Naloxegol for Opioid-Induced Constipation in Patients with Noncancer Pain

Chey, William D.; Webster, Lynn R.; Sostek, Mark; Lappalainen, Jaakko; Barker, Peter; Tack, Jan

doi:10.1056/nejmoa1310246

Cited by 295 publications

(438 citation statements)

References 17 publications

Supporting

Mentioning

406

Contrasting

Unclassified

Order By: Relevance

“…Peripheral agonists, such as loperamide and asimadoline, for example, have been developed for the treatment of diarrhea and irritable bowel syndrome, respectively (asimadoline: Mangel et al, 2008; Loperamide: Mainguet and Fiasse, 1977;Shannon and Lutz, 2002). Peripherally acting antagonists, on the other hand, such as methylnaltrexone (Yuan and Foss, 2000) and naloxegol, a pegylated form of naloxol (Chey et al, 2014), can block some of the peripheral side effects of centrally acting agonists. We have described a neutral antagonist of the m-opioid receptor 6b-naltrexol, which can alleviate opiate-induced constipation in rodents and humans (Yancey-Wrona et al, 2009.…”

Section: Introductionmentioning

confidence: 99%

Preferential Delivery of an Opioid Antagonist to the Fetal Brain in Pregnant Mice

Oberdick

Ling

Phelps

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Prolonged fetal exposure to opioids results in neonatal abstinence syndrome (NAS), a major medical problem requiring intensive care and increased hospitalization times for newborns with NAS. Multiple strategies are currently available to alleviate withdrawal in infants with NAS. To prevent NAS caused by opioid maintenance programs in pregnant women, blocking fetal dependence without compromising the mother's opiate therapy is desirable. Here we tested in pregnant mice whether a peripherally selective opioid antagonist can preferentially enter the fetal brain and, thereby, in principle, selectively protect the fetus. We show using mass spectrometry that 6b-naltrexol, a neutral opioid antagonist with very limited ability to cross the bloodbrain barrier (BBB), readily crosses the placental barrier and enters the fetal brain at high levels, although it is relatively excluded from the maternal brain. Furthermore, owing to the late development of the BBB in postnatal mice, we show that 6b-naltrexol can readily enter the juvenile mouse brain until at least postnatal day 14. Taking advantage of this observation, we show that long-term exposure to morphine starting in the second postnatal week causes robust and quantifiable dependence behaviors that are suppressed by concomitant administration of 6b-naltrexol with much greater potency (ID 50 0.022-0.044 mg/kg, or 1/500 the applied dose of morphine) than previously demonstrated for either the suppression of central nervous system opioid effects or the induction of withdrawal in adults. These results indicate that peripherally selective opioid antagonists capable of penetrating the placenta may be beneficial for preventing or reducing neonatal dependence and NAS in a dose range that should not interfere with maternal opioid maintenance.

show abstract

Section: Introductionmentioning

confidence: 99%

Preferential Delivery of an Opioid Antagonist to the Fetal Brain in Pregnant Mice

Oberdick

Ling

Phelps

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

show abstract

“…21 Lower response rates in patients with noncancer pain have been reported with naloxegol (a pegylated μ-opioid receptor antagonist; 34.9%-44.4%) and lubiprostone (a ClC-2 chloride channel agonist, 27.1%), but whether this reflects reduced efficacy or differences in study responder criteria is unknown. 22 The tolerability profile of patients who crossed over to methylnaltrexone in the OLE was similar to their tolerability profile during exposure to placebo in the RCT. The most frequently reported AE during methylnaltrexone treatment was abdominal pain.…”

Section: Discussionmentioning

confidence: 71%

(451) Efficacy and safety of methylnaltrexone for opioid-induced constipation in patients with chronic noncancer pain: a placebo crossover analysis

Viscusi¹,

Barrett²,

Paterson³

et al. 2014

The Journal of Pain

View full text Add to dashboard Cite

“…In two large studies (total 1352 participants), the frequency of spontaneous bowel movements increased in 40% and 44% of patients. This was 10 -15% greater than the response rate to placebo (Chey et al, 2014).…”

Section: Treating Oic With Opioid Antagonistsmentioning

confidence: 68%

Management of opioid-induced constipation

2016

View full text Add to dashboard Cite

Up to 40% of patients taking opioids develop constipation. Opioid induced constipation (OIC) may limit the adequate dosing of opioids for pain relief and reduce quality of life.Hence, healthcare providers must inquire about bowel function in patients receiving opioids.The management of OIC includes carefully reevaluating the necessity, type, and dose of opioids at each visit. Lifestyle modification and alteration of aggravating factors, the use of simple laxatives, and when essential, the addition of newer laxatives or opioid antagonists (naloxone, naloxegol or methylnaltrexone) can be used to treat OIC. This review discusses the recent literature regarding the management of OIC and provides a rational approach to assessing and managing constipation in individuals receiving opioids.Abstract word count -115

show abstract

Naloxegol for Opioid-Induced Constipation in Patients with Noncancer Pain

Abstract: Treatment with naloxegol, as compared with placebo, resulted in a significantly higher rate of treatment response, without reducing opioid-mediated analgesia. (Funded by AstraZeneca; KODIAC-04 and KODIAC-05 ClinicalTrials.gov numbers, NCT01309841 and NCT01323790, respectively.).

Cited by 295 publications

References 17 publications

Preferential Delivery of an Opioid Antagonist to the Fetal Brain in Pregnant Mice

Preferential Delivery of an Opioid Antagonist to the Fetal Brain in Pregnant Mice

(451) Efficacy and safety of methylnaltrexone for opioid-induced constipation in patients with chronic noncancer pain: a placebo crossover analysis

Management of opioid-induced constipation

Contact Info

Product

Resources

About