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Opioid Receptor Modulators

Last updated on October 8, 2021


Opioid Receptor ModulatorsOpioids are a family of receptors and ligands that profoundly affect the neural circuits that modulate pain and motility in the gut. Both agonists and antagonists at the various opioid receptors represented in the periphery (kappa, mu, delta, and sigma) are under investigation for the treatment of irritable bowel syndrome. Pfizer has an agent in preclinical development (JO-2871, a sigma opioid receptor modulator and novel antidiarrheal), while both GSK (UK-321130, a delta opioid antagonist) and Eli Lilly (alvimopan, a mu receptor antagonist) have compounds in Phase I development for irritable bowel syndrome. Compounds targeting opioid receptors in the later stages of development are targeting pain symptoms.

Mechanism Of Action

Modulation of opioid receptors in the gut is associated with improvements in irritable bowel syndrome symptoms, including reduced visceral hypersensitivity and modulated gastrointestinal motility.


Pain Therapeutics had been developing a low-dose formulation of the opioid antagonist naltrexone hydrochloride for the potential treatment of irritable bowel syndrome, the drug had advanced to Phase III clinical trials in the United States. The company had hoped to capitalize on PTI-901 ‘s unique mechanism of restoring the balance of opioid activity in the gut through antagonism of opioid receptors. (Some researchers believe that an imbalance of opioid activity in the gut — triggered by the release of intrinsic opioids from neurons in the gut, metabolic disorders, or emotional stress — contributes to irritable bowel syndrome symptoms. However, Pain Therapeutics discontinued development of PTI-901 in December 2005 after data from a randomized, double-blinded, multicenter U.S. study in 600 women showed that the drug provided no meaningful benefit after three months of treatment compared with placebo.

Clinical information on the actions of PTI-901 in irritable bowel syndrome patients is limited. A pilot study assessing the agent’s safety and efficacy was carried out in Israel. In this open-label study, 50 patients diagnosed with irritable bowel syndrome were treated with 0.5 mg of PTI-901 daily for four weeks. According to the study results released in May 2003, the response to treatment rate was 76.5% (n = 17) in males and 75.0% (n = 25) in females. Patients given PTI-901 reported a 193% (n = 37) increase in the number of pain-free days at week 4 compared with baseline. They also reported improvements in bowel urgency, stool consistency, and number of stool-free days. The study found PTI-901 to be safe and well tolerated.


In June 2005, Tioga Pharmaceuticals, under license from Merck KGaA, was seeking funding to conduct its own Phase lib efficacy trials of asimadoline, a kappa opioid agonist being developed as an irritable bowel syndrome treatment (Merck KGaA had conducted a Phase Ha study of the drug in 2002). In June 2005, the companies reported that Tioga Pharmaceuticals would be funded by Forward Ventures, a San Diego-based venture capital firm, while additional funds to conduct Phase lib trials would be raised.

According to Tioga Pharmaceuticals, asimadoline is a peripherally active analgesic that amplifies the body’s own pain protection mechanisms and inhibits the release of substance P. Opioid kappa receptors are located on sensory afferent pathways and thought to be involved in visceral nociception. Agents that target these receptors can, theoretically, reduce pain without affecting gut motility.

A randomized, double-blind, placebo-controlled study involving 20 females with irritable bowel syndrome and a pain threshold below 32 mmHg (millimeters of mercury) compared 0.5 mg of oral asimadoline with placebo. Following treatment, the patients were subject to a series of left colonic distensions (5-40 mmHg pressure). Results showed that asimadoline significantly reduced the intensity of abdominal pain. The effects observed were more pronounced at intermediate pressure distension steps, and the mean pain score was significantly lower at 20, 25, and 30 mmHg distension with respect to placebo. Asimadoline was well tolerated, and no serious adverse events were reported.

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