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From the Department of Anesthesia, Stanford University School of Medicine, Stanford, California.
Address correspondence and reprint requests to Brendan Carvalho, MBBCh, FRCA, Department of Anesthesia, H3580, Stanford University School of Medicine, Stanford, CA 94305. Address e-mail to bcarvalho{at}stanford.edu.
Abstract
BACKGROUND: A single-dose of neuraxial morphine sulfate provides good post-Cesarean analgesia; however, its efficacy is limited to the first postoperative day. In a recent phase III study, extended-release epidural morphine (EREM) formulation provided more effective, prolonged analgesia after Cesarean delivery, compared to conventional epidural morphine. However, the study protocol did not allow for the use of nonsteroidal antiinflammatory drugs, used various postoperative analgesics, and monitoring and treatment of respiratory depression were not standardized. Our aims in this study were to compare postoperative analgesic consumption, pain scores and side effects of EREM with conventional morphine for the management of post-Cesarean pain in a setting more reflective of current obstetric practice.
METHODS: Seventy healthy parturients undergoing elective Cesarean delivery were enrolled in this randomized, double-blind study. Using a combined spinal epidural technique, patients received an intrathecal injection of bupivacaine 12 mg and fentanyl 10 mcg. After closure of the fascia, a single-dose of either conventional morphine 4 mg or EREM 10 mg was administered epidurally. Postoperatively, all patients received ibuprofen 600 mg orally every 6 h. Oral oxycodone and IV morphine were available for breakthrough pain. All patients received pulse oximetry and respiratory monitoring for 48 h post-Cesarean delivery.
RESULTS: Single-dose EREM significantly improved pain scores at rest and during activity. The median (interquartile range) of supplemental opioid medication usage for 48 h post-Cesarean (in milligram-morphine equivalents) decreased from 17 (22) to 10 (17) mg with EREM compared to conventional epidural morphine (P = 0.037). Both drugs were well tolerated with no significant difference in adverse event profiles.
CONCLUSION: EREM provides superior and prolonged post-Cesarean analgesia compared to conventional epidural morphine with no significant increases in adverse events.
Neuraxial opioids provide superior postoperative pain relief compared to IV analgesia (1,2). The postoperative analgesia provided by a single dose of epidural or intrathecal morphine shifts the pain experienced after Cesarean delivery (CD) from the first day to the second postoperative day (2), with peak levels around 36 h post-CD. (3) Peak pain levels coincide with maternal mobilization and breast-feeding activity and may delay recovery (2–4). Continuous epidural catheter techniques prolong analgesia, but reduce patient mobility and increase nursing workload (4).
Single-dose, extended-release epidural morphine (EREM) (DepoDurTM, Endo Pharmaceuticals, Chadds Ford, PA) is a novel drug that delivers conventional morphine sulfate using DepoFoam (SkyePharma, San Diego, CA) technology. DepoFoam is a drug delivery system composed of multivesicular lipid particles containing nonconcentric aqueous chambers that encapsulate the active drug. This extended-release morphine technology is formulated to provide an epidural depot of morphine for up to 48 h after a single administration without the need for repeat dosing (5,6). EREM therefore has the potential to extend analgesia into the second postoperative day, when a single dose of conventional neuraxial morphine is no longer effective and peak post-CD pain levels are experienced (2,3). A multicenter, phase III post-CD study found that analgesia was significantly prolonged in patients who received single-dose epidural EREM compared to conventional epidural morphine (7). However, the study design had a number of weaknesses:
The study hypothesis was that EREM significantly reduces post-CD analgesic consumption compared to conventional epidural morphine. The objectives of this study were to compare postoperative analgesic consumption, pain scores, and side effects of a single-dose of epidurally administered EREM 10 mg versus conventional morphine 4 mg for the management of post-CD for 48 h after delivery. To ensure accurate efficacy and safety assessments, we aimed to study EREM in a setting more reflective of current obstetric anesthesia practice, in particular, using NSAIDs and providing standardized postoperative pain management, respiratory monitoring, and treatment protocols.
