Involvement of the Peripheral µ-Opioid Receptor in Tramadol-Induced Constipation in Rodents.

Tramadol is a weak opioid that produces analgesic effect via both the µ-opioid receptor (MOR) and non-opioid targets. Constipation is the most common opioid-related side effect in patients with cancer and non-cancer pain. However, the contribution of MOR to tramadol-induced constipation is unclear. Therefore, we used naldemedine, a peripherally acting MOR antagonist, and MOR-knockout mice to investigate the involvement of peripheral MOR in tramadol-induced constipation using a small intestinal transit model. A single dose of tramadol (3-100 mg/kg, per os (p.o.)) inhibited small intestinal transit dose-dependently in rats. Naldemedine (0.01-10 mg/kg, p.o.) blocked the inhibition of small intestinal transit induced by tramadol (30 mg/kg, p.o.) in rats. The transition rate increased dose-dependently over the range of naldemedine 0.01-0.3 mg/kg, and complete recovery was observed at 0.3-10 m/kg. Additionally, tramadol (30 and 100 mg/kg, subcutaneously (s.c.)) inhibited small intestinal transit in wild-type mice but not in MOR-knockout mice. These results suggest that peripheral MOR participates in tramadol-induced constipation.

An opioid receptor-independent mechanism underlies motility dysfunction and visceral hyperalgesia in opioid-induced bowel dysfunction.

Constipation and abdominal pain are commonly encountered in opioid-induced bowel dysfunction (OBD). The underlying mechanisms are incompletely understood, and treatments are not satisfactory. As patients with OBD often have fecal retention, we aimed to determine whether fecal retention plays a pathogenic role in the development of constipation and abdominal pain in OBD, and if so to investigate the mechanisms. A rodent model of OBD was established by daily morphine treatment at 10 mg/kg for 7 days. Bowel movements, colonic muscle contractility, visceromotor response to colorectal distention, and cell excitability of colon-projecting dorsal root ganglion neurons were determined in rats fed with normal pellet food, or with clear liquid diet. Morphine treatment (Mor) reduced fecal outputs starting on day 1, and caused fecal retention afterward. Compared with controls, Mor rats demonstrated suppressed muscle contractility, increased neuronal excitability, and visceral hypersensitivity. Expression of cyclooxygenase-2 (COX-2) and nerve growth factor (NGF) was upregulated in the smooth muscle of the distended colon in Mor rats. However, prevention of fecal retention by feeding rats with clear liquid diet blocked upregulation of COX-2 and NGF, restored muscle contractility, and attenuated visceral hypersensitivity in Mor rats. Moreover, inhibition of COX-2 improved smooth muscle function and fecal outputs, whereas anti-NGF antibody administration attenuated visceral hypersensitivity in Mor rats. Morphine-induced fecal retention is an independent pathogenic factor for motility dysfunction and visceral hypersensitivity in rats with OBD. Liquid diet may have therapeutic potential for OBD by preventing fecal retention-induced mechanotranscription of COX-2 and NGF.NEW & NOTEWORTHY Our preclinical study shows that fecal retention is a pathogenic factor in opioid-induced bowel dysfunction, as prevention of fecal retention with liquid diet improved motility and attenuated visceral hyperalgesia in morphine-treated animals by blocking expression of cyclooxygenase-2 and nerve growth factor in the colon.

Evaluating naloxegol for the treatment of opioid-induced constipation.

INTRODUCTION: Due to the increased use of opioids for pain and their abuse globally, the rate of restrictive side effects is elevating. Opioid-induced constipation (OIC) is probably the most widespread, underdiagnosed, and yet common adverse effect. Naloxegol, as an opioid antagonist, is associated with beneficial impacts in OIC. Indeed, blocking mu (µ)-opioid receptors in the gastrointestinal tract (GI) may lead to neutralization of the GI adverse events of opioids. AREAS COVERED: This review is based on a PubMed and Clinicaltrials.gov search for studies undertaken over the past 20 years (2000-2020) using the following keywords: Movantik®, Moventig®, Naloxegol, Opioids, Opioid-induced constipation and Opioid antagonists. EXPERT OPINION: Similar to the management of functional constipation, non-pharmacological therapies are applied as the first step of the procedure. However, in most cases, laxative therpaies with or without stool softeners, which may not result in satisfactory relief are applied. In these instances, administration of prokinetic agents is recommended. Furthermore, studies have shown that the best second-line therapy option is a peripherally acting µ-opioid receptor antagonist (PAMORA), which antagonizes GI adverse events.