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OBSTETRIC ANESTHESIA

Single-Dose, Sustained-Release Epidural Morphine in the Management of Postoperative Pain After Elective Cesarean Delivery: Results of a Multicenter Randomized Controlled Study

Brendan Carvalho, MBBCh, FRCA^*, Edward Riley, MD^*, Sheila E. Cohen, MBChB, FRCA^*, David Gambling, MB, BS, FRCPC, Craig Palmer, MD, H. Jane Huffnagle, DO, Linda Polley, MD^||, Holly Muir, MD^¶, Scott Segal, MD^#, Christine Lihou, CCRA^**, Garen Manvelian, MD^** for the DepoDur Study Group

*Department of Anesthesia, Stanford University School of Medicine, Stanford, California; Sharp Mary Birch Hospital for Women, San Diego, California; Department of Anesthesiology, University of Arizona Health Sciences Center, Tucson, Arizona; Department of Anesthesiology, Thomas Jefferson University, Philadelphia, Pennsylvania; ||Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan; ¶Department of Anesthesiology, Duke University, Durham, North Carolina; #Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, Massachusetts; and **SkyePharma, Inc., San Diego, California

Address correspondence and reprint requests to Brendan Carvalho, MBBCh, FRCA, Department of Anesthesia, Stanford University School of Medicine, 300 Pasteur Dr., Stanford, CA 94305. Address e-mail to bcarvalho{at}stanford.edu.

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
In this multicenter, randomized, controlled study, we compared the analgesic efficacy and safety profile of a new single-dose extended-release epidural morphine (EREM) formulation (DepoDur^TM) with that of epidural morphine sulfate for the management of postoperative pain for up to 48 h after elective cesarean delivery. ASA physical status I or II parturients (n = 75) were anesthetized with a combined spinal/epidural technique. Parturients received intrathecal bupivacaine 12–15 mg and fentanyl 10 µg for spinal anesthesia and a single epidural injection of either 5 mg of standard (conventional preservative-free) morphine or 5, 10, or 15 mg of extended-release morphine after cord clamping for postoperative pain control. Single-dose EREM 10 and 15 mg groups significantly decreased total supplemental opioid medication use and improved functional ability scores for 48 h after surgery compared with those receiving 5 mg of standard morphine. Visual analog scale pain scores at rest and with activity at 24 to 48 h after dosing were significantly better in the 10- and 15-mg single-dose EREM groups versus the standard morphine group. There were no significant differences between the two 5 mg (single-dose EREM and standard morphine) groups. Single-dose EREM was well tolerated, and most adverse events were mild to moderate in severity. Single-dose EREM is a potentially beneficial epidural analgesic for the management of post-cesarean delivery pain and has particular advantages over standard morphine for the period from 24 to 48 h after surgery.

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Epidural analgesia with morphine provides good control of postoperative pain, including post-cesarean delivery (CD) pain (1–3). When comparing epidural and IV analgesia, treatment with epidural analgesia is associated with decreased postoperative pain and fewer opioid-related side effects (4). Patients receiving IV patient-controlled analgesia and IM opioids report more severe pain after CD compared with those receiving intrathecal (IT) and epidural-administered opioids (5). Additionally, postoperative epidural analgesia has been associated with an improvement in the mother’s ability to mobilize and interact with her newborn infant (6,7).

In the setting of CD, the primary limitation of epidural analgesia with conventional morphine has been the duration of analgesia, which is typically <24 h (2,5,8,9). Current data indicate that post-CD pain relief and patient satisfaction are often inadequate after conventional therapy, including intraoperative IT or epidural opioids, postoperative oral analgesics, parenteral opioids, or a combination of these. This is particularly evident on Day 2, when pain may be more intense than during the first 24 h (1,5,8). Even with the addition of nonsteroidal antiinflammatory drugs (NSAIDs), pain on the second postoperative day is often inadequately controlled (8). Continuous epidural catheter techniques prolong analgesia but reduce patient mobility and increase the nursing workload (1). IT morphine administration does not increase the efficacy or duration of analgesia compared with epidural morphine (10). A long-acting drug such as morphine sulfate extended-release liposome injection (DepoDur^TM; SkyePharma Inc., San Diego, CA) may be a better analgesic option after CD, because there is often more pain on postoperative Day 2 when single conventional morphine neuraxial injections are no longer effective (5,8).

