The propensity score matching analysis showed that the incidence of OIC in patients with and without prophylactic laxatives was comparable, suggesting that prophylactic laxatives are not necessarily required when initiating opioid therapy. In addition, age ≥ 65 years and ECOG PS ≥ 3 were shown in multivariate logistic analysis to be significant risk factors in the incidence of OIC.
We found that age ≥ 65 years was a risk factor for OIC. Previous studies also showed that age ≥ 50 years [19] and increased age [21] were associated with the incidence of OIC. Constipation occurs due to structural and functional changes of the anorectum in elderly people [22], so elderly patients may be especially prone to constipation. However, the association between OIC and age varies in the studies: one study found no association with age [23], while another study found that age ≥ 65 years decreased the risk of OIC [16]. Further investigation of the potential relationship between OIC and age is therefore warranted. We also found that ECOG PS ≥ 3 was another risk factor for OIC. To the best of our knowledge, the previous studies did not examine the association between performance status and the incidence of OIC. Poor general performance status has been associated with the incidence of constipation in patients with cancer and receiving palliative care [24]. In patients receiving chemotherapy, ECOG PS ≥ 2 has been reported to have an association with higher severity of constipation [25]. This evidence suggests that the patients with decreased physical performance status are prone to constipation.
Our results suggest that prophylactic laxatives do not affect the incidence of OIC. Despite using the same OIC criteria as the J-RIGID study, our findings were different: the J-RIGID study found significant effectiveness of prophylactic laxatives in preventing OIC. The incidence of OIC with prophylactic laxatives in our study (48.1%) was higher than that in the J-RIGID study (33.7%), although the incidences were comparable between our study and the J-RIGID study in those without prophylactic laxatives (48.9% vs 54.6% respectively) [5]. Comparing patient background, performance status was different between these studies. While the J-RIGID study did not include ECOG PS ≥ 3 patients [5], our study included 305 patients (32.9%) with ECOG PS ≥ 3. Our study showed that ECOG PS ≥ 3 is a risk factor for OIC, so difference in performance status may affect the results. In actual clinical settings, performance status of patients receiving strong opioid analgesics vary, from ECOG PS 1 to 4. Therefore, our result is suggested to reflect the real-world clinical practice.
Various types of laxatives are currently available for clinical use. In our study, osmotic laxatives, stimulant laxatives, PAMORA, other types, either alone or in combination, were administered, with osmotic laxatives being utilized in approximately 50% of patients. Recently, PAMORA, including naldemedine, has become part of clinical practice and is recommended for patients with OIC refractory to traditional laxative [11, 12]. Several studies have demonstrated the effectiveness of PAMORA in treating OIC [26, 27], but few studies have investigated the preventive effects of prophylactic laxatives on OIC. Ozaki et al. compared prophylactic naldemedine with prophylactic magnesium oxide in terms of the incidence of OIC. The incidence of OIC was found to be significantly lower in patients receiving naldemedine compared with those receiving prophylactic magnesium oxide. Additionally, they reported that naldemedine significantly prevented the decline in constipation-specific QOL and promoted complete spontaneous bowel movements [28]. However, there has been no investigation into whether the incidence of OIC is significantly lower in patients receiving prophylactic naldemedine compared with those not receiving it. In our study, PAMORA was used as a prophylactic laxative in 24.6% of patients. Although the incidence of OIC in patients with prophylactic naldemedine (36.4%) tended to be lower than in those receiving other treatments (osmotic laxatives 54.9%, stimulant laxatives 43.6%, others 57.1%, and their combinations 47.8%), no statistical difference was found. Therefore, prospective studies are warranted to investigate the preventive effect of naldemedine on OIC.
Several limitations of our study need to be considered. First, it was performed in a single-center, it may be difficult to generalize the findings. Second, our study was a retrospective approach, which may reduce the validity of the data. Although propensity score matching analysis was used to adjust for comparative bias in patient background as much as possible to enhance the level of evidence, an RCT is needed to investigate the more accurate effects of prophylactic laxatives. Third, some studies have reported that transdermal fentanyl and buprenorphine have significantly lower incidence of OIC than slow-release oral morphine [29, 30]. Therefore, the type of opioid analgesics used may affect the preventive effect of prophylactic laxatives on OIC. Some patients in our study had a change in the type of opioid analgesics changed during the observation period. Therefore, we did not perform a subgroup analysis based on the type of opioid analgesics. In the future, studies are needed to investigate whether the incidence of OIC with prophylactic laxatives varies depending on the type of opioid analgesics used. Finally, our data were collected from medical records over an 11-year period, during which several types of laxatives, especially naldemedine, were used.