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Using Medication Wisely
Published in Melissa G. Hunt, Aaron T. Beck, Reclaim Your Life From IBS, 2022
Melissa G. Hunt, Aaron T. Beck
Viberzi (eluxadoline) is another prescription medication that affects opioid receptors in the gut. It is also a controlled substance, although it actually has a very low potential for abuse or dependence because it mostly stays in the gut and doesn’t affect the central nervous system (including the brain) much. Taking too much can cause constipation and nausea.
How can we develop better antispasmodics for irritable bowel syndrome?
Published in Expert Opinion on Drug Discovery, 2019
Sheyda Ranjbar, Seyed Afshin Seyednejad, Shekoufeh Nikfar, Roja Rahimi, Mohammad Abdollahi
The opioid system contributes to the modulation of motor and secretory activity of GI through four major opioid receptors mu (MOR), kappa (KOR), delta (DOR) and nociceptin (NOR) [47,48]. MOR agonists decrease GI transit and secretion. Loperamide, a well-known anti-diarrheal opioid, exerts its effects by activating MOR. On the other hand, KOR and DOR are involved in visceral perception and activating these receptors provides anti-nociceptive and even anti-depressant effects [49]. Eluxadoline is a mixed MOR and KOR agonist and DOR antagonist that was approved for IBS-D patients [50]. Inhibiting DOR modulates the motility inhibitory effects exerted through activating MOR and prevents constipation or increased sphincter tone. Therefore, eluxadoline improves patients’ bowel movement frequency without constipating adverse effects and lightens their abdominal pain. Biphalin, an octapeptide encephalin analogue, is a mixed MOR/DOR agonist that inhibited colonic and ileum SMCs contraction in vitro and also the GI motility in a mouse IBS-D model [49]. It was also significantly effective in relieving abdominal pain in a mouse model [51]. Altogether, these features suggest biphalin as a suitable agent for further evaluation in IBS-D patients. In addition, two novel agents, an oral cyclic derivative of morphiceptin (P-317) [52] and a novel mixed MOR/NOR agonist (BU08070), produced significant antidiarrheal and analgesic effects in separate studies on mouse models mimicking symptoms of IBS-D [53,54].
Pharmacological approaches to treat intestinal pain
Published in Expert Review of Clinical Pharmacology, 2023
Mikolaj Swierczynski, Adam Makaro, Agata Grochowska, Maciej Salaga
On the way to improve opioid analgesia, numerous studies evaluate the use of peripherally restricted opioids. These agents are not able to cross the blood-brain barrier at therapeutic doses, which prevents side effects dependent on ORs located in the central nervous system. In contrast to common central opioids, peripheral ones are a promising approach to treat chronic non-cancer pain [132]. A peripheral KOR agonist, asimadoline, was extensively studied as a potential drug for IBS patients with moderate to severe pain. It was showed that analgesic doses of asimadoline additionally decrease bowel movements and do not trigger side effects. However, its effectiveness remains questionable and asimadoline has never been commercially available [133,134]. Another peripheral opioid, eluxadoline, was approved for use by FDA in 2015. Eluxadoline is an effective analgesic in IBS-D, which mechanism of action includes KOR and MOR agonism. Additionally, MOR agonism is modulated by DOR antagonism to increase analgesia and reduce the risk of constipation [89]. On the other hand, studies on IBD show that activation, not inhibition, of DOR plays key role in analgesia since this receptor is significantly upregulated in inflammatory sites. It is activated by endogenous enkephalins and endorphins, which are produced by CD4+ lymphocytes migrating to inflamed intestinal wall. Thus, the development of new therapies based on interaction with DOR is urgently needed to improve strategies for IBD-related pain treatment. The design of new DOR agonists, inhibitors of enkephalin-degrading enzymes as well as the use of CD4+ lymphocytes in active or inactive immunotherapy, seems to be promising directions to achieve this goal [135–137].
Advancements in drug development for diarrhea-predominant irritable bowel syndrome
Published in Expert Opinion on Investigational Drugs, 2018
Giovanni Dothel, Maria Raffaella Barbaro, Emanuel Raschi, Giovanni Barbara, Fabrizio De Ponti
Effectiveness and safety of medical compounds for IBS-D will benefit mostly by clinical trial design fulfilling primary and/or secondary clinical end points included in the latest regulatory requirements. Eluxadoline development reflects this kind of approach showing last decade’s most remarkable results in terms of efficacy, albeit the expected AEs associated with opioid receptor agonists (i.e. sphincter of Oddi spasm, pancreatitis). Although the low rate of cases reported so far, FDA contraindicated eluxadoline in subjects with history of alcohol abuse, known or suspected biliary duct obstruction, or sphincter of Oddi disease or dysfunction, history of pancreatitis, severe hepatic impairment.