naloxegol and Pain

Due to the increased use of opioids for pain and their abuse globally, the rate of restrictive side effects is elevating. Opioid-induced constipation (OIC) is probably the most widespread, underdiagnosed, and yet common adverse effect. Naloxegol, as an opioid antagonist, is associated with beneficial impacts in OIC. Indeed, blocking mu (μ)-opioid receptors in the gastrointestinal tract (GI) may lead to neutralization of the GI adverse events of opioids.. This review is based on a PubMed and Clinicaltrials.gov search for studies undertaken over the past 20 years (2000-2020) using the following keywords: Movantik®, Moventig®, Naloxegol, Opioids, Opioid-induced constipation and Opioid antagonists.. Similar to the management of functional constipation, non-pharmacological therapies are applied as the first step of the procedure. However, in most cases, laxative therpaies with or without stool softeners, which may not result in satisfactory relief are applied. In these instances, administration of prokinetic agents is recommended. Furthermore, studies have shown that the best second-line therapy option is a peripherally acting μ-opioid receptor antagonist (PAMORA), which antagonizes GI adverse events.

Topics: Analgesics, Opioid; Humans; Laxatives; Morphinans; Narcotic Antagonists; Opioid-Induced Constipation; Pain; Polyethylene Glycols; Receptors, Opioid, mu

Opioid-induced constipation (OIC) is a major side effect of opioid use. Centrally acting antagonists result in opioid withdrawal or worsening of pain and lead to use of peripherally acting mu-opioid receptor antagonists (PAMORAs). The required doses of the PAMORAs, methylnaltrexone and naloxegol, in the treatment of OIC are well established in chronic opioid users. OIC may occur after short duration of opioid treatment; the required doses of naloxone, naltrexone, and PAMORAs in opioid-naïve subjects (with no opioid use for at least 3 months) are unclear. The aim of this review was to evaluate the PAMORA dose required for opioid-naïve subjects to achieve similar beneficial effects on symptoms or valid surrogates to those observed in chronic opioid users.. A PubMed search of μ-opioid antagonists to counter μ-opioid effects included terms: naloxone, naltrexone, methylnaltrexone, alvimopan, and naloxegol, as well as OIC and colonic transit.. The approved dose of methylnaltrexone in chronic opioid users, 0.3 mg/kg subcutaneous (SQ), did not affect motility in opioid-naïve subjects. Trials investigating the required dose of alvimopan showed 0.5-1 mg dose was efficacious in treating OIC; a 10-fold higher dose (12 mg) of alvimopan is needed to block effects of codeine on small bowel and colonic transit in opioid-naïve subjects compared to chronic opioid users. Opioid-naïve users need 125 mg of naloxegol to reverse the effects of opioids on transit; this is in contrast to the 12.5 to 25 mg needed to treat OIC in chronic opioid users.. Opioid-naïve subjects require a higher dose of PAMORA than chronic opioid users to achieve μ-opioid antagonist effect.

Topics: Analgesics, Opioid; Constipation; Dose-Response Relationship, Drug; Gastrointestinal Agents; Humans; Morphinans; Narcotic Antagonists; Pain; Piperidines; Polyethylene Glycols; Receptors, Opioid, mu; Treatment Outcome

Opioid-related bowel dysfunction is a common and potentially severe adverse effect from treatment with opioid analgesics. Its development is not dose related, nor do patients develop tolerance. Opioid-induced constipation (OIC) can lead to fecal impaction, bowel obstruction, and bowel perforation as well as noncompliance with opioid analgesics and poor quality of life. Routine administration of laxatives is necessary to maintain bowel function, and, in refractory cases, other modalities must be pursued. Available options are limited but include peripherally acting μ-opioid receptor antagonists (PAMORAs), including methylnaltrexone. Naloxegol is a newly developed PAMORA that is available through the oral route. At the therapeutic dose of 25 mg daily, naloxegol is effective and safe, with a limited side effect profile and is associated with preservation of centrally mediated analgesia. In this article, we discuss the pharmacokinetics, pharmacodynamics, adverse effects, clinical trials, and cost considerations of naloxegol. Finally, we discuss its potential role as a novel key treatment for OIC in palliative medicine patients.