METHODS
Study Design and Patient Population
After IRB approval and written informed consent, 70 ASA 1 or 2 parturients having an elective CD under spinal anesthesia were enrolled in this single-center, randomized, double-blind study. Patients were excluded from study participation if they met any of the following criteria: morbid obesity (body mass index >40 kg/m2); emergency CD; significant surgical complications during the operation; use of general anesthesia for the CD; history of sleep apnea; any contraindication to regional anesthesia; hypersensitivity or previous reaction to opioid medications; history of chronic opioid use; or intolerance to NSAIDs. In addition, the study drug was not administered if there was accidental dural puncture or if local anesthetic was administered through the epidural catheter before the study drug administration. No epidural test dose was administered to any of the study patients, as per study protocol, due to concern for a potential physicochemical interaction with EREM and epidural local anesthetics that may reduce the sustained-release derived from the DepoFoam. Patients were randomized before their CD. If the study drug could not be administered due to a contraindication noted above, the patient was excluded from the primary and secondary efficacy analyses.
Parturients received spinal anesthesia via a combined spinal–epidural technique with hyperbaric bupivacaine 12 mg and fentanyl 10 µg administered intrathecally via the spinal component of the technique. A single epidural injection of either 4 mg morphine (n = 35) or 10 mg of EREM (n = 35) was given via the epidural catheter at the time of fascial closure. Group allocation was done using computer-generated random number allocation. To maintain blinding, the EREM and morphine were prepared by the pharmacy in equally sized syringes and secured in an opaque envelop. The study drugs were administered by an anesthesiologist not involved in the study and data collection. The investigator and all study staff remained blinded to the assigned treatment. The epidural catheter was removed after completion of the CD.
Postoperative Analgesic Management
All patients received ibuprofen 600 mg orally every 6 h for the 48-h study period with the first dose administered in the postanesthetic care unit 30 min after the end of surgery. Breakthrough pain was managed according to a strict study protocol flow-sheet (Appendix). The primary oral opioid analgesic for breakthrough postoperative pain was oral oxycodone 5 mg with acetaminophen 325 mg (Percocet®, Endo Pharmaceuticals, Chadds Ford, PA). IV morphine was available for severe pain or pain not responding to oral opioid analgesics. All other NSAIDs, cycloxygenase-2 inhibitors and opioids were prohibited during the postoperative period.
Assessments
Analgesic Efficacy
The primary efficacy end-point was the total amount of supplemental opioid analgesic medication used in the 48-h postoperative period after the administration of the study drug. For analysis, all doses of oral oxycodone were converted to IV morphine milligram equivalents using a conversion ratio of 20 mg oral oxycodone equivalent to 10 mg IV morphine (9).
Pain intensity was recorded at rest and during activity (sitting up at 90 degree) using a verbal rating scale for pain (VRSP 0–10 with 0 = no pain to 10 = worst pain imaginable) at regular intervals postoperatively (2, 6, 12, 24, 30, 36, and 48 h) by study investigators. The end of the CD was taken as time zero. Patient's overall ratings of pain control (VRSP 0–10) and satisfaction with analgesia (0–100, 0 = totally unsatisfied to 100 = totally satisfied) were assessed at 24 and 48 h post-CD. The proportion of patients requiring IV morphine and the proportion of patients who received no postoperative opioid medication were recorded. In addition, time to first request for opioid-analgesic medication was measured.
Functional ability (ability to walk without assistance) was assessed at 24 and 48 h post-CD by study investigators. The time to first breastfeed, the number of times the woman managed to breastfeed in each 24 h period, as well as whether pain limited the parturient's ability to breastfeed (0 = not at all, 1 = minimally, 2 = somewhat, 3 = very much, and 4 = unable to do so because of postoperative pain) were measured. The number of sleep hours, sleep quality (0–10 with 0 = completely unsatisfactory sleep quality, 10 = completely satisfactory sleep quality), and the number of awakenings per night due to pain were recorded for the first and second night post-CD. The length of hospital stay from the end of CD was also measured.
