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OBSTETRIC ANESTHESIA

Postoperative Epidural Morphine for Postpartum Tubal Ligation Analgesia

Department of Anesthesiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois

Address correspondence to R-Jay L. Marcus, MD, Department of Anesthesiology, Feinberg School of Medicine, Northwestern University, 251 E. Huron, F 5–704, Chicago, IL 60611. Address e-mail to r-marcus{at}northwestern.edu.

	Abstract

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Women undergoing postoperative postpartum tubal ligation (PPTL) often experience considerable pain. We hypothesized that epidural morphine, as part of a multi-modal analgesic regimen, would decrease postoperative pain and the need for systemic analgesia after PPTL. In a double-blinded study, patients were randomized to receive epidural saline or morphine 2 mg, 3 mg, or 4 mg after epidural anesthesia for PPTL. Postoperatively, ibuprofen 600 mg was administered every 6 h and patients could request acetaminophen 325 mg/hydrocodone 10 mg. The primary outcome variable was time to first request for supplemental analgesia. Verbal rating scores for pain and the incidence and severity of side effects were recorded for 24 h. Morphine group subjects requested supplemental analgesia later and received fewer doses compared with the saline group subjects. Peak cramping and incisional verbal rating scores for pain and the area under the verbal rating scores for pain x time curve for cramping pain were less after epidural morphine compared with saline, but there were no differences among morphine groups. Nausea, vomiting, and pruritus occurred more often in all morphine groups and subjects who received morphine 4 mg required treatment for these side effects more frequently than the saline or morphine 2 mg groups. In conclusion, epidural morphine 2 mg as part of a multi-modal analgesic regimen improved analgesia and decreased the need for supplemental analgesics after PPTL. The need to treat side effects with morphine 2 mg was not increased compared to a regimen of oral acetaminophen/opioid/nonsteroidal antiinflammatory analgesics.

	Introduction

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In the United States 700,000 women annually undergo permanent sterilization by way of an infraumbilical mini-laparotomy and bilateral tubal ligation. One-half of these procedures are performed as postpartum tubal ligation (PPTL), often under epidural anesthesia (1). Because PPTL is generally regarded as a minor procedure, postoperative pain management usually consists of rapid transition to oral analgesics. Pilot data from our institution and the results of other studies suggest, however, that women undergoing PPTL often experience considerable postoperative pain and that this pain may be undertreated¹ (2–5). Parturients with inadequate pain control may have difficulty tending to activities of daily living and bonding with their newborns.

The etiology of pain after PPTL is multifactorial, consisting of direct tissue injury to the skin, fascia, peritoneum, and fallopian tubes, ischemic pain from tubal ligation, and pain resulting from uterine manipulation and postpartum uterine contractions (2). Because there is both visceral and somatic nociceptive input, multi-modal pain therapy may be appropriate. Postoperative epidural morphine is widely used to treat pain after cesarean delivery and is associated with less sedation than systemically administered opioids (6).

We hypothesized that the addition of epidural morphine to oral ibuprofen would improve analgesia after postoperative PPTL and reduce the need for oral supplementation with acetaminophen/hydrocodone compared with an analgesia protocol without epidural morphine. The purpose of this randomized, double-blind, placebo-controlled study was to compare analgesia, the need for supplemental analgesics, and side effects in patients who received epidural morphine as part of a multi-modal analgesic regimen.

	Methods

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The study was approved by the Northwestern University IRB. Healthy women scheduled for bilateral postpartum tubal ligation after spontaneous vaginal delivery with indwelling epidural catheters that had been used successfully for labor analgesia were eligible to participate in the study. Subjects were recruited between December, 2001 and December, 2003. Exclusion criteria included inability to communicate in English, multiple gestation, history of obstructive sleep apnea, body mass index >40 kg/m², allergies or contraindications to morphine, ibuprofen, acetaminophen, or hydrocodone, history of drug abuse or chronic pain syndromes, intrapartum use of epidural chloroprocaine, or failed epidural anesthesia.

Subjects were premedicated with 0.3 M oral sodium citrate (30 mL), IV ranitidine 50 mg, and metoclopramide 10 mg. All subjects voided within 30 min before the procedure start time. Surgical anesthesia was initiated with incremental epidural boluses of lidocaine 20 mg/mL with epinephrine 5 µg/mL and sodium bicarbonate 1 mEq per 10 mL lidocaine solution. Subjects were randomized via a computer-generated random number sequence to one of four study groups: placebo (M-0), morphine 2 mg (M-2), 3 mg (M-3), or 4 mg (M-4). Group assignments were sealed in sequentially numbered opaque envelopes. Subjects and care providers were blinded as to group assignment. After verifying the presence of surgical anesthesia, a syringe labeled "study drug" was prepared by an anesthesiologist not involved in the subject’s care. The study drug syringe was prepared with preservative-free morphine (morphine 0.5 mg/mL, Abbott Laboratories, North Chicago, IL) 0, 2, 3, or 4 mg and preservative-free normal saline to a final volume of 8 mL. Study drug was injected through the epidural catheter at the time of skin incision.

