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PAIN MEDICINE

A Comparison of Depodur^TM, a Novel, Single-Dose Extended-Release Epidural Morphine, with Standard Epidural Morphine for Pain Relief After Lower Abdominal Surgery

David Gambling, MB, BS, FRCPC^*, Thomas Hughes, MD, Gavin Martin, MD, William Horton, MD, Garen Manvelian, MD^|| for the Single-Dose EREM Study Group

*Sharp Mary Birch Hospital for Women, San Diego, California; Woodland Memorial Hospital, Woodland, California; Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina; Progressive Research, LLC, Greenville, South Carolina; and ||SkyePharma, Inc., San Diego, California

Address correspondence and reprint requests to David Gambling, MB, BS, FRCPC, Sharp Mary Birch Hospital for Women, Department of Anesthesiology (Second Floor), 3003 Health Center Dr., San Diego, CA 92123. Address e-mail to dgamb{at}san.rr.com.

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
In this randomized, controlled, dose-ranging study, we evaluated the analgesic efficacy of a novel single-dose extended-release epidural morphine (Depodur^TM) in patients undergoing lower abdominal surgery. Five-hundred-forty-one patients were randomly assigned to one of six epidural treatments administered approximately 30 min before surgery. The 6 treatments were 5 mg of standard epidural morphine sulfate (MS) (active comparator); 5 mg of single-dose extended-release epidural morphine (EREM) (dose control); and 10, 15, 20, and 25 mg of single-dose EREM. The main study objective was to assess the efficacy of single-dose EREM 10, 15, 20, or 25 mg versus single-dose EREM 5 mg for the management of postoperative pain. This was done by plotting a linear dose-response relationship to assess postoperative IV patient-controlled analgesia (PCA) fentanyl consumption for breakthrough pain for 48 h after surgery. Secondary safety and efficacy analyses compared the 10-, 15-, 20-, and 25-mg single-dose EREM groups with the 5-mg single-dose EREM group and compared each single-dose EREM group with 5 mg of MS. As shown by the dose-response relationship, there was a dose-related reduction in the use of postoperative IV fentanyl through 48 h (estimated slope, –22.2; P = 0.0002). Patients treated with 10, 20, and 25 mg of single-dose EREM used significantly less IV fentanyl (mean ± sd: 995 ± 987 µg, P = 0.0446; 972 ± 982 µg, P = 0.0221; and 683 ± 620 µg, P < 0.0001, respectively) through 48 h after surgery compared with the 5-mg single-dose EREM group (1218 ± 894 µg). At 48 h postdose, significantly more single-dose EREM patients (13%) than MS patients (2%) had required no IV fentanyl (P < 0.01). Although all treatment groups had access to PCA fentanyl and there was more frequent PCA fentanyl use in the MS group, patients in the single-dose EREM 15, 20, and 25 mg groups reported significantly lower pain-intensity scores and greater satisfaction with their pain relief. Overall, single-dose EREM was well tolerated, with 97% of adverse events rated as mild to moderate. As expected, the adverse events reported were consistent with those of other epidural opioids (i.e., nausea, vomiting, pruritus, and hypotension). In conclusion, this controlled study demonstrated that single-dose EREM can provide up to 48 h of postoperative analgesia, but supplementation for breakthrough pain is still required in most patients. Within the context of this study, the side effect profile of single-dose EREM was acceptable and predictable.

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Most surgical patients experience postoperative pain that persists for several days after surgery. Despite current pain-management guidelines, postoperative pain often remains under-treated (1), and studies demonstrate that ineffective postoperative pain management can lead to poor clinical outcomes and serious adverse events, including deep vein thrombosis, myocardial infarction, and coronary ischemia (1). Additionally, inadequate analgesia can hinder recovery and result in severe, uncontrolled pain (2). Effective pain control can contribute to several clinically valuable outcomes, including earlier patient mobilization and quicker recovery, which can result in a shortened hospital stay and reduced costs (1).

