Extendedrelease Epidural Morphine For Postoperative Pain

DepoMorphine (Endo Pharmaceuticals) is a novel sustained release injectable formulation of morphine for the control of postoperative pain, and is approved by the FDA. It utilizes morphine suspended in a liposomal sustained-release epidural delivery system (DepoFoam, SkyePharma PLC). DepoFoam consists of microscopic spherical particles composed of numerous nonconcentric internal aqueous chambers containing morphine (Figure III-77).

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Internal Morphine Pump
Figure III-76. Unspecific portions of fentanyl bound to epidural fat, substantia grisea and alba of the spinal cord respectively
Extended Release Epidural Morphine
Figure III-77. Principle of liposomes containing morphine for sustained-release in the epidural space

Each chamber is separated from its neighbor by a single bilayer lipid membrane. In a physiologic milieu, the chambers break down and slowly release the drug contained within [240]. DepoMorphine is given as a single epidural injection before surgery, and clinical studies have shown that the formulation provides pain relief for 48 h, at which time a transition to an oral agent may be appropriate for many patients. This delivery system bypasses the need for an indwelling epidural catheter and infusion pump, thereby avoiding potential problems, which may be associated with these devices. A randomized, double-blind, placebo-controlled study in 194 hip arthroplasty patients evaluated the reduction in postoperative i.v. fentanyl requirement in patients who received a single epidural injection (15 mg, 20 mg, 25 mg) of DepoMorphine (Figure III-78). Patients were administered the test drug or placebo before induction of general or intrathecal anesthesia for surgery. Postop-eratively, fentanyl was provided via I.V. PCA pump. Fentanyl consumption, the primary outcome measure, was markedly reduced for the data collection period, extending to 48 h after surgery. The time to first fentanyl request also showed a strong dose-dependent relationship and was significantly longer for the aggregate test group (p < 0.0001). Furthermore, patient and physician satisfaction scores for pain control were improved for the test group compared to the control group. In this study, DepoMorphine provided extended, dose-related analgesia for 48 hours during the postoperative period. Adverse events were not significantly different between study groups. The investigators concluded that DepoMorphine might offer an effective and safe alternative to the use of an indwelling epidural catheter. Side effects were as expected with systemic opioid therapy, and were readily managed [241]. Another double-blind, randomized study in 75 patients undergoing Caesarean section showed similar results with regard to postoperative analgesia. A combined spinal/epidural technique was utilized in which patients received spinal anesthesia

Cumulative fentanyl usage over 48 hours after hip arthroplasty (mean, SE}'

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0 DepoDur™ 15 mg (r^50)*


•DepoDur™ 20 !rç(ns4ïf

Time (hours after administration of DepoDur™)

' P < 0.05 compared with placebo at all time pointa after 4 hours,

Figure III-78. Significant reduction of additional fentanyl postoperatively in patients having received epidural DepoDur preoperatively

(bupivacaine 12-15 mg intrathecally and fentanyl 10 ^g). After clamping of the umbilical cord, a single epidural dose of either 5mg of conventional morphine sulfate or 5mg, 10 mg, or 15-mg DepoMorphine was administered. Postoperatively, patients received oral or i.v. opioids as needed. Rescue analgesic usage was converted to i.v. morphine equivalents for purposes of analysis. Throughout the 48-h postsurgical period, opioid analgesic use was significantly reduced for patients who had received DepoMorphine.

Functional ability scores at 24 and 48 h were also significantly improved. The authors of this study suggested that DepoMorphine is a promising new epidural analgesic for the long-term management of pain after cesarean section [242]. Surgeons who participated in these studies noted a consistent level pain of relief throughout the 48-h postoperative period, when pain intensity is most severe. A single injection consistently maintained analgesia, with minimal need for rescue medication, low analgesic gaps, and no catheter or pump maintenance issues. Clinical benefits were noted in that, unlike epidurals delivering local anesthetics, intermittent adjustment of medication levels was not needed. In addition, incidence of hypotension was rare. Epidural DepoMorphine analgesia was compatible with anticoagulation therapy, and this was considered an important benefit for orthopedic surgery populations. Postoperative ileus was not found to be a problem in abdominal surgery patients, as no difference was noticed with respect to the return of normal bowel function. Also, the absence of an additional pump and an i.v. pole with extra tubing, which can sometimes limit the patient's ambulation, clinically is advantageous.

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