open access

Vol 13, No 3 (2019)
Review paper
Published online: 2019-09-13
Get Citation

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

Wojciech Leppert1
·
Palliat Med Pract 2019;13(3):113-122.
Affiliations
  1. Laboratory of Quality of life Research, Poznan University of Medical Sciences, Poznan, Poland

open access

Vol 13, No 3 (2019)
Review paper
Published online: 2019-09-13

Abstract

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. Palliat Med Pract 2019; 13, 3: 113–128

Abstract

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. Palliat Med Pract 2019; 13, 3: 113–128

Get Citation

Keywords

adverse effects, naldemedine, opioid–induced bowel dysfunction; opioid-induced constipation; PAMORA

About this article
Title

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

Journal

Palliative Medicine in Practice

Issue

Vol 13, No 3 (2019)

Article type

Review paper

Pages

113-122

Published online

2019-09-13

Page views

838

Article views/downloads

763

DOI

10.5603/PMPI.2019.0015

Bibliographic record

Palliat Med Pract 2019;13(3):113-122.

Keywords

adverse effects
naldemedine
opioid–induced bowel dysfunction
opioid-induced constipation
PAMORA

Authors

Wojciech Leppert

References (43)
  1. Brock C, Olesen S, Olesen A, et al. Opioid-Induced Bowel Dysfunction. Drugs. 2012; 72(14): 1847–1865.
  2. Reimer K, Hopp M, Zenz M, et al. Meeting the challenges of opioid-induced constipation in chronic pain management - a novel approach. Pharmacology. 2009; 83(1): 10–17.
  3. Olesen AE, Drewes AM. Validated tools for evaluating opioid-induced bowel dysfunction. Adv Ther. 2011; 28(4): 279–294.
  4. Abramowitz L, Béziaud N, Caussé C, et al. Further validation of the psychometric properties of the Bowel Function Index for evaluating opioid-induced constipation (OIC). J Med Econ. 2013; 16(12): 1434–1441.
  5. Marquis P, De La Loge C, Dubois D, et al. Development and validation of the Patient Assessment of Constipation Quality of Life questionnaire. Scand J Gastroenterol. 2005; 40(5): 540–551.
  6. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol. 1997; 32(9): 920–924.
  7. Chojnacki J. Itopride in the treatment of kinetic disorders of gastrointestinal tract. Gastroenterology Review. 2011; 3: 139–145.
  8. Bouras EP, Camilleri M, Burton DD, et al. Prucalopride accelerates gastrointestinal and colonic transit in patients with constipation without a rectal evacuation disorder. Gastroenterology. 2001; 120(2): 354–360.
  9. Tack J, van Outryve M, Beyens G, et al. Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives. Gut. 2009; 58(3): 357–365.
  10. Thayalasekeran S, Ali H, Tsai HH. Novel therapies for constipation. World J Gastroenterol. 2013; 19(45): 8247–8251.
  11. Cuppoletti J, Chakrabarti J, Tewari K, et al. Methadone but not morphine inhibits lubiprostone-stimulated Cl- currents in T84 intestinal cells and recombinant human ClC-2, but not CFTR Cl- currents. Cell Biochem Biophys. 2013; 66(1): 53–63.
  12. Müller-Lissner S. Pharmacokinetic and pharmacodynamic considerations for the current chronic constipation treatments. Expert Opin Drug Metab Toxicol. 2013; 9(4): 391–401.
  13. Busby RW, Kessler MM, Bartolini WP, et al. Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. J Pharmacol Exp Ther. 2013; 344(1): 196–206.
  14. Larkin PJ, Sykes NP, Centeno C, et al. European Consensus Group on Constipation in Palliative Care. The management of constipation in palliative care: clinical practice recommendations. Palliat Med. 2008; 22(7): 796–807.
  15. Holzer P, Ahmedzai SH, Niederle N, et al. Opioid-induced bowel dysfunction in cancer-related pain: causes, consequences, and a novel approach for its management. J Opioid Manag. 2009; 5(3): 145–151.
  16. Meissner W, Schmidt U, Hartmann M, et al. Oral naloxone reverses opioid-associated constipation. Pain. 2000; 84(1): 105–109.
  17. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med. 2008; 358(22): 2332–2343.
  18. Ford AC, Brenner DM, Schoenfeld PS. Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: systematic review and meta-analysis. Am J Gastroenterol. 2013; 108(10): 1566–74; quiz 1575.
  19. Webster L, Dhar S, Eldon M, et al. A phase 2, double-blind, randomized, placebo-controlled, dose-escalation study to evaluate the efficacy, safety, and tolerability of naloxegol in patients with opioid-induced constipation. Pain. 2013; 154(9): 1542–1550.
  20. Chey WD, Webster L, Sostek M, et al. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med. 2014; 370(25): 2387–2396.
  21. Blair HA. Naldemedine: A Review in Opioid-Induced Constipation. Drugs. 2019; 79(11): 1241–1247.
