Opioid receptor agonists, particularly those that activate µ-opioid receptors (MORs),
are essential analgesic agents for acute or chronic mild to severe pain treatment.
However, their use has raised concerns including, among others, intestinal dysbiosis.
In addition, growing data on constipation-evoked intestinal dysbiosis have been reported.
Opioid-induced constipation (OIC) creates an obstacle to continuing treatment with
opioid analgesics. When non-opioid therapies fail to overcome the OIC, opioid antagonists
with peripheral, fast first-pass metabolism, and gastrointestinal localized effects
remain the drug of choice for OIC, which are discussed here. At first glance, their
use seems to only be restricted to constipation, however, recent data on OIC-related
dysbiosis and its contribution to the appearance of several opioid side effects has
garnered a great of attention from researchers. Peripheral MORs have also been considered
as a future target for opioid analgesics with limited central side effects. The properties
of MOR antagonists counteracting OIC, and with limited influence on central and possibly
peripheral MOR-mediated antinociception, will be highlighted. A new concept is also
proposed for developing gut-selective MOR antagonists to treat or restore OIC while
keeping peripheral antinociception unaffected. The impact of opioid antagonists on
OIC in relation to changes in the gut microbiome is included.
