Jonathan Moss, MD, PhD, Carl E. Rosow, MD, PhD Mayo Clinic Proceedings

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Development of Peripheral Opioid Antagonists: New Insights Into Opioid Effects Jonathan Moss, MD, PhD, Carl E. Rosow, MD, PhD Mayo Clinic Proceedings Volume 83, Issue 10, Pages 1116-1130 (October 2008) DOI: 10.4065/83.10.1116 Copyright © 2008 Mayo Foundation for Medical Education and Research Terms and Conditions

FIGURE 1 Chemical structures of naltrexone (left) and methylnaltrexone (right). Mayo Clinic Proceedings 2008 83, 1116-1130DOI: (10.4065/83.10.1116) Copyright © 2008 Mayo Foundation for Medical Education and Research Terms and Conditions

FIGURE 2 Oral-cecal transit time (OCTT) in 12 volunteers given placebo, morphine (MS), or intravenous methylnaltrexone (MNTX) plus MS. The dashed line represents the mean response. From Clin Pharmacol Ther,39 with permission. Mayo Clinic Proceedings 2008 83, 1116-1130DOI: (10.4065/83.10.1116) Copyright © 2008 Mayo Foundation for Medical Education and Research Terms and Conditions

FIGURE 3 Laxation responses among patients with opioid-induced bowel dysfunction and advanced illness who were given either subcutaneous methylnaltrexone (0.15 mg/kg every other day for 1 week, with option of doubling dose in second week) or placebo. A, Primary efficacy measures: laxation within 4 hours after the first dose and laxation within 4 hours after 2 or more of the first 4 doses (P<.001); B, Rescue-free laxation within 4 hours after each dose during a 13-day period (P<.005). On days 9, 11, and 13, variations in doses were permitted on the basis of efficacy and adverse events; C, Kaplan-Meier curves for the time to laxation within 4 hours after the first dose (P<.001). From N Engl J Med,48 with permission from the Massachusetts Medical Society. © 2008. All rights reserved. Mayo Clinic Proceedings 2008 83, 1116-1130DOI: (10.4065/83.10.1116) Copyright © 2008 Mayo Foundation for Medical Education and Research Terms and Conditions

FIGURE 4 Chemical structure of alvimopan. Mayo Clinic Proceedings 2008 83, 1116-1130DOI: (10.4065/83.10.1116) Copyright © 2008 Mayo Foundation for Medical Education and Research Terms and Conditions

FIGURE 5 Kaplan-Meier estimates of probability of reaching end points among 78 patients with postoperative ileus who were given alvimopan (ADL 8-2698, 1 mg or 6 mg) or placebo 2 hours before surgery and then twice daily until hospital discharge, for a maximum of 7 days. Significant differences were observed among the groups in time to first passage of flatus (P=.03), time to first bowel movement (P=.01), and time until patient was ready for discharge (P=.03). From N Engl J Med,58 with permission from the Massachusetts Medical Society. © 2001. All rights reserved. Mayo Clinic Proceedings 2008 83, 1116-1130DOI: (10.4065/83.10.1116) Copyright © 2008 Mayo Foundation for Medical Education and Research Terms and Conditions

FIGURE 6 Volume of urine voided by male volunteers during urodynamic testing. Measurements were made at baseline, during infusion of remifentanil (0.15 μg/kg per minute), and after injection of saline placebo, naloxone (0.01 mg/kg), or methylnaltrexone (MNTX, 0.3 mg/kg). Remifentanil greatly reduced or eliminated voiding in almost every case. The incidence of successful voiding was 0/6, 7/7, and 5/12 after saline, naloxone, and MNTX, respectively (P=.0013). Adapted from Clin Pharmacol Ther,74 with permission. Mayo Clinic Proceedings 2008 83, 1116-1130DOI: (10.4065/83.10.1116) Copyright © 2008 Mayo Foundation for Medical Education and Research Terms and Conditions

FIGURE 7 Rates of human endothelial cell migration into media containing bovine serum albumin (BSA), as a result of increasing concentrations of morphine, naloxone, methylnaltrexone (MNTX), or MNTX plus morphine. HPF = high-power field; VEGF = vascular endothelial growth factor. The line marked BSA represents background migration, and the line marked VEGF is a positive control. Increasing amounts of morphine increased cell migration, whereas naloxone and MNTX did not. Methylnaltrexone produced a concentration-dependent block of the morphine effect. From Microvasc Res,88 with permission. Mayo Clinic Proceedings 2008 83, 1116-1130DOI: (10.4065/83.10.1116) Copyright © 2008 Mayo Foundation for Medical Education and Research Terms and Conditions