Despite their effectiveness, opioids have significant drawbacks, notably the development of analgesic tolerance and physical dependence, sedation, respiratory depression and bowel dysfunction. Opioid-induced constipation (OIC) is common, affecting more than 50% of patients receiving chronic morphine treatment for cancer pain and, unlike the majority of opioid-induced effects, is not prone to tolerance.
Consisting of constipation, delayed gastric emptying, abdominal discomfort, and nausea, OIC can be debilitating in patients. The phenomenon of OIC results from the interaction of an opioid agonist with receptors on enteric neurons in the myenteric and submucous plexuses and smooth muscle to inhibit coordinated rhythmic contractions associated with GI transit and secretion.4 The ability of prototypical μ-opioid receptor antagonists, such as naltrexone and naloxone, to attenuate OIC has been demonstrated clinically.
However, because these agents readily cross the blood brain barrier, attenuation of opioid induced analgesia and provocation of an opioid behavioral withdrawal syndrome can occur. TD-1211 is an investigational, orally-administered, peripherally selective, multivalent inhibitor of the mu-opioid receptor designed with the goal of alleviating gastrointestinal side effects of opioid therapy without affecting analgesia. This Phase 2b study evaluated the safety, tolerability, and efficacy of three doses of TD-1211 compared to placebo.