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.

Association between opioid usage and rectal dysfunction in constipation: A cross-sectional study of 2754 patients.

BACKGROUND: Opioid use has reached epidemic proportions. In contrast to the known effect of opioids on gut transit, the effect on rectal sensorimotor function has not been comprehensively investigated. METHODS: Cross-sectional (hypothesis-generating) study of anorectal physiology studies in 2754 adult patients referred to a tertiary unit (2004-2016) for investigation of functional constipation (defined by "derived" Rome IV core criteria). Statistical associations between opioid usage, symptoms, and anorectal physiological variables were investigated. Opioids were sub-classified as prescriptions for mild-moderate or moderate-severe pain. KEY RESULTS: A total of 2354 patients (85.5%) were classified as non-opioid users, 162 (5.9%) as opioid users for mild-moderate pain, and 238 (8.6%) for moderate-severe pain. Opioids for moderate-severe pain were associated with increased symptomatic severity (Cleveland Clinic constipation score 18.5 vs 15.1; mean difference 2.9 [95%-CI 2.3-3.6]; P < .001), rectal hyposensitivity (odds ratio 1.74 [95%-CI 1.23-2.46]; P = .002), functional evacuation disorders (odds ratio 1.73 [95%-CI 1.28-2.34]; P < .001), and delayed whole-gut transit (odds ratio 1.68 [95%-CI 1.19-2.37]; P = .003). Differences in anorectal variables between opioid users for mild-moderate pain and non-opioid users were not statistically significant. Hierarchical opioid use (non vs mild-moderate vs moderate-severe) was associated with decreasing proportions of patients with no physiological abnormality on testing (40.2% vs 38.1% vs 29.2%) and increasing proportions with both delayed whole-gut transit and rectal sensorimotor dysfunction (16.6% vs 17.5% vs 28.5%). CONCLUSIONS AND INFERENCES: Opioid use is over-represented in patients referred for investigation of constipation. Opioids for moderate-severe pain are associated with rectal sensorimotor abnormalities. Further studies are required to determine whether this association indicates causation.