Topics: Analgesics, Opioid; Constipation; Drug Interactions; Humans; Morphinans; Naltrexone; Narcotic Antagonists; Pain; Polyethylene Glycols; Quality of Life; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic

Naloxegol is a PEGylated, oral, peripherally acting μ-opioid receptor antagonist approved in the United States for treatment of opioid-induced constipation in patients with noncancer pain. Naloxegol is metabolized by CYP3A, and its properties as a substrate for the P-glycoprotein (PGP) transporter limit its central nervous system (CNS) permeability. This double-blind, randomized, 2-part, crossover study in healthy volunteers evaluated the effect of quinidine (600 mg PO), a CYP3A/PGP transporter inhibitor, on the pharmacokinetics and CNS distribution of naloxegol (25 mg PO). In addition, the effects of quinidine on morphine (5 mg/70 kg IV)-induced miosis and exposure to naloxegol were assessed. Coadministration of quinidine and naloxegol increased naloxegol's AUC 1.4-fold and Cmax 2.5-fold but did not antagonize morphine-induced miosis, suggesting that PGP inhibition does not increase the CNS penetration of naloxegol. Naloxegol pharmacokinetics was unaltered by coadministration of morphine and either quinidine or placebo; conversely, pharmacokinetics of morphine and its metabolites (in the presence of quinidine) were unaltered by coadministration of naloxegol. Naloxegol was safe and well tolerated, alone or in combination with quinidine, morphine, or both. The observed increase in exposure to naloxegol in the presence of quinidine is primarily attributed to quinidine's properties as a weak CYP3A inhibitor.

Topics: Adult; Analgesics, Opioid; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Central Nervous System; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Morphinans; Morphine; Pain; Polyethylene Glycols; Quinidine; Receptors, Opioid, mu

Opioid-induced constipation is common and debilitating. We investigated the efficacy and safety of naloxegol, an oral, peripherally acting, μ-opioid receptor antagonist, for the treatment of opioid-induced constipation.. In two identical phase 3, double-blind studies (study 04, 652 participants; study 05, 700 participants), outpatients with noncancer pain and opioid-induced constipation were randomly assigned to receive a daily dose of 12.5 or 25 mg of naloxegol or placebo. The primary end point was the 12-week response rate (≥3 spontaneous bowel movements per week and an increase from baseline of ≥1 spontaneous bowel movements for ≥9 of 12 weeks and for ≥3 of the final 4 weeks) in the intention-to-treat population. The key secondary end points were the response rate in the subpopulation of patients with an inadequate response to laxatives before enrollment, time to first postdose spontaneous bowel movement, and mean number of days per week with one or more spontaneous bowel movements.. Response rates were significantly higher with 25 mg of naloxegol than with placebo (intention-to-treat population: study 04, 44.4% vs. 29.4%, P=0.001; study 05, 39.7% vs. 29.3%, P=0.02; patients with an inadequate response to laxatives: study 04, 48.7% vs. 28.8%, P=0.002; study 05, 46.8% vs. 31.4%, P=0.01); in study 04, response rates were also higher in the group treated with 12.5 mg of naloxegol (intention-to-treat population, 40.8% vs. 29.4%, P=0.02; patients with an inadequate response to laxatives, 42.6% vs. 28.8%, P=0.03). A shorter time to the first postdose spontaneous bowel movement and a higher mean number of days per week with one or more spontaneous bowel movements were observed with 25 mg of naloxegol versus placebo in both studies (P<0.001) and with 12.5 mg of naloxegol in study 04 (P<0.001). Pain scores and daily opioid dose were similar among the three groups. Adverse events (primarily gastrointestinal) occurred most frequently in the groups treated with 25 mg of naloxegol.. 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.).

Topics: Adult; Analgesics, Opioid; Constipation; Defecation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Morphinans; Narcotic Antagonists; Pain; Polyethylene Glycols; Receptors, Opioid, mu

Opioid-induced constipation (OIC) is a common adverse effect of opioid therapy.. To evaluate the long-term safety and tolerability of naloxegol, an oral, peripherally acting μ-opioid receptor antagonist (PAMORA), in patients with noncancer pain and OIC.. A 52-week, multicenter, open-label, randomised, parallel-group phase 3 study was conducted in out-patients taking 30-1000 morphine-equivalent units per day for ≥4 weeks. Patients were randomised 2:1 to receive naloxegol 25 mg/day or usual-care (UC; investigator-chosen laxative regimen) treatment for OIC.. The safety set comprised 804 patients (naloxegol, n = 534; UC, n = 270). Mean exposure duration was 268 days with naloxegol and 297 days with UC. Frequency of adverse events (AEs) was 81.8% with naloxegol and 72.2% with UC. Treatment-emergent AEs occurring more frequently for naloxegol vs. UC were abdominal pain (17.8% vs. 3.3%), diarrhoea (12.9% vs. 5.9%), nausea (9.4% vs. 4.1%), headache (9.0% vs. 4.8%), flatulence (6.9% vs. 1.1%) and upper abdominal pain (5.1% vs. 1.1%). Most naloxegol-emergent gastrointestinal AEs occurred early, resolving during or after naloxegol discontinuation and were mild or moderate in severity; 11 patients discontinued due to diarrhoea and nine patients owing to abdominal pain. Pain scores and mean daily opioid doses remained stable throughout the study; no attributable opioid withdrawal AEs were observed. Two patients in each group had an adjudicated major adverse cardiovascular event unrelated to study drug; no AEs were reported nor adjudicated as bowel perforations.. In patients with noncancer pain and opioid-induced constipation, naloxegol 25 mg/day up to 52 weeks was generally safe and well tolerated.

