Naldemedine in Japanese patients with opioid-induced constipation and chronic noncancer pain: open-label Phase III studies

Saito, Yoji; Yokota, Takaaki; Arai, Masatsugu; Tada, Yukio; Sumitani, Masahiko

doi:10.2147/jpr.s175900

Cited by 22 publications

(25 citation statements)

References 22 publications

(27 reference statements)

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“…Significant and sustained improvements in PAC-SYM and PAC-QOL scores were also observed in both studies (all p < 0.05). AE of naldemedine were mostly mild or moderate in severity, and the results suggest that naldemedine improve bowel function and QOL in Japanese patients with OIC receiving regular-use opioids or PR oxycodone for chronic noncancer pain [31].…”

Section: Studies In Non-cancer Patientsmentioning

confidence: 80%

“…In two open-label, single-arm, Phase III studies, the safety and efficacy of naldemedine was assessed in Japanese patients with OIC receiving regular-use opioids (COMPOSE-6) or PR oxycodone (COMPOSE-7) for chronic noncancer pain [31]. Eligible Japanese adults with OIC and chronic noncancer pain received once-daily oral naldemedine 0.2 mg for 48 weeks, irrespective of food intake.…”

Section: Studies In Non-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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Section: Studies In Non-cancer Patientsmentioning

confidence: 80%

Section: Studies In Non-cancer Patientsmentioning

confidence: 99%

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

Leppert

2019

Palliat Med Pract

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“…28 These were followed by two long-term studies from Japan, COMPOSE-6 and COMPOSE-7, which enrolled chronic noncancer pain patients for 48 weeks (43 and 10 patients, respectively). 29 Treatment-emergent adverse events occurred in 88% and 90% of patients, respectively. Pain relief and symptoms of opioid withdrawal were stable in patients over the course of the study.…”

Section: The Compose Suite Of Studiesmentioning

confidence: 99%

“…Responders based on frequency of bowel movements were 81.0% in COMPOSE-6 (95% confidence interval, 65.9-91.4%) and 90.0% in COMPOSE-7 (95% confidence interval, 55.5-99.7%). 29…”

Section: The Compose Suite Of Studiesmentioning

confidence: 99%

<p>The Use of Peripheral μ-Opioid Receptor Antagonists (PAMORA) in the Management of Opioid-Induced Constipation: An Update on Their Efficacy and Safety</p>

Pergolizzi

Christo

LeQuang

et al. 2020

DDDT

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Peripherally acting μ-opioid receptor antagonists (PAMORAs) constitute a class of drugs which reverse opioid-induced constipation (OIC) with similar opioid analgesic effects. OIC differs from other forms of constipation in that it is an iatrogenic condition that occurs when an opioid acts on the dense network of μ-opioid receptors in the enteric system, which affect a variety of functions including gastrointestinal motility, secretion, and other factors that can cause bowel dysfunction. Unfortunately, laxative products, bowel regimens, dietary changes, and lifestyle modifications have limited effectiveness in preventing OIC, Opioidassociated adverse effect which occurs in 40% to 80% of opioid patients and may led to cessation of the treatment. PAMORAs are μ-receptor opioid antagonists specifically developed so that they have very limited ability to cross the blood-brain barrier and thus they are able to antagonize peripheral but not central μ-opioid receptors. PAMORAs are designed to have no effect on the analgesic benefits of opioid pain relievers but to relieve but antagonizing the effects of the opioid in the gastrointestinal system. The three main PAMORAS are methyltrexone (oral or parenteral), naldemedine (oral only), and naloxegol (oral only). Clinical studies demonstrate the safety and efficacy of these agents for alleviating constipation without diminishing the analgesic effect of opioid therapy. The aim of this narrative review to update the current status of PAMORAs for treating OIC in terms of safety and efficacy.

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“…Naldemedine is indicated for the treatment of OIC, as a once-daily oral drug at a dose of 0.2 mg, in adult patients with chronic non-cancer pain in US, in patients with chronic non-cancer pain and cancer in Japan, and in adult patients who have previously been treated with a laxative in the EU. The effectiveness of naldemedine was established in seven phase III randomized, double-blind and placebo-controlled trials of 0.2 mg once-daily treatment for patients with non-cancer pain or cancer pain (Hale M et al, 2017;Webster LR et al, 2018;Katakami N et al, 2017;Saito Y et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Profile of Naldemedine, a Peripherally Actingμ-Opioid Receptor Antagonist: Comparison with Naloxone and Naloxegol

Kanemasa

Koike

Takase

et al. 2020

J Pharmacol Exp Ther

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Opioid-induced constipation (OIC), a typical side effect of opioids, is due to activation of the μ-opioid receptors in the enteric nervous system. Peripherally acting μ-opioid receptor antagonists (PAMORAs) can reverse OIC by inhibiting the peripheral action of opioids without affecting centrally mediated analgesia. Naldemedine is a PAMORA with potent antagonist activity against μ-, δ-, and κ-opioid receptors. In this study, the pharmacological profiles of naldemedine, compared to those of naloxone and naloxegol, were evaluated. In vitro, Schild plot analysis indicated that naldemedine was a noncompetitive antagonist of μ-opioid receptors, while other compounds were competitive antagonists. Also, naldemedine showed slower association and dissociation kinetics than the other compounds. In vivo, naldemedine dose-dependently ameliorated morphine-induced inhibition of small intestinal transit (SIT). The dose response curve was not shifted at 1 and 3 mg/kg morphine. On the contrary, that of naloxegol was significantly shifted to the right from 1 to 3 mg/kg morphine. In morphine-dependent rats, naldemedine caused peripheral withdrawal symptoms (diarrhea) at doses higher than 1 mg/kg, while the dose that produced half the maximal preventive effect (ED 50) against constipation was 0.03 mg/kg. Naldemedine showed slower onset and a lesser severity of diarrhea than the other compounds at close to the ED50 value in the SIT model. Our results reveal that naldemedine has different pharmacological profiles (type of antagonism and binding kinetics) to the other compounds. This might explain the differential inhibition of morphine-induced SIT and withdrawal symptoms among the three antagonist compounds. Significance Statement Naldemedine is a novel PAMORA with potent antagonist activity against μ-, δ-, and κ-opioid receptors. Naldemedine showed a non-competitive antagonism and slower association and dissociation kinetics against μ-opioid receptors than naloxone and naloxegol. Naldemedine showed insurmountable antagonism of morphine-induced SIT inhibition and lower and slower peripheral withdrawal symptoms (diarrhea) than the other compounds. Therefore, naldemedine has a different pharmacological profile (the type of antagonism and binding kinetics) to the other compounds.

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Naldemedine in Japanese patients with opioid-induced constipation and chronic noncancer pain: open-label Phase III studies

Cited by 22 publications

References 22 publications

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

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

<p>The Use of Peripheral μ-Opioid Receptor Antagonists (PAMORA) in the Management of Opioid-Induced Constipation: An Update on Their Efficacy and Safety</p>

Pharmacological Profile of Naldemedine, a Peripherally Actingμ-Opioid Receptor Antagonist: Comparison with Naloxone and Naloxegol

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