Opioids are considered a "gold standard" in clinical practice for the treatment of postoperative pain. Epidural morphine sulfate (MS) has proven analgesic efficacy and superiority over systemically administered morphine for the treatment of postoperative pain (2,3). Epidural analgesia has also been shown to have a positive effect on the recovery process and to provide substantially longer analgesia at smaller doses than IM morphine (4). However, pain relief after a single epidural injection of morphine lasts <24 h (2). Techniques used to administer and prolong opioid epidural analgesia, such as patient-controlled analgesia (PCA) pumps, continuous epidural infusion, and frequent reinjection, can be costly and inconvenient (5,6), and complications can arise from indwelling epidural catheterization, particularly in patients receiving anticoagulants (7–9). The ASA Task Force on Acute Pain Management has advised caution when using continuous infusion modalities, because drug accumulation may contribute to adverse events (10). Other problems associated with indwelling epidural catheters include displacement, uneven spread of analgesics, requirement for regular monitoring by an acute pain service, and a small risk of infection. In addition to these clinical concerns, the current managed-care environment demands that physicians and health care systems use cost-effective pain-management strategies (11).

An epidural formulation of morphine that could provide adequate, extended, uninterrupted pain relief with a single dose could greatly simplify postoperative pain management by reducing the need for PCA pumps, continuous epidural infusions, or repeated parenteral injections. Subsequent economic benefits could be realized in a reduced need for equipment (e.g., pumps and infusor sets) and more efficient nursing/physician time dealing with uncontrolled pain in the postoperative setting.

Depodur^TM is a novel encapsulated single-dose extended-release epidural morphine (EREM). It uses an extended drug-release delivery system known as Depofoam^TM (5,12,13), which is composed of multivesicular lipid particles that contain nonconcentric aqueous chambers that encapsulate the active drug and slowly release it (5,12,14). In a study of cesarean delivery patients, single-dose EREM prolonged analgesia compared with MS (15). Additionally, in a study of total hip arthroplasty patients, single-dose EREM provided significantly improved analgesia for up to 48 h (13).

This phase III dose-ranging study evaluated the analgesic efficacy of 10, 15, 20, and 25 mg of single-dose EREM versus 5 mg of single-dose EREM. Secondary safety and efficacy analyses compared all larger doses of single-dose EREM with 5 mg of single-dose EREM; additionally, all EREM groups (including the dose-control group) were compared with MS.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Eligible patients included men and women aged 18 years who were scheduled to undergo lower abdominal surgery under general or intrathecal anesthesia. Lower abdominal surgery was defined as surgery via an abdominal incision below the umbilicus; the following surgeries were excluded from this study: laparoscopy, transurethral prostatectomy, cesarean delivery, hernia repair, appendectomy, and lower abdominal vascular surgery. ASA physical status I, II, or III men and sterile or nonpregnant, nonlactating women practicing adequate contraception were eligible unless they were morbidly obese (body mass index 40 kg/m²) or at significantly higher risk for surgery-related complications or adverse consequences of epidural opioid injection. Eligible patients agreed to use only IV fentanyl via a PCA pump for 48 h postdose to control breakthrough pain. Patients also agreed to remain hospitalized for assessments for at least 48 h after study drug administration.

This Phase III randomized double-blind parallel-group dose-ranging study was conducted at 55 clinical sites in the United States and 8 clinical sites in Australia (49 of these sites enrolled patients and are listed in Appendix 1). The study was approved by the IRB at each clinical site, and all subjects provided informed written consent. Single-dose EREM 5 mg was the dose control, and MS 5 mg was the active comparator. The main study objective was to assess the efficacy of single-dose EREM (10, 15, 20, or 25 mg) versus single-dose EREM 5 mg in the management of postoperative pain after lower abdominal surgery, by plotting a linear dose-response relationship to assess changes in total postoperative IV fentanyl use. Secondary safety and efficacy analyses compared 10, 15, 20, and 25 mg of single-dose EREM with 5 mg of single-dose EREM; additionally, all single-dose EREM groups, including the dose-control group, were compared with MS. The study was designed to enroll at least 84 patients in each of the 6 treatment arms for a total of 504 patients. Patients were randomized in a 1:1:1:1:1:1 ratio.

