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Anesth Analg 2003;97:247-252 © 2003 International Anesthesia Research Society
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Abstract |
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We investigated the duration of labor analgesia produced by a small dose of spinal bupivacaine/fentanyl alone or in combination with a small dose of morphine. Sixty parturients were enrolled in this placebo-controlled, double-blinded, randomized trial. All women received a spinal injection of 12.5 µg of fentanyl with 2 mg of bupivacaine. The morphine group (MBF) also received 125 µg of morphine; the placebo group (BF) received saline. Pain scores were <3 of 10 within 10 min of injection. The median duration of analgesia was similar between groups (89 min versus 84 min; P = not significant), and only 20% of the MBF group experienced prolonged analgesia. During subsequent epidural analgesia, the MBF group had a significantly lesser rate of breakthrough pain (0.15 ± 0.14 episodes per hour versus 0.26 ± 0.18 episodes per hour; P = 0.02). Also, during the first 24 h postpartum, the MBF group required significantly fewer medications (3.3 ± 3.7 doses versus 4.7 ± 3.5 doses; P = 0.04). Intrathecal injection of this small dose of bupivacaine/fentanyl produced a rapid onset of labor analgesia; the addition of a small dose of morphine did not significantly prolong analgesia, but it improved subsequent pain relief, as measured by the rate of breakthrough pain and postpartum medication requirements. This may provide a clinically useful means of improving intra- and postpartum pain relief.
IMPLICATIONS: A small dose of intrathecal fentanyl 12.5 µg and bupivacaine 2 mg produces effective labor analgesia lasting for approximately 85 min. The addition of a small 125-µg dose of morphine improves pain control during subsequent epidural analgesia and reduces the requirements for postpartum pain medications.
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Introduction |
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The combined spinal-epidural (CSE) technique is a popular method of providing labor analgesia because of a rapid onset of pain relief achieved with the spinal injection and prolonged analgesia maintained via epidural infusion. Several drugs have been used to initiate the spinal component of analgesia. Large doses of lipid soluble opioids produce rapid and profound analgesia but are associated with significant side effects (1–6). Because of the synergistic effect of combining local anesthetics, the dose of opioids required to provide effective labor analgesia can be significantly reduced (7,8). Indeed, some investigations have shown that reducing the dose of spinal medications diminishes the duration of analgesia but does not affect the quality of pain relief (1,7,9–11).
Intrathecal morphine is occasionally used for labor analgesia. When used in large doses, it produces long-lasting labor pain relief associated with slow onset and significant side effects; however, when combined with rapid acting medications, morphine may be of clinical value (12,13). Yeh et al. (14) found 150 µg of morphine to prolong spinal analgesia, with significant side effects in one third of subjects. Because the side effects associated with morphine seem to be dose-dependent, a smaller dose may be desirable (15). We hypothesized that an intrathecal injection of a smaller combined dose of bupivacaine and fentanyl would provide rapid and effective labor analgesia in a clinically relevant population, and the addition of 125 µg of morphine would increase the duration of pain relief.
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Methods |
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This placebo-controlled, double-blinded, randomized trial was approved by the hospital Committee on Clinical Investigations, and informed consent was obtained from the patients. Sixty ASA physical status 1 or 2 parturients who requested neuraxial analgesia for labor with a term singleton fetus in a vertex position were randomized via a computer-generated list to receive a small dose of morphine or placebo during their CSE placement. Randomization cards were maintained in opaque envelopes and opened by the investigator who mixed the medication; neither the patient nor assessor knew the randomization group. Women who had received analgesics within 4 h and those with chronic pain, pregestational diabetes, morbid obesity, or fetal abnormalities were excluded. A CSE needle-through-needle technique was performed at the L3-4 or L4-5 interspaces. Spinal injection consisted of 12.5 µg of fentanyl with 2 mg of bupivacaine through a 24-gauge Sprotte spinal needle (150 mm) with the patient in the sitting position. The morphine group (MBF) received an additional 125 µg of morphine, whereas the placebo group (BF) received an equal volume of saline. After successful spinal injection, a 3-holed epidural catheter (Sims-Portex) was placed via a 17-gauge Tuohy (105 mm) needle. The tip of the Sprotte needle extends 22 mm beyond the tip of the Tuohy needle.
