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Pharmacology of Opioids
Published in Pamela E. Macintyre, Stephan A. Schug, Acute Pain Management, 2021
Pamela E. Macintyre, Stephan A. Schug
Peripherally acting μ-opioid antagonists such as methylnaltrexone, alvimopan, naloxegol, and naldemedine do not penetrate the blood–brain barrier (Schumacher & Fukuda, 2020) and so do not enter the CNS and will not reverse central opioid effects including analgesia. They act on opioid receptors in the GI tract wall and have been used to treat opioid-induced constipation. Alvimopan is an effective treatment for postoperative ileus (Schug et al, 2020).
Classes of Compounds with GI Tract Toxicity
Published in Shayne C. Gad, Toxicology of the Gastrointestinal Tract, 2018
Amy L. Mihalchik, Erica N. Rogers
OBD/OIC and postoperative ileus are commonly treated to limited effect with standard laxatives or prokinetic drugs. A survey of patients taking opiates for non-cancer pain found that only 46% of subjects requiring laxatives for OIC reported adequate relief >50% of the time, suggesting that alternative therapies are required for treatment of this adverse effect (Camilleri, 2011; Pappagallo, 2001). The value of OBD and postoperative ileus treatment with prokinetic drugs, which may stimulate GI motility, intestinal tone, or colonic transit, has not been fully substantiated clinically (Holzer, 2007). Therefore, management of OBD and postoperative ileus has shifted towards use of peripherally acting µ-opioid receptor antagonists (PAMORAs), which cannot cross the blood-brain barrier and permits desired analgesic activity of opiates in the CNS. PAMORAs, including naloxegol (Movantik®, formerly NKTR-118), methylnaltrexone (Relistor®), and naldemedine (Symproic®), as well as alvimopan (Entereg®) have been FDA-approved for use in treating opiate-induced constipation and post-operative ileus, respectively (Camilleri, 2011; Holzer, 2007, 2009). Lubiprostone (Amitiza®), a chloride channel activator that induces intestinal secretions, promotes increased passage of stool aiding in treatment of opiate-induced GI effects (Camilleri, 2011).
An update on the use of pharmacotherapy for opioid-induced bowel dysfunction
Published in Expert Opinion on Pharmacotherapy, 2023
Taraneh Mousavi, Shekoufeh Nikfar, Mohammad Abdollahi
Existing background on the clinical efficacy and safety of naldemedine could be derived from COMPOSE I–VII clinical trials on OIC patients with non-cancer-related pain (COMPOSE I, II, III, VI, VII) and those with cancer (COMPOSE IV and V). The detailed information regarding inclusion/exclusion criteria, endpoints, and results of each trial was already mentioned elsewhere [1,6,50–55]. To come straight to the outcomes, naldemedine, particularly at a dose of 0.2 mg per day, had positive effects on the frequency of SBMs, PAC-SYM, PAC-QoL, straining, and stool consistency in both populations [55]. More notably, naldemedine neither affected opioid analgesia nor brought about opioid withdrawal symptoms [56]. Naldemedine was well tolerated in all OIC patients, and diarrhea, nausea, and abdominal pain were the most reported adverse effects [6].
A meta-analysis of naldemedine for the treatment of opioid-induced constipation
Published in Expert Review of Clinical Pharmacology, 2019
Xuesong Song, Dunwei Wang, Xiaoyu Qu, Naifu Dong, Shiyong Teng
Five phase II and phase III clinical trials reported the efficacy and safety of naldemedine in two weeks treatment of opioid-induced constipation. This meta-analysis showed that participants who were receiving naldemedine 0.1 mg, 0.2 mg or 0.4 mg once per day for two weeks had statistically significantly higher SBM response rates than participants receiving placebo. Naldemedine 0.2 mg or 0.4 mg (but not 0.1 mg) once per day showed statistically significant improvements in changes of weekly SBM frequency from baseline than placebo. Although the incidence of the common AEs was significantly higher in participants with naldemedine 0.2 mg or 0.4 mg group (but not 0.1 mg group) than placebo, most of these AEs were predominantly mild or moderate. The incidence of serious AEs in all trials was low both in naldemedine and placebo group, and there was a significant difference of the incidence of serious AEs between the total naldemedine group and placebo group but no significant difference between naldemedine subgroup and placebo group.
Absorption, distribution, metabolism, and excretion of radiolabeled naldemedine in healthy subjects
Published in Xenobiotica, 2019
Shuichi Ohnishi, Kazuya Fukumura, Ryuji Kubota, Toshihiro Wajima
Naldemedine is a PAMORA that received approval in 2017 for the treatment of OIC in adults with chronic noncancer pain in the US and Japan, and in patients with cancer in Japan (Symproic PI, 2018). Naldemedine is a derivative of the opioid receptor antagonist naltrexone (Fukumura et al., 2018). The amide side chain increases the molecular weight and polar surface area of naldemedine, reducing its ability to cross the blood–brain barrier (Symproic PI, 2018). Naldemedine is a substrate of the P-glycoprotein efflux transporter, further contributing to its low penetration of the central nervous system and limiting the potential for interference with centrally mediated opioid analgesia (Stern & Brenner, 2018; Symproic PI, 2018).