Single-dose EREM was provided as a 2-mL (10 mg/mL) vial of sterile, nonpyrogenic, preservative-free, homogenous morphine suspension encapsulated into multivesicular lipid-based particles (Depofoam^TM drug-delivery system). It was diluted with 0.9% preservative-free saline to a final volume of 5 mL. Thirty minutes before surgery was initiated and before the induction of general or intrathecal anesthesia, single-dose EREM was administered via epidural injection over 15 s. Unencapsulated epidural MS was supplied by the institutional pharmacy as either Astramorph/PF® or Duramorph®. Study drugs were administered via a needle or catheter at the discretion of the principal investigator.

Because single-dose EREM and unencapsulated MS are visually distinguishable (the former is an opaque suspension, and the latter is a clear aqueous solution), an unblinded anesthesiologist who was not involved in patient care, clinical assessments, or data collection administered the epidural. This allowed the principal investigator and all study staff involved with the conduct of the study (including the surgeons) to remain blinded.

Improper placement in the epidural space was eliminated by aspiration to check for the absence of blood or cerebrospinal fluid in all cases; at the investigator's discretion, a 3-mL test dose of 1.5% lidocaine with epinephrine (1:200,000) could also be administered. To exclude inadvertent intravascular injection, patients who received a test dose were observed for a tachycardic response to epinephrine, and inadvertent intrathecal injection was excluded by a lack of sensory block. The interval between test dose and study drug administration was at least 15 min to prevent a potential drug-drug interaction between the lidocaine/epinephrine test dose and single-dose EREM.

In the postoperative period, all patients had immediate access to IV PCA and were instructed to self-administer doses of fentanyl to maintain adequate pain control. The PCA pump was programmed to deliver on-demand IV boluses of 10–20 µg of fentanyl (titrated according to level of pain) with 6-min lockout intervals. Total fentanyl use through 48 h postdose was recorded.

Use of long-acting opioids was to be avoided during the 24 h before surgery. Infiltration of local anesthetic into the edges of the incision and bolus injections of fentanyl or ketorolac near the end of surgery were prohibited. The total amount of intraoperative analgesic administered was not to exceed 250 µg of IV fentanyl, and opioid medications besides IV fentanyl were not permitted for 48 h after study drug administration. After surgery, acetaminophen (for fever or headache only) and aspirin (for platelet aggregation inhibition) were allowed, but cyclooxygenase inhibitors were not allowed. Use of sedating medications was discouraged, but the administration of these drugs, other postoperative medications, and nondrug therapies was allowed at the investigator's discretion.

The primary efficacy end-point was total IV fentanyl use through 48 h after the administration of study drug; this was assessed with a linear dose-response relationship. For the primary outcome variable, IV fentanyl use in the 10-, 15-, 20-, and 25-mg single-dose EREM groups was compared with IV fentanyl use in the 5-mg single-dose EREM group (dose control) at successive 4-h intervals. Secondary end-points included evaluation of the time to first postoperative IV fentanyl use, the proportion of patients receiving no postoperative fentanyl, pain-intensity evaluations at rest and with activity, and patient and surgeon ratings of pain control. In these secondary evaluations, the 10-, 15-, 20-, and 25-mg single-dose EREM groups were compared with the 5-mg single-dose EREM group and the 5-mg MS group.

Pain intensity was recorded on a 100-mm visual analog scale (VAS) ranging from 0 (no pain) to 100 (the most severe pain possible) and a four-point categorical score (CAT) with descriptive categories of none, mild, moderate, and severe. Pain intensity was measured at rest (VAS-R and CAT-R) and with activity (VAS-A and CAT-A) at the time of the patient's first request for pain medication and at regular postdose intervals. Pain with activity was elicited by asking the patient to take a deep breath followed by a forceful cough. A pain assessment was obtained immediately after the cough. Area-under-the-curve analyses were performed on VAS scores during the first 48 h after surgery by using the trapezoid rule. To account for the effect of opioid analgesic use on pain intensity, an integrated rank assessment was used (16). In each of the five single-dose EREM groups and in the MS group (n = 487), subjects' VAS scores were ranked at rest and with activity by using VAS pain scores and IV fentanyl use data. The mean rank for all study subjects was determined [(1 + 487)/2 = 244]. Then each individual subject's VAS score was expressed as a percentage difference from 244. Patients' fentanyl use was also ranked. For each subject, the percentage differences for both variables (VAS and fentanyl use) were added to derive a total percentage difference between the individual subject score and the overall population score (the integrated rank score). Integrated rank scores for the various treatment groups were compared: lower scores reflected combined lower pain scores, less total IV fentanyl use, or both. Pain control was rated on Days 2 and 3 (Day 1 was the day of surgery) by the patient and surgeon by using a four-point CAT scale with descriptive categories of poor, fair, good, or very good.

