Safety and efficacy of naldemedine in cancer patients with opioid-induced constipation: a pooled, subgroup analysis of two randomised controlled studies

Osaka, Iwao; Ishiki, Hiroto; Yokota, Takaaki; Tada, Yukio; Sato, Hiroki; Okamoto, Masaharu; Satomi, Eriko

doi:10.1136/esmoopen-2019-000527

Cited by 26 publications

(30 citation statements)

References 16 publications

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“…It is anticipated that a limited opioid withdrawal response inside the intestinal tract could result from this inhibition by NAL administration. In phase III clinical trials, a significant difference in the clinical opioid withdrawal scale (COWS) was not observed in patients receiving or not receiving NAL [ 6 , 9 ]. Although COWS is a rating scale evaluating both central and peripheral withdrawal symptoms, it is mainly intended for central withdrawal symptoms.…”

Section: Discussionmentioning

confidence: 99%

Opioid therapy duration before naldemedine treatment is a significant independent risk of diarrhea: a retrospective cohort study

Okamoto

Ikemura

Mizutani

et al. 2021

J Pharm Health Care Sci

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Background The most common adverse event (AE) associated with opioid analgesics is opioid-induced constipation (OIC). Naldemedine (NAL) is widely used for the treatment of OIC. However, diarrhea has been reported as the most common treatment-emergent AE of NAL, and little is known about the risk factors associated with the development of diarrhea during NAL administration. This study examined the risk factors for NAL-induced diarrhea via a retrospective chart review of hospitalized patients. Methods The data of 101 hospitalized adult patients who received NAL for the first time for the treatment of OIC at Mie University Hospital between June 2017 and December 2018 were extracted from electronic medical records. According to the inclusion and exclusion criteria, 70 of the 101 patients were enrolled in this study. Diarrhea was defined as “diarrhea” on the medical record within 2 weeks of NAL administration. Univariate and multivariate analyses were performed to identify risk factors for the development of diarrhea in patients receiving NAL. Results Twenty-two of the 70 patients enrolled (31%) developed diarrhea within 2 weeks of NAL administration. The median duration (range) of NAL treatment before diarrhea onset was 3 (1–12) days. Patients with diarrhea had a significantly longer duration of opioid therapy before NAL administration than patients without diarrhea (P=0.002). Multivariate logistic regression analysis indicated that the independent risk factors for the development of NAL-induced diarrhea were NAL administration after more than 17 days of opioid therapy (odds ratio [OR]=7.539; P=0.016) and pancreatic cancer (OR=6.217; P=0.025). In fact, the incidence of diarrhea in patients who were administered NAL within a day of opioid therapy was significantly lower than that in patients who were administered NAL after more than 17 days of opioid therapy (13% vs. 54%, P=0.030). Conclusions These results suggested that a prolonged duration of opioid therapy prior to NAL initiation is associated with increased incidence of diarrhea.

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Section: Discussionmentioning

confidence: 99%

Opioid therapy duration before naldemedine treatment is a significant independent risk of diarrhea: a retrospective cohort study

Okamoto

Ikemura

Mizutani

et al. 2021

J Pharm Health Care Sci

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“…Naldemedine was approved for OIC treatment based on the outcomes of this long-term study. Multiple studies show that naldemedine is effective and safe to use in cancer patients as well [ 26 - 27 ].…”

