There has been a continuing scientific debate on the use of epidural lipophilic opioids. Pharmacokinetic studies in animals demonstrate that these drugs have a small spinal cord bioavailability (1,2). However, most human studies that have administered epidural lipophilic opioids by bolus injection have demonstrated a spinal mechanism of action, with either a segmental analgesic response, (3) an increased analgesic efficacy for the epidural route (4–12), or a lack of correlation between epidural analgesia and effective plasma drug levels (4,6,7,13). Conversely, most human studies that administered these drugs by continuous infusion concluded that these opioids were exhibiting a systemic mechanism of action, mediated by drug absorption and redistribution to the brain. These infusion studies demonstrated equal spinal and supraspinal analgesia (14), equal efficacy between epidural and IV routes of administration (14–23), and equal plasma drug levels for equipotential analgesic regimens (16–22).
Based on these clinical data, we hypothesized that the predominant site of analgesic action (direct spinal cord action or systemic redistribution to the brain) is dependent on whether the drug is administered as a bolus or as a continuous infusion (24).
In an experimental pain study in healthy volunteers, we demonstrated that, in the absence of local anesthetics, bolus administration of epidural fentanyl elicited segmental analgesia that was independent of plasma fentanyl levels. In contrast, continuous infusion of epidural fentanyl elicited an equal analgesic response in both spinal and supraspinal sites, suggesting a predominantly systemic mechanism of action (24).
This finding might challenge the use of continuous infusions of epidural fentanyl. In clinical practice, particularly for relief of labor pain, continuous infusions of epidural opioids are widely used; however, in these cases, fentanyl is typically coadministered with infusions of local anesthetics.
The current study examined the hypothesis that, in the presence of local anesthetics, epidural fentanyl elicits analgesia by a predominantly spinal mechanism even when administered as a continuous infusion. To examine this hypothesis, we adapted the design of a previously published study (11) that compared epidural and IV bolus administration of fentanyl for their effects on the median effective concentration (EC50) of a fixed-volume bolus dose of bupivacaine in labor. This EC50 is otherwise known as the minimum local analgesic concentration (MLAC). Unlike previous studies (11,25,26) that assessed MLAC for a fixed-volume bolus at the initiation of analgesia, this study assessed MLACinfusion for a fixed-rate infusion for the maintenance of analgesia.
The current study compared epidural and IV continuous infusions of fentanyl for their local anesthetic-sparing effects during the maintenance of epidural analgesia in the first stage of nulliparous labor.
This prospective, randomized double-blinded study compared the median effective concentrations of fixed rate epidural bupivacaine infusions in two groups of patients receiving co-administered fentanyl infusions: an IV fentanyl infusion group and an epidural fentanyl infusion group (EPI).
Forty-eight women were enrolled in this study between November 2000 and June 2001 in. the Labor and Delivery Unit of the Lucile Packard Children’s Hospital, Stanford University Hospitals. Subjects were enrolled after obtaining IRB approval and signed informed consent.
Inclusion criteria were: nulliparity, early active labor, cervical dilation <5 cm, request for epidural analgesia, age 18–40 yr, ASA physical status class I or II, body weight <110 kg, gestational age >36 completed weeks, singleton pregnancy, and vertex presentation. Exclusion criteria were: narcotic administration in the previous 3 h, previous uterine surgery, preeclampsia, and the inability to adequately understand the consent. Induction of labor (oxytocin or Cervidil) and augmentation of established labor (oxytocin) before enrollment were not exclusion criteria; these factors were recorded in the demographic data.
Before randomization, an epidural catheter was placed under the supervision of one of the authors. All epidural catheters were placed at the L2-3 or L3-4 interspace with the patient in the sitting position. The epidural space was identified by the loss of resistance to saline and a multiport epidural catheter was threaded 3–5 cm into the epidural space. Incremental doses of 0.125% bupivacaine were administered to a minimum volume of 20 mL. Analgesia was assessed using a 100-mm visual analog pain score (VAPS). Adequate analgesia was considered to be achieved if the VAPS was reduced to <10 mm. If adequate analgesia was not obtained by 15 min, a further 5 mL of 0.125% bupivacaine was injected and repeated once more if necessary (giving a total cumulative epidural induction dose of 20–30 mL of 0.125% bupivacaine). No other drugs were administered via the epidural catheter before randomization. If a patient did not have a VAPS <10 after 30 min, they were not enrolled. Once pain-free, subjects were assigned to one of the two study groups prerandomized by computer-generated random allocation and included in paired, opaque envelopes.
