Clinical trial: asimadoline in the treatment of patients with irritable bowel syndrome

Abstract

SUMMARY BackgroundIn models of irritable bowel syndrome (IBS), asimadoline, a kappa-opioid agonist, improves pain and abnormal bowel function.

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

“…In line with our animal studies, this indicates that immune cell-derived opioids do not produce cross-tolerance to exogenous opioid agonists, but may, in fact, prevent the development of tolerance at peripheral opioid receptors (Zöllner et al, 2008). Additional evidence for this notion has been provided using a peripherally acting -agonist in patients with irritable bowel disease, where a significant reduction in pain was observable over a treatment period of 3 months (Mangel et al, 2008). This implies that the use of peripherally acting opioid agonists for the prolonged treatment of inflammatory pain is not necessarily accompanied by tolerance.…”

“…In vitro studies in transfected cells also showed receptor endocytosis induced by END and a correlation between the internalization/signaling potency of opioid ligands and -opioid receptor resensitization (Koch et al, 2005). Other studies of prolonged peripheral opioid receptor activation in the presence of different types of inflammatory stimuli also indicated a lack of tolerance development (Tokuyama et al, 1998;Börzsei et al, 2008;Mangel et al, 2008). These findings imply that the use of peripherally acting opioid agonists for the prolonged treatment of inflammatory pain is not necessarily accompanied by tolerance.…”

“…Others reported that naloxone methiodide had no effect on opioid analgesia (Ramabadran, 1982;Ramabadran et al, 1982), but at much lower doses than those examined in the study by Lewanowitsch and Irvine (2002). Human studies indicate that opioid agonists that do not readily cross the blood-brain barrier (e.g., morphine-6-glucuronide) are beneficial in patients with visceral and neuropathic pain (Eisenach et al, 2003;Wallace et al, 2006;Mangel et al, 2008) and can have the same analgesic efficacy as conventional opioids, with significantly fewer central nervous system side effects (Tegeder et al, 2003;Hanna et al, 2005;van Dorp et al, 2008). Thus, one may expect that peripherally restricted opioid agonists are active in both acute and chronic pain.…”

“…Novel peripherally restricted -agonists were investigated in humans with chronic painful pancreatitis (Eisenach et al, 2003), neuropathic pain (Wallace et al, 2006), irritable bowel syndrome (Mangel et al, 2008), and after abdominal surgery (Menzaghi et al, 2010). These trials showed significant analgesia without central side effects.…”

Treatment of irritable bowel syndrome: beyond fiber and antispasmodic agents

“…However, further large RCTs of the latter drug have been disappointing. [Mangel et al 2008;Szarka et al 2007]. One RCT demonstrated no difference in achievement of the primary end point, average reduction in pain severity 2 hours after treatment, between asimadoline and placebo [Szarka et al 2007], although in a post hoc analysis, there appeared to be a benefit in those with an alternating bowel habit.…”