Mortality due to intestinal perforation is one of the most serious side effects of a peripherally acting μ-opioid receptor antagonist such as naldemedine. It has been reported to occur in 16.9%─33.3% of patients [7, 8]. Therefore, naldemedine is contraindicated in patients with known or suspected gastrointestinal obstruction or at increased risk for recurrent obstruction because of the risk of gastrointestinal perforation [6]. Our patient did not have a history of gastrointestinal obstruction, but diverticulitis was found at surgery, suggesting that the gastrointestinal tract was vulnerable. Therefore, we suggest that the administration of naldemedine led to intestinal perforation, as a result of the relative activation of intestinal function by the antagonistic effect of naldemedine on the μ-opioid receptors in the intestinal tract.

Opioids have been reported to act directly on the μ-opioid receptors of intestinal neurons to induce constipation by suppressing peristalsis through contraction of the circular muscle layer [9]. Since contractions are stronger in the distal regions (rectum, distal and transverse colon) than proximal regions (proximal colon, jejunum, and ileum), naldemedine may have antagonized the contractions in those regions. The intestinal perforation in our patient occurred in the distal colon near the rectum, suggesting that the release of contractions by the circular muscle layer caused by naldemedine led to a relative activation of peristalsis, followed by the onset of intestinal perforation. Moreover, peripherally restricted opioid receptor antagonists may manifest prokinetic activity [10, 11]. Endogenous opioids mediate inhibition of peristalsis in the guinea pig intestine via μ- and κ-opioid receptors [12]. Naldemedine has a potent antagonist activity against μ- and κ-opioid receptors [13]. Therefore, naldemedine may have inhibited the suppression of opioid-induced intestinal motility and promoted gastrointestinal motility. Meanwhile, stimulant laxatives, including sennoside and bisacodyl, act locally at the nerve plexus of smooth muscle in the intestine to promote colonic motility. Long-term or high-dose stimulant laxatives have been shown to cause morphological changes, neuronal damage, and functional impairment of the intestine [14]. However, in our case, they were administered over a short-term period and used at recommended therapeutic doses. Moreover, the chronic consumption of anthraquinone laxatives containing senna could have led to melanosis coli [15, 16], which was not confirmed by the histopathological or surgical findings.

To the best of our knowledge, this is the first report describing an intestinal perforation induced by the administration of naldemedine. There have been reports of gastrointestinal perforation following administration of methylnaltrexone bromide, which is an analog of naldemedine [5, 17]. Similarly, there have been case reports of stercoral perforation associated with the administration of the combination of buprenorphine and naloxone, which is an opioid antagonist [18]. The perforations described in these reports occurred immediately after or less than 1 week after the start of the administration of the drug, which is different from the timing of perforation in our patient. The rate of dissociation of the binding of naldemedine to the µ-opioid receptors that is caused by noncompetitive antagonism has been reported to be slower than that of N-methylnaltrexone or naloxone [13, 19]. The differences between the rates of dissociation have led to differences between the times of onset of peripheral withdrawal symptoms such as diarrhea from various μ-opioid receptor antagonists. Therefore, the time of the onset of side effects in our patient may also have been delayed in relation to the intestinal perforation that occurred after naldemedine administration.

Naldemedine was administered to our patient before bedtime. Administration of naldemedine without food has been reported to cause a 1.5-fold increase in maximal plasma concentration compared to the administration of naldemedine with food [6]. The concentrations of naldemedine in the intestinal tract may have been temporarily high, which may have contributed to the greatly enhanced peristaltic movements. However, the extent to which the timing of the administration of naldemedine in relation to the timing of food intake would be affected in clinical practice remains unknown.

The histopathological findings of our patient revealed a large number of diverticula. Patients with diverticulitis have been reported to develop complications, including perforation, stricture, fistula, and abscesses [20]. In addition, smoking is also a risk factor for severe colonic diverticulitis with perforations [21, 22], and our patient had a long history of smoking. Therefore, he was considered to be at risk for diverticulitis with perforations. In other words, the risk of intestinal perforation during administration of naldemedine should be considered in patients with pre-existing diverticular disease.

The patient had a decreased frequency of defecation one week before the onset of abdominal pain. Constipation has been reported to be another risk factor for perforation [23]. Our patient had OIC, Parkinson syndrome, and received palonosetron, a 5-HT3 receptor antagonist used during chemotherapy, which may have contributed to his chronic constipation [24, 25].

In clinical practice, the presence of diverticular disease in a patient may be unknown before the administration of naldemedine. Moreover, the incidence of diverticulitis increases with age [26]. Therefore, clinicians should consider changing to alternative medications rather than continuing the prolonged use of ineffective laxatives especially in elderly patients. Moreover, clinicians should minimize the use of medications that may induce constipation. In addition to peripheral μ-opioid receptor antagonists, other effective drugs for OIC in Japan include osmotic laxatives, stimulant laxatives, and lubiprostone, according to the Evidence-Based Clinical Practice Guidelines for Chronic Constipation 2023 [27]. The patient had a decreased frequency of defecation one week before the onset of abdominal pain. When constipation persists and does not improve despite naldemedine administration, a change to another laxative should be considered. In this case, magnesium oxide was started after the discontinuation of naldemedine, which improved the frequency of defecation. Furthermore, for constipated patients taking opioids for pain, a change to fentanyl, an opioid that has been reported to have less impact on constipation [28], should also be considered.

A rapid increase in the CRP levels and WBC counts was seen in our patient after the onset of abdominal pain, which was shown on abdominal CT to be an intestinal perforation. Because elevated markers of inflammation such as CRP and WBC have been reported to be predictive of perforation in patients with acute sigmoid diverticulitis [29], it is important to monitor for rapid increases in CRP levels and WBC counts during treatment with naldemedine.

This case report has limitations. The patient had both diverticulitis and constipation, which may have influenced the development of intestinal perforation. Smoking, a risk factor for diverticulitis, has been reported to be a risk factor for oral cavity and pharyngeal cancer [30]. Further research is needed to investigate the potential association between oral cancer and naldemedine-induced intestinal perforation. Additionally, because naldemedine is used to treat OIC, it was difficult to completely exclude the effects of constipation on perforation. Nevertheless, naldemedine is likely to be commonly prescribed in clinical practice for patients with OIC. Therefore, we think that this case report contains clinically significant findings.

In conclusion, we reported a patient with a diverticular perforation in his sigmoid colon that occurred after naldemedine administration. When using naldemedine for OIC in patients with pre-existing diverticular disease, we should be aware of the risk for intestinal perforation. During naldemedine administration, we should evaluate for abdominal tenderness and carefully monitor for increasing WBC counts and CRP levels. Furthermore, during the treatment of OIC, the selection of an appropriate laxative or change to another opioid should be considered frequently, depending on the patient's condition.