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

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.

Opioid-induced gastrointestinal side effects, the role of naldemedine in their therapy

“…W znakomitej większości przypadków objawy mają niewielkie natężenie i nie wymagają odstawienia leku [9,12,14]. Skuteczność naldemedyny w leczeniu OIBD udowodniono w licznych badaniach klinicznych, wykazując optymalny profil skuteczności i bezpieczeństwa stosowanego leku.…”

Therapy with PAMORA (peripherally acting μ-opioid receptor antagonists) drugs in patients receiving palliative care

“…The American Society of Gastroenterology recommends the application of naldemedine in patients with OIC and nonresponse to laxatives (strong recommendation, high-quality evidence), naloxegol (strong recommendation, moderate-quality evidence) and methylnaltrexone (conditional recommendation, moderate-quality evidence) [3]. Similarly, ESMO also recommends the use of PAMORA and a combination of opioid with naloxone in the treatment of patients with OIC, non-responding to laxatives (preferred osmotic drugs and rectal nerve plexus stimulants; psyllium sand plantain and other drugs increasing stool volume not recommended) (IIB) [4].…”

“…W pracy przeglądowej opublikowanej w "Palliative Medicine in Practice" 3/2019 autor cytuje przeglądy systematyczne badań klinicznych, w których naldemedynę oceniono, jako lek skuteczny i dobrze tolerowany przez pacjentów oraz jako odpowiedni wybór w leczeniu zaparć wywołanych opioidami u chorych na nowotwory i z innymi schorzeniami [4].…”

“…Amerykańskie Towarzystwo Gastroenterologiczne zaleca stosowanie naldemedyny u chorych z OIC i brakiem odpowiedzi na leki przeczyszczające (silna rekomendacja, wysoka jakość dowodów), naloksegolu (silna rekomendacja, umiarkowana jakość dowodów), a także metylnaltreksonu (warunkowa rekomendacja, umiarkowana jakość dowodów) [3]. Podobnie ESMO zaleca stosowanie PAMORA i połączenia opioidu z naloksonem, jako leczenie u chorych z OIC nieodpowiadającym na leki przeczyszczające (preferowane leki osmotyczne i pobudzające sploty nerwowe jelita grubego, nie zalecane babka płesznik i inne leki zwiększające objętość stolca) (IIB) [4].…”

“…In your overview study published in "Palliative Medicine in Practice" 3/2019 you quote systematic reviews of clinical trials in which naldemedine was assessed as effective and well tolerated by patients and as a suitable choice in the treatment of opioid-induced constipation in patients with cancer and other diseases [4].…”