Progresses in Questing for the Truth of Opioid-Related Constipation in Cancer Patients

Abstract

Opioids are extensively utilised to manage pain in cancer patients, but may cause constipation which significantly impacts their prognosis and quality of life. Opioid-induced constipation (OIC) lacks effective drugs and management strategies. Opioids act on the enteric nervous system, intestinal barrier, intestinal immunity and intestinal microbiota, implying that OIC is a multifactorial process. This paper aims to examine the effects of opioids on the intestine, specifically the enteric nervous system, intestinal barrier and interstitial cells of Cajal (ICCs), and elucidate the primary mechanisms underlying OIC development and deterioration. This review suggests that enteric neurons, intestinal immunity and intestinal flora could serve as potential therapeutic targets for OIC.

Keywords: cancer; constipation; enteric nervous system; intestinal cells of Cajal; intestinal flora; opioid.

FIGURE 1

(A) Opioids cause abnormal physiological processes in the body. The secretion of mucins by the GCs in the intestine decreases, ultimately resulting in a thinner protective mucous layer. Concurrently, the composition of intestinal microbiota changes, leading to a decrease in the production of SCFAs and indole derivatives. These effects disrupt the energy supply to IECs and diminish the secretion of 5‐HT from EECs. Furthermore, the inflammatory response triggered by the influx of immune cells into the myenteric plexus causes macrophage infiltration, further exacerbating the impairment of intestinal barrier function. Additionally, the shift in intestinal flora composition promotes the production of LPS, which can induce neuronal cell damage in the intestine. This damage reduces the population of ICCs, leading to dysfunctional intestinal smooth muscle and subsequent dysmotility. Overall, exposure to opioids triggers a cascade of events that culminate in the impairment of intestinal barrier function and gastrointestinal dysmotility. (B) Inadequate Ca²⁺ influx of VGCC closure due to opioid receptor activation, highlighting blocked secretory neural mediators in anterior vesicles. The binding of opioid ligands to opioid receptors prevents the binding of neural medium and postsynaptic receptors, which affects nerve conduction. (C) α‐GTP, γ‐GTP and G β G γ generated as opioid receptors bind with opioid ligands are all involved in intracellular signalling, and α‐GTP and γ‐GTP affect VGCC opening by inhibiting the AC/cAMP/PKA pathway to generate SAHP. G β G γ affects neuronal signalling by blocking calcium channels, opening potassium channels and inhibiting SNARE.