Continuous pulse oximetry was performed for 24 h postdose, and vital signs were recorded through 48 h. Patients were monitored according to individual hospital practices during intraoperative procedures. Physical and neurological examinations were conducted at screening and on Day 3. Additional safety data were collected by performing brief neurological checks and measuring sedation scores through 48 h postdose and by conducting routine laboratory tests at screening and on Day 3. All adverse events were recorded and rated in terms of severity and relationship to study medication. The study protocol provided guidelines to promote consistency across study sites in reporting certain adverse events, such as hypotension, bradycardia, hypoventilation, hypoxia, and urinary retention. However, a definition of respiratory depression was not provided in the protocol but was left as a clinical diagnosis made by each investigator. A neurologic assessment questionnaire was administered to identify any potential neurological sequelae resulting from the epidural analgesia. The neurologic assessment questionnaire was administered before surgery and on Day 30. Questions assessing muscle weakness, peripheral neuropathy, bowel and genitourinary function, arachnoiditis, seizure, and stroke were administered. Global evaluation of potential neurological sequelae was performed on Day 30.

Randomized patients who underwent the planned surgical procedure, regardless of whether they received their assigned study drug (intent-to-treat (ITT) population), were included in the analysis of primary and secondary efficacy variables. Safety evaluations were performed on all randomized patients who received any study drug, whether or not they underwent the planned surgical procedure.

Statistical analyses were performed with a significance level of 5% and a 95% confidence interval. Continuous study variables were summarized with means, standard deviations, and medians. CAT variables were summarized by the frequency and number of patients in corresponding categories. Patient demographic information and baseline characteristics were analyzed with analysis of variance (ANOVA) with terms for treatment group and type of anesthesia. CAT variables were analyzed with the Cochran-Mantel-Haenszel test and were also stratified by type of anesthesia.

The primary efficacy end-point was compared across treatment groups by using ANOVA; if this primary analysis showed a significant effect across treatment groups, Dunnett's test was used to compare each dose of single-dose EREM with 5 mg of single-dose EREM and 5 mg of MS. A linear dose-response relationship comparing the total IV fentanyl used for 48 h after study drug administration was also assessed with a least-squares regression analysis adjusted for type of anesthesia. ANOVA was used to compare mean VAS and CAT scores across treatment groups; if the overall test was significant, the 10-, 15-, 20-, and 25-mg single-dose EREM doses were each compared with 5 mg of single-dose EREM.

Time from study drug administration to the first dose of IV fentanyl was summarized with medians and Kaplan-Meier survival curves. A log-rank test stratified by type of anesthesia was used to compare these times among treatment groups. The proportion of patients receiving no postoperative fentanyl through 24 and 48 h postdose was compared by using a logistic analysis.

Safety data were summarized with descriptive statistics. In addition, laboratory values were summarized with shift tables (e.g., low-normal-high at baseline versus low-normal-high at 48 h postdose) to assess changes. The incidence of adverse events and serious adverse events among all study groups was compared by using Fisher's exact test.

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
A total of 541 patients were enrolled in this study: 452 patients were randomly assigned to the single-dose EREM treatment groups, and 89 were assigned to the 5-mg MS group. Of the 541 patients enrolled, 515 received the study drug and were included in the safety analysis. Of the 541 patients enrolled, 487 patients were randomly assigned to a treatment group and then underwent their planned surgical procedure (ITT population). Patients were excluded from the ITT population if they withdrew consent or did not undergo the planned surgical procedure.

