naloxegol and Constipation

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

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

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

Naloxegol is a peripherally acting μ-opioid receptor antagonist that was developed for the treatment of opioid-induced constipation. Modeling and simulation of naloxegol efficacy and tolerability informed selection of doses for phase III studies and provided comprehensive dosage recommendations for the naloxegol US package insert.

Topics: Analgesics, Opioid; Animals; Constipation; Dose-Response Relationship, Drug; Drug Labeling; Humans; Models, Biological; Morphinans; Narcotic Antagonists; Polyethylene Glycols; 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

Opioid analgesics are frequently prescribed and play an important role in chronic pain management. Opioid-induced bowel dysfunction, which includes constipation, hardened stool, incomplete evacuation, gas, and nausea and vomiting, is the most common adverse event associated with opioid use. Mu-opioid receptors are specifically responsible for opioid-induced bowel dysfunction, resulting in reduced peristaltic and secretory actions. Agents that reverse these actions in the bowel without reversing pain control in the central nervous system may be preferred over traditional laxatives. The efficacy and safety of these agents in chronic noncancer pain were assessed from publications identified through Ovid and PubMed database searches. Trials that evaluated the safety and efficacy of oral agents for opioid-induced constipation or opioid-induced bowel dysfunction, excluding laxatives, were reviewed. Lubiprostone and naloxegol are approved in the United States by the Food and Drug Administration for use in opioid-induced constipation. Axelopran (TD-1211) and sustained-release naloxone have undergone phase 2 and phase 1 studies, respectively, for the same indication. Naloxegol and axelopran are peripherally acting μ-opioid receptor antagonists. Naloxone essentially functions as a peripherally acting μ-opioid receptor antagonist when administered orally in a sustained-release formulation. Lubiprostone is a locally acting chloride channel (CIC-2) activator that increases secretions and peristalsis. All agents increase spontaneous bowel movements and reduce other bowel symptoms compared with placebo in patients with noncancer pain who are chronic opioid users. The most common adverse events were gastrointestinal in nature, and none of the drugs were associated with severe adverse or cardiovascular events. Investigations comparing these agents to regimens using standard laxative and combination therapy and trials in special populations and patients with active cancer are needed to further define their role in therapy.

Topics: Administration, Oral; Analgesics, Opioid; Chronic Pain; Constipation; Humans; Lubiprostone; Morphinans; Narcotic Antagonists; Polyethylene Glycols; Randomized Controlled Trials as Topic; Receptors, Opioid, mu; Treatment Outcome

To describe the effectiveness of naloxegol for the treatment of opioid-induced constipation (OIC) in chronic non-cancer pain patients.. Citations in PubMed, Google Scholar, Cochrane Library, CINAHL, ScienceDirect, and ProQuest were obtained. Reference lists from individual articles obtained were reviewed for additional sources.. All English-language publications available as poster presentations, abstracts, and peer-reviewed articles ranging from preclinical to phase III trials and published between 2007 and September 14, 2014, were reviewed and summarized.. Naloxegol was shown to be effective for increasing the average weekly number of spontaneous bowel movements (SBMs) in a single phase II trial enrolling 208 patients. Phase III trials (KODIAC-04/-05) enrolling a total of 1352 patients developed a new primary end point with a more strict responder criteria. This entailed a mean increase in SBMs, at least 3 SBMs per week, efficacy in 9 of 12 weeks, and efficacy in 3 of the final 4 weeks of the study period. Both groups receiving naloxegol 25 mg had significant improvement over the placebo group. The improvement was similar in patients who reported failure with laxatives in the past and regardless of daily opioid dose. A long-term trial (KODIAC-08) showed safety over 52 weeks.. OIC affects many individuals treated with opioids for chronic non-cancer pain. Previous over-the-counter or prescription treatment options were limited by a lack of adequate and well-controlled studies, multiple daily dosing, or need for injections. Cost issues may limit therapy with naloxegol to select patients.

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

With increasing chronic opioid use, opioid-induced constipation (OIC) is becoming a relevant clinical challenge. Presently, only few treatments have been demonstrated to be more effective than placebo in treating OIC but most of them have a restricted clinical application because of side effects. Naloxegol , an orally administered, peripherally acting, μ-opioid receptor antagonist (PAMORA), was developed for the treatment of OIC.. This review summarizes published information and presentations at meetings on the effects of naloxegol in OIC. Pharmacodynamic studies have demonstrated that naloxegol inhibits gastrointestinal opioid effects while preserving central analgesic actions. Phase II and Phase III studies in patients with non-cancer OIC have confirmed the efficacy of naloxegol to inhibit OIC, and the most consistent efficacy was seen with the 25 mg dose once daily. Adverse events were mainly gastrointestinal in origin and usually transient and mild. There were no signs of opioid withdrawal in the studies. Safety and tolerability were also shown in a long-term safety study. Regulatory authorities have recently approved the use of naloxegol in OIC.. Naloxegol is the first approved, orally available PAMORA. The drug has the potential to substantially improve management of OIC patients.

Topics: Analgesics, Opioid; Animals; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Constipation; Humans; Morphinans; Polyethylene Glycols

Oral naloxegol (Movantik™, Moventig(®)), a peripherally acting μ-opioid receptor antagonist, inhibits opioid binding in μ-opioid receptors in the gastrointestinal tract. This article reviews the pharmacological properties of naloxegol and its clinical efficacy and tolerability in patients with opioid-induced constipation. It demonstrated clinical efficacy and was well tolerated