Patient assessments before spinal injection included vital signs, pain score, and cervical dilation. After spinal injection, vital signs, pain score, sensory level to cold and pinprick, motor blockade, and side effects were evaluated at 5, 10, 15, 30, 45, and 60 min, and then every 30 min until the end of the spinal analgesia. Vital signs included blood pressure, heart rate, and SpO2. Hypotension was defined as a decrease in systolic blood pressure more than 30% of baseline or <90 mm Hg. All pain scores were evaluated using a Numeric Pain Score of 0 to 10, with 0 being "no pain" and 10 representing "worst possible pain." Motor blockade was assessed using the modified Bromage scale described by Breen et al. (16), with 0 defined as no movement and 5 defined as no weakness on hip flexion. Evaluation of side effects included direct questioning at each interval for pruritus, nausea, and sedation rated as "none, mild, moderate, or severe."
Successful spinal analgesia was defined as the relief of labor pain in the first 15 min such that the subject did not request rescue medication. The end of spinal analgesia was defined as the time when the subject’s labor pain began to return, prompting a request for rescue medication; subjects were told not to wait until the pain had returned to previous levels. On request for rescue analgesia, an epidural test dose was given (3 mL of 1% lidocaine with 1:200,000 epinephrine). After a negative test dose, the epidural was initiated with a 15-mL bolus and maintained with a 15-mL/h infusion of our standard epidural solution (0.04% bupivacaine and 1.7 µg/mL of fentanyl). During subsequent labor epidural analgesia, breakthrough pain was defined as subjective discomfort because of pain or pressure increasing during a contraction that was successfully treated with supplemental medications. Rate of breakthrough pain was calculated as the number of episodes of pain divided by the duration of epidural analgesia. Cervical dilation rate was calculated from the time of epidural catheter placement until full cervical dilation. Vital signs and pain scores were assessed at 1 h and 24 h after delivery. All parturients received frequent monitoring for respiratory depression, which is the hospital standard for patients who receive intrathecal morphine. Postpartum pain medications were prescribed by standard orders, including ibuprofen 600 mg every 6 h and 1 or 2 tabs of Percocet (at patient request) every 4 h. The total number of medications used during the first 24 h after delivery was recorded.
The primary outcome was the time from injection of spinal mediation until the end of spinal analgesia. Normally distributed continuous variables were compared using the t-test. The Mann-Whitney test was used for non-normal distributions and 
2 analysis for frequencies. Kaplan-Meier survival analysis was used to assess the cumulative proportion of continued spinal analgesia after injection; the median time of cumulative analgesic duration obtained from these tables was compared using log-rank analysis. Maternal pain scores, vital signs, and sensory level were analyzed using a general linear model for repeated measures. Because the rate of breakthrough pain fits a Poisson distribution, comparison between groups was performed after a log transformation.
Subjects who delivered under spinal analgesia and before a request for rescue medications were removed from analysis of intrapartum effects but were included in postpartum analysis. Subjects who had a cesarean or assisted vaginal delivery or who had additional surgical procedures after delivery were excluded from postpartum analysis. A priori power analysis showed that if there were a 25% difference in the duration of spinal analgesia, we would need to enroll 18 patients in each group to have a power of 0.08 to detect a significance of 0.05. Because we expected approximately a 30% dropout rate because of early delivery before the end of spinal analgesia and Cesarean delivery, we increased our sample size by 50%. Baseline characteristics were examined using an intent-to-treat analysis and outcomes compared after elimination of dropouts. Data were analyzed using SPSS for windows 9.0.0 1999 (SPSS Inc, Chicago, IL). The level of significance was set at P < 0.05.
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Results |
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Of the 60 parturients enrolled, three were eliminated because of protocol violations. Two subjects were in the BF group: one because of an inadvertent dural puncture with the epidural needle and one because of the spinal medications being spilled during injection. The one subject in the MBF group was excluded because of receiving inappropriate medications. There were no failed spinals using the needle-through-needle technique. There were no differences between groups in baseline maternal demographic, obstetric characteristics, or obstetric outcomes (Table 1). Nine subjects delivered shortly after spinal injection (five in the MBF and four in the BF group) without requesting additional medications and were not included in analysis of spinal duration or intrapartum effects. Two subjects had their epidural catheters replaced and were not included in the analysis of effect on epidural analgesia. In one of these, the epidural catheter failed immediately upon request for rescue. In the second, the catheter became dislodged after several hours of successful analgesia. Fifteen subjects were excluded from postpartum analysis, with similar causes in each group (Table 2). There were no cases of respiratory depression (rate <12) in the 24 h after delivery.
