Epidural opioids may provide pain relief during the first stage of labor. Doses between 150 and 200 μg of epidural fentanyl (1,2) or between 5 and 50 μg of sufentanil (3,4) have been reported to provide adequate labor analgesia. The IV potency ratio between sufentanil and fentanyl did not apply to epidural administration (5), and when these two opioids were given in combination with bupivacaine for labor analgesia, their potency ratio was approximately 5:1 (6).
In a previous study, it was reported that an epidural bolus of 100 μg of fentanyl or 20 μg of sufentanil produced comparable labor analgesia after the administration of a lidocaine and epinephrine test dose (7). The lidocaine test dose, however, may contribute to the analgesic effects of epidural opioids (8). Comparisons between epidural fentanyl and sufentanil, when given as the sole analgesic for labor analgesia without the addition of local anesthetics, have not been performed.
The minimum local analgesic concentration (MLAC) has been established as a research tool to determine the median effective concentrations of local anesthetics and the relative potencies for epidural analgesia in labor (9). More recently, the median effective dose (ED50) has been used to develop the concept of minimum analgesic doses (MAD) for epidural opioids in labor (10).
Both epidural fentanyl and sufentanil are often used in combination with various concentrations of local anesthetic solutions for labor analgesia. However, there is little information regarding the analgesic potency, which is important to determine the best possible analgesia at the smallest dosage with the fewest possible maternal and fetal side effects. The aim of this study was to determine the ED50 of fentanyl and sufentanil and the relative potency ratio of these opioids when they are used as the sole epidural analgesic in the first stage of labor.
After institutional ethical approval and written, informed consent, 66 ASA physical status I or II nulliparous parturients at term, with spontaneous onset of labor and requesting epidural analgesia, were enrolled into this prospective, double-blinded, randomized, sequential-allocation study. Women were randomized according to a computer-generated table of random numbers. To include parturients at comparable stages of labor, only women having a cervical dilation from 2 to 4 cm immediately before the epidural block were enrolled. Exclusion criteria were the presence of at least one of the following: women scoring <50 on a visual analog pain scale (VAPS) (0–100 mm), with presenting part below the ischial spines, those receiving oxytocin augmentation before or during the study, and those who received opioid analgesic medications.
Lumbar epidural analgesia was performed, by loss of resistance to saline, at the L2-3 or L3-4 interspace in the left lateral position, and a multiorifice catheter was inserted 3–4 cm into the epidural space and then aspirated. No test dose was given.
Each woman received a 10-mL volume of epidural drug that comprised fentanyl (Fentanest; Pharmacia & Upjohn) or sufentanil (Fentatienil; Angelini) diluted with 0.9% wt/vol saline to achieve the desired dose. The dose of the study drug for each parturient was determined by the response of the previous parturient in the same group to a larger or smaller dose according to up-down sequential allocation. The exception to this was the first woman in each group, for whom the starting dose was arbitrarily chosen to be 125 μg for fentanyl and 25 μg for sufentanil. A blinded anesthesiologist who was unaware of the dose or drug given performed all assessments.
Efficacy was assessed by using a 100-mm VAPS, for which 0 represented no pain and 100 represented the worst possible pain, at 0, 10, 20, and 30 min after the injection of the study drugs. VAPS was assessed at the peak of contraction by using a slide rule with the patient’s side unmarked and the observer’s side marked from 0 to 100 mm. We evaluated three possible outcomes:
1. Effective: this outcome required a VAPS ≤10 mm within 30 min from the epidural injection and directed a decrement of 5 μg of fentanyl or 1 μg of sufentanil of the dose for the next parturient assigned to that group.
2. Ineffective: this outcome required a VAPS >10 mm within 30 min from the epidural injection. In this case, a rescue bolus of 15 mL of bupivacaine 0.125% (Marcaina; Astra) was given. If the rescue bolus produced a VAPS ≤10 mm within the next 30 min, an increment of 5 μg of fentanyl or 1 μg of sufentanil was directed for the next parturient assigned to that group.