All women received an epidural infusion of bupivacaine at a fixed rate of 20 mL/h, the concentration of which was determined by the response of the previous woman in the same group to the analgesic regimen used. The initial epidural bupivacaine concentration was 0.07% for the first patient in both groups. All subjects received two infusions: an epidural infusion of bupivacaine with or without fentanyl and an IV infusion of either fentanyl or saline. The IV group (n = 24) received an IV infusion of fentanyl of 30 μg/h with no epidural narcotics added to the bupivacaine infusion. The EPI group (n = 24) received a placebo IV infusion of saline and an epidural infusion of fentanyl of 30 μg/h. Epidural infusions were prepared from 250 mL preservative-free saline bags after first withdrawing a volume of saline equal to the total volume of drug(s) to be added. IV infusions were connected close to the IV catheter. Epidural infusions were administered at a rate of 20 mL/h. IV infusions were administered at a rate of 3 mL/h. Women were informed that they could receive supplemental epidural analgesia on request. Bolus rescue was with bupivacaine 0.25%, using incremental doses up to a total of 12 mL if needed. Vaginal examination was performed immediately after additional bolus administration (the obstetrician and/or nurse-midwife were blinded as to the study group). To avoid bias, neither the patient nor the obstetrician/nurse-midwife was informed that supplemental analgesia requirement and cervical dilation at supplementation were principal end-points of this study. The patient and all medical personnel, including the anesthesiologist making the assessments, were blinded as to the bupivacaine concentration used and to the IV/EPI group allocation.
As with previous applications of the up-down sequential analysis design in similar studies, the three possible outcomes were “success,” “failure,” and “reject.”
- Success: No supplemental analgesia requested until 8 cm cervical dilation or more. Alternatively, supplemental analgesia was requested but a vaginal examination performed immediately after its administration was ≥8 cm. The consequence of a “success” was that the next patient in that group would have a 0.01% weight/volume (w/v) reduction in the bupivacaine concentration for the epidural infusion.
- Failure: Supplemental analgesia was requested (and where doses of up to 12 mL of 0.25% bupivacaine provided adequate analgesia) and a vaginal examination performed immediately after its administration was <8 cm. The consequence of a “failure” was that the next patient in that group would have a 0.01% w/v increase in the bupivacaine concentration for the epidural infusion.
- Reject: As for “failure” but where doses up to 12 mL of 0.25% bupivacaine failed to relieve labor pain within 15 min (presumably resulting from a catheter problem). Other reasons for rejection were the need for supplemental analgesia within 2 h from the start of the study infusion, the progression to full cervical dilation within 2 h from the start of the study infusion, or the progression to cesarean delivery before 8 cm cervical dilation without any prior request for supplemental analgesia. The consequence of a “reject” was that the next patient in that group would have the same bupivacaine concentration for the epidural infusion.
The VAPS during uterine contraction was measured hourly after the start of the epidural and IV study infusions. The anchors for the VAPS were 0 = no pain and 100 = worst pain imaginable. The sensory level was also determined at hourly intervals and was defined as the lowest dermatome at which ice was perceived as cold.
In the first hour after delivery, the patient was asked to record pruritus, nausea and maternal satisfaction, all on a VAS scale with the anchors being 0 = none and 100 = worst imaginable (for pruritus and nausea), and 0 = maximally dissatisfied and 100 = maximally satisfied (for maternal satisfaction).
The following demographic variables were recorded on enrollment in the study: age, height, weight, gestational age, induction of labor (mode and indication), augmentation of established labor, premature rupture of membranes (PROM), and artificial rupture of membranes (AROM). The following obstetric outcome variables were recorded after delivery: first stage duration, second stage duration, baby weight, instrumental delivery, and cesarean delivery for dystocia or for other indications.
Based on data obtained from the Polley et al. study (11), with sd approximately 0.03% w/v, to detect a 0.04% w/v reduction in MLAC with a power of 0.8, 18 subjects would be needed to be included in each group (not including rejected subjects).