Side effects and Safety Profile
Side effects (nausea, pruritus, and sedation) were measured at regular intervals postoperatively (2, 6, 12, 24, 30, 36, and 48 h). Nausea and pruritus were assessed using a visual analog scale (0–100 mm with 0 = no nausea/pruritus and 100 = worst nausea/pruritus imaginable). Sedation scores were assessed using a 5-point ordinal scale: 0 = alert, 1 = occasionally drowsy, 2 = frequently drowsy, 3 = sleepy but easy to arouse, 4 = somnolent and difficult to arouse). Vomiting was recorded at 24 and 48 h post-CD as yes/no and number of episodes per 24 h. Any patient request for either nausea or pruritus medication was recorded at 24 and 48 h postoperatively. Nausea was treated with ondansetron 4–8 mg IV followed by metoclopramide 10–20 mg IV as needed. Pruritus was treated with up to four doses of nalbuphine 2.5 mg.
Respiratory rate and oxygen saturation were observed by nursing staff at 1-h intervals between 1 and 24 h after dose and at 2-h intervals between 24 and 48 h after dose. The following definitions of adverse events were provided in the study protocol: respiratory depression (respiratory rate <8 breaths/min), hypoxic event (pulse oximeter oxygen saturation on room air <93%), hypotension (>25% reduction in systolic blood pressure from baseline), and bradycardia (heart rate <40 bpm). Patients were considered to have urinary retention if they were unable to void or if they had bladder distension or discomfort 6 h after urinary catheter removal. The time (hours post-CD) to urinary catheter removal and the incidence of urinary retention were documented at the end of the study period. The decision to remove the urine catheter was left to the obstetrician caring for the patient.
Hypoxic events and respiratory depression were managed with oxygen (nasal oxygen at 4 L/min). Naloxone (in 100 mcg increments) was reserved for respiratory depression unresponsive to oxygen administration. The number of patients requiring supplemental oxygen and/or naloxone was also recorded.
Statistical Analyses
The previous multicenter post-CD study found that total 48 h postoperative rescue supplemental opioid consumption (in IV morphine milligram-equivalents) was 25 ± 21 mg in the EREM 10 mg group compared to 47 ± 34 mg in the conventional epidural 5 mg morphine group (7). Based on these findings, a priori power analysis predicted that we required 35 subjects per study arm to detect a clinically meaningful 33% reduction in milligram-morphine equivalents of opioid analgesic consumption (Power 0.8, P < 0.05).
Analyses were done on an intent-to-treat basis using all parturients who met inclusion and exclusion criteria and who received the study drugs. Descriptive statistics were used to summarize demographic, outcome, and adverse events data. Outcome measures of interest between the two groups were compared using Student's t-test for normally distributed variables and Mann–Whitney test for corresponding nonparametric comparisons. Normal distribution was determined using QQ plots and the Kolmogorov–Smirnov test. Associations among discrete variables were investigated using Pearson's 
2 and Fisher's exact test where appropriate. Longitudinal data analyses were performed using repeated measures ANOVA taking time as a repeated measure. Sphericity of the common covariance matrix of the transformed within-subject variables was tested using Mauchly's sphericity test. Unadjusted univariate P values are presented when sphericity is valid and multivariate Wilks' Lambda P values are presented when the sphericity assumption is violated. Kaplan–Meier curves and survival analyses were computed and compared using log-rank tests with SAS PROC LIFEREG. Analyses were performed with Microsoft Excel and SAS 9.1 statistical package (Cary, NC) with P < 0.05 considered statistically significant.
RESULTS
Patient Characteristics
Of the 70 randomized patients, seven were excluded from the primary and secondary efficacy analysis. Six patients did not receive the study drug due to the following exclusion criteria: inadequate spinal block requiring local anesthetic administration through the epidural catheter (two subjects in the morphine group and three subjects in the EREM group) and one subject in the EREM group after accidental dural puncture with the epidural needle. One patient in the EREM group who received the study drug was excluded from analysis due to determination in the postanesthetic care unit that the patient met exclusion criteria of a previous reaction to opioid medications. No patients were lost to follow-up or noncompliance. Demographic and baseline characteristics were similar between treatment groups (Table 1).