3. Reject: if the rescue bolus produced a VAPS >10 mm within the next 30 min, indicating a failure of the epidural block, this directed the repetition of the same dose for the next parturient assigned to that group. A further cervical examination was performed at 30 min, and parturients with progression of labor beyond a 4-cm cervical dilation or descent of the fetal head below the ischial spines were withdrawn from the study; this was considered to be a reject outcome. In such cases, the dose was repeated for the next woman.
Maternal heart rate, noninvasive blood pressure and pulse oximetry, uterine contractions, and fetal heart rate were monitored from 30 min before the epidural block until the completion of the study. The occurrence of maternal side effects, such as sedation, pruritus, nausea, and vomiting, was recorded on a visual analog scale by using a slide rule; the parturient’s side was unmarked, and the observer’s side was marked from 0 to 100 mm (0, no effect; 100, worst effect).
Demographic and obstetric data were collected and are presented as mean (sd) or median (interquartile range), as appropriate. Means (sd) were analyzed with unpaired Student’s t- or Welch’s t-tests for differing variances, and medians (interquartile ranges) were analyzed with the Mann-Whitney U-test. After log-dose transformation, the ED50 values were estimated from the up-down sequences by using the method of independent pairs. This enabled the estimation of MAD with 95% confidence intervals (CI). The relative analgesic potency ratio of sufentanil to fentanyl with 95% CI was then derived. The sequences were also subjected to probit regression of log-logistic distributions as a backup or sensitivity analysis. Analyses were performed with the following software: Excel 2000 (Microsoft Corp., Redmond, WA), Number Crunching Statistical System (NCSS) 2001 (NCSS Inc., Kaysville, UT), and GraphPad Prism 3.02 (GraphPad Software Inc., San Diego, CA). Statistical significance was defined for an overall α error at the 0.05 level. All P values were two sided.
Of the 66 women enrolled in the study, 1 in the fen-tanyl group and 3 in the sufentanil group were excluded, leaving respectively 32 and 30 parturients in the fentanyl and sufentanil groups for analysis. These four parturients were excluded because their labor progressed beyond a 4-cm cervical dilation or descent of the fetal head progressed below the ischial spines during the study period. No subject was rejected for epidural failure.
Demographic and obstetric data were similar in both groups (Table 1). The sequences of effective and ineffective analgesia are shown in Figure 1. With analysis of up-down independent pairs, the MAD of fentanyl was 124.2 μg (95% CI, 118.1–130.6 μg), and the MAD of sufentanil was 21.1 μg (95% CI, 20.2–21.9 μg). The sufentanil/fentanyl potency ratio was 5.9 (95% CI, 5.6–6.3). The probit regression results are shown, in addition, in Table 2.
The mean duration of analgesia in the “effective” subjects was 85.2 min (sd, 28.1 min) in the fentanyl group and 93.3 min (sd, 37.9 min) in the sufentanil group, and this difference was not significant. Table 3 reviews maternal side effects. Pruritus was more intense in the fentanyl group (P < 0.02), but no parturient required or received treatment for side effects.
In this study we established the MAD of fentanyl and sufentanil when these are used as the sole epidural analgesic for the first stage of spontaneous labor in nulliparous parturients and determined that sufentanil was 5.9 times more potent than fentanyl. Doses of epidural fentanyl between 150 and 200 μg without local anesthetic have been reported to provide adequate analgesia during the first, but not the second, stage of labor (1,2).
A dose of 30 μg of epidural sufentanil, after a 3-mL lidocaine test dose, was able to produce satisfactory analgesia in early labor but provided analgesia of less certain quality and shorter duration when given subsequently at a later time (4). Based on these previous findings and assuming a potency ratio for sufentanil to fentanyl with bupivacaine to be 5:1 (6), we chose our starting dose to be 125 μg for fentanyl and 25 μg for sufentanil, and the dosing interval was chosen to be 5 μg and 1 μg. In addition, we have reported an almost threefold increase in MLAC as labor progresses (11). In accordance with these previous findings, we performed our study on nulliparous parturients who requested analgesia in early labor. We included only parturients at comparable stages of labor, and we excluded parturients whose labor progressed too rapidly during the study period. It has been reported that the administration of <10 mL of epidural fentanyl is less effective in producing labor analgesia (12), and for this reason we decided, as have many other authors (1–3,10), to dilute our sufentanil and fentanyl doses up to a total volume of 10 mL.