DepoDur^TM is a novel drug that delivers standard morphine by using DepoFoam^TM technology. DepoFoam^TM (SkyePharma, Inc.) is a drug-delivery system composed of multivesicular lipid particles containing nonconcentric aqueous chambers that encapsulate the active drug (Fig. 1). With this technology, single-dose extended-release epidural morphine (EREM) provides an epidural depot of morphine for prolonged analgesia (up to 48 h) without the need for repeat dosing (11).

View larger version (96K): [in this window] [in a new window]   Figure 1. Electron micrograph of DepoFoam particles. The nonconcentric vesicles are surrounded by a lipid membrane, and each contains an internal aqueous chamber with encapsulated morphine sulfate solution.

Pharmacokinetic and clinical pharmacology studies support the sustained-release properties of single-dose EREM. The terminal half-life of single-dose EREM is dose dependent; it lasts up to 21 h after a 40-mg dose, compared with 2.6 h after 2.5 mg of standard morphine (Study DTC 96-003; SkyePharma internal report). When the plasma morphine concentrations of 5 mg of standard morphine are compared with those of 5 mg of EREM, the terminal half-lives are comparable, but peak concentrations are significantly smaller, and peak systemic absorption occurs later with EREM. In addition to the sustained release derived from the DepoFoam^TM drug-delivery system, it also allows for larger doses to be administered without proportionally excessive peak levels and related side effects.

This study was designed to compare the analgesic efficacy and safety of single-dose EREM versus a single epidural dose of standard epidural morphine for the management of postoperative pain for 48 h after elective CD. We hypothesized that single-dose EREM would provide superior and more prolonged analgesia in this patient population.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
The study protocol and its amendments were approved by the IRB at each study center (Appendix 1). After ethics board approval and written informed consent, 79 ASA physical status I or II parturients undergoing elective CD under spinal anesthesia were enrolled in this multicenter, randomized, double-blind study. Of the 79 randomized patients, 60 were randomized to the single-dose EREM treatment groups (19, 21, and 20 to the 5-, 10-, and 15-mg doses, respectively) and 19 to the 5-mg standard epidural morphine (MS) group. Parturients received a combined spinal/epidural anesthetic with hyperbaric bupivacaine 12–15 mg and fentanyl 10 µg administered IT, followed by a single epidural injection of either 5 mg of morphine or 5, 10, or 15 mg of EREM after cord clamping.

The investigator and all study staff remained blinded to the assigned treatment. After surgery, at the investigator’s discretion, patients received either an oral opioid or IV morphine for breakthrough pain relief as needed. Doses of oral opioids were converted to IV morphine milligram equivalents for analysis (Table 1).

Patients were excluded from study participation if they met any of the following criteria: morbid obesity (body mass index 40 kg/m²); weight gain >20 kg during pregnancy; emergency CD; use of general anesthesia for the CD; history of sleep apnea; any contraindication to regional anesthesia; hypersensitivity or previous reaction to opioid medications; or chronic opioid use (daily opioids for >7 days before enrollment). In addition, the study drug was not administered if there was accidental dural puncture or if there were significant surgical complications during the operation. The administration of local anesthetic through the epidural catheter before study drug administration precluded use of the study drug because a potential physicochemical interaction with epidural local anesthetics and EREM may reduce the sustained release derived from the DepoFoam^TM.

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 opioids were converted to IV morphine milligram equivalents (Table 1). The proportion of patients who received no postoperative opioid medication was also recorded.

At the time of the first request for analgesic medication and at regular intervals postspinal dose (4, 8, 12, 24, 30, 36, and 48 h), the visual analog scale (VAS; scale of 0 mm ["no pain"] to 100 mm ["most severe pain possible"]) was used to measure pain intensity at rest (VAS-R) and pain intensity with activity (VAS-A). Area under the curve analyses (AUC) were performed on VAS scores during the 48-h period by using the trapezoid rule. Pain-intensity measures were also recorded by using the categorical scale at rest (CAT-R) and with activity (CAT-A). On the CAT scale, pain intensity was described as none, mild, moderate, or severe. Patient ratings of pain control were assessed at 24 and 48 h postdose (very good, good, fair, or poor).

The effect of pain on functional ability was assessed at 24 and 48 h postdose for each of four functions (resting in bed, sitting, walking, and using the toilet) by assigning scores to reflect the level of difficulty of each function (0, not difficult at all; 1, minimally difficult; 2, somewhat difficult; 3, fairly difficult; 4, very difficult; 5, unable to do). The effect of pain on the overall functional ability score was quantified as the sum of the scores for all four functions (0–20, where 0 is the highest and 20 is the lowest functional ability).

