Opioid analgesics such as morphine continue to play a critical role in chronic cancer and non-cancer pain control. 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 tolerance3. 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. 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 a peripherally selective µ-opioid receptor antagonist which has the potential to be effective in the treatment of OIC without interfering with centrally mediated opioid effects.
Preclinically, TD-1211 demonstrates a high degree of peripheral selectivity, a safety profile which supports further clinical studies, and favorable pharmacokinetics. This study represents the first multiple dose administration of TD-1211 to humans in an OIC patient population, and the results of this study collectively demonstrate that oral, once-daily TD-1211 increased the frequency of SBMs and CSBMs while decreasing rescue laxative use in OIC patients without impacting analgesia.