For the ITT population, patient demographic information and baseline characteristics were similar across groups (Table 1). Most patients were Caucasian, female, ASA physical status II, and younger than 65 years and underwent general anesthesia (86%).

As shown by the linear regression analysis, there was a dose-related reduction in the need for postoperative IV fentanyl through 48 h (estimated slope, –22.2; P = 0.0002) (Fig. 1). There was a significant reduction in postoperative fentanyl consumption across the 10-, 20-, and 25-mg single-dose EREM treatment groups from 0 to 48 h, compared with 5 mg of single-dose EREM. Fentanyl consumption was also reduced in the 10-, 15-, 20-, and 25-mg single-dose EREM groups compared with 5 mg of MS.

View larger version (8K): [in this window] [in a new window]   Figure 1. Mean fentanyl use through 48 h and regression analysis. The estimated slope (dose-response variable) was –22.2 (P = 0.0002 for the evaluation of the rank-transformed data [slope different from 0]).

The median time to first postoperative IV fentanyl use ranged from 3.6 to 4.0 h and was similar across treatment groups. Through 48 h postdose, there was an approximately sevenfold increase in the percentage of single-dose EREM-treated patients who did not require IV fentanyl (13%) compared with MS-treated patients (2%) (P = 0.0096) (Fig. 2).

View larger version (24K): [in this window] [in a new window]   Figure 2. Patients who received no supplemental fentanyl. EREM = single-dose epidural morphine; MS = unencapsulated morphine sulfate. P = 0.0096 for overall test among all treatment groups (EREM and MS). *P = 0.0223 versus 5 mg of single-dose EREM and 0.0015 versus 5 mg of MS; P = 0.0318 versus 5 mg of single-dose EREM and 0.0029 versus 5 mg of MS; P = 0.0121 versus 5 mg of MS; P = 0.0328 versus 5 mg of single-dose EREM and 0.0028 versus 5 mg of MS.

Although all patients had access to postoperative PCA fentanyl, the VAS-R (area under the curve) scores (mean ± sd) over 48 h were significantly lower in patients receiving 15, 20, or 25 mg of single-dose EREM than in patients receiving 5 mg of single-dose EREM. Patients receiving 15, 20, or 25 mg of single-dose EREM had lower VAS-R scores over 48 h than did those who received 5 mg of MS (Table 2). VAS-R scores were also lower in the 15-, 20-, and 25-mg single-dose EREM groups than in the 10-mg single-dose EREM group. Among patients who received 10, 15, 20, and 25 mg of single-dose EREM, VAS-A scores over 48 h were also significantly lower than they were for patients who received 5 mg of single-dose EREM (Table 2). Significant reductions in pain with activity were also seen with 20 and 25 mg of single-dose EREM compared with 5 mg of MS. Findings for CAT pain-intensity data (CAT-R and CAT-A) were similar.

Integrated rank scores for pain intensity at rest (VAS-R) and IV fentanyl use (Table 3) indicate that patients in the 10-, 15-, 20-, and 25-mg single-dose EREM treatment groups achieved significantly lower pain-intensity scores with less use of PCA fentanyl than patients in the 5-mg MS group.

At Day 2, more patients in the large-dose EREM groups than in the 5-mg single-dose EREM group had better ratings of pain control (80%–90% versus 76%). At Day 3, the 25-mg single-dose EREM group had significantly better ratings of pain control than the 5-mg single-dose EREM group (P = 0.0097).

The most frequently reported adverse events in the single-dose EREM and MS treatment groups were nausea (66% of patients), pruritus (51% of patients), pyrexia (33% of patients), vomiting (25% of patients), and hypotension (22% of patients). Significant differences were observed between the single-dose EREM and MS treatment groups in the incidence of pruritus (P < 0.05) and urinary retention (P < 0.05). Otherwise, there were no significant differences in the incidence of adverse events or sedation among treatment groups (Table 4). More than 75% of all patients who received one or more doses of an opioid antagonist had no change in VAS pain scores after antagonist administration. Of the remaining patients, all but one had a transient increase in VAS pain scores that returned to preantagonist levels within 6 h.