Adverse events were recorded for 7 days postoperatively. Serious adverse events (fatal, life-threatening, disabling, and neurological) were recorded for 30 days. Respiratory rate, heart rate, arterial blood pressure, and sedation scores were also assessed after surgery. All adverse events were reported, and the outcome, severity, and possible relationship to study drug were documented. The number of patients requiring supplemental oxygen or naloxone was recorded. 1) Postoperative monitoring with pulse oximetry and 2) respiratory depression and its treatment were not dictated by protocol and were institution specific. The following definitions of adverse events were provided in the study protocol: hypotension, >25% reduction in systolic blood pressure from baseline; bradycardia, heart rate <40 bpm; hypoventilation, respiratory rate <8 breaths/min; hypercapnia, Paco₂ consistently >53 mm Hg; hypoxia, clinically significant reduction in oxygen saturation; and urinary retention, absence of spontaneous voiding >7 h after removal of bladder catheter.

The study protocol stated that the preferred treatment for breakthrough pain was acetaminophen with codeine orally or IV morphine either as an intermittent bolus or via a patient-controlled analgesia pump (1-mg bolus with a 10-min lockout period; no background infusion) for 48 h postdose. However, to accommodate varying practices at the sites enrolling patients, the selection of postoperative analgesics was at the discretion of the site investigators, and patients received other medications as well (e.g., oxycodone, hydrocodone, and codeine). All opioids were converted to morphine milligram equivalents for analysis (Table 1). NSAIDs and cyclooxygenase 2 inhibitors were prohibited during the postoperative period.

On the basis of a prior study of single-dose EREM in hip surgery patients, we predicted that the mean ± sd analgesic requirement in our study during the first 48 h in the standard morphine group would be 117 ± 78 mg. According to this calculation, the minimum sample size needed to detect a 50% decrease in total opioid use between the single-dose EREM and standard morphine groups was estimated to be 20 patients per group.

The intent-to-treat (ITT) population, consisting of all patients who were randomized with the exception of those who did not receive study drug because of study exclusion criteria, was analyzed for the primary efficacy end-point. One-way analysis of variance after a rank transformation of data was used to compare the mean total amount of opioid analgesic medication used during the first 48 h postdose among the treatment groups. If the primary analysis revealed a significant effect (P < 0.05), Dunnett’s test was then performed to compare each dose of single-dose EREM with 5 mg of standard morphine. The time from study drug administration to the first postoperative opioid medication use was summarized with medians and Kaplan-Meier curves. A log-rank test was used to compare treatment groups. All other secondary end-points were analyzed by using the Cochran-Mantel-Haenszel test, analysis of variance, Dunnett’s test, or the Kruskal-Wallis test, followed by pairwise tests with comparisons with standard morphine if the overall effect was significant. Descriptive statistics were used to summarize safety data. The incidence of adverse events among treatment groups was compared by using Fisher’s exact test.

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Of the 79 randomized patients, 6 did not receive the study drug. In 4 patients this was due to the following exclusion criteria: IT catheter (10-mg single-dose EREM group); inadequate spinal block requiring use of the epidural catheter (15-mg single-dose EREM group); CD complicated by placenta accreta resulting in a hysterectomy (10-mg single-dose EREM group); and dural puncture with the epidural needle (5-mg MS group). In 2 additional patients there were protocol violations: fentanyl was not given with the spinal bupivacaine (15-mg single-dose EREM group), and there was accidental loss of the IT dose of bupivacaine and fentanyl that required a second IT dose (10-mg single-dose EREM group).

Seventy-five of the 79 randomized patients were included in the ITT population used for efficacy analysis. The ITT population consisted of all those randomized, with the exception of the four patients who did not receive the study drug because of the exclusion criteria enumerated above. The ITT population did include two patients (one in the 10-mg and one in the 15-mg single-dose EREM group) who were randomized but did not receive study drug because of protocol violations not included in the original study exclusion criteria.

Seventy-three of the 79 randomized patients were included in the safety analysis (6 terminated the study early because of noncompliance or loss to follow-up). Of the 73 patients included in the safety analysis, there were 19, 18, and 18 in the 5-, 10-, and 15-mg single-dose EREM groups, respectively, and 18 in the MS group. Demographic and baseline characteristics were similar among treatment groups (Table 2). The mean duration of surgery was 44 min, and the mean duration of time from cord clamp to end of surgical procedure was 32 min. Most patients (72 of 75; 96%) received supplemental analgesics during the 48-h study period, including acetaminophen, oral opioid analgesics (e.g., oxycodone, hydrocodone, and codeine), and IV morphine sulfate, fentanyl or meperidine.

