardless of diluent volume, will result in systemic absorption of sufficient drug to produce therapeutic blood levels and thereby obscure the differences between epidural and systemic administration or between various epidural diluent volumes and systemic administration. In our study we used the smallest amount of fentanyl that we knew from our prior clinical experience would provide adequate comfort for our patients. The administration into the epidural space of IV-size doses of fentanyl negates the advantages of using this route.
In conclusion, our data support the growing body of evidence that epidural fentanyl analgesia occurs primarily by a spinal mechanism and our data further show that the enhancement of fentanyl’s efficacy by very small dose epidural bupivacaine and epinephrine requires an interaction of these drugs at the spinal level.
The authors wish to thank Gilbert J. Grant, MD, NY University Medical Center for analyzing the fentanyl samples, Stephanie Bitijeman, NNP for helping with neurobehavioral assessment, and Vivek Das, MD and Barbora Hronkova, MD for helping with data collection. We also wish to thank the obstetric floor nurses at RWJUH for their assistance, Patricia Sheffield, MA for editorial assistance and Nancy Szkodny for preparing the manuscript.
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© 2002 International Anesthesia Research Society
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