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The mean duration of spinal analgesia was longer in the MBF group than in the BF group (101 ± 43 min versus 80 ± 21 min; P = 0.03); however, using Kaplan-Meyer analysis, the median duration of cumulative successful analgesia was not significantly prolonged (89 min versus 84 min; P = 0.12; see Fig. 1). This difference in results was caused by a small number of parturients in the MBF group (approximately 20%) that experienced long lasting analgesia and skewing of the mean. In such a case, the nonparametric log-rank analysis is the preferred method of comparison. Pain scores and vital signs did not differ between groups immediately before spinal injection. Pain scores were reported as 3 of 10 or less in 78% of subjects at 5 min after injection and in 100% of subjects by 10 min. There were no differences between groups when comparing pain scores throughout the duration of spinal analgesia (Table 3). Vital signs, sensory levels, and motor blockade were similar between groups. No subject had a systolic blood pressure less than 90 mm Hg at any time during observation. One subject’s systolic blood pressure decreased by more than 30% from preanalgesia baseline requiring additional fluid for treatment. Sixty-seven percent of subjects in both groups had a modified Bromage score of 5 throughout the period of spinal analgesia. One-third of subjects in both groups had a modified Bromage score of 4 at 15 min, but only 10% remained by 60 min after injection. Pruritus was reported by the majority of subjects in both groups (P = not significant) and was characterized as moderate in 17% of the MBF group and 26% of the BF group. Although nausea was not statistically different between groups, it was only reported by subjects in the MBF group. There was no difference in Apgar scores between groups at either 1 or 5 min.
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During subsequent epidural analgesia for labor, the hourly rate of breakthrough pain was significantly less in the MBF group (0.15 ± 0.14 episodes per hour versus 0.26 ± 0.18 episodes per hour; P = 0.02) (Fig. 2). Because breakthrough pain fits a Poisson distribution, comparison of requirements for the treatment of breakthrough pain is best performed examining the rate of occurrence, especially where the duration of observation is not uniform. Although not controlled by a protocol, the treatment of breakthrough pain was similar between groups. The initial dose of medication was a repeated bolus of the epidural infusion for the first episode of pain, followed by 8 to 10 mL of bupivacaine 0.125% with fentanyl 100 µg for further discomfort. Postpartum assessment revealed no differences in reported pain scores between groups (Table 3), but the MBF groups required significantly fewer medications during the first 24 h (3.3 ± 3.7 doses versus 4.7 ± 3.5 doses; P = 0.04).
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Discussion |
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A clinically relevant finding in our study was that the women in the MBF group had a rate of breakthrough labor pain during epidural analgesia that was 40% less than the BF group and required 30% less medication than the BF group on the first postpartum day. We believe that this is an important finding with potential application to both labor pain relief and postpartum pain control. The use of intrathecal morphine as a supplement to an epidural infusion could be considered for parturients who are at high risk for recurrent breakthrough pain. For example, women who request pain relief at early cervical dilation and those with large fetuses and nulliparas may be more likely to suffer from recurrent breakthrough pain (17). Likewise, intrathecal morphine may be of considerable benefit in situations where postpartum pain control may be difficult, such as with large episiotomies or perineal tears. Yeh et al. (14) found a 70% increase in the mean duration of analgesia when 150 µg of morphine was added to their spinal medications. Several factors could explain why we did not find a result of similar magnitude. Our smaller dose of bupivacaine/fentanyl injectate had a significantly shorter duration of pain relief; thus, it is possible that the morphine-induced analgesia did not reach full effectiveness before the spinal medications had worn off. Second, the smaller dose of morphine used in the current study may not have had as significant an effect. Finally, cross-study comparisons are difficult, especially where there may be significant cultural differences.