At 48 h, there was a significant difference between the single-dose EREM treatment groups and the MS group in reduction of total supplemental opioid analgesic use (Fig. 2). In the single-dose EREM groups, the mean ± sd total supplemental opioid use (in morphine milligram equivalents) ranged from 25 ± 21 (10-mg single-dose EREM group) to 35 ± 24 (5-mg single-dose EREM group), versus 47 ± 34 in the MS group. These reductions were statistically significant in the 10-mg and 15-mg single-dose EREM groups (P = 0.0108 and 0.0065, respectively), but not in the 5-mg EREM group. During the second day (24–48 h postdose), significantly fewer patients required IV opioids in the 10-mg and 15-mg single-dose EREM groups (10% in both groups) versus the MS group (44%; P = 0.029 in both groups).

View larger version (27K): [in this window] [in a new window]   Figure 2. Use of supplemental opioid analgesics (in morphine milligram equivalents) during the 48 h after the study dose. *P = 0.0134; P = 0.0001; P = 0.0108; P = 0.0065.

There were no significant differences among treatment groups in the proportion of patients who received no supplemental medication, although there was a trend toward fewer single-dose EREM-treated patients requiring supplemental opioids (Table 3). There were no significant differences in the type of analgesic received among the groups studied.

According to AUC analysis, which represents patients’ pain experience over the entire 48-h study period, there were significant differences in the mean ± sd AUC VAS-R scores (Figure 3) in the 10-mg and 15-mg single-dose EREM groups versus standard morphine (454 ± 334 and 484 ± 425, respectively, versus 1186 ± 939; P = 0.0031 and 0.0029, respectively). Similarly, pain-intensity scores with activity (VAS-A) were significantly lower in patients who received the 10-mg and 15-mg single-dose EREM compared with standard epidural morphine when analyzed as AUC (0–48 h) (1235 ± 775 and 1036 ± 726 versus 2086 ± 875, respectively; P = 0.0051 and 0.0003, respectively).

View larger version (20K): [in this window] [in a new window]   Figure 3. Pain intensity over time (visual analog scale at rest). *P < 0.05 for all single-dose EREM groups versus morphine sulfate. DM = DepoMorphine; EREM = extended-release epidural morphine.

There were no differences in the time to the first request for additional postoperative analgesia among the groups. The time to first analgesic request was 3 h (95% confidence interval [CI], 1.7–3.7 h) in the 5-mg MS group, compared with 2.2 h (95% CI, 1.8–3.0 h), 3.0 h (95% CI, 1.9–4.4 h), and 3.1 h (95% CI, 1.9–6.3 h) in the 5-, 10-, and 15-mg single-dose EREM groups, respectively.

Patients who received the 10- or 15-mg single-dose EREM had significantly better overall functional ability scores than those who received standard morphine (Table 4). When each of the scores for the individual functional domains was analyzed separately, significantly better functional scores were reported in the 10-mg and 15-mg single-dose EREM groups compared with the MS group at both 24 and 48 h (P < 0.05), with the exception of the value for sitting at 48 h postdose in the 15 mg group.

At 48 h postdose, the mean ± sd rating of pain control was significantly better in the 10- and 15-mg single-dose EREM groups compared with the MS group (3.5 ± 0.7 and 3.8 ± 0.4, respectively, versus 2.8 ± 0.9; P = 0.0321 and 0.0009, respectively). Thirty-two percent, 53%, and 74% of patients in the 5-, 10-, and 15-mg single-dose EREM groups, respectively, rated their pain control as "very good," compared with 22% in the MS group.

Sixty-six patients (90%) reported an adverse event from Days 1 through 7. Most events were mild to moderate in intensity, and there were no significant differences in the incidence of adverse events among the treatment groups (Table 5). There was no statistical relationship between the dose of single-dose EREM and the incidence or severity of adverse events. Ten neurologic adverse events were reported (six in the single-dose EREM groups and four in the MS group; not significant). Nine of the 10 events were considered mild, and none was serious. There were two transient foot paresthesias, one in a patient who received single-dose EREM 15 mg and one in a patient who received the morphine 5 mg control. There was also a peripheral neuropathy in the right leg in a patient who received single-dose EREM 10 mg. All resolved spontaneously, and none of these events was considered related to the administration of study drug.