Demographic and anesthetic/obstetric outcome data were collected and presented as means (sd) with the following exceptions: cervical dilation and sensory level, which were presented as median (interquartile range); and incident data (AROM, PROM, induction, augmentation, cesarean delivery, instrumentation, and incidence of pruritus), which were presented as number counts. Means (sd) were analyzed using unpaired Student’s or Welch’s t-tests for differing variances, medians (interquartile ranges) by Mann-Whitney U-test, and counts or proportions by Fisher’s exact test. The median effective concentrations were estimated from the up-down sequences using the method of Dixon and Massey (27) that enabled MLAC with 95% confidence interval (CI) to be derived. The sequences were also subjected to Wilcoxon and Litchfield probit regression analyses using ln (1+x) transform as back-up or sensitivity tests. Analyses were performed using the following software; Excel 2000 (Microsoft, Redmond, WA), GraphPad Instat 3.05 (GraphPad Software Inc., San Diego CA), and Statistical Package for the Social Sciences (SPSS) 10.0 (SPSS, Chicago IL). Statistical significance was defined for overall α error at the 0.05 level. All P values were two-sided.
Of the 48 women enrolled in the study, 8 were rejected from MLACinfusion analysis (Table 1). These women were also excluded from demographic, anesthesia outcome, and obstetric outcome data analyses.
The demographic data were the same for both groups (Table 2), and there were no significant differences between the study groups for obstetric outcome data (Table 3), as might be expected for a study of this size. The duration of epidural infusion in the two groups was not significantly different (Table 4).
The sequential data for the MLACinfusion analysis in the IV group and the EPI group are shown in Figure 1. The MLACinfusion of epidural bupivacaine in the IV fentanyl group was 0.063 (95% CI, 0.058–0.068) by the Dixon Massey analysis, and 0.063 (95% CI, 0.058–0.067) by probit regression analysis. The MLACinfusion of epidural bupivacaine in the EPI group was 0.019 (95% CI, 0.000–0.038) by the Dixon Massey method and 0.002 (95% CI, 0.000–0.034) by probit regression. The relative potency ratio for the epidural:IV routes of administration (Dixon Massey) was 3.3 (95% CI, 1.7–10.7). This was highly significant (P = 0.0017; 95% CI difference, 0.021–0.068, Welch’s t-test).
Of the anesthesia outcome data (Table 4), the only significant difference was the incidence and severity of pruritus, which affected 11 of 16 patients in the EPI group (4 patients with no recorded pruritus data) and 1 of 15 patients in the IV group (5 patients with no recorded pruritus data) (P = 0.005, Fisher’s exact test). The relative risk of pruritus in the EPI group was 4.9 (1.3–18.5). The median pruritus assessment (visual analog score) was 0 in the IV group as compared with 28 in the EPI group (P = 0.0005; Mann-Whitney U-test). The severity of pruritus in symptomatic patients was also significantly greater in the EPI group; the median visual analog score was 30 mm in those patients versus 12 mm for the one patient in the IV group. Despite this difference in pruritus, no patient in either group required treatment for pruritus and there was no difference in maternal satisfaction between groups. There was no significant difference in the hourly VAPS, or the incidence or severity of nausea. There was also no significant difference in the upper dermatomal level of the block (either mean height or maximal height) between the two groups, despite the fact that the mean concentration of bupivacaine administered in the IV group was 0.063% (±0.008%) vs 0.027% (±0.0194%) in the EPI group.
In this study we demonstrated that, when coadministered with dilute epidural bupivacaine, a continuous infusion of fentanyl was more than three times as potent when administered by the epidural route than when administered IV. This marked increase in potency for the epidural route is highly suggestive for a predominantly spinal mechanism of action for infused epidural fentanyl under the conditions of this study.
The fentanyl dose of 30 μg/h is a clinically applicable dose (a currently typical labor epidural regimen uses varying dilutions of bupivacaine with fentanyl 2 μg/mL infused at a rate of 15 mL/h, which is equal to 30 μg/h of fentanyl). Moreover, this infused dose exactly matches the dose used in our experimental pain study in which, in the absence of coadministered local anesthetics, 30 μg/h of fentanyl administered as a continuous epidural infusion elicited analgesia predominantly by systemic redistribution to the brain (24). In the current study, keeping the dose the same but adding local anesthetic, we demonstrated a threefold more potent effect than that observed for systemically administered fentanyl, implying a spinal mechanism of analgesia.
