New Study Sheds Light on Why Opioids Can Cause Gastrointestinal Problems

Opioids are the gold standard for treatment of chronic and acute pain; however, their use may result in significant gastrointestinal side effects, including nausea, vomiting, and constipation. The reasons behind these side effects are not well understood. A new study is the first report of how opioids like morphine cause gastric inflammation.

“Because of a lack of better alternatives, morphine is still considered one of the best pain management drugs despite its association with significant comorbidities,” explained lead investigator Sabita Roy, PhD. 

Opioid users, compared with non-users, have a higher incidence of gastric dysfunction, greater levels of gastric retention, worse quality of life, increased hospitalizations, and increased use of antinausea and pain medications.

To investigate the effect of morphine on gastric inflammation, the researchers treated mice with morphine or a placebo. They found that morphine-mediated gastric damage is a consequence of the accumulation of acid in the stomach due to increased gastric acid secretion and delayed gastric emptying, thereby increasing the retention time of acid in the stomach. Dramatic gastric damage included significant disruption of the gastric mucosal cells, a reduced glandular region and increased gastric cell death.

Dr. Roy and co-investigators hypothesized the cytokine IL-6 is involved in the regulation of opioid-induced delay in gastric emptying and gastric damage. Morphine-treated mice had elevated levels of IL-6. Mice that lack IL-6 were treated with morphine, and delays in gastric emptying were reduced. No gastric inflammation was detected in these mice, and pH levels were similar to the placebo group. This demonstrates that an acute increase in IL-6 after morphine treatment causes a delay in gastric emptying, leading to the accumulation of acid and resulting in gastric inflammation.

An important novel finding of this study is that co-administration of the proton pump inhibitor omeprazole with morphine provides gastroprotection by blocking gastric acid secretion, directly reducing gastric delaying and inflammation, and improving morphine tolerance.

“Our studies have clear clinical implications and suggest that omeprazole treatment at the time of morphine administration is a promising, safe, and inexpensive approach for reducing morphine-induced gastrointestinal pathology, improving morphine analgesic tolerance, and prolonging its efficacy as an analgesic agent,” Dr. Roy observed.


Nillu Ghosh, Kousik Kesh, Sundaram Ramakrishnan, Sabita Roy. Opioid Use in Murine Model Results in Severe Gastric Pathology that May Be Attenuated by Proton Pump Inhibition. The American Journal of Pathology, 2022; DOI: 10.1016/j.ajpath.2022.04.005

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Photo by Hiroshi Tsubono