- Department of Orthopaedic Surgery, URMC Orthopaedics and Rehabilitation, 601 Elmwood Ave, USA
- Department of Orthopaedics and Rehabilitation, UF Orthopaedics and Sports Medicine Institute, Gainesville, FL, USA
- Department of Veterans Affairs, Bay Pines VA Health Care System, Bay Pines, Florida and Department of Orthopaedics, URMC Orthopaedics and Rehabilitation, Rochester, NY, USA
Glenn R. Rechtine
Department of Orthopaedic Surgery, URMC Orthopaedics and Rehabilitation, 601 Elmwood Ave, USA
DOI:10.4103/2152-7806.109424Copyright: © 2013 Offley SC This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
How to cite this article: Offley SC, Coyne E, Horodyski M, Rubery PT, Zeidman SM, Rechtine GR. Randomized trial demonstrates that extended-release epidural morphine may provide safe pain control for lumbar surgery patients. Surg Neurol Int 22-Mar-2013;4:
How to cite this URL: Offley SC, Coyne E, Horodyski M, Rubery PT, Zeidman SM, Rechtine GR. Randomized trial demonstrates that extended-release epidural morphine may provide safe pain control for lumbar surgery patients. Surg Neurol Int 22-Mar-2013;4:. Available from: http://sni.wpengine.com/surgicalint_articles/randomized-trial-demonstrates-that-extended-release-epidural-morphine-may-provide-safe-pain-control-for-lumbar-surgery-patients/
Background:Safe and effective postoperative pain control remains an issue in complex spine surgery. Spinal narcotics have been used for decades but have not become commonplace because of safety or re-dosing concerns. An extended release epidural morphine (EREM) preparation has been used successfully in obstetric, abdominal, thoracic, and extremity surgery done with epidural anesthesia. This has not been studied in open spinal surgery.
Methods:Ninety-eight patients having complex posterior lumbar surgery were enrolled in a partially randomized clinical trial (PRCT) of low to moderate doses of EREM. Surgery included levels from L3 to S1 with procedures involving combinations of decompression, instrumented arthrodesis, and interbody grafting. The patients were randomized to receive either 10 or 15 mg of EREM through an epidural catheter placed under direct vision at the conclusion of surgery. Multiple safety measures were employed to prevent or detect respiratory depression. Postoperative pain scores, narcotic utilization, and adverse events were recorded.
Results:There were no significant differences between the two groups as to supplemental narcotic requirements, pain scores, or adverse events. There were no cases of respiratory depression. The epidural narcotic effect persisted from 3 to 36 hours after the injection.
Conclusion:By utilizing appropriate safety measures, EREM can be used safely for postoperative pain control in lumbar surgery patients. As there was no apparent advantage to the use of 15 mg, the lower 10 mg dose should be used.
Keywords: Epidural morphine, extended-release, lumbar, pain control, postoperative, surgery
Epidural narcotics, originally used in obstetrics and over the past 30 years, may now also be safely used following spinal surgery.[
There are over 400,000 spinal surgeries performed in the United States annually, representing a significant number of patients who would potentially benefit from better postoperative pain control. Extended release epidural morphine (EREM: liposomal formulation DepoDurTM), has already been demonstrated to be superior to short-acting epidural narcotics and to intravenous opioids alone when utilized for postoperative pain control in obstetric, abdominal, and lower extremity surgery.[
The purpose of this study was to assess the safety of utilizing EREM in lumbar surgery at a dose of 10 and 15 mg to avoid respiratory depression. Previously, Hartrick, et al. reported and demonstrated the effectiveness of EREM for patients undergoing total knee replacement patients, but respiratory depression occurred at a dose of 20-30 mg. They advocated future trials of lower doses (10-15 mg) to avoid this complication.[
The study, registered with the National Institute of Health (NIH) (number NCT 00335517), was approved by the Research Subjects Review Board. This prospective, randomized (by computer) study involved 98 patients presenting to three spine surgeons for elective lumbar surgery who were to receive either 10 mg (Group I) or 15 mg (Group II) of EREM. Patients who gave informed consent had to be at least 18 years of age, underwent lumbar surgery from the L3-S1 levels, and anticipated being hospitalized for at least 48 hours. Patients were excluded if they were unable to give consent, were incarcerated, pregnant, or had allergies to narcotic analgesics.
All patients underwent lumbar surgery with their attending surgeons. Details of the surgery included: The operating surgeon, the number of surgical levels, and the number of levels fused with and without instrumentation [
Intervention: Catheter advancement to the L1 level and injection with 10 or 15 mg of extended release epidural morphine
At the conclusion of surgery, an epidural catheter was placed under direct visualization and was advanced at least 4 cm to the L1 level prior to the injection of 2 mL air to ensure patency. Surgical levels were confirmed with intraoperative radiography (fluoroscopy or portable X-ray). Aspiration was also performed to ensure no intradural injections. Subsequently, the undiluted (1 or 1.5 mL, corresponding to 10 or 15 mg) EREM was injected. The catheter was then removed.