Three patients died during the study and 30-day follow-up period. The first patient was a 79-yr-old woman with a history of myocardial infarction who had undergone sigmoid colectomy. She had a myocardial infarction 2 wk after surgery; the investigator deemed the infarction exacerbated by respiratory distress secondary to pneumonia, and it was classified as unrelated to the study drug. The second patient was a 74-yr-old man scheduled to undergo a sigmoid colon resection that was canceled for surgical reasons. He died 21 h after receiving 20 mg of single-dose EREM. The patient was found unresponsive with assumed aspiration. Through the last scheduled clinical assessment, vital signs showed no indication of respiratory depression, and sedation scores did not show evidence of oversedation. The death was classified as possibly related to the study drug; no autopsy was performed. The third death occurred in a 62-yr-old woman before administration of the study drug.

Changes in respiratory rate from baseline in both the single-dose EREM and MS treatment groups were observed after study drug administration. Significant differences were seen among treatment groups at 2 h (P < 0.05), 10 h (P < 0.05), 11 h (P < 0.01), 12 h (P < 0.05), 13 h (P < 0.05), 19 h (P < 0.05), and 20 h (P < 0.05) postdose. Overall, mean decreases from baseline in respiratory rate were more pronounced in the 25-mg single-dose EREM group. Similarly, although they were not clinically significant, statistically significant differences in mean systolic and diastolic blood pressures were observed between the single-dose EREM and MS treatment groups, and these were largest in the 20- and 25-mg single-dose EREM groups. Heart rate changes from baseline were similar among treatment groups.

There were no significant differences in sedation level among treatment groups at 4, 18, 24, 30, 36, or 48 h. At 8 h (P < 0.0461) and 12 h (P < 0.0284), there was significantly more sedation among single-dose EREM-treated patients than MS-treated patients. Supplemental oxygen was administered to 417 (93%) single-dose EREM-treated patients and 63 (95%) MS-treated patients. In all, 12% of single-dose EREM patients and 9% of MS patients received supplemental oxygen in response to an adverse event.

Fifty-four (12%) single-dose EREM patients and three (4.5%) MS patients received an opioid antagonist (naloxone). More patients in the 2 largest-dose EREM groups, 20 and 25 mg, required naloxone (14 and 16 patients, respectively). Across groups, the most common reason for opioid antagonist administration was pruritus. Rates of naloxone use for respiratory depression were 0% for the 5- and 10-mg single-dose EREM groups; 1.1% and 1.5%, respectively, for the 15 mg single-dose EREM group and the 5-mg MS group; 2.4% for the 20-mg single-dose EREM group; and 4.5% for the 25-mg single-dose EREM group. The time to first naloxone administration (mean ± sd) was 8 ± 4 h and 16 ± 12 h in the single-dose EREM and MS groups, respectively. No significant differences were observed among treatment groups when opioid antagonist administration was analyzed by patient characteristics (sex, age, race, ASA physical status, and whether patients received or did not receive the test dose).

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
The results of this randomized, dose-ranging, controlled study demonstrate that this novel epidural formulation of morphine, single-dose EREM (Depodur^TM), provides up to 48-hour pain control with superior pain scores at rest and with activity compared with epidural MS. Single-dose EREM provided prolonged analgesia compared with MS, as evidenced by a significant overall reduction in IV PCA fentanyl use and a significantly larger percentage of patients who required no IV fentanyl from 24 to 48 hours after study drug administration. Even though single-dose EREM-treated patients used less IV PCA fentanyl, they reported lower pain-intensity scores than MS-treated patients. The type of anesthetic (general versus spinal anesthetic) had no effect on the results. Both types of anesthetic were included in this study to better reflect normal clinical practice.

