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Evaluation of a Single-Dose, Extended-Release Epidural Morphine Formulation for Pain After Knee Arthroplasty
Craig T. Hartrick, MD1; Gavin Martin, MD2; George Kantor, MD3; John Koncelik, DO4; Garen Manvelian, MD5
1 Department of Anesthesia, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, MI 48073. E-mail address: chartrick@beaumont.edu
2 Department of Anesthesiology, Duke University Medical Center, P.O. Box 3094, Erwin Road, Room 3438 Duke North, Durham, NC 27710
3 Palm Beach Gardens Medical Center, 11211 Prosperity Farms Road, Suite C114, Palm Beach Gardens, FL 33410-3454
4 Sewickley Valley Hospital, 720 Blackburn Road, Sewickley, PA 15143
5 SkyePharma, Inc., 10450 Science Center Drive, San Diego, CA 92121
View Disclosures and Other Information
In support of their research for or preparation of this manuscript, one or more of the authors received grants or outside funding from SkyePharma, Inc., San Diego, California. In addition, one or more of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity (SkyePharma, Inc.). Also, a commercial entity (SkyePharma, Inc.) paid or directed, or agreed to pay or direct, benefits to a research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2006 Feb 01;88(2):273-281. doi: 10.2106/JBJS.D.02738
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Abstract

Background: DepoDur is a single-dose, extended-release epidural morphine formulation designed to provide forty-eight hours of pain relief. The drug offers potential advantages over continuous epidural infusions, particularly in patients being treated with anticoagulation therapy. The purpose of this study was to evaluate the efficacy and safety of single-dose epidural DepoDur for pain control following knee arthroplasty.

Methods: In this multicenter, randomized, double-blind, parallel-group study, patients were randomized to receive a single-dose of DepoDur (20 or 30 mg) or a sham epidural injection thirty minutes before administration of general or regional anesthesia for knee arthroplasty. At their first request for postoperative analgesia, patients who had received DepoDur were given an intravenous bolus of hydromorphone followed by placebo patient-controlled analgesia. Patients who had received the sham epidural were given an intravenous bolus of morphine followed by patient-controlled analgesia with morphine. Patient ratings of pain intensity at rest and with activity, their rating of overall pain control, and postoperative opioid use were recorded. The ability to tolerate physical therapy, the range of motion of the knee, and the need for physical support were assessed as well. Adverse events and vital signs were recorded.

Results: Of 168 patients randomized to receive the 20-mg injection of DepoDur, the 30-mg injection of DepoDur, or the sham epidural injection, fifty-one, fifty-eight, and fifty-five patients, respectively, were included in the efficacy analysis. Compared with the patients treated with intravenous patient-controlled analgesia with morphine, the patients treated with DepoDur had significantly reduced mean pain-intensity-recall scores during the four to eight, four to twelve, four to twenty-four, and four to thirty-hour postdose intervals (p < 0.05 for all comparisons). The patients treated with DepoDur used approximately a threefold lower amount of postoperative opioids in total, with a significant percentage requiring no supplemental opioids. Adverse events common to all groups were nausea (78%), pyrexia (46%), vomiting (43%), pruritus (43%), and hypotension (36%). Respiratory depression was the most common serious adverse event, with serious respiratory depression observed in four DepoDur-treated patients, who were more than sixty-five years of age.

Conclusions: With appropriate patient selection and monitoring, perioperative single-dose epidural DepoDur was a safe and effective analgesic alternative to postoperative intravenous patient-controlled analgesia following knee arthroplasty, with younger patients benefiting from the 20-mg dose. Additional studies of 10 to 15-mg doses for older patients are warranted.

Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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    Craig T. Hartrick, M.D., DABPM, FIPP
    Posted on May 23, 2006
    Dr. Hartrick et al reply to Dr. Boezaart
    William Beaumont Hospital, Royal Oak, MI

    We appreciate both Dr. Boezaart’s interest and his concern. The facts do indeed speak for themselves. The adverse event figures as quoted above (from the abstract) were for all groups, which included the ivPCA morphine arm. This highlights an important point that we hope we made clear in our discussion, but welcome the opportunity to emphasize. Morphine produces similar adverse effects regardless of the route of administration. The incidence of side effects in all groups should be taken in the context of the study protocol, where no prophylaxis with drugs such as ondansetron was allowed. Further, DepoDur was not dosed according to age, but rather by random assignment.