Larger doses of intrathecal morphine provide labor pain relief and prolong the duration of a single bolus of epidural bupivacaine but at the cost of significant side effects, especially pruritus, nausea, and vomiting (12,18). We found no difference in the incidence of pruritus between the MBF and BF groups with the small dose used in this study. The MBF group had a 16% incidence of nausea and vomiting, whereas no patient in the BF group experienced this side effect. Respiratory depression has been reported as a rare complication of intrathecal fentanyl and morphine in combination (19). The incidence of respiratory depression after 5 mg of epidural morphine is 0.25%, and the incidence after intrathecal morphine is not known (20). If prolonged spinal analgesia is the primary desirable goal, then early initiation of an epidural infusion should be considered. Beilin et al. (21) recently reported a significant prolongation in effective analgesia among parturients who received epidural medications immediately after spinal injection. Because our investigation was designed to determine the duration of spinal analgesia, our results may not apply if the epidural infusion is initiated immediately after spinal injection. Further studies will be required.
We found that the intrathecal dose of 12.5 µg of fentanyl and 2 mg of bupivacaine was a clinically useful combination that produced a rapid onset of analgesia (median pain scores were 0 only five minutes after injection) that lasted approximately 85 minutes. The duration of spinal analgesia using these small doses seems to be slightly shorter than that reported from investigations with larger doses (7). This shorter duration would be consistent with a pharmokinetic explanation. However, several other factors may also account for this, including our suggestion to subjects to request analgesia when their pain began to return compared with investigations where this was emphasized to a lesser degree. Furthermore, because the duration of analgesia is less when given to women at advanced cervical dilation, (22) our inclusion of multiparas, who are more likely to have rapid labor, may have decreased the length of spinal analgesia. The doses of intrathecal medications used in this current study were based on the estimates of the median effective dose (ED50) for both bupivacaine and fentanyl as sole analgesics (1,7,11). Palmer et al. (11) estimated the ED50 to be 14 µg, with no advantage to doses larger than 25 µg, whereas Herman et al. (1) found the ED50 to be only 5.5 µg. Stocks et al. (7) estimated the ED50 of intrathecal bupivacaine for labor to be approximately 2 mg but <1 mg when used in combination with fentanyl. Our combination of the median effective doses of two synergistic medications resulted in a frequent rate of success.
Reducing the dose of spinal medications would be desirable if pain relief were maintained while the incidence and severity of side effects were diminished. Using our reduced dose of medications, we found a very small incidence of hypotension (2%) and minimal motor blockade. This study did not attempt to have the subjects walk during spinal or epidural analgesia. Our methods included the administration of lidocaine with an epinephrine test dose, which has been reported to diminish the parturients ability to walk when used with larger concentrations of bupivacaine (23). However, in that study, the subjects who received the smaller concentration of bupivacaine did not experience a decrease in their ability to ambulate but had an increased success of early analgesia. As discussed by Birnbach and Chestnut (24), the test dose is an important part of ensuring the careful and safe practice of epidural analgesia and does not seem to adversely affect motor strength when using very small concentrations. Pruritus is a frequent side effect of intrathecal opioids, and our incidence is within the range others have reported (25). Most of our patients described none or only mild pruritus and did not require treatment. We found it surprising that there was no detectable nausea in the BF group because this is not our clinical impression of women in active labor. By contrast, Yeh et al. (14) reported a 27% incidence in their placebo and 34% in their morphine groups. It is possible that reductions in the doses of opioids used in the current study resulted in reducing this side effect.
We can identify several limitations to our study. First, the subjects in our study consisted of both multiparous and nulliparous women. This limits the ability to compare the results to studies that use a homogenous population and may have shortened the effective duration of analgesia. A second limitation is the number of dropouts for both the intra-labor and postdelivery periods. Based on the Cesarean rate at our hospital and the expectation that several subjects may deliver before requesting rescue medication, we adjusted the number of subjects in our study by increasing enrollment. Despite the dropouts, post hoc analysis showed a power of 0.8 for the bolus rates, but it showed a power of only 0.4 for postpartum medications. The success of the subsequent epidural analgesia and postpartum pain control were secondary outcomes and were not controlled by strict protocols. We believe the results are valid because the randomization was not broken until after the subjects had completed all of the study periods, and thus, the study grouping should not have swayed the management of these patients. Finally, because of the small incidence of side effects, this investigation does not have adequate numbers of patients to effectively compare side effects between groups. This may be especially relevant in the comparison of nausea between groups.
In conclusion, the small dose of intrathecal fentanyl and bupivacaine used in this investigation produced rapid and effective labor analgesia lasting for approximately 85 minutes. The addition of a small dose of morphine did not extend the spinal analgesia for most parturients but improved the control of pain during subsequent epidural analgesia and reduced the requirements for postpartum pain medications.