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Analgesic Efficacy
Analgesic Consumption
There was a statistically significant reduction in the total and second day (24–48 h after dose) supplemental opioid analgesic consumption between the study groups (Table 2). The median (IQR) of acetaminophen consumption was 2113 (3250) mg in the EREM group and 3250 (3900) mg in the morphine group (P = 0.07). The majority of patients (83% in the EREM group and 94% in the morphine group) received supplemental analgesics during the 48 h study period (P = 0.24 between treatment groups). IV opioids for severe or unresponsive pain were required in 3% and 13% of patients in the EREM and morphine groups respectively (P = 0.36).
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Pain Intensity
There was a significant decrease in postoperative pain (VRSP at rest and during activity) in the EREM compared to the morphine group over the 48 h study period after CD. (Figs. 1 and 2; P = 0.033 and 0.003, respectively).
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Functional Ability, Breast-Feeding Success, Hospital Stay, and Postoperative Sleep Patterns
Important secondary end-points are outlined in Table 4. Postoperative pain did not limit any patient's ability to breastfeed, and there was no difference in time to first successful breast-feeding in the EREM and morphine groups respectively (log-rank test = 0.65). There were no differences in the sleep quality reported during the first (P = 0.74) and second day (P = 0.45) post-CD, and no patients reported awakenings during the night due to pain.
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Side Effects and Safety
There were no difference in respect to nausea (P = 0.33), pruritus (P = 0.79), or sedation scores (P = 0.82) over the 48 h study period between groups using repeated measures ANOVA. We found no significant differences between groups in terms of the incidence of vomiting (Table 5). There were no differences between study groups in the total number of vomiting episodes per patient (P = 0.50). Antiemetic and antipuritis use were similar in both groups (Table 5). No patients experienced any hypotension or bradycardia related to the study drugs. Time to urinary catheter removal post-CD was similar (25 ± 5 h and 24 ± 5 h) in the EREM and morphine groups respectively (P = 0.281). The number of patients with urinary retention between the study groups was not significantly different (3 patients in the EREM group versus 0 in the morphine group, P = 0.097).
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Respiratory Depression and Hypoxic Events
No patients in either group had any significant respiratory depression (respiratory rate <8/min) during the entire study period. Three patients had hypoxic events (oxygen saturations <93%), one patient in the morphine group and two patients in the EREM group (P = 0.607). The lowest recorded oxygen saturation was 91%. All hypoxic events were at isolated time points, occurring between 11 and 18 h and resolved spontaneously or were responsive to oxygen administration. No patients in the morphine group and two patients in the EREM group received postoperative supplemental oxygen in response to oxygen saturations <93% (P = 0.223). No patient in either group required naloxone postoperatively for respiratory depression.
DISCUSSION
This study demonstrates that single-dose EREM 10 mg provides superior and prolonged analgesia post-CD compared to conventional epidural morphine 4 mg. The prolonged pharmacodynamic action of EREM was demonstrated by a divergence both in pain scores and analgesic consumption on the second post-CD day.
A reduction in our primary outcome measure, supplemental opioid analgesic consumption, has been observed in previous EREM studies in a number of settings including post-CD, after total hip and knee arthroplasty as well as after lower abdominal surgery (7,10–12). In this current study, EREM reduced the supplemental pain medication over the 48 h study period by approximately 40% (60% in the 24–48 h post-CD period). This reduction in analgesic consumption is similar to the previous phase III, multicenter, post-CD EREM study that showed a decrease in overall supplemental opioid use post-CD of approximately 50% when comparing the 10 mg EREM and morphine 5 mg study groups (7). However, in this previous post-CD EREM study, many different postoperative analgesics were used and analgesic management protocols varied among institutions, making precise calculations of analgesic consumption difficult and potentially unreliable.
