Phase III Trial of Alvimopan, a Novel, Peripherally Acting, Mu Opioid Antagonist, for Postoperative Ileus After Major Abdominal Surgery

Delaney, Conor P.; Weese, James L.; Hyman, Neil; Bauer, Joel J.; Techner, Lee; Gabriel, Kathie; Du, Wei; Schmidt, William K.; Wallin, Bruce A.

doi:10.1007/s10350-005-0035-7

Cited by 202 publications

(216 citation statements)

References 50 publications

(24 reference statements)

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“…In study 14CL302, the lower incidence of vomiting in the alvimopan 12 mg group was statistically signifi cant compared to that in the placebo group. 54 A smaller proportion of patients in the alvimopan (6 and 12 mg) groups had serious adverse events that required prolonged hospitalization or readmission in comparison to those receiving placebo. 58 Discontinuations as a result of adverse events occurred to similar extents for alvimopan and placebo in the Phase 3 trials (Table 6), and of the few deaths reported, none was considered drug-related.…”

Section: Preclinical Studiesmentioning

confidence: 92%

“…[53][54][55][56][57][58][59][60] The primary reason for surgery was rectal or colon cancer. 53,60 All were randomized, double-blind, placebo-controlled parallel studies comparing the effi cacy of alvimopan to that of placebo in hospitalized patients.…”

Section: Phase 3 Studiesmentioning

confidence: 99%

“…In study 14CL302, 54 patients undergoing partial colectomy or simple or radical hysterectomy were randomized to receive alvimopan (6 or 12 mg) or placebo orally two hours prior to surgery and b.i.d. thereafter until hospital discharge, or for up to 7 days.…”

Section: Phase 3 Studiesmentioning

confidence: 99%

“…nausea, vomiting and abdominal distension), and consistent with those expected in patients undergoing bowel resection under general anesthesia with opioid analgesic therapy. 54,55,[57][58][59][60] The overall incidence of these adverse events was somewhat lower in alvimopan treated patients compared to those receiving placebo (Table 5). In study 14CL302, the lower incidence of vomiting in the alvimopan 12 mg group was statistically signifi cant compared to that in the placebo group.…”

Section: Preclinical Studiesmentioning

confidence: 99%

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Safety and efficacy update: Alvimopan in postoperative ileus

Beattie

2009

Clinical Medicine. Therapeutics

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Postoperative ileus (POI) in patients undergoing abdominal surgery is associated with signifi cant morbidity. In 2008, alvimopan (Entereg ® ) was approved by the Food and Drug Administration (FDA), and is the only available POI therapy in the United States for patients undergoing bowel resection. Data from preclinical studies demonstrate that alvimopan and its primary metabolite, ADL 08-0011, behave as potent μ opioid receptor antagonists. In animals, alvimopan and ADL 08-0011 attenuate opioid agonist-induced reductions in gastrointestinal (GI) transit. Higher doses of alvimopan are required to inhibit opioid-induced analgesia as a result of its inability to penetrate the central nervous system (CNS). ADL 08-0011 is also peripherally selective, although to a lesser degree than alvimopan. In multiple species, including humans, alvimopan has low oral bioavailability, while ADL 08-0011, following its generation by human gut microfl ora, is more readily absorbed and achieves higher exposures. Three Phase 2 and fi ve Phase 3 clinical trials have been conducted to investigate the effi cacy and tolerability of alvimopan in patients undergoing bowel resection. An additional Phase 3 study was conducted in hysterectomy patients. In the majority of the studies, statistically signifi cant, and clinically meaningful, acceleration of GI recovery has been demonstrated. Consistent with animal data, alvimopan has no effect on opioid agonist-induced analgesia in healthy human subjects and POI patients. Clinical experience to date in POI patients indicates that alvimopan is well tolerated when used according to its approved dosing regimen (12 mg b.i.d. for up to 7 days). In this article, the preclinical and clinical properties of alvimopan are reviewed.

