The role of naloxegol in the management of opioid-induced bowel dysfunction

Leppert, Wojciech; Woroń, Jarosław

doi:10.1177/1756283x16648869

Cited by 36 publications

(25 citation statements)

References 37 publications

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“…Naloxegol is a pegylated modification of naloxone. Naloxegol is a substrate for the blood brain barrier P-glycoprotein transporter and together with its large molecular weight (652 g/mol) limits naloxegol penetration across the blood brain barrier (Bui et al , 2016; Leppert & Woron, 2016). Naloxegol is approved for treatment of opioid-induced constipation especially in non-cancer pain patients (Chey et al , 2014; Leppert & Woron, 2016).…”

Section: Drugs Acting At Opioid Receptors In the Gastrointestinal Tractmentioning

confidence: 99%

Insights into the Role of Opioid Receptors in the GI Tract: Experimental Evidence and Therapeutic Relevance

Galligan

Sternini

2016

Handbook of Experimental Pharmacology

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Opioid drugs are prescribed extensively for pain treatment but when used chronically they induce constipation that can progress to opioid-induced bowel dysfunction. Opioid drugs interact with three classes of opioid receptors: mu opioid receptors (MORs), delta opioid receptors (DOR), and kappa opioid receptors (KORs), but opioid drugs mostly target the MORs. Upon stimulation, opioid receptors couple to inhibitory Gi/Go proteins that activate or inhibit downstream effector proteins. MOR and DOR couple to inhibition of adenylate cyclase and voltage-gated Ca channels and to activation of K channels resulting in reduced neuronal activity and neurotransmitter release. KORs couple to inhibition of Ca channels and neurotransmitter release. In the gastrointestinal tract, opioid receptors are localized to enteric neurons, interstitial cells of Cajal, and immune cells. In humans, MOR, DOR, and KOR link to inhibition of acetylcholine release from enteric interneurons and motor neurons and purine/nitric oxide release from inhibitory motor neurons causing inhibition of propulsive motility patterns. MOR and DOR activation also results in inhibition of submucosal secretomotor neurons reducing active Cl secretion and passive water movement into the colonic lumen. Together, these effects on motility and secretion account for the constipation caused by opioid receptor agonists. Tolerance develops to the analgesic effects of opioid receptor agonists but not to the constipating actions. This may be due to differences in trafficking and downstream signaling in enteric nerves in the colon compared to the small intestine and in neuronal pain pathways. Further studies of differential opioid receptor desensitization and tolerance in subsets of enteric neurons may identify new drug or other treatment strategies of opioid-induced bowel dysfunction.

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Section: Drugs Acting At Opioid Receptors In the Gastrointestinal Tractmentioning

confidence: 99%

Insights into the Role of Opioid Receptors in the GI Tract: Experimental Evidence and Therapeutic Relevance

Galligan

Sternini

2016

Handbook of Experimental Pharmacology

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“…29 Naloxegol, the newest PAM-OR antagonist in the group, has demonstrated positive results in both studies in this review and agrees with the findings of other reviews. 19 Leppert and Woron 19 reported that naloxegol was effective in up to 49% of patients not responsive to standard laxatives and that naloxegol has been shown to be more effective than placebo in patients with OIC and noncancer pain. No studies have been performed in cancer patients.…”

Section: Discussionmentioning

confidence: 99%

“…No studies have been performed in cancer patients. 19 The approved dose is 25 mg. 16 Comparison of naloxegol to oral methylnaltrexone is difficult because the primary end points are not the same from the published studies. However, the available data suggest that although both agents are effective, adverse effects occurred at a greater frequency with naloxegol compared with placebo, 36,37 whereas patients who received oral methylnaltrexone had a similar rate of adverse effects as the placebo group.…”

Section: Discussionmentioning

confidence: 99%

“…15 The most recent addition to the PAM-OR antagonists, naloxegol, has been in clinical use since its approval in 2014 as "an opioid antagonist indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic noncancer pain." 16 Several randomized trials involving PAM-OR antagonists have recently been published 17,18 ; in addition, previous reviews have focused solely on a single agent 19,20 or either OIC 21 or POI 7 but not both. Therefore, an update that discusses strengths and limitations of the evidence is warranted.…”