The sufentanil/fentanyl analgesic potency ratio has been reported to be 8:1 to 9:1 (13), but the IV potency ratio between sufentanil and fentanyl did not apply to epidural administration (5). The difference between the epidural ratio and the parenteral ratio probably relates to the site of administration. The greater lipid solubility of sufentanil (octanol/water partition coefficient 1227, versus 955 for fentanyl) (14) probably imparts larger transfer across the blood-brain barrier and, thereby, increased potency when administered parenterally. When it is given into the epidural space, closer to the site of action, the greater lipid solubility of sufentanil may result in larger uptake into epidural fat, which would account for the decreased potency ratio of sufentanil to fentanyl for epidural administration than for IV administration.
Epidural sufentanil and fentanyl were used at the arbitrary ratio of 2:1 or 2.6:1 in combination with small-dose bupivacaine and epinephrine, respectively, for postoperative analgesia after cesarean delivery (15) and for labor analgesia (16). In both of these studies, sufentanil produced increased analgesic effects compared with fentanyl.
In a dose-response study, the analgesic potency of epidural sufentanil was reported to be approximately five times that of fentanyl when it was administered, as the sole analgesic, after lidocaine anesthesia for cesarean delivery (17). One study (7) reported similar analgesic properties of 20 μg of sufentanil with 100 μg of fentanyl after a lidocaine and epinephrine test dose in nulliparous parturients. These results were consistent with those of another study (6) that reported the potency ratio for epidural sufentanil and fentanyl, when mixed with 0.125% bupivacaine, to be approximately 5:1. We found that sufentanil is approximately sixfold more potent than fentanyl when given epidurally for the first stage of labor analgesia.
Differences from previous studies might be due to the method of estimating the potency ratio. In this study, we determined the potency ratio by using the ED50 of both drugs with the up-down method, whereas others reported the potency ratio by extrapolating the data obtained from comparing arbitrarily chosen doses or by using a dose-response method (3).
In addition, previous studies dealing with the potency ratio of epidural opioids for labor analgesia have combined opioids with local anesthetic solutions or used a local anesthetic test dose before the administration of the opioid. It is now clear that even the local anesthetic test dose may contribute to labor analgesia (8). In this study, we determined the ED50 and the potency ratio of both epidural fentanyl and sufentanil when these were given as the sole analgesic during labor without use of any local anesthetic test dose before the opioid administration.
The MAD is not a dose recommendation, but, because the target VAPS was set at 10 mm, it may suggest the lower end of the therapeutic range to be used. In clinical practice, a VAPS ≤10 mm is a lower level of analgesia than is required for clinical comfort, because it has been reported that parturients request further intervention during epidural analgesia only when the VAPS exceeds 30 mm (18). Our ED50 for epidural sufentanil was comparable to the dose of sufentanil (20 μg) that produced adequate analgesia after a lidocaine test dose in a group of both nulliparous and multiparous parturients (3). Exploration of the dose-response relationships for sufentanil and fentanyl (Fig. 2) demonstrates a parallel relationship in the log-dose scale consistent with both drugs acting as agonists at the same receptor sites. The estimates for ED95 (Table 2) for both epidural fentanyl and sufentanil were consistent with the effective doses used in previous studies (1–4). Our findings, however, differ from those recently reported in an up-down sequential study of intrathecal opioids (19), which estimated that intrathecal sufentanil is 4.4 times more potent than intrathecal fentanyl for labor analgesia. Because sufentanil is much more lipid soluble than fentanyl, perhaps this difference in lipid solubility may be more important when these drugs are administered epidurally rather than into the subarachnoid space, and this may help to explain our different potency ratio.
At the doses given for the purpose of our study, almost all mothers experienced moderate somnolence and pruritus. The intensity of pruritus was increased in parturients who received epidural fentanyl as compared with sufentanil. The incidence of pruritus after epidural opioids is dose related and increases as the concentration of opioid in the cerebrospinal fluid increases, and thus it may be decreased by the use of more lipophilic drugs, such as sufentanil (20). However, our study was not designed to investigate side effects, and to comment on this is thus beyond the scope of this article.