    Because no significant differences were observed between groups in the adverse events cited above, they were reported in aggregate. More specifically, adverse events for each subgroup (ivPCA morphine, DepoDur 20mg and DepoDur 30mg), as provided in the supplementary material (appendix Table E2)[1], were as follows: Nausea: ivPCA (76%); DepoDur 20mg (77%); DepoDur 30mg (82%); p=0.7 Vomiting: ivPCA (35%); DepoDur 20mg (41%); DepoDur 30mg (54%); p=0.13 Hypotension: ivPCA (29%); DepoDur 20mg (39%); DepoDur 30mg (39%); p=0.45 Hypoxia: ivPCA (9%); DepoDur 20 mg (4%); DepoDur 30mg (9%); p=0.56

    Supplemental oxygen is recommended to prevent the well-described reductions in oxygen saturation associated with ivPCA morphine use [2]. However, all three groups experienced decreased oxygen saturation with similar frequency (ivPCA, 36%; DepoDur 20mg, 27%; DepoDur 30mg, 32%; p=0.63) [1]. Consequently, supplemental oxygen should be considered for all patients, but especially elderly patients, receiving opioids.

    Our conclusion remains: “With appropriate patient selection and monitoring, perioperative single-dose epidural DepoDur was a safe and effective analgesic alternative to postoperative intravenous patient- controlled analgesia following knee arthroplasty,…”. Inherent in this statement is the assumption that the “gold standard”, ivPCA morphine, can be administered in a safe and effective manner. It cannot be overemphasized that the risk of respiratory depression with opioids is increased in the elderly. DepoDur is not recommended in patients over 65 years of age in doses exceeding 15mg.

    References:

    1. Hartrick CT, Martin G, Kantor G, Koncelik J, Manvelian G. Evaluation of a single-dose, extended-release epidural morphine formulation for pain after knee arthroplasty. J Bone Joint Surg Am 2006;88:273-281 (http://www.ejbjs.org/cgi/content/full/88/2/273/DC1).

    2. Stone JG, Cozine KA, Wald A. Noctural oxygenation during patient- controlled analgesia. Anesth Analg 1999;89:104-10.

    André P. Boezaart, M.B.Ch.B., FFA(CMSA, MMed(Anaesth), Ph.D. Professor
    Posted on May 12, 2006
    Extended Release Epidural Morphine
    University of Iowa, Iowa City, IA

    To the Editor:

    It is with interest and concern that I read the article by Hartrick, et al, concerning Extended Release Epidural Morphine(1).

    The authors should be commended on this well-executed and well- written study. Although the facts speak for themselves (160 of 162 patients experienced adverse events, highlighted by 78% nausea, 43% vomiting, 36% hypotension and 32% hypoxia, while 96% of these mostly elderly patients required supplemental oxygen), the authors conclude that “...epidural DepoDur was a safe and effective analgesic alternative...”. This is clearly an incorrect conclusion. A more appropriate conclusion should read: “...epidural DepoDur was poorly tolerated and was an unsafe alternative due to severe and frequent respiratory depression...”, and “...the drug was more effective than intravenous PCA for the first 24 hours only...”

    I find it surprising that the authors suggest that smaller doses of the drug should be further evaluated, since three of the authors, including a company representative, were co-authors of a similar study on the use of DepoDur for total hip arthroplasty by Viscusi, et al,(2). This study reported very similar results for 15mg DepoDur, and the conclusions of that study were similarly somewhat “softened”.

    References:

    1. Hartrick CT, Martin G, Kantor G, Koncelik J, Manvelian G. Evaluation of single-dose extended-release epidural morphine formulation for pain after knee arthroplasty. J Bone Joint Surg Am 2006; 88: 273 – 281.

    2. Viscusi ER, Martin G, Hartrick CT, Singla N, Marvelian G. Forty-eight hours of postoperative pain relief after total hip arthroplasty with a novel, extended-release epidural morphine formulation. Anesthesiology 2005; 102:1014 – 1022.

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