Topics: Adult; Aged; Analgesics, Opioid; Constipation; Female; Humans; Laxatives; Male; Middle Aged; Morphinans; Morphine; Narcotic Antagonists; Pain; Polyethylene Glycols

Opioid-induced constipation is the most prevalent adverse effect of opioid drugs. Peripherally acting mu opioid receptor antagonists (PAMORAs), including naloxegol, are indicated for the treatment of opioid-induced constipation. The aim of this study was the in vitro and in vivo pharmacological characterization of naloxegol in comparison with naloxone. In vitro experiments were performed to measure calcium mobilization in cells coexpressing opioid receptors and chimeric G proteins and mu receptor interaction with G protein and β-arrestin 2 using bioluminescence resonance energy transfer. In vivo experiments were performed in mice to measure pain threshold using the tail withdrawal assay and colonic transit using the bead expulsion assay. In vitro, naloxegol behaved as a selective and competitive mu receptor antagonist similarly to naloxone, being 3-10-fold less potent. In vivo, naloxone was effective in blocking fentanyl actions when given subcutaneously (sc), but not per os (po). In contrast, naloxegol elicited very similar effects with sc or po administration counteracting in a dose dependent manner the constipating effects of fentanyl without interfering with the fentanyl mediated analgesia. Thus, a useful PAMORA action could be obtained with naloxegol both after po and sc administration.

Topics: Administration, Oral; Analgesics, Opioid; Animals; Behavior, Animal; Calcium; CHO Cells; Constipation; Cricetulus; Fentanyl; Injections, Subcutaneous; Male; Mice; Morphinans; Morphine; Naloxone; Narcotic Antagonists; Pain; Polyethylene Glycols; Receptors, Opioid, mu

Many patients on chronic opioid therapy suffer from constipation, one of the most common side effect of opioids. Movantik™ (naloxegol) is an opioid antagonist that is recently introduced in the market to treat opioid-induced constipation and contains naloxegol as the active ingredient. Naloxegol is a pegylated (polyethylene glycol-modified) derivative of α-naloxol. Detection of naloxone in the patients urine after consumption of naloxegol was not reported by the manufacturer and may mislead the prescribing clinicians. This study was conducted to investigate the presence of naloxone in the urine of patients that consume movnatik in pain management clinics.. The presence of naloxone and naloxol in the urine of 45 patients that consumed naloxegol and 25 patients that consumed suboxone™ were investigated using a liquid chromatography mass spectrometry (LCMS) method. The urinary concentration of naloxone, naloxol, and their glucuronide conjugates were evaluated in five volunteers that took one pill of naloxegol for one day and one volunteer who took the pill for three days.. Naloxone was detected in the urine of 45 individuals that were prescribed naloxegol. Urinary concentration of naloxone showed a distribution with a mean of 25 ± 18 ng/ml. Consumption of one pill of 25 mg naloxegol resulted in the detection of naloxol and naloxone in the urine of 5 volunteers 1 h after taking the pill. Evaluation of urine specimens from 25 patients that consumed suboxone™, resulted in the detection of naloxone (180 ± 187 ng/ml) and naloxol (6.3 ± 7.2 ng/ml).. This study demonstrated that consumption of naloxegol leads to appearance of naloxone in the urine of patients receiving opioid therapy in pain management clinics.

Topics: Adult; Female; Humans; Male; Middle Aged; Morphinans; Naloxone; Pain; Polyethylene Glycols; Retrospective Studies; Substance Abuse Detection

The paper describes a case report of a patient with a significant history of opioid-induced dysfunction of the sphincter of Oddi, who required morphine sulfate to manage oral mucositis pain, and who was successfully treated with concomitant oral naloxegol (Moventig: Kyowa Kirin, Galashiels, UK).

Topics: Administration, Oral; Analgesics, Opioid; Carcinoma, Squamous Cell; Humans; Male; Middle Aged; Morphinans; Morphine; Mucositis; Narcotic Antagonists; Pain; Polyethylene Glycols; Spasm; Sphincter of Oddi Dysfunction; Tonsillar Neoplasms