In conclusion, we determined the MAD of fentanyl and sufentanil when these were used as the sole epidural analgesic for the first stage of spontaneous labor in nulliparous parturients. The ED50 estimates and the potency ratio established in this study should help to provide benchmarks both for the clinical use of epidural fentanyl and sufentanil for labor analgesia and for future comparisons with other analgesic techniques.
1. Carrie LES, O’Sullivan GM, Seegobin R. Epidural fentanyl in labour. Anaesthesia 1981; 36: 965–9.
2. Justins DM, Francis D, Houlton PG, Reynolds F. A controlled trial of extradural fentanyl in labour. Br J Anaesth 1982; 54: 409–14.
3. Steinberg RB. Epidural sufentanil for analgesia for labor and delivery. Reg Anesth 1989; 14: 225–8.
4. Steinberg RB, Dunn SM, Dixon DE, et al. Comparison of sufentanil, bupivacaine, and their combination for epidural analgesia in obstetrics. Reg Anesth 1992; 17: 131–8.
5. Coda BA Cleveland Brown M, Schaffer R, et al. Pharmacology of epidural fentanyl, alfentanil and sufentanil in volunteers. Anesthesiology 1994; 81: 1149–61.
6. Herman NL, Sheu KL, Van Decar TK, et al. Determination of the analgesic dose-response relationship for epidural fentanyl and sufentanil with bupivacaine 0.125% in laboring patients. J Clin Anesth 1998; 10: 670–711.
7. Connelly NR, Parker RK, Vallurupalli V, et al. Comparison of epidural fentanyl versus epidural sufentanil for analgesia in ambulatory patients in early labor. Anesth Analg 2000; 91: 374–8.
8. Cohen SE, Yeh J, Riley E, Vogel T. Walking with labor epidural analgesia: the impact of bupivacaine concentration and a lidocaine-epinephrine test dose. Anesthesiology 2000; 92: 387–92.
9. Columb MO, Lyons G. Determination of minimum local analgesic concentrations of epidural bupivacaine and lidocaine in labor. Anesth Analg 1995; 81: 833–7.
10. Capogna G, Parpaglioni R, Lyons G, et al. Minimum analgesic dose of epidural sufentanil for first-stage labor analgesia. Anesthesiology 2001; 94: 740–4.
11. Capogna G, Celleno D, Lyons G, et al. Minimum local analgesic concentration of extradural bupivacaine increases with progression of labour. Br J Anaesth 1998; 80: 11–3.
12. Birnbach DJ, Johnson MD, Aracario T, et al. Effect of diluent volume on analgesia produced by epidural fentanyl. Anesth Analg 1989; 68: 808–10.
13. van de Walle J, Lauwers EP, Adriaensen H. Double blind comparison of fentanyl and sufentanil in anesthesia. Acta Anaesthesiol Belg 1976; 27: 129–38.
14. Rosen CE. Sufentanil citrate: a new opioid analgesic for use in anesthesia. Pharmacotherapy 1984; 4: 11–8.
15. Cohen S, Amar D, Pantuck CB. Postcesarean delivery epidural patient-controlled analgesia: fentanyl or sufentanil? Anesthesiology 1993; 78: 486–91.
16. Cohen S, Amar D, Pantuck CB, et al. Epidural analgesia for labour and delivery: fentanyl or sufentanil? Can J Anaesth 1996; 43: 341–6.
17. Grass J, Sakima NT, Schmidt R, et al. A randomized, double blind, dose response comparison of epidural fentanyl versus sufentanil analgesia after cesarean section. Anesth Analg 1997; 85: 365–71.
18. Brownridge P. Epidural analgesia in the first stage of labour. Curr Anaesth Crit Care 1991; 2: 92–100.
19. Kenneth N, Rauch T, Terebuh V, D’Angelo R. A comparison of intrathecal fentanyl and sufentanil for labor analgesia. Anesthesiology 2002; 96: 1070–3.
20. Ross BK, Hughes SC. Epidural and spinal narcotic analgesia. Clin Obstet Gynecol 1987; 30: 552–64.