Multimodal analgesia and NSAIDs have been shown to greatly enhance analgesic efficacy after neuraxial morphine for CD. (3,8,13,14) NSAIDs are particularly effective for relieving visceral pain of a cramping nature post-CD. (14) In the current study, patients in both groups consumed significantly less opioid analgesics post-CD compared to the previous post-CD EREM study. This was probably due to the addition of NSAIDs to the current study protocol. The addition of the NSAIDs in our study, however, did not abolish the difference in analgesia between the EREM and conventional epidural morphine study groups found in previous EREM studies that did not allow NSAIDs administration (7,10–12). Although NSAIDs reduced analgesic consumption they did not eliminate the use of supplemental oral opioids and most patients received supplemental opioid analgesics.
Although all parturients were given equal access to supplemental opioids, patients who received the EREM had better pain control, both at rest and during activity, especially 24–48 h post-CD. This analgesic advantage is consistent with the previous postoperative EREM studies (7,10–12); however, the pain scores in this current study were lower compared with those in the previous post-CD EREM study (7). Improved analgesia in the current post-CD study was probably due to the addition of NSAIDs. The prolonged analgesic effect was not at the expense of a slower onset, and there were no differences in the time to first request for analgesia.
In assessing the impact of pain on daily function post-CD, we evaluated a number of secondary outcomes including maternal functional ability, length of hospital stay, and sleep. Similar to the previous post-CD EREM study, functional activity was improved in the second post-CD day (7). Although superior postoperative pain control has been associated with a shorter hospital stay (15,16), we did not find that improved pain control and functional ability resulted in a shorter hospital stay. However, we did not determine when patients were clinically ready for discharge and external factors, including infant care, insurance coverage, home situation, and availability of transportation may have had a greater impact on the length of hospital stay than surgical recovery. Pain can affect the ability to sleep and lead to frequent night-time awakenings (16,17). Lack of sleep can affect daytime functioning and maternal–infant interaction. The post-CD period is very disruptive to sleep patterns; however, we did not find any difference in maternal sleep patterns between the study groups, despite superior prolonged analgesia in the EREM group. Previous studies have shown that infant-care and breast-feeding success can be improved by superior postoperative analgesia (18–20). There was a trend towards more successful breast-feedings in the EREM group, but no patient in either study group reported that postoperative pain limited their ability to breastfeed.
EREM was well tolerated, and we found no significant differences in the incidence of adverse events between the study groups. The adverse events profiled were typical of epidural opioids and were similar when compared to the previous post-CD EREM study (7). Although the EREM group received more epidural morphine, the conventional morphine group took more supplemental opioids. Given that opioids by any route (oral, IV, epidural, or intrathecal) have similar adverse events, it is not surprising that we found no differences in the side effect profiles. It is interesting to note that the conventional morphine group did not take enough supplemental opioids to treat their pain to the same degree as the EREM group, perhaps because patients limit their analgesic consumption secondary to adverse events or because the study post-CD analgesic protocol was too conservative to allow patients enough opioids to match the relative analgesic efficacy of EREM compared to conventional morphine.
There were no significant respiratory depression or hypoxic events with the dosages used in this study. Unlike in the previous post-CD EREM study, we monitored maternal oxygen saturations post-CD. This may have allowed us to better identify the patients at risk for opioid-related respiratory depression. However, in keeping with findings from the previous post-CD EREM study (7), we encountered no significant problems with respiratory depression. The overall prevalence of postoperative respiratory depression attributable to neuraxial opioid administration is very low (21), and neuraxial opioids have a long safety record in the post-CD setting. The young, healthy, obstetric population is ideally suited to receive sustained- release neuraxial opioids, because postoperative respiratory depression is less likely compared to other postsurgical populations. However, although we observed no significant respiratory depression, this study was not primarily designed to assess differences in adverse respiratory events between treatment groups, and future studies involving larger cohorts of patients are needed to adequately address this issue.
