Study reports how opioids cause gastric inflammation

Opioids are the gold standard for the treatment of chronic and acute pain; however, their use can cause significant gastrointestinal side effects, including nausea, vomiting, and constipation. The reasons behind these side effects are not well understood. A new study in American Journal of Pathologypublished by Elsevier, is the first report on how opioids such as morphine cause stomach inflammation and how this condition can be reversed through treatment with proton pump inhibitor drugs such as omeprazole, an over-the-counter drug commonly used to reduce stomach acid.

Due to the lack of better alternatives, morphine is still considered one of the best pain management drugs despite its association with significant comorbidities. Several research groups, including our own, have worked for a long time to understand this phenomenon and to decipher the mechanisms underlying the gastrointestinal side effects of morphine.”

Sabita Roy, PhD, Principal Investigator, Department of Surgery, Miller School of Medicine, University of Miami; and Sylvester Comprehensive Cancer Center, Miami, FL, USA

Opioid users, compared with nonusers, had a higher incidence of gastric dysfunction, greater rates of gastric retention, poorer quality of life, increased hospitalization, and increased use of antinausea and pain medications.

To investigate the effects 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 acid accumulation in the stomach due to increased gastric acid secretion and delayed gastric emptying, thereby increasing acid retention time in the stomach. In vivo imaging confirmed that morphine-treated mice had delayed gastric emptying. Dramatic gastric damage includes significant disruption of gastric mucosal cells, reduced glandular area and increased gastric cell death.

Treatment with naloxone, a synthetic drug that blocks opioid receptor function, reduced this effect in morphine-treated mice, suggesting that classical opiate receptors are involved. Opioid receptors are found in high concentrations in the stomach antrum, the lower part (near the small intestine).

Dr. Roy and co-investigators hypothesized that the IL-6 cytokine is involved in the regulation of opioid-induced delays in gastric emptying and gastric damage. The morphine-treated mice had increased levels of IL-6. IL-6-deficient mice were treated with morphine, and the delay in gastric emptying was reduced. No gastric inflammation was detected in these mice, and the pH levels were similar to those of the placebo group. This suggests that the acute increase in IL-6 after morphine treatment causes a delay in gastric emptying, causes acid accumulation and results in gastric inflammation.

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

The study also addresses important concerns about whether the gastroprotective effect of omeprazole in any way compromises the analgesic effect of morphine. The investigators found that pretreatment resulted in a significant improvement in morphine-induced analgesic tolerance. In previous studies they have found that morphine can activate proinflammatory cytokines that promote morphine tolerance. They hypothesized that omeprazole broke the cycle of chronic morphine tolerance by reducing levels of this cytokine.

“Our study has clear clinical implications and suggests that omeprazole treatment at the time of morphine administration is a promising, safe, and inexpensive approach to reduce morphine-induced gastrointestinal pathology, improve morphine analgesic tolerance, and prolong its efficacy as an analgesic agent,” Dr Roy observed. .

Source:

Journal reference:

Gosh, N., et al. (2022) Use of Opioids in Murine Models Resulting in Severe Gastric Pathology That Can Be Attenuated by Proton Pump Inhibition. American Journal of Pathology. doi.org/10.1016/j.ajpath.2022.04.005.

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