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Section: Preclinical Studiesmentioning

confidence: 92%

Section: Phase 3 Studiesmentioning

confidence: 99%

Section: Phase 3 Studiesmentioning

confidence: 99%

Section: Preclinical Studiesmentioning

confidence: 99%

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Safety and efficacy update: Alvimopan in postoperative ileus

Beattie

2009

Clinical Medicine. Therapeutics

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“…Investigators evaluated patients from the placebo arms of 3 phase III trials assessing the efficacy of an oral peripherally acting μ-opioid receptor antagonist for the management of POI. 5,13,16,51 Their findings represent an important source of postoperative recovery data from a controlled setting and a homogeneous patient population. The analysis of postoperative GI recovery and LOS patterns provides important insights into upper and lower GI recovery, symptoms, morbidity and mortality, LOS, and readmission after bowel resection (BR) in a large group of patients (n=383) receiving a standardized multimodal postoperative management protocol.…”

mentioning

confidence: 94%

Complication avoidance and management in anterior lumbar interbody fusion

Than

Wang

Rahman

et al. 2011

FOC

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The goal of this study was to review the literature to compare strategies for avoiding and treating complications from anterior lumbar interbody fusion (ALIF), and thus provide a comprehensive aid for spine surgeons. A thorough review of databases from the US National Library of Medicine and the National Institutes of Health was conducted. The complications of ALIF addressed in this paper include pseudarthrosis and subsidence, vascular injury, retrograde ejaculation, ileus, and lymphocele (chyloretroperitoneum). Strategies identified for improving fusion rates included the use of frozen rather than freeze-dried allograft, cage instrumentation, and bone morphogenetic protein. Lower cage heights appear to reduce the risk of subsidence. The most common vascular injury is venous laceration, which occurs less frequently when using nonthreaded interbody grafts such as iliac crest autograft or femoral ring allograft. Left iliac artery thrombosis is the most common arterial injury, and its occurrence can be minimized by intermittent release of retraction intraoperatively. The risk of retrograde ejaculation is significantly higher with laparoscopic approaches, and thus should be avoided in male patients. Despite precautionary measures, complications from ALIF may occur, but treatment options do exist. Bowel obstruction can be treated conservatively with neostigmine or with decompression. In cases of postoperative lymphocele, resolution can be attained by creating a peritoneal window. By recognizing ways to minimize complications, the spine surgeon can safely use ALIF procedures.

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Gastrointestinal Tract Recovery in Patients Undergoing Bowel Resection

Ludwig¹

2008

Arch Surg

134

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Objective: To investigate the efficacy and safety of alvimopan, 12 mg, administered orally 30 to 90 minutes preoperatively and twice daily postoperatively in conjunction with a standardized accelerated postoperative care pathway for managing postoperative ileus after bowel resection. Design, Setting, and Patients: This multicenter, randomized, placebo-controlled, double-blind, phase 3 trial enrolled adult patients undergoing partial bowel resection with primary anastomosis by laparotomy and scheduled to receive intravenous, opioid-based, patientcontrolled analgesia. A standardized accelerated postoperative care pathway including early ambulation, oral feeding, and postoperative nasogastric tube removal was used to facilitate gastrointestinal (GI) tract recovery in all of the patients. Main Outcome Measures: The primary end point was time to GI-2 recovery (toleration of solid food and first bowel movement). Secondary end points included time to GI-3 recovery (toleration of solid food and first flatus or bowel movement), hospital discharge order written, and actual hospital discharge. Postoperative length of hospital stay based on calendar day of hospital discharge order written, opioid consumption, and overall postoperative ileus-related morbidity were recorded. Results: Alvimopan, 12 mg, was well tolerated and significantly accelerated GI-2 recovery, GI-3 recovery, and actual hospital discharge compared with a standardized accelerated postoperative care pathway alone (hazard ratio=1.5, 1.5, and 1.4, respectively; PϽ.001 for all). Time to hospital discharge order written as measured by hazard ratio (1.4) and by postoperative calendar days (mean for alvimopan, 5.2 days; mean for placebo, 6.2 days) was also accelerated. Opioid consumption was comparable between groups, and alvimopan was associated with reduced postoperative ileus-related morbidity compared with placebo. Conclusions: Alvimopan, 12 mg, administered 30 to 90 minutes before and twice daily after bowel resection is well tolerated, accelerates GI tract recovery, and reduces postoperative ileus-related morbidity without compromising opioid analgesia.

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Phase III Trial of Alvimopan, a Novel, Peripherally Acting, Mu Opioid Antagonist, for Postoperative Ileus After Major Abdominal Surgery

Abstract: In patients undergoing major abdominal surgery, alvimopan accelerated gastrointestinal recovery and time to the hospital discharge order written compared with placebo and was well tolerated.

Cited by 202 publications

References 50 publications

Safety and efficacy update: Alvimopan in postoperative ileus

Safety and efficacy update: Alvimopan in postoperative ileus

Complication avoidance and management in anterior lumbar interbody fusion

Gastrointestinal Tract Recovery in Patients Undergoing Bowel Resection

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