methylnaltrexone and naloxegol

To summarize and evaluate the existing literature regarding medications to treat opioid-induced constipation (OIC) in patients with chronic noncancer pain (CNCP).. PubMed, EMBASE, and Web of Science were searched using the following terms: constipation, opioid, chronic, pain, noncancer, nonmalignant, methylnaltrexone, alvimopan, lubiprostone, naloxegol, and naldemedine.. The search was limited to randomized controlled trials reporting human outcomes. Data extracted included the following: study design, population, intervention, control, outcomes related to OIC and safety, and potential biases assessed using Cochrane Collaboration's Risk of Bias Assessment Tool.. After assessment, 16 of the 190 studies were included: methylnaltrexone (n = 4), naloxegol (n = 3), naldemedine (n = 2), lubiprostone (n = 3), and alvimopan (n = 4). Lubiprostone was the only nonperipherally acting µ-opioid receptor antagonist included. Only 1 study (naloxegol) used "usual care" (nonstudy laxative) rather than placebo as a comparator. Placebo-controlled trials demonstrated benefit for methylnaltrexone, naloxegol, naldemedine, and lubiprostone, with conflicting evidence for alvimopan. No data suggest that one agent is better than another. Overall risk of bias across all studies was low to moderate.. With risk of bias determined to be low to moderate, published data to date suggest that methylnaltrexone, naloxegol, and naldemedine may be appropriate to treat OIC in patients with CNCP.

Topics: Analgesics, Opioid; Chronic Pain; Constipation; Evidence-Based Practice; Humans; Laxatives; Lubiprostone; Morphinans; Naltrexone; Narcotic Antagonists; Piperidines; Polyethylene Glycols; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic

Topics: Analgesics, Opioid; Cancer Pain; Constipation; Enema; Gastrointestinal Agents; Gastrostomy; Humans; Laxatives; Morphinans; Naltrexone; Piperidines; Polyethylene Glycols; Practice Guidelines as Topic; Quaternary Ammonium Compounds

Opioids have been used for centuries, mostly as a sedative and to treat pain. Currently, they are used on a global scale for the treatment of acute and chronic pain in diseases as osteoarthritis, fibromyalgia, and low back pain. Binding of opioids on opioid receptors can cause a range of different effects such as changes in stress response, analgesia, motor activity and autonomic functions. This review provide a synthetic summary of the most recent literature on the use of drugs acting on mu-receptors to treat two prevalent functional bowel disorders, presenting with opposite bowel habit. Eluxadoline and naloxegol, methylnaltrexone and naldemedine are recently FDA and/or EMA approved drugs demonstrated to be effective and safe for treatment respectively of irritable bowel syndrome subtype diarrhea and opioid induced constipation.

Topics: Analgesics, Opioid; Animals; Antidiarrheals; Constipation; Defecation; Diarrhea; Gastrointestinal Motility; Gastrointestinal Tract; Humans; Imidazoles; Inflammatory Bowel Diseases; Laxatives; Morphinans; Naltrexone; Narcotic Antagonists; Phenylalanine; Polyethylene Glycols; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Signal Transduction

More than 6 million people in Germany suffer from chronic pain which greatly impairs their wellbeing. Often the only therapeutic option is to use class 2 or 3 analgesic opioids in the WHO classification, as class 1 analgesics may be toxic or of limited efficacy. However, the high incidence of opioid side effects leads to high discontinuation rates. Thus, the success of opioid treatment is also highly dependent on the management of the safety and tolerability of the treatment. Most opioid side effects, such as nausea and sedation, predominantly occur in the initial phase of therapy. In contrast, opioid-induced constipation can last throughout opioid therapy. First-line treatment with laxatives does not solve the problem in all patients. Possible second-line therapies include opioid receptor antagonists, such as Naloxone, oral-administered Naloxegol, or subcutaneously given Methylnaltrexone. The discussion also covers the management of other common side effects of opioids, such as nausea, vomiting, sedation, pruritus, micturition disorder, and further symptoms.

Topics: Administration, Cutaneous; Administration, Oral; Analgesics, Opioid; Chronic Pain; Constipation; Drug-Related Side Effects and Adverse Reactions; Germany; Humans; Morphinans; Naltrexone; Narcotic Antagonists; Polyethylene Glycols; Quaternary Ammonium Compounds; 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

Opioid-based management of noncancer pain has become much more prevalent over the last 2 decades and is responsible for a wide range of side-effects, particularly affecting the intestinal tract causing opioid-induced constipation (OIC). This review will consider results of recent clinical trials that have provided evidence of new pharmacological management options for the treatment of OIC.. Supportive use of conventional agents, such as stool softeners, osmotic laxatives, and stimulating laxatives in OIC has limited efficacy. The peripheral μ-opioid receptor antagonist (PAMORA) methylnaltrexone (MNTX) was first FDA approved for OIC in patients with advanced illness and later also for OIC in noncancer pain patients; clinical trial results indicated MNTX did not reverse opioid analgesia and did not trigger central opioid withdrawal. Another PAMORA, the orally available naloxegol, has also gained recent FDA approval for the treatment of OIC in adults with chronic, noncancer pain. Lubiprostone, a bicyclical fatty acid acting via activation of intestinal chloride channel-2 (ClC-2), was also approved for OIC treatment in patients with noncancer pain.. PAMORA MNTX and naloxegol and the intestinal chloride channel-2 (ClC-2) activator lubiprostone represent additional possible therapeutic options for the management of OIC in patients with chronic noncancer pain.