Although we did not identify any safety concerns among our study patients, we recommend careful postoperative respiratory monitoring and management protocols when using any neuraxial opioid, especially EREM. There were no complications from inadvertent intrathecal administration, but there is the potential of accidentally administering a large dose of EREM intrathecally, and adequate protocols and facilities for treating such a complication should be available.
We did not use any epidural local anesthetics, including a lidocaine test dose before administration of EREM. Early pharmacokinetic studies indicated that there may be a potential physicochemical interaction with EREM and epidural local anesthetics that may reduce the sustained-release derived from the DepoFoam. However, a recent study by Gambling et al. (22) demonstrated similar EREM pharmacokinetics and pharmacodynamics when EREM was administered 15, 30, and 60 min after epidural bupivacaine 0.25%. Until further data are obtained, we would recommend following the package insert recommendation, which states that local anesthetics other than a 3 mL test dose of lidocaine are not permitted and that if the 3 mL test dose is used, the epidural catheter should be flushed, after waiting 15 min, with 1 mL of saline before administration of EREM.
A potential limitation of the study is the dose selection for analgesic efficacy comparison and adverse events profiling. We selected a 10 mg EREM dose based on data from the previous post-CD EREM study. In that study, there appeared to be an analgesic ceiling at approximately 10 mg, with little added benefit beyond this dose (7). An active control of 4 mg epidural morphine was chosen based on a study by Palmer et al. (23) that demonstrated an analgesic ceiling at approximately 3.75 mg of epidural morphine post-CD. The equianalgesic doses of EREM and conventional morphine in the post-CD setting are not known. Analgesic efficacy and adverse events are often dose-related, and the higher doses of neuraxial opioids may increase adverse events (24). However, given that the EREM and conventional morphine had similar analgesic efficacy and side effect profiles in the first 24 h, we believe we used doses that were approximately equianalgesic.
Another potential limitation is the use of both oral and IV opioids for breakthrough analgesia. This protocol design allowed the study to be conducted under conditions reflecting current post-CD management. We limited patients to only one oral opioid and used a standardized conversion to IV milligram-morphine equivalents (9). In addition, very few patients required IV morphine, and thus the majority of the supplemental analgesics were oxycodone. This suggests that differences in opioid consumption found in the study were probably related to analgesic efficacy differences between EREM and conventional epidural morphine.
In conclusion, this novel formulation of single-dose EREM decreased the need for supplemental analgesics and improved post-CD pain compared with that of conventional epidural morphine. The prolonged pharmacodynamic action of EREM was demonstrated by both a divergence in pain scores and analgesic consumption on the second post-CD day. We also found that patients who received EREM were better able to mobilize post-CD. EREM was well tolerated and we identified no significant safety issues. EREM (DepoDur) is a potentially beneficial analgesic in the treatment of post-CD pain and appears to provide superior, prolonged analgesia compared to the "gold standard" neuraxial opioid, conventional morphine sulfate.
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Footnotes
Accepted for publication March 15, 2007.
Supported by Endo, Pharmaceuticals Chadds Ford, PA (Endo Pharmaceuticals had no input in the study design, study conduct, data analysis, or manuscript preparation); Office of Research on Women's Health and National Institute of Child Health and Human Development of the National Institutes of Health, grant 5K12 HD043452 (to Dr. Carvalho), and a career development award from the National Institute of General Medical Sciences of the National Institutes of Health, grant 5K23GM071400-02 (to Dr. Chu).
REFERENCES
This article has been cited by other articles:
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  B. Roboubi Extended Release Epidural Morphine, Far from Ideal for Postcesarean Delivery Pain Control Anesth. Analg., December 1, 2007; 105(6): 1864 - 1864. [Full Text] [PDF]
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B. Carvalho and E. Riley Extended Release Epidural Morphine, Far from Ideal for Postcesarean Delivery Pain Control Anesth. Analg., December 1, 2007; 105(6): 1864 - 1865. [Full Text] [PDF]
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