Supplemental oxygen was administered to eight patients (15%) treated with single-dose EREM and four patients (22%) treated with MS in response to decreased oxygen saturation. One standard morphine-treated and two single-dose EREM-treated patients required a single dose of an opioid antagonist postoperatively. Both patients were in the 15 mg group and received the opioid antagonist between 12 and 24 h postdose, one for pruritus and the other for respiratory depression. The latter patient received naloxone for a respiratory rate of 8 breaths/min and oxygen saturations on air of 91%–93% while asleep and 93%–96% when awake. She was easily arousable and had not been given oxygen first, as was indicated in the protocol. The standard morphine-treated patient required an opioid antagonist for pruritus at 5 h postdose.

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
In this study, single-dose EREM provided prolonged analgesia during the 48-hour study period, as indicated by a significant reduction in the need for supplemental pain medication in the 10- and 15-mg single-dose EREM groups. We allowed patients access to a number of commonly used analgesics to reflect current post-CD pain management. Because of the various postoperative analgesics consumed, we used standardized opioid conversions to determine the morphine milligram equivalents (12). Exact opioid equivalence and conversions may vary among sources. This study used conversion values from Goodman and Gillman’s text (12). Although there are limitations in using opioid conversions, in particular, accounting for analgesic duration, it allowed the study to be conducted under conditions reflecting current post-CD management. However, the types of opioids consumed within each group were similar, and thus the differences between groups demonstrate an effect of the study drug and not the opioid conversions used.

To accommodate the varying practices at sites enrolling patients, we allowed the postoperative analgesic threshold to be determined by the site investigators. Although varying analgesic thresholds may potentially affect a patient’s analgesic supplementation, we were unable to detect any significant differences among enrolling sites with regard to analgesic consumption.

Even though all parturients were given equal access to supplemental opioids, patients who received the 10- and 15-mg EREM had better pain control, especially in the 24- to 48-hour post-CD period. These findings in women undergoing CD are consistent with the results of a previous single-dose EREM study in patients undergoing hip arthroplasty that showed that single-dose EREM at 15, 20, and 25 mg significantly reduced fentanyl use and improved postoperative pain control compared with placebo (13).

There were no differences in the time to first request for analgesia or in pain-intensity scores at first analgesic request. The median time to first request for analgesia was approximately 3 hours in all study groups. This coincides with the expected offset of action of the bupivacaine and fentanyl in the spinal anesthetic. We were surprised that neither epidural morphine nor EREM extended the time to first request for analgesia, as has been demonstrated in previous studies with EREM (13) and epidural morphine (10). In post-CD patients, epidural morphine may provide incomplete analgesia for painful postpartum uterine contractions and fundal massage, which the patient experiences once the spinal block starts to recede. Under the study conditions, subjects were also repeatedly told that they could request additional analgesia, and this might have altered their behavior in comparison with patients under usual postoperative conditions.

The single-dose EREM 10- and 15-mg doses significantly improved patients’ ability to function, as indicated by measures of resting, sitting, walking, and ability to use the toilet. Better function was especially apparent at the 48-hour assessment compared with standard epidural morphine. Assessing the effect of pain on functional tasks by using an overall functional ability score is novel and has not been validated in other studies. However, because it is simple, objective, and involves important activities of daily living, we believe that it is a valid way to assess post-CD function and quantify the effects of varying degrees of pain relief. Epidural analgesia has been associated with better self-care and infant care compared with other forms of analgesia (6).

Adverse events reported in this study demonstrate that single-dose EREM was well tolerated, with no significant differences in the incidence of adverse events and with an adverse event profile typical of other epidural opioids. Although this study does not have adequate power to accurately determine the true incidence of side effects, there is a suggestion that improved analgesia may come at the cost of increased side effects such as pruritus. These differences may become apparent when data from larger numbers of parturients are studied.

With the doses used in this study, respiratory depression was not a problem. The one patient who received naloxone for a slow respiratory rate and mild oxygen desaturation while asleep was easily arousable and had a normal saturation when awakened. The nurse administered naloxone because she was unable to immediately contact the investigator, rather than first administering oxygen, as was indicated in the protocol and as is the usual institutional practice. We believe that, given the clinical situation, opioid antagonism was not necessary in this case. Despite no incidence of profound respiratory depression in our study of 79 parturients, we can only conclude that the true incidence is 5% (on the basis of binomial expansion of our study population within 95% confidence limits). Because this study was not powered to assess safety, more experience is needed to ascertain the risk of adverse events such as respiratory depression with single-dose EREM relative to standard epidural, IT, or IV morphine.