Section: Reviewmentioning

confidence: 99%

Opioid-Induced Constipation in Advanced Cancer Patients

ALMouaalamy

2021

Cureus

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The present study discusses opioid-induced constipation (OIC) in advanced cancer patients, focusing on the OIC definition, pathophysiology, and treatment. OIC is any change from baseline defecation patterns and bowel habits that developed after starting opioid therapy. The condition is characterized by bowel frequency reduction, worsening or development of straining, a sensation of incomplete defecation, or distress associated with bowel habits. OIC is common in advanced cancer patients, with a prevalence of approximately 51%-87% in patients taking opioids for pain management. Patients are likely to experience severe distress, work productivity reduction, poor quality of life, and increased healthcare utilization. OIC has a complex pathophysiology that involves propulsive and peristalsis impairment, intestinal mucosal secretion inhibition, intestinal fluid absorption enhancement, and anal sphincters function impairment. The Rome III criteria are used to assess and diagnose clinical OIC and can also be diagnosed through the Patient Assessment of Constipation (PAC) measures, including the symptom survey (PAC-SYM) and quality of life survey (PAC-QOL). Non-pharmacological treatment of OIC involves lifestyle habits and dietary adjustments, although these interventions might be insufficient to manage the condition. Pharmacological treatments involve the use of traditional laxatives and newer agents like peripherally acting mu-opioid receptor agonists (PAMORAs), including naldemedine, naloxegol, and methylnaltrexone. More novel treatments for OIC that target the pathophysiology are still needed and should be studied carefully for safety and efficacy.

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“…Greater proportions of SBM responders and patients who experienced diarrhea were observed with naldemedine vs. placebo in all subgroups. Changes from baseline in NRS and COWS scores were similar with naldemedine or placebo in patients with or without brain metastases [35].…”

Section: Studies In Cancer Patientsmentioning

confidence: 73%

“…Although not powered to detect statistically significant differences in treatment effect among subgroups, this study demonstrated that naldemedine appeared to benefit cancer patients with OIC and cancer, irrespective of baseline characteristics, and did not seem to affect analgesia or withdrawal even in patients with potential BBB disruptions. Baseline characteristics did not appear to affect the incidence of diarrhea in patients who received naldemedine [35].…”

Section: Studies In Cancer Patientsmentioning

confidence: 82%

“…In a post-hoc, pooled, subgroup analysis [35] of two randomized studies [28,33] baseline characteristics was evaluated that may influence the efficacy and safety of naldemedine in patients with OIC and cancer [35]. Data for patients who received 0.2 mg naldemedine or placebo were pooled from randomized, placebo-controlled, phase IIb and phase III studies.…”

Section: Studies In Cancer Patientsmentioning

confidence: 99%

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The role of naldemedine in the treatment of patients with opioid-induced constipation

Leppert

2019

Palliat Med Pract

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Opioid-induced bowel dysfunction (OIBD) and opioid-induced constipation (OIC) significantly decrease patients' quality of life (QoL), lead to complications and opioid non-compliance resulting in pain exacerbation. Traditional laxatives are first-line preventive and therapeutic measures, although they display limited efficacy and several adverse effects (AE). Non-pharmacology measures, prokinetics, opioid switch, all have little evidence and do not target OIBD and OIC pathophysiology both associated with activation of predominantly µ-opioid receptors mostly peripherally in the gastrointestinal (GI) tract. A combination of prolonged-release (PR) oxycodone with PR naloxone in one tablet with a ratio of 2:1 is available, although limitations include maximal daily dose of 160 mg/80 mg, respectively, and normal liver function. Peripherally acting µ-opioid receptor antagonists (PAMORA) block opioid receptors in the GI tract without compromising analgesia as they do not cross the blood-brain barrier. Currently three drugs are available: methylnaltrexone, naloxegol and naldemedine. Naldemedine has proven efficacy superior to placebo in the treatment of OIC in both cancer and non-cancer patients while improving patient-reported constipation symptoms and patients' QoL. It is well tolerated with mostly mild to moderate intensity GI adverse effects such as abdominal, pain, nausea, and diarrhea, without compromising analgesia. Naldemedine dosing is convenient as it is administered once daily by an oral route. Moreover, naldemedine may be safely used in patients with renal failure and mild to moderate hepatic impairment. Effective prevention and treatment of OIC is of paramount importance in patients receiving long-term opioid therapy.

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Safety and efficacy of naldemedine in cancer patients with opioid-induced constipation: a pooled, subgroup analysis of two randomised controlled studies

Cited by 26 publications

References 16 publications

Opioid therapy duration before naldemedine treatment is a significant independent risk of diarrhea: a retrospective cohort study

Opioid therapy duration before naldemedine treatment is a significant independent risk of diarrhea: a retrospective cohort study

Opioid-Induced Constipation in Advanced Cancer Patients

The role of naldemedine in the treatment of patients with opioid-induced constipation

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