A possible weakness in our data is the lack of some information regarding the patient pain management before entry into the study (VAPS before enrollment, whether additional epidural bupivacaine (0.125%, 5–10 mL) was used as a supplementary bolus before enrollment, and whether these variables differed between the groups). This information would have strengthened this study to some degree, as it could refute a potential argument that the MLACinfusion for the study groups was affected by selection bias. Selection bias is a potential concern when randomizing in pairs, particularly if the group allocation becomes apparent during the study. In this study, the adequacy of blinded enrollment was enhanced by the lack of apparent difference in analgesic effect between study groups as both the IV and EPI groups oscillated about their own ED50. Furthermore, patients were not recruited if the VAPS during uterine contractions was more than 10 mm 30 minutes after the initial bolus. Even if we knew the VAPS on enrollment, it is unlikely that a clinically significant difference between groups would have emerged over such a narrow range (0–10 of 100).
Our methodology adapted a previously described approach for determining the EC50 or MLAC. The strength of the Dixon Massey up-down sequential analysis lies in its economical design; it was originally proposed to determine the amount of dynamite to be used for explosions in mining (27). This technique has been used to compare potencies of epidural local anesthetics (25,28,29), to assess the impact of adjuvant analgesic regimens (26,30,31), and to compare the analgesic requirements of specific obstetric demographic groups (32,33). MLACinfusion is a novel application of the MLAC design that may be of use to other investigators, as many clinical questions in obstetric anesthesia are not easily addressed by the MLAC bolus design for the induction of epidural analgesia, and may be more appropriate for the MLAC infusion design for analgesia maintenance.
In a previous MLAC study, Polley et al. (11) assessed the relative potency of bupivacaine to successfully induce epidural analgesia when coadministered with either IV or epidural fentanyl, dispensed as a bolus. That study demonstrated that a bolus of epidural fentanyl elicits analgesia by a predominantly spinal mechanism. In this study, we demonstrated the same finding, but for epidural fentanyl administered by continuous infusion. The factor by which epidural fentanyl increased the potency of epidural bupivacaine was more in our study than was observed by Polley et al. (3.3 vs 1.88).
In an experimental pain study in healthy volunteers (24), we demonstrated that, rather than acting by a predominantly spinal mechanism, continuous infusions of epidural fentanyl elicit analgesia by systemic redistribution to the brain.
The most likely explanation for this seeming contradiction is that our experimental pain study (24) used infusions of fentanyl without local anesthetic, whereas this clinical study in laboring women involved the coadministration of an epidural local anesthetic infusion of varying dose. Interestingly, of the 12 published studies in humans that support a spinal mechanism of action for epidural fentanyl, only one other study administered epidural fentanyl exclusively by continuous infusion with no bolus supplementation (10); in that study there was coadministration of bupivacaine. In contrast, all five studies in which continuous infusions of epidural fentanyl were not accompanied by local anesthetics concluded that epidural fentanyl had a systemic mechanism of action (15,16,18,20,22).
We speculate that, in the presence of local anesthetics, the otherwise clinically insignificant spinal analgesic effect of the epidural fentanyl infusion becomes more pronounced and even predominates. Our data may reflect the previously described synergistic interaction between epidural opioids and local anesthetics. Epidural local anesthetics and exogenous opioids have been shown to have a synergistic interaction in animals (34–40) and in humans (41). It is likely that the most important factor in this synergy is that each drug has an independent and potent pathway for effecting analgesia. The synergy between epidural local anesthetics and epidural opioids may be the consequence of both these independent processes occurring simultaneously, with some degree of central neural amplification accounting for the synergistic (rather than additive) interaction. Alternatively one drug (or both) may directly interact with either the other drug’s spinal cord bioavailabilty or with the mechanism of the other drug’s bioavailability.
This study demonstrated an almost five-fold increase in the incidence of pruritus in the EPI group, although no patients in either group had pruritus severe enough to warrant treatment. These data are consistent with most previous reports (11), although some studies reported no difference in pruritus between IV and epidural fentanyl (10).
This study demonstrates that when coadministered with local anesthetics, a continuous infusion of epidural fentanyl has a marked local anesthetic-sparing effect when compared with an equal dose of fentanyl infused IV. This observation suggests that infused epidural fentanyl elicits analgesia by a predominantly spinal mechanism in the presence of local anesthetics. This finding is important in view of previous observations that epidural fentanyl elicits analgesia by systemic redistribution to the brain when administered as a continuous infusion in the absence of local anesthetics. A comparison of these data may suggest the occurrence of synergy between epidural opioids and epidural local anesthetics. These data strongly support the use of epidural fentanyl in labor, even when administered as a continuous infusion, as long as it is administered in the presence of local anesthetics. Under these conditions, women in labor who receive epidural fentanyl are likely to require smaller doses of local anesthetic and be more comfortable with a lower intensity motor block.
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