When data were reanalyzed to demonstrate the best analgesia with the fewest side effects from single-dose EREM, the 15-mg dose was superior to all others. In general, older patients should be dosed at the lower end of the dose range (10). Furthermore, it is possible that the dose of EREM required could be reduced by the addition of a nonsteroidal antiinflammatory drug as part of a multimodal approach to postoperative pain management (10,17). In turn, a multimodal approach could reduce the incidence of opioid-related adverse effects. Single-dose EREM was well tolerated, and adverse events observed after its administration were consistent with those of neuraxial opioid therapy in general. Overall, more adverse events and a larger number of patients requiring opioid antagonist administration were observed with the two largest single-dose EREM groups (20 and 25 mg). The one death considered possibly related to study drug occurred in a patient who did not undergo surgery and, therefore, did not have postoperative pain. It is our recommendation that if surgery is canceled after single-dose EREM administration, then the patient be monitored in an intensive care unit setting for at least 48 hours. In this situation, a naloxone infusion may be justified. Naloxone use for clinically important respiratory depression increased as the dose of EREM increased. However, such use was reported in 1.1% of subjects who received 15-mg single-dose EREM, compared with 1.5% of patients who received 5 mg of standard epidural MS. It is important to note that respiratory depression was not specifically defined in the study protocol and therefore was left to the discretion of the individual investigator at each site. This must be considered when interpreting the rates of respiratory depression in this study. Some instances of "respiratory depression" were not treated with naloxone, so the question remains as to whether these cases represented true respiratory depression with clinical hypoventilation. Most patients in this study received supplemental oxygen as part of routine perioperative care. Its use, however, was left to the discretion of the investigator. This study was not powered to assess safety, so further study of the risk of clinically important respiratory depression from higher doses of single-dose EREM is warranted.

Findings from this study show that single-dose EREM decreases the need for IV PCA in the postoperative period; this could potentially reduce costs. With up to 48 hours of pain control after preoperative single-dose EREM, these data suggest that many patients could be transitioned directly to an oral analgesic. Other rescue medications may be more effective than IV PCA fentanyl in this setting. Single-dose EREM may decrease the need for infusion pumps and possibly limit complications associated with their use. These potential advantages may lead to a reduction in direct (e.g., drug, devices, and infusor sets) and indirect (e.g., nursing/physician time) costs attributed to pain management in the postoperative setting. In addition, because single-dose EREM improves pain control for up to 48 hours, indwelling epidural catheters may be avoided. Although earlier studies have demonstrated better postoperative analgesia from a single dose of epidural morphine compared with IV PCA (18,19), the superiority of single-dose EREM over other analgesic therapies warrants further investigation.

In conclusion, this controlled study demonstrated that single-dose EREM can provide up to 48 hours of postoperative analgesia after lower abdominal surgery, but supplementation for breakthrough pain is still required in most patients. However, there was a 7-fold increase in the number of patients receiving single-dose EREM who required no analgesic supplements for 48 hours. Thus, single-dose EREM may provide clinicians and patients with a valuable new option for the management of postoperative pain after lower abdominal surgery. Although we did not identify any new safety concerns among the study patients, we recommend adequate postoperative monitoring and respiratory management protocols after the use of any neuraxial opioid.