Postoperatively, each patient was admitted to a nonacute level of care (floor bed). All patients were provided an intravenous patient-controlled analgesia (IV-PCA) system (morphine or hydromorphone) and oral analgesics (hydrocodone, oxycodone, or propoxyphene) as needed. The majority started with morphine PCA. This was at the surgeon's discretion. Narcotic consumption was recorded in morphine equivalents.
Postoperative orders included clear identification of “spinal narcotic” at patient's bedside and in patient's chart, and required multiple safety measures. First, elevation of the head of the bed to 30° avoided cephalad diffusion to the respiratory center. Second, the addition of 0.4 mg naloxone (low dose) to each liter of IV fluid minimized side effects like pruritis, nausea, and vomiting while avoiding reversal of the high concentration of narcotics at the spinal cord receptors. Third, continuous pulse oximetry monitoring allowed personnel to detect respiratory depression by an audible alarm. Vital signs, including respiratory rate and pupil size were recorded every hour for the first four hours and every four hours subsequently. As the receptors for pupil size and the respiratory center are located in close proximity, the observation of pin point pupils could signal the potential onset of respiratory depression.
Perioperative data recorded for all patients included; the time of EREM injection, the amount of pain medication used at 6-hour intervals, and the patient reported pain scores during the 48-hour postoperative period. These data were used to compare the safety of the two EREM doses and differences based on the surgical details, as well as to evaluate the onset and duration of the EREM analgesia. Pain scores were also routinely recorded with vital signs using the Visual Analog Scale. Adverse outcomes were recorded, including respiratory depression, reoperation, rehospitalization, pulmonary embolism (PE), and mortality. For ease of comparison, all narcotic analgesics were converted to equivalent doses of IV morphine (per our institution's algorithm). [
Significance was defined by P < 0.05. Data comparisons of total narcotic equivalent usage (NE) and pain scores between surgeon, surgical level, fusion level, instrumentation level, and use of interbody arthrodesis were made using analysis of variance (ANOVA). Additional comparisons of NE during consecutive 6-hour intervals were made using paired t-tests, and comparisons of EREM dose were made using independent Sample t-tests. Statistical analyses were performed with SPSS version 18 (SPSS Inc., Chicago, Illinois).
Endo Pharmaceuticals provided funding, but played no role in the planning, conduct, or analysis of this study.
None of the participants in the study experienced serious adverse effects using an epidural narcotic including: Hypoxia/respiratory depression, hypotension, and bradycardia.
Total narcotic equivalent usage highly variable between subjects
Although there was a highly variable narcotic requirement between individual subjects, there was no significant difference for any specific parameter between patients receiving the 10 or 15 mg doses of EREM. Ranges, means, and standard deviations of total cumulative narcotic equivalent usage are provided in
Onset and duration of depodur analgesia
Mean interval narcotic equivalent usage is enumerated and illustrated in
This suggests that the onset of DepoDur® analgesia does not fully take place immediately after injection. Similarly diminished mean narcotic equivalent usage during all subsequent 6-hour intervals also suggests that DepoDur® continues to provide significant analgesia for the entire 48 hours. A study of the pain scores show that the mean reported pain during the 6-12 hours interval (2.71 ± 2.43) was 31% less than that during the 0-6 hours interval (3.93 ± 2.60) (P < 0.001) [
The pain scores were higher in the 0-3 hour time frame than the 3-6 hour window. This suggests the onset of the narcotic effect was about 3 hours after injection. This is consistent with Martin's observations.[
The collective pain scores indicate that the patients were relatively comfortable with our combination, multimodal anesthetic regimen. The average of all patients’ pain scores varied between an average pain of 2.75 to 4.6 and a maximum pain of 3.7 to 6 during the 48 hours of monitoring [
Common side effects of narcotic analgesia – whether via regional, intravenous, or oral routes – include nausea, vomiting, and pruritis. These side effects were successfully prevented by treating all patients with naloxone preemptively in IV fluid. This approach is supported by previous studies.[
Adverse events were reported in four patients, while there was one death. Two patients were readmitted on postoperative days 11 and 19, respectively, and returned to the operating room for irrigation, debridement, and reclosure of draining incisions; cultures were negative for infection. Two patients with histories of atrial fibrillation, developed pulmonary emboli on the first postoperative day; both received inferior venal cava (IVC) filters and heparin followed by warfarin, and were discharged home. One patient with a history of coronary artery disease succumbed to an acute myocardial infarction 5 days postoperatively in a rehabilitation facility.