IV midazolam and fentanyl were administered intraoperatively at the discretion of the anesthesiologist for anxiolysis and supplemental analgesia, respectively. Nausea and/or vomiting were treated with ondansetron. Epidural catheters were removed immediately postoperatively. All subjects received ibuprofen 600 mg PO within 30 min of postanesthesia care unit arrival. Subjects were discharged from the postanesthesia care unit to the postpartum unit when they were hemodynamically stable and their sensory level had regressed two dermatomes as assessed by temperature sensation with an alcohol pad.

Subjects received ibuprofen 600 mg every 6 h unless they refused. They were instructed to request treatment for breakthrough pain. At the first request for supplemental analgesia, subjects were given acetaminophen 325 mg with hydrocodone 10 mg by mouth with an additional dose after 1 h if needed. This sequence was repeated every 4 h if requested. Pruritus was treated at the request of the subject with IV nalbuphine 2.5 mg per protocol or diphenhydramine 25 mg at the discretion of the obstetric staff. Nausea and/or vomiting were treated with IV ondansetron 4 mg or promethazine 12.5 mg.

Respiratory rate was assessed every hour for the first 12 h after the study drug was given. Pain, nausea, and pruritus scores were determined on admission to the postpartum unit and every 4 h for 24 h thereafter. Subjects were asked to rate their pain (incisional and cramping) using an 11-point Verbal Rating Score for Pain (VRSP, 0 to 10 scale where 0 is no pain and 10 is the worst pain imaginable). At the same time patients were also asked to rate pruritus and nausea on a 3-point scale (none, mild, moderate-to-severe). Episodes of vomiting or treatment for pruritus, nausea and/or vomiting within the first 24 h were recorded. The time and method of first void (spontaneous or bladder catheterization) were documented. Age, race, height, weight, presence and type of perineal laceration, time interval from delivery to PPTL procedure, volume of lidocaine used for surgical anesthesia, intraoperative systemic medications, and dermatomal level of temperature sensation on discharge from the postanesthesia care unit were recorded.

The primary outcome variable was time to first request for supplemental analgesia. Secondary outcomes included areas under the VRSP and pruritus and nausea scores versus time curves, peak VRSP, incidence and severity of nausea, vomiting, pruritus, the time and method of first void, and the rate of treatment of side effects among groups. The area under the curve for 24 h was calculated using the trapezium rule.

A sample size estimate was calculated using pain score data from patients who received analgesia with oral ibuprofen and acetaminophen/hydrocodone after PPTL.¹ For 4 groups, a total sample of 88 subjects was estimated to achieve 80% power to detect differences among the VRSP means versus the alternative of equal means using an F test with a 0.05 significance level. The size of the variation in the means represented by the standard deviation was estimated to be 0.83, with a common standard deviation within a group of 2.30. To account for subject dropout, 100 subjects were randomized to 4 groups.

Categorical data were compared using the ² test and interval data were compared using Kruskal-Wallis one-way analysis of variance corrected for multiple post hoc comparisons using the z-value test. Kaplan-Meier survival analysis and the log-rank test were used to compare time to first supplemental analgesia request. Cox-Mantel hazard ratios were used to determine the relative risk for request for supplemental analgesia for the morphine groups compared with saline group. All tests were two-sided. P < 0.05 was considered significant.

	Results

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One-hundred women gave informed consent to participate in this study. Ten subjects were excluded from data analysis because of incomplete data collection (n = 4), cancelation of the procedure after randomization (n = 5), and allergy to the study drug (n = 1). Group characteristics were similar except that subjects in the M-2 group were younger than those in M-0 (Table 1).