  22. Kanemasa T, Koike K, Arai T, et al. Pharmacologic effects of naldemedine, a peripherally acting μ-opioid receptor antagonist, in in vitro and in vivo models of opioid-induced constipation. Neurogastroenterol Motil. 2019; 31(5): e13563.
  23. Watari R, Matsuda A, Ohnishi S, et al. Minimal contribution of P-gp on the low brain distribution of naldemedine, a peripherally acting μ-opioid receptor antagonist. Drug Metab Pharmacokinet. 2019; 34(2): 126–133.
  24. Kubota R, Fukumura K, Wajima T. Population Pharmacokinetics and Exposure-Response Relationships of Naldemedine. Pharm Res. 2018; 35(11): 225.
  25. Fukumura K, Yamada T, Yokota T, et al. The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Naldemedine. Clin Pharmacol Drug Dev. 2019 [Epub ahead of print].
  26. Rizmoic. Summary of Product Characteristics. https://www.ema.europa.eu/en/documents/product-information/rizmoic-epar-product-information_en.pdf (6.09.2019).
  27. Webster LR, Yamada T, Arjona Ferreira JC. A Phase 2b, Randomized, Double-Blind Placebo-Controlled Study to Evaluate the Efficacy and Safety of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Chronic Noncancer Pain. Pain Med. 2017; 18(12): 2350–2360.
  28. Katakami N, Oda K, Tauchi K, et al. Phase IIb, Randomized, Double-Blind, Placebo-Controlled Study of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients With Cancer. J Clin Oncol. 2017; 35(17): 1921–1928.
  29. Hale M, Wild J, Reddy J, et al. Naldemedine versus placebo for opioid-induced constipation (COMPOSE-1 and COMPOSE-2): two multicentre, phase 3, double-blind, randomised, parallel-group trials. Lancet Gastroenterol Hepatol. 2017; 2(8): 555–564.
  30. Webster LR, Nalamachu S, Morlion B, et al. Long-term use of naldemedine in the treatment of opioid-induced constipation in patients with chronic noncancer pain: a randomized, double-blind, placebo-controlled phase 3 study. Pain. 2018; 159(5): 987–994.
  31. Saito Y, Yokota T, Arai M, et al. Naldemedine in Japanese patients with opioid-induced constipation and chronic noncancer pain: open-label Phase III studies. J Pain Res. 2019; 12: 127–138.
  32. Wild J, Yamada T, Arjona Ferreira JC, et al. Onset of action of naldemedine in the treatment of opioid-induced constipation in patients with chronic noncancer pain: results from 2 randomized, placebo-controlled, phase 3 trials. Pain. 2019 [Epub ahead of print].
  33. Katakami N, Harada T, Murata T, et al. Randomized Phase III and Extension Studies of Naldemedine in Patients With Opioid-Induced Constipation and Cancer. J Clin Oncol. 2017; 35(34): 3859–3866.
  34. Katakami N, Harada T, Murata T, et al. Randomized phase 3 and extension studies. Efficacy and impacts on quality of life of naldemedine in subjects with opioid-induced constipation and cancer. Ann Oncol. 2018 [Epub ahead of print].
  35. Osaka I, Ishiki H, Yokota T, et al. Safety and efficacy of naldemedine in cancer patients with opioid-induced constipation: a pooled, subgroup analysis of two randomised controlled studies. ESMO Open. 2019; 4(4): e000527.
  36. Leppert W. Emerging therapies for patients with symptoms of opioid-induced bowel dysfunction. Drug Des Devel Ther. 2015; 9: 2215–2231.
  37. Leppert W, Woron J. The role of naloxegol in the management of opioid-induced bowel dysfunction. Therap Adv Gastroenterol. 2016; 9(5): 736–746.
  38. Stern EK, Brenner DM. Spotlight on naldemedine in the treatment of opioid-induced constipation in adult patients with chronic noncancer pain: design, development, and place in therapy. J Pain Res. 2018; 11: 195–199.
  39. Dzierżanowski T. The role of peripherally acting mu-opioid receptor antagonists (PAMORA) in the treatment of constipation in palliative care. Palliative Medicine. 2019; 11(2): 51–57.
  40. Larkin PJ, Cherny NI, La Carpia D, et al. ESMO Guidelines Committee. Diagnosis, assessment and management of constipation in advanced cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2018; 29(Suppl 4): iv111–iv125.
  41. Leppert W, Dzierżanowski T, Stachowiak A, et al. Constipation in cancer patients – the management recommendations of the Expert Group of the Polish Association for Palliative Medicine. Med Paliat. 2014; 6: 1–10.
  42. Luthra P, Burr NE, Brenner DM, et al. Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: systematic review and network meta-analysis. Gut. 2018 [Epub ahead of print].
  43. Esmadi M, Ahmad D, Hewlett A. Efficacy of naldemedine for the treatment of opioid-induced constipation: A meta-analysis. J Gastrointestin Liver Dis. 2019; 28(1): 41–46.

Regulations

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

By VM Media Group sp. z o.o., ul. Świętokrzyska 73 , 80–180 Gdańsk, Poland

phone:+48 58 320 94 94, fax:+48 58 320 94 60, e-mail: viamedica@viamedica.pl