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References |
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- Herman NL, Choi KC, Affleck PJ, et al. Analgesia, pruritus, and ventilation exhibit a dose-response relationship in parturients receiving intrathecal fentanyl during labor. Anesth Analg 1999; 89: 378–83.
[Abstract/Free Full Text] - Eisenach JC. Respiratory depression following intrathecal opioids. Anesthesiology 1991; 75: 712.
- Fragneto RY, Fisher A. Mental status change and aphasia after labor analgesia with intrathecal sufentanil/bupivacaine. Anesth Analg 2000; 90: 1175–6.
[Free Full Text] - Hays RL, Palmer CM. Respiratory depression after intrathecal sufentanil during labor. Anesthesiology 1994; 81: 511–2.[Web of Science][Medline]
- Hepner DL. Neuraxial opioids and respiratory depression. Anesth Analg 2000; 91: 1560–1.
[Free Full Text] - Katsiris S, Williams S, Leighton BL, Halpern S. Respiratory arrest following intrathecal injection of sufentanil and bupivacaine in a parturient. Can J Anaesth 1998; 45: 880–3.[Web of Science][Medline]
- Stocks GM, Hallworth SP, Fernando R, et al. Minimum local analgesic dose of intrathecal bupivacaine in labor and the effect of intrathecal fentanyl. Anesthesiology 2001; 94: 593–8.[Web of Science][Medline]
- Camann W, Abouleish A, Eisenach J, et al. Intrathecal sufentanil and epidural bupivacaine for labor analgesia: dose-response of individual agents and in combination. Reg Anesth Pain Med 1998; 23: 457–62.[Web of Science][Medline]
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[Abstract/Free Full Text] - Celeski DC, Heindel L, Haas J, Vacchiano CA. Effect of intrathecal fentanyl dose on the duration of labor analgesia. AANA J 1999; 67: 239–44.[Medline]
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- Grieco WM, Norris MC, Leighton BL, et al. Intrathecal sufentanil labor analgesia: the effects of adding morphine or epinephrine. Anesth Analg 1993; 77: 1149–54.
[Abstract/Free Full Text] - Leighton BL, DeSimone CA, Norris MC, Ben David B. Intrathecal narcotics for labor revisited: the combination of fentanyl and morphine intrathecally provides rapid onset of profound, prolonged analgesia. Anesth Analg 1989; 69: 122–5.
[Free Full Text] - Yeh HM, Chen LK, Shyu MK, et al. The addition of morphine prolongs fentanyl-bupivacaine spinal analgesia for the relief of labor pain. Anesth Analg 2001; 92: 665–8.
[Abstract/Free Full Text] - Palmer CM, Emerson S, Volgoropolous D, Alves D. Dose-response relationship of intrathecal morphine for postcesarean analgesia. Anesthesiology 1999; 90: 437–44.[Web of Science][Medline]
- Breen TW, Shapiro T, Glass B, et al. Epidural anesthesia for labor in an ambulatory patient. Anesth Analg 1993; 77: 919–24.
[Abstract/Free Full Text] - Hess PE, Pratt SD, Lucas TP, et al. Predictors of breakthrough pain during labor epidural analgesia. Anesth Analg 2001; 93: 414–8.
[Abstract/Free Full Text] - Caldwell LE, Rosen MA, Shnider SM. Subarachnoid morphine and fentanyl for labor analgesia. Efficacy and adverse effects Reg Anesth 1994; 19: 2–8.[Web of Science][Medline]
- Palmer CM. Early respiratory depression following intrathecal fentanyl-morphine combination. Anesthesiology 1991; 74: 1153–5.[Web of Science][Medline]
- Fuller JG, McMorland GH, Douglas MJ, Palmer L. Epidural morphine for analgesia after caesarean section: a report of 4880 patients. Can J Anaesth 1990; 37: 636–40.[Web of Science][Medline]
- Beilin Y, Nair A, Arnold I, et al. A comparison of epidural infusions in the combined spinal/epidural technique for labor analgesia. Anesth Analg 2002; 94: 927–32,Table.
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- Birnbach DJ, Chestnut DH. The epidural test dose in obstetric patients: has it outlived its usefulness? Anesth Analg 1999; 88: 971–2.
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