Although we did not identify any safety concerns among our study patients, we recommend careful postoperative respiratory monitoring and management protocols during preliminary use of these large-dose neuraxial opioids. We had no complications from inadvertent IT administration; however, there is a potential for administering a large dose of IT morphine, 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, in this study. There is a potential physicochemical interaction with epidural local anesthetics and EREM that may reduce the sustained release derived from the DepoFoam^TM. While the full extent of this interaction is being investigated, the manufacturer recommends flushing the epidural catheter with saline and waiting 15 minutes after local anesthetic use (including a test dose) before the administration of EREM.

Post-CD pain differs from other postsurgical pain models and poses a number of additional challenges for clinicians. Current data indicate that pain relief after CD is often incomplete, particularly on Day 2 (5,8). This pain peak on Day 2 coincides with parturients starting to mobilize and begin infant-care activities (1,5,8). This study demonstrates that single-dose EREM is effective and that the analgesic benefit over standard epidural morphine 5 mg is most apparent in the second 24 hours (24–48 hours postspinal) after CD.

Although this study demonstrated improved analgesia and reduced analgesic supplementation, single-dose EREM does not completely relieve post-CD pain. The addition of NSAIDs to conventional IT morphine has been shown to greatly enhance analgesic efficacy after CD (8,14,15). Oral analgesics (e.g., NSAIDs) used in conjunction with single-dose EREM may provide even better post-CD analgesia. Further studies are required to investigate single-dose EREM as part of a multimodal post-CD pain-management protocol.

The ideal dose of conventional epidural morphine for post-CD analgesia has not been established. However, there may be an analgesic ceiling at approximately 3.75 mg, although variability in patient response makes predicting an ideal dose very difficult (16). We chose a 5-mg epidural morphine control dose to ensure that it was definitely above the analgesic threshold but within a safe and effective dose range often used in this setting (17).

Despite using significantly less postoperative opioid rescue medication, patients in the single-dose EREM 10 and 15 mg groups reported improved pain scores and functional ability compared with standard epidural morphine. This novel formulation of sustained-release epidural morphine decreased the need for supplemental analgesics and was well tolerated. Single-dose EREM (DepoDur^TM) is a potentially beneficial analgesic in the treatment of post-CD pain.

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
The DepoDur Study Group included Brendan Carvalho, MBBCh, FRCA, Sheila E. Cohen, MBChB, FRCA, and Edward Riley, MD, Department of Anesthesia, Stanford University School of Medicine, Stanford, CA; David Gambling, MD, Sharp Mary Birch Hospital for Women, San Diego, CA; Brenda Gentz, MD, Wallace Nogami, MD, and Craig Palmer, MD, Department of Anesthesiology, University of Arizona Health Sciences Center, Tucson, AZ; H. Jane Huffnagle, DO, Department of Anesthesiology, Thomas Jefferson University, Philadelphia, PA; Christine Lihou, CCRA, and Garen Manvelian, MD, SkyePharma, Inc., San Diego, CA; Holly Muir, MD, Duke University, Durham, NC; Linda Polley, MD, University of Michigan, Ann Arbor, MI; and Lawrence Tsen, MD, and Scott Segal, MD, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, MA.

	Footnotes

 
A complete list of the DepoDur Study Group, along with affiliations, is located in Appendix 1.

This study was supported by SkyePharma, Inc. (San Diego, CA). This manuscript was supported by Endo Pharmaceuticals (Chadds Ford, PA).

Accepted for publication October 20, 2004.

	References

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 

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				B. Carvalho, L. M. Roland, L. F. Chu, V. A. Campitelli III, and E. T. Riley Single-Dose, Extended-Release Epidural Morphine (DepoDurTM) Compared to Conventional Epidural Morphine for Post-Cesarean Pain Anesth. Analg., July 1, 2007; 105(1): 176 - 183. [Abstract] [Full Text] [PDF]

				E. R. Viscusi Emerging treatment modalities: Balancing efficacy and safety Am. J. Health Syst. Pharm., March 15, 2007; 64(6_Supplement_4): S6 - S11. [Abstract] [Full Text] [PDF]

				R. Sinatra Opioid Analgesics in Primary Care: Challenges and New Advances in the Management of Noncancer Pain J Am Board Fam Med, March 1, 2006; 19(2): 165 - 177. [Abstract] [Full Text] [PDF]

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