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confidence: 99%

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The Efficacy of Peripheral Opioid Antagonists in Opioid-Induced Constipation and Postoperative Ileus

Schwenk

Grant²,

Torjman

et al. 2017

Regional Anesthesia and Pain Medicine

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Opioid-induced constipation has a negative impact on quality of life for patients with chronic pain and can affect more than a third of patients. A related but separate entity is postoperative ileus, which is an abnormal pattern of gastrointestinal motility after surgery. Nonselective μ-opioid receptor antagonists reverse constipation and opioid-induced ileus but cross the blood-brain barrier and may reverse analgesia. Peripherally acting μ-opioid receptor antagonists target the μ-opioid receptor without reversing analgesia. Three such agents are US Food and Drug Administration approved. We reviewed the literature for randomized controlled trials that studied the efficacy of alvimopan, methylnaltrexone, and naloxegol in treating either opioid-induced constipation or postoperative ileus. Peripherally acting μ-opioid receptor antagonists may be effective in treating both opioid-induced bowel dysfunction and postoperative ileus, but definitive conclusions are not possible because of study inconsistency and the relatively low quality of evidence. Comparisons of agents are difficult because of heterogeneous end points and no head-to-head studies.

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“…The clinical efficacy of naloxegol for the treatment of OIC has been demonstrated in several clinical studies. 26,31,79,80 Following oral administration, the C max of Movantik ® is achieved in less than two hours, with a secondary peak 0.4-3 hours later. Of note, clinical efficacy in patients not responsive to laxatives has been demonstrated in patients with OIC and non-malignant pain.…”

Section: Naloxegol (Movantik® Previously Nktr-118)mentioning

confidence: 99%

Treating opioid‐induced constipation in patients taking other medications: Avoiding CYP450 drug interactions

2019

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Summary What is known and objective When patients fail other treatment regimens and still suffer from pain sufficiently severe, opioid analgesics are appropriate and required. Unfortunately, constipation is a common adverse effect of opioids. Opioid‐induced constipation (OIC) can be treated with one of the new peripherally acting µ‐opioid receptor antagonist (PAMORA) agents. We summarize the mechanism of action of these drugs, with an emphasis on comparison of their potential for metabolic drug interactions. Methods Internet sources were searched for English‐language abstracts related to the topic. Emphasis was placed on the mechanism of the PAMORAs, their metabolic pathways, drugs co‐administered with opioids and potential drug‐drug interactions (particularly at the level of CYP450 isozyme drug metabolism). Each source was evaluated and synthesized into the review. Results and discussion PAMORAs dose‐dependently antagonize the access of agonist molecules to opioid receptors, thereby directly eliminating or reducing OIC. But they differ from other opioid antagonists in that they are restricted to the periphery. Hence, they block constipation, but leave central opioid receptor‐mediated pain relief undiminished. The PAMORAs have similar efficacy and safety profiles, but many pain patients have comorbidities and thus are taking other medications, which increases the potential for metabolic drug interactions. What is new and conclusion Managing OIC in patients who have failed OTC or other therapies can be accomplished using a PAMORA, but healthcare providers must make prudent decisions that avoid or at least mitigate the potential for metabolic drug interactions in those patients with other comorbidities being managed medically by rational polypharmacy strategies.

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The role of naloxegol in the management of opioid-induced bowel dysfunction

Cited by 36 publications

References 37 publications

Insights into the Role of Opioid Receptors in the GI Tract: Experimental Evidence and Therapeutic Relevance

Insights into the Role of Opioid Receptors in the GI Tract: Experimental Evidence and Therapeutic Relevance

The Efficacy of Peripheral Opioid Antagonists in Opioid-Induced Constipation and Postoperative Ileus

Treating opioid‐induced constipation in patients taking other medications: Avoiding CYP450 drug interactions

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