Ninety-five percent of subjects (95% confidence interval [CI], 77%–99%) in the saline group required supplemental analgesia within 24 h. Epidural morphine decreased the rate of subjects requiring supplemental analgesia by 43% (95% CI of the difference, 22%–65%), 43% (95% CI of the difference, 20%–66%), and 56% (95% CI of the difference, 34%–78%) for 2 mg, 3 mg, and 4 mg, respectively (P < 0.005). The time to first request for supplemental acetaminophen/hydrocodone analgesia was longer in all epidural morphine groups compared with placebo (Fig. 1). The odds ratios (95% CI) for time to first supplemental analgesia for morphine 2 mg, 3 mg, and 4 mg compared with saline were 2.5 (1.3–4.8, P < 0.005), 2.2 (1.2–4.5, P < 0.005), and 2.6 (1.3–5.1, P < 0.005), respectively. In addition, supplemental analgesia consumption for 24 h postoperatively was less in all morphine groups (P < 0.005) (Fig. 2). Median peak VRSP values for cramping and incisional pain were higher in the saline group compared with all morphine groups (P < 0.005); however, there was no difference among the morphine groups. As measured by the area under the curve, cramping pain severity was less in all morphine groups compared with the saline group; however, incisional pain severity did not differ among groups (Table 2).

View larger version (30K): [in this window] [in a new window]   Figure 1. Kaplan Meier plot of percent of subjects who received supplemental analgesia with hydrocodone/acetaminophen after postpartum tubal ligation. Median time to first supplemental analgesia for morphine 2 mg, 3 mg, and 4 mg are longer compared with saline (log-rank test, P < 0.005)

View larger version (23K): [in this window] [in a new window]   Figure 2. Box plot of number of hydrocodone 10 mg plus acetaminophen 325 mg tablets received in the first 24 h after postpartum tubal ligation. Median difference in number of tablets and 95% confidence intervals of the difference between morphine groups and saline for M-2 (–2, 95% confidence interval –1 to –4), M-3 (–3, 95% confidence interval –2 to –4), M-4 (–3, 95% confidence interval –2 to –4). Different from epidural saline, = 0.05.

Peak pruritus scores were greater in all morphine groups compared with saline, but only M-4 subjects required more treatment interventions (Table 2). Peak nausea scores were higher in M-4 compared with saline. Vomiting occurred more frequently in the M-3 and M-4 groups compared with control and in the M-4 group compared with M-2. As measured by area under the curve, pruritus severity was greater in all morphine groups compared with saline, and nausea severity was greater in M-4 compared with saline. Treatment for nausea/vomiting was administered more frequently to M-4 subjects compared with M-2 and control. There was no difference in the need for bladder catheterization among groups. No subject had an observed respiratory rate <10 breaths/min or required treatment for respiratory depression.

	Discussion

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The important findings of this study are that epidural morphine, as part of a multi-modal analgesia regimen after PPTL, decreases "pain burden" and reduces the need for supplemental oral analgesics compared with a regimen without epidural morphine. These findings have important clinical implications because PPTL pain is often under-appreciated and under-treated¹ (2–5). In a pilot study at our institution 72% of VRSP in the first 24 hours after PPTL were 4, compared with 38% in a cohort of postpartum women who did not have PPTL.¹ In addition, women undergoing PPTL required significantly more oral acetaminophen/hydrocodone than the control cohort. Because inadequate pain management in the early postpartum period may adversely affect maternal-infant bonding, it is important to provide adequate analgesia to these patients.

Other investigators have studied methods of improving PPTL postoperative analgesia. Injecting the fallopian tubes with local anesthetic as part of a multi-modal analgesia regimen was found to improve postoperative analgesia (2,7). Intrathecal morphine as part of a spinal anesthetic provided better analgesia after PPTL compared with placebo (3,5). Because many patients scheduled for PPTL have epidural anesthesia via an indwelling epidural catheter placed for labor analgesia, the addition of epidural morphine to the postoperative analgesia regimen is easily accomplished. Epidural anesthesia was successful using the in situ catheter in all subjects in the current study. Although the median interval between delivery and PPTL was only 2.5 hours, this supports data from other studies that report frequent success of epidural anesthesia after epidural labor analgesia (8,9).

We found that epidural morphine 2 mg, 3 mg, or 4 mg provided better analgesia, increased the time until the first supplemental analgesia request, and decreased the supplemental analgesic use compared with epidural saline. The analgesic-sparing effect and increased time until the first supplemental analgesia request were similar to those observed with intrathecal morphine 50 µg and 100 µg after spinal anesthesia for PPTL (3,5). In the current study peak VRSP for cramping and incisional pain were better after epidural morphine, although pain severity as assessed by the area under the curve (VRSP x time) was only reduced for cramping pain. This was not an unexpected finding, as opioids are more effective for visceral pain and less effective for sharp or burning pain (10). Similar to the current study, both peak cramping and incisional pain scores were improved in patients undergoing PPTL after intrathecal morphine (3).