Single-dose EREM: Effective epidural analgesia (L1 level) in spine surgery
In this randomized, prospective trial, low-moderate single-dose EREM (10 and 15 mg) injected through an epidural catheter at the L1 level at the end of surgery provided adequate pain control for 98 patients undergoing elective lumbar spine surgery. Patients also underwent multiple types of surgical procedures performed by three surgeons. [
Two low dose EREM regimens produced comparable results
EREM (5-30 mg) provides equivalent or superior analgesia compared with standard morphine (5 mg) following lower extremity, abdominal, and obstetric surgery.[
Duration of epidural analgesia following single low-dose EREM for spinal surgery
In addition, this study confirms the findings of others that the EREM analgesic effect does not occur until approximately 3 hours postinjection. The superiority of epidural analgesia over parenteral opioids for postoperative pain has been previously established. Cata et al. specifically reported how short-acting narcotics administered via patient-controlled epidural analgesia systems (PCEA) after lumbar spine surgery was superior to IV-PCA.[
Orthopedic patients treated with EREM required less rescue narcotics
Orthopedic patients treated with EREM have also required less overall rescue narcotic, and none at all in some cases. Hartrick and colleagues showed that 48 hours after knee arthroplasty, patients averaged a cumulative narcotic consumption of 132 mg morphine when treated with PCA alone, 44 mg when treated with 20 mg EREM and PCA, and 39 mg when treated with 30 mg EREM and PCA. In that study, the incidence of respiratory depression was a dose-related phenomenon beginning with 20 mg and even stronger at 30 mg.[
36-Hour perceived duration of efficacy of EREM
In our own study, both nursing staff and surgeons anecdotally noted that patients subjectively appeared comfortable postoperatively, and around 36 hours postoperatively began to experience more discomfort with increased mobility. However, like Hartrick et al.,[
Advantage of single-dose EREM: Avoidance of in-dwelling catheter/risk infection
In addition to effective pain control, EREM affords other benefits. Because EREM does not require an in-dwelling catheter, the risk of catheter infection and concern for catheter failure or premature removal are eliminated while still ensuring steady analgesia. Extended release delivery allows for a lower peak systemic concentration and less sedation. Good pain control and reduced sedation is a desirable combination for patient comfort, mobility, and overall recovery.
EREM enables better mobility potentially reducing risk of PE and length of stay (LOS)
Utilizing EREM for pain control enables better mobility, thereby reducing risk of PE and hospital stay duration. Previous studies report a 0.5-6% incidence of symptomatic PE after spinal surgery.[
Low to moderate dose EREM administered without respiratory depression
With any form of opioid analgesia, the risk of respiratory depression must be considered, especially with older patients and patients with preexisting respiratory compromise.[
Close attention paid to safety measures
Close attention must be paid to the safety measures employed in this study. (1) Mark the chart as an epidural narcotic patient, (2) Keep the head of bed elevated at least 30°, (3) add 0.4 mg of naloxone to each liter of IV fluid starting at the time of injection, (4) continuous pulse oximetry, and (5) monitor pupil size with vital signs. This series was done without intensive care unit monitoring but if the individual surgeon has concerns, a step down unit or other monitoring device could be used.
Weaknesses of this study
One major weakness of this study was the heterogeneous population of patients (including prior surgeries, use of narcotics, etc.), the multiple types of surgical procedures performed, and the fact that three different surgeons participated in the study. Furthermore, no control group was included as the efficacy of epidural narcotics and EREM have been established by multiple studies.
Questions regarding specific method of administration
The two questions to be answered were related to the specifics of the method of administration; through open surgery versus an epidural injection. Here the question was whether the open wound (delivery of single dose at L1 level at the end of surgery) impacts the release of the drug with the potential of creating a higher risk of respiratory depression? In this study, there was no suggestion that either was true.
Low to moderate dose EREM (10 or 15 mg) with concomitant use of a PCA, while following safety precautions appropriate for epidural narcotic use, provides safe and effective postoperative pain control for patients undergoing lumbar spine surgery. Both dosages resulted in significant reduction in the demand for narcotic analgesics starting 6-12 hours postoperatively, and this effect persisted for the rest of the 48-hour postoperative period. Because both doses were equally effective, and because unwanted side effects are typically dose-related, we recommend using 10 mg EREM for postoperative pain control after lumbar surgery.
The authors wish to thank Kimberly A. Napoli and Rachel Johnston for assistance in preparing this manuscript.
The following disclosure applies:
“Glenn Rechtine is the Associate Chief of Staff, Department of Veterans Affairs, Bay Pines VA Healthcare System, Bay Pines, Florida.” “This material is the result of work supported with resources and the use of facilities at the Bay Pines VA Healthcare System.” “The contents of this paper do not represent the views of the Department of Veterans Affairs or the United States Government.”
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