NICE - naloxegol for opioid - induced constipation

Opioid receptors mu, kappa and delta, belonging to the class of G-protein coupled receptors are expressed widely on gastrointestinal tract with mu receptors seen over intestinal submucosa and ileal mucosa

• whereas kappa and delta receptors predominate in stomach and proximal colon
  
  
• predominant actions of opioids on gastrointestinal tract are mediated by mu receptors located prejunctional modulating the release of acetylcholine and on postjunctional receptors decrease the release of neurotransmitters and inhibit calcium channels
• this leads to delay in intestinal transit leading to a decrease in peristalsis, inhibit gastric emptying; also leads to a reduction in mucosal secretions
  • effects are complicated wherein opioids also stimulate non-propulsive motility and increase the tone of anal sphincters and segmentation in intestines, facilitating fluid absorption from intestines
  • these effects result in the development of constipation, to which there is no development of tolerance even on chronic use

Naloxegol (NKTR-118) is a novel PEGylated form of naloxol, a naloxone analog

• strong selectivity (more than 6000 folds) toward peripheral mu receptors and has been approved as first oral Peripheral Acting Mu Opioid Receptor Antagonists (PAMORAs) for opioid induced constipation (OIC) due to use of opioids for non-cancer pain

NICE state (3):

• Naloxegol is recommended, within its marketing authorisation, as an option for treating opioid induced constipation in adults whose constipation has not adequately responded to laxatives
  
  
  • an inadequate response is defined as opioid-induced constipation symptoms of at least moderate severity in at least 1 of the 4 stool symptom domains (that is, incomplete bowel movement, hard stools, straining or false alarms) while taking at least 1 laxative class for at least 4 days during the prior 2 weeks.

Reference:

• Holzer P. Opioid receptors in the gastrointestinal tract. Regul Pept. 2009;155:11-7.
• Chey WD, Webster L, Sostek M, Lappalainen J, Barker PN, Tack J. Naloxegol for opioid-induced constipation in patients with non-cancer pain. N Engl J Med. 2014;370:2387-96
• NICE (July 2015). Naloxegol for treating opioid-induced constipation