Patients receiving IV morphine patient-controlled analgesia (PCA) after PPTL can have 24-hour morphine consumption similar to that of patients after cesarean delivery (3). The doses of epidural morphine tested in this study were similar to doses that have been used after cesarean delivery. A dose-response study of epidural morphine without other analgesics after cesarean delivery found a dose-response for morphine doses up to 3.75 mg, but there was a ceiling effect at 5 mg (11). We chose to study a maximum morphine dose similar to the dose commonly used after cesarean delivery. We were unable to demonstrate a difference in analgesia efficacy between the morphine doses studied. Possible explanations for this finding are that after PPTL the analgesia ceiling dose is smaller or that the study was under-powered to find a difference. Alternatively, patients were treated in this study with oral rescue analgesics rather than IV PCA, and the differences in the pharmacokinetics of these modes of drug administration could have obscured subtle differences in analgesic needs.

Patient acceptance of systemic or neuraxial opioids is limited by bothersome side effects, including pruritus, nausea and vomiting, and urinary retention. These side effects may require treatment, leading to further side effects, increased cost, and delayed discharge from the hospital. The dose-response for nausea and vomiting observed in this study and a previous study of intrathecal morphine (5) was not reported in other studies of neuraxial morphine (3,11). The likely explanation for this difference is that control group subjects in the studies that did not demonstrate a dose-response received significant amounts of IV opioid (3,11) compared with the current study and a similar study that both treated breakthrough pain with oral analgesics (5). This may also explain the lack of side effects in our control group. Because subjects in the current study who received morphine 4 mg received treatment for pruritus and nausea/vomiting more frequently without analgesia benefit, our data suggest that a morphine dose of 2 mg reduces "analgesic burden" with an acceptable side effect profile.

Respiratory depression is the dose-limiting side effect of opioids administered by any route. Similar to other studies using small doses of intrathecal and epidural morphine, we did not observe any changes in respiratory rate or evidence of clinically significant respiratory depression at any dose studied (3,5,11). It is unclear whether the risk of respiratory depression is increased with these doses of epidural morphine compared with other opioid analgesia techniques of similar efficacy or whether increased respiratory monitoring is necessary when using small-dose epidural morphine in this patient population.

There are several limitations to the current study design and conclusions. The study was under-powered to detect differences in analgesia effectiveness of the intermediary doses (morphine 2 mg and 3 mg), and we did not study a morphine dose <2 mg. A smaller dose was not studied because the dose-response investigation of epidural morphine after cesarean delivery failed to demonstrate any improvement in analgesia with morphine 1.25 mg compared with saline (11). However, because the analgesic dose-response for epidural morphine after PPTL may be shifted to the left, a dose smaller than 2 mg may provide analgesia in these cases.

An additional factor that may affect the generalization of our conclusions was the selection of epidural lidocaine as the local anesthetic for PPTL procedure. There is some evidence that epidural opioids are not as effective when combined with 2-chloroprocaine compared with other local anesthetics and therefore, our results may not be valid when epidural morphine is injected after 2-chloroprocaine anesthesia (12,13). Finally, most of our patients underwent PPTL within several hours of delivery, as this is routine in our institution. It is unclear whether our results would be different if the procedure was delayed or whether discharge planning would be adversely affected.

We choose to study epidural morphine/oral ibuprofen analgesia compared to oral acetaminophen/hydrocodone/ibuprofen analgesia because the latter is the standard of care at our institution and most women undergoing PPTL have in situ epidural catheters. However, any analgesia technique requires a balance between efficacy, side effects, and cost. We did not compare epidural morphine with other analgesia techniques, including a round-the-clock oral opioid regimen, or injection of the fallopian tubes with local anesthetic (2) or opioid (4).

In conclusion, our study suggests that epidural morphine 2 mg, as part of a multi-modal analgesic regimen, improves analgesia and decreases the need for supplemental analgesics after PPTL. The need to treat side effects with this dose was not increased compared with a regimen of oral acetaminophen/opioid/nonsteroidal antiinflammatory analgesics. This regimen should be considered in patients who undergo PPTL with epidural anesthesia.

	Footnotes

 
¹Marcus RL, Wong CA, Maly J, et al. Postoperative pain after "minor" surgery (postpartum tubal ligation) is not minor [abstract]. Anesthesiology 2001;94:98A.

Supported, in part, by the Department of Anesthesiology, Northwestern University Feinberg School of Medicine.

Accepted for publication January 26, 2005.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Marcus, R-J. L. Articles by Yilmaz, M. Search for Related Content PubMed PubMed Citation Articles by Marcus, R-J. L. Articles by Yilmaz, M. Related Collections Obstetrics Regional Anesthesia Pain Pharmacology