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
The Single-Dose EREM Study Group included the following: Warren Bagley, MD, Volunteer Research Group, LLC, University of Tennessee Medical Center, Knoxville, TN; Courtney Mitchell Bailey, MD, Utah Valley Regional Medical Center, Provo, UT; David Beilby, MBBS, Box Hill Hospital, Box Hill, Victoria, Australia; Donald Boos, MD, Hot Springs Mercy Pain Clinic, St. Joseph's Hospital, Hot Springs, AR; Steve Boozalis, MD, Greater Houston Anesthesiology Clinical Research, Houston, TX; Voytek Bosek, MD, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; John Butterworth, MD, Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC; James Colson, MD, University of Michigan Pain Center, Ann Arbor, MI; Dennis Dailey, MD, Department of Anesthesiology, UT M. D. Anderson Cancer Center, Houston, TX; Pankaj Desai, MD, University of Alabama-Birmingham, Birmingham, AL; Michael K. Dishart, MD, Department of Anesthesiology, The Western Pennsylvania Hospital, Pittsburgh, PA; Michael Drass, MD, Altoona Hospital, Altoona, PA; Michel Dubois, MD, NYU Medical Center, Great Neck, NY; Laura Fisher-Meadows, MD, Jackie Jones, MD, Lowell Wayne Reynolds, MD, and Desiree Wallace, PharmD, Loma Linda University Center for Pain Management, Loma Linda, CA; David Gambling, MB, BS, FRCPC, and Alexander Pue, MD, Sharp Mary Birch Hospital for Women, San Diego, CA; Scott Groudine, MD, Department of Anesthesia, Albany Medical College, Albany, NY; Dennis Hall, MD, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ; Richard Halliwell, MBBS, Westmead Hospital, Westmead, New South Wales, Australia; Jonathan Hamburger, MD, Greater Baltimore Medical Center, Baltimore, MD; Craig Hatrick, MD, Department of Anesthesia, William Beaumont Hospital, Royal Oak, MI; Robert Hirsh, MD, Department of Anesthesia, Cooper Hospital University Medical Center, Camden, NJ; William Horton, Jr, MD, Progressive Research, LLC, Greenville, SC; Thomas Hughes, PharmD, MD, Department of Anesthesiology and Pain Medicine, Woodland Memorial Hospital, Woodland, CA; Joel Johnson, MD, University of Missouri Hospital, Columbia, MO; R. Kevin Jones, MD, Accurate Clinical Trial, San Clemente, CA; Bupesh Kaul, MD, Department of Anesthesiology, Magee-Women's Hospital, Pittsburgh, PA; Alan Kaye, MD, PhD, Department of Anesthesiology, Texas Tech University Health Sciences Center, Lubbock, TX; James Kindscher, MD, University of Kansas Medical Center, Kansas City, KS; Dan Kopacz, MD, Department of Anesthesiology, Virginia Mason Medical Center, Seattle, WA; Gavin Martin, MD, and David Wright, MD, Department of Anesthesiology, Duke University Medical Center, Durham, NC; Robert McQuillan, MD, Department of Anesthesiology, Creighton University School of Medicine, Omaha, NE; Daniel Meenan, DMD, MD, Keystone Clinical Solutions, Inc., Altoona, PA; Timothy Melson, MD, Helen Keller Hospital, Sheffield, AL; Paul S. Myles, MBBS, Alfred Hospital, Praharan, Victoria, Australia; Edward Ochroch, MD, Department of Anesthesiology, University of Pennsylvania, Philadelphia, PA; Christopher E. P. Orlikowski, MB BCh, Royal Hobart Hospital, Hobart, Tasmania, Australia; Michael J. Paech, MBBS, King Edward Memorial Hospital for Women, Subiaco, WA, Australia; Sunil J. Panchal, MD, Department of Anesthesiology, Weill Medical College of Cornell University, New York, NY; George F. Rich, MD, PhD, Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA; Edward Riley, MD, Department of Anesthesia, Stanford University School of Medicine, Stanford, CA; Richard Rosenquist, MD, Department of Anesthesia, University of Iowa Hospitals and Clinics, Iowa City, IA; Jeffrey Silverstein, MD, Mount Sinai Medical Center, Great Neck, NY; Adam Smith, DO, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX; Janet S. Smith, MBBS, Concord Repatriation General Hospital, Concord, New South Wales, Australia; Daneshvari Solanki, MD, University of Texas Medical School, Galveston, TX; Lauraine Stewart, MD, and Hunter Holmes McGuire, VAMC, Richmond, VA; Robert Ulseth, MD, The Florida Wellcare Alliance, LLC, Inverness, FL; Jeffrey Varga, MD, Forbes Regional Hospital, Monroeville, PA; and Eugene Viscusi, MD, Department of Anesthesiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA.

	Footnotes

 
See Appendix 1 for a complete list of the Extended-Release Epidural Morphine (EREM) Study Group.

This study was supported by SkyePharma, Inc. (San Diego, CA). Endo Pharmaceuticals (Chadds Ford, PA) provided assistance with data collection and statistical analyses.

Accepted for publication August 30, 2004.

	References

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 

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