Real-World Evidence for the Safety and Effectiveness of Naldemedine in the Management of Opioid-Induced Constipation in Patients With Cancer Pain: Post-hoc Subgroup Analysis of Post-marketing Surveillance in Japan

Abstract

Background: Opioid-induced constipation is common and greatly affects the quality of life but is often under-recognised and undertreated. This study aimed to investigate the safety and effectiveness of naldemedine for opioid-induced constipation with cancer pain according to specific subgroups of clinical interest.Methods: In this exploratory post-hoc subgroup analysis of post-marketing surveillance from Japan (UMIN: 000042851), data were investigated by the subgroups: age (≥75, <75 years), Eastern Cooperative Oncology Group performance status (PS 0-2, 3-4), constipation severity (mild, moderate, severe), brain metastasis (yes, no), anticancer drug treatment (yes, no), opioid at naldemedine initiation (fentanyl only, only strong opioids other than fentanyl, weak opioids only, other), and prior or concomitant use of laxative (only osmotic/saline laxatives, only stimulant laxatives, other, none). Enrolled patients (n = 1184) received naldemedine (0.2 mg once daily) orally for up to 12 weeks. Regarding safety endpoints, the incidence of adverse drug reactions, including diarrhoea, was determined within each subgroup. Regarding effectiveness endpoints, improvement rates in the frequency and condition of bowel movements were investigated by subgroups.Results: The incidence of adverse drug reactions, including diarrhoea, among subgroups ranged from 7.74% to 16.08% (diarrhoea: 5.95% to 13.19%), compared to 11.30% (diarrhoea: 9.09%) in the total population. Through week two to week 12, improvement rates in the frequency and condition of bowel movement among subgroups ranged from 63.6% to 89.7% and 67.6% to 94.9%, compared to 75.0% to 83.2% and 80.0% to 88.0% in the total population, respectively.Conclusions: Naldemedine was well tolerated and effective in patients with opioid-induced constipation and cancer pain regardless of the subgroups investigated.

A Systematic Review of Naldemedine and Naloxegol for the Treatment of Opioid-Induced Constipation in Cancer Patients

“…Only five of the studies were randomized blinded placebo-controlled studies [ 32 , 33 , 38 , 39 , 40 ], two of which were unable to enroll sufficient participants [ 32 , 33 ]. The other seven studies were all non-interventional prospective open label extension/post-marketing surveillance studies [ 41 , 42 , 43 , 44 , 45 , 46 , 47 ], and therefore the quality of most of the discussed studies was not very high.…”

“…Table 2 describes the three randomized placebo-controlled trials included in this review for naldemedine [ 38 , 39 , 40 ], as well as results from a pooled subgroup analysis of patients from both 2017 Katakami studies [ 14 ] and two post-marketing surveillance studies of naldemidine [ 42 , 43 ]. It also details the six studies included for nalexogol, of which two were unsuccessful randomized controlled clinical studies due to insufficient enrollment [ 32 , 33 ], and four were non-interventional prospective observational studies in cancer patients lasting between 4 weeks and 1 year [ 44 , 45 , 46 , 47 ].…”

“…However, we reviewed all in the absence of any better evidence, as our clinical question was about use of PAMORAs specificially in cancer patients with OIC. The ‘real world’ studies were also the only studies able to follow patients taking PAMORAs over a longer period of time, While the RCTs only administered the study drug for two weeks [ 33 , 38 , 39 , 40 ], the ‘real world’ open label extension studies were either up to four weeks [ 45 , 46 ], three months [ 39 , 40 , 41 , 42 , 43 , 44 ] or even up to one year [ 47 ] long.…”

“…Most studies were conducted in Japan [ 38 , 39 , 40 , 41 , 42 , 43 ], and some in Europe [ 44 , 45 , 46 , 47 ], while the few studies conducted in the US [ 32 , 33 ] were unable to recruit enough participants; therefore, it is not clear if results would be fully applicable to patients in North America.…”

“…Naya N, 2023, Cureus, Japan [43] Non-interventional exploratory post hoc subgroup analysis of post-marketing surveillance, same dataset as [42] naldemedine 0. OIC = opioid-induced constipation, SBM = spontaneous bowel movement, CBSM = complete spontaneous bowel movement, AE = adverse events, TEAE = treatment emergent adverse events, NRS = numerical rating scale, COWS = clinical opioid withdrawal scale, ECOG = Eastern Cooperative Oncology Group (assessment of functional status), PAC-SYM stool domain = patient assessment of constipation-symptoms, PAC-QOL dissatisfaction domain = patient assessment of constipation-quality of life, QoL = quality of life.…”