Topics: Analgesics, Opioid; Chloride Channel Agonists; Chronic Pain; Constipation; Humans; Lubiprostone; Morphinans; Naltrexone; Narcotic Antagonists; Polyethylene Glycols; Quaternary Ammonium Compounds; Receptors, Opioid, mu

Peripherally acting μ-opioid receptor antagonists (PAMORAs) are indicated to treat laxative-refractory opioid-induced constipation (OIC). While several PAMORAs exist, no head-to-head comparative data are available. This study evaluated the efficacy, safety, and cost of oral naloxegol vs subcutaneous methylnaltrexone for OIC in the hospital.. In this multicenter retrospective chart review, patients who received oral naloxegol or subcutaneous methylnaltrexone as an inpatient were included if they were at least 18 years old, were still admitted to the hospital 48 hours after the first PAMORA dose, and either had an outpatient opioid prescription or received at least 30 morphine milligram equivalents in the 24 hours before the first PAMORA dose. The primary outcome was achievement of a bowel movement (BM) within 48 hours of the first dose. Secondary outcomes included a BM in 24 hours, time to the first BM, antimotility agent use, PAMORA cost per patient, and use of a second PAMORA due to failure of the first agent.. A total of 330 patients were included with 2:1 allocation (220 patients receiving methylnaltrexone vs 110 patients receiving naloxegol). Baseline characteristics were similar between the groups, except for body mass index and weight. Naloxegol met a prespecified noninferiority margin of 15% in production of a BM within 48 hours (risk difference, -4.6%; 90% confidence interval, -13.6% to 4.5%; P = 0.028). Achievement of a BM within 24 hours and time to first BM were also noninferior. Antimotility agent use was higher with naloxegol, naloxegol cost $193.16 less per patient, and 2 patients switched from naloxegol to methylnaltrexone.. Oral naloxegol may be an effective, cost-efficient alternative to subcutaneous methylnaltrexone for treatment of OIC in the hospital setting.

Topics: Adolescent; Analgesics, Opioid; Constipation; Hospitals; Humans; Narcotic Antagonists; Opioid-Induced Constipation; Retrospective Studies

Opioid-induced constipation (OIC) is common and can significantly affect quality of life. Naloxegol and methylnaltrexone are peripherally acting µ-opioid receptor antagonists (PAMORAs) which are effective for the management of OIC. We report on a case in the palliative care setting where a patient with established OIC had an inadequate response to naloxegol but an effective and immediate response to methylnaltrexone at the dose recommended for her weight. This is the first reported case of two PAMORAs used concomitantly.

Topics: Analgesics, Opioid; Female; Humans; Middle Aged; Morphinans; Naltrexone; Narcotic Antagonists; Opioid-Induced Constipation; Palliative Care; Polyethylene Glycols; Quality of Life; Quaternary Ammonium Compounds

Naloxegol is an opioid antagonist which has been developed for the treatment of patients with opioid induced constipation. In the nonclinical safety program naloxegol was shown to have a very benign toxicity profile. In the rat, but not the mouse, 2-year carcinogenicity study a change in tumour pattern with an increase in testicular Leydig cell tumours (LCT) was observed after dosing at high (supra-pharmacological) concentrations. To establish the basis of the increase in LCT and to assess its potential relevance to humans, studies to exclude and potentially identify mode-of-action (MoA) were performed. A genotoxic mechanism was ruled out following negative results in the Ames, mouse lymphoma, and micronucleus assays. An effect on androgen metabolism was excluded since the treatment of rats with naloxegol for 14days did not result in any induction of CYP protein levels. It was demonstrated that administration of centrally restricted opioid antagonists naloxegol or methylnaltrexone at high doses induced an increase in LH release with no clear increase in testosterone, in contrast to the centrally acting opioid antagonist naloxone, which showed marked increases in both LH and testosterone. LCT due to increased LH stimulation is common in rats but not documented in humans. Collectively, the lack of genotoxicity signal, the lack of androgen effect, the increase in LH secretion in rats, which is no considered to be relevant for LCT formation in humans, and high margins to clinical exposures, the observed increase in LCT in the rat is not expected to be clinically relevant.

Topics: Animals; Biomarkers; Blood-Brain Barrier; Capillary Permeability; Dogs; Female; Humans; Leydig Cell Tumor; Luteinizing Hormone; Male; Mice; Morphinans; Naltrexone; Narcotic Antagonists; Polyethylene Glycols; Quaternary Ammonium Compounds; Rabbits; Rats, Sprague-Dawley; Risk Assessment; Species Specificity; Testicular Neoplasms; Testosterone; Time Factors; Toxicity Tests; Up-Regulation

Topics: Analgesics, Opioid; Constipation; Humans; Morphinans; Naloxone; Naltrexone; Narcotic Antagonists; Polyethylene Glycols; Quaternary Ammonium Compounds

Topics: Adult; Analgesics, Opioid; Chronic Pain; Constipation; Drug Approval; Humans; Morphinans; Naltrexone; Narcotic Antagonists; Polyethylene Glycols; Quaternary Ammonium Compounds; United States; United States Food and Drug Administration