Naloxegol Explained

Naloxegol (INN; PEGylated naloxol;[1] trade names Movantik and Moventig) is a peripherally acting μ-opioid receptor antagonist developed by AstraZeneca, licensed from Nektar Therapeutics, for the treatment of opioid-induced constipation.[2] It was approved in 2014 in adult patients with chronic, non-cancer pain.[3] Doses of 25 mg were found safe and well tolerated for 52 weeks.[4] When given concomitantly with opioid analgesics, naloxegol reduced constipation-related side effects, while maintaining comparable levels of analgesia.[5]

The most common side effects are abdominal pain, diarrhea, nausea, flatulence, vomiting, and headache.

Naloxegol was previously a Schedule II drug in the United States because of its chemical similarity to opium alkaloids. It was officially decontrolled in January 2015. It was reclassified as a prescription drug after the FDA and DEA concluded that the impermeability of the blood–brain barrier to this compound made it non-habit-forming, and so without the potential for abuse.[6]

Medical use

Naloxegol is indicated for the treatment of opioid-induced constipation (OIC) in people with chronic non-cancer pain.[7] [8]

Side effects

The most common side effects are abdominal pain, diarrhea, nausea, flatulence, vomiting, and headache.

Pharmacodynamic properties

Naloxegol inhibits opioid binding in μ-opioid receptors in the gastrointestinal tract, thus decreasing the constipating effects (slowing of gastrointestinal motility and transit, hypertonicity, increased fluid reabsorption) associated with opioids.[9]

If naloxegol is coadministered with other opioid antagonists, there is a potential for additive effect and increased risk of opioid withdrawal.

Mechanism of action

Chemically, naloxegol is a pegylated (polyethylene glycol-modified) derivative of α-naloxol. Specifically, the 6-α-hydroxyl group of α-naloxol is connected via an ether linkage to the free hydroxyl group of a monomethoxy-terminated n=7 oligomer of PEG, shown extending at the lower left of the molecule image at right. The "n=7" defines the number of two-carbon ethylenes, and so the chain length, of the attached PEG chain, and the "monomethoxy" indicates that the terminal hydroxyl group of the PEG is "capped" with a methyl group.[10] The pegylation of the 6-α-hydroxyl side chain of naloxol prevents the drug from crossing the blood–brain barrier (BBB).[5]

Notes and References

  1. Book: Seifert R, Wieland T, Mannhold R, Kubinyi H, Folkers G . G Protein-Coupled Receptors as Drug Targets: Analysis of Activation and Constitutive Activity . 14 May 2012 . 17 July 2006 . John Wiley & Sons . 978-3-527-60695-5 . 227.
  2. Web site: Nektar | R&D Pipeline | Products in Development | CNS/Pain | Oral Naloxegol (NKTR-118) and Oral NKTR-119 . 2012-05-14 . dead . https://web.archive.org/web/20120213133752/http://www.nektar.com/product_pipeline/cns_pain_oral_nktr-118and119.html . 2012-02-13 .
  3. News: FDA approves MOVANTIK™ (naloxegol) Tablets C-II for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain. 16 September 2014. https://web.archive.org/web/20150510025921/http://www.astrazeneca-us.com/media/press-releases/Article/20140916-fda-approves-movantik-naloxegol-tablets-cii. 2015-05-10. live.
  4. Webster L, Chey WD, Tack J, Lappalainen J, Diva U, Sostek M . Randomised clinical trial: the long-term safety and tolerability of naloxegol in patients with pain and opioid-induced constipation . Alimentary Pharmacology & Therapeutics . 40 . 7 . 771–9 . October 2014 . 25112584 . 10.1111/apt.12899 . 34286557 . free .
  5. Garnock-Jones KP . Naloxegol: a review of its use in patients with opioid-induced constipation . Drugs . 75 . 4 . 419–25 . March 2015 . 25666542 . 10.1007/s40265-015-0357-2 . 207488539 .
  6. Web site: Schedules of Controlled Substances: Removal of Naloxegol From Control. www.deadiversion.usdoj.gov. 2016-02-27. https://web.archive.org/web/20160309173010/http://www.deadiversion.usdoj.gov/fed_regs/rules/2015/fr0123_3.htm. 2016-03-09. live.
  7. Web site: Movantik prescribing information highlights. 2019-08-14.
  8. Web site: Naloxegol for Opioid-Induced Constipation in Patients with Noncancer Pain .
  9. Garnock-Jones KP . Naloxegol: a review of its use in patients with opioid-induced constipation . Drugs . 75 . 4 . 419–25 . March 2015 . 25666542 . 10.1007/s40265-015-0357-2 . 207488539 .
  10. Technically, the molecule that is attached via the ether link is O-methyl-heptaethylene glycol [that is, methoxyheptaethylene glycol, CH<sub>3</sub>OCH<sub>2</sub>CH<sub>2</sub>O(CH<sub>2</sub>CH<sub>2</sub>O)<sub>5</sub>CH<sub>2</sub>CH<sub>2</sub>OH], molecular weight 340.4, CAS number 4437-01-8. See Book: https://pubchem.ncbi.nlm.nih.gov/compound/4437-01-8#section=Top. PubChem Compound Database . NCBI, U.S. NLM. 2016. Bethesda, MD . Compound Summary for CID 526555, Pubchem Compound 4437-01. 28 January 2016. https://web.archive.org/web/20160205030929/http://pubchem.ncbi.nlm.nih.gov/compound/4437-01-8#section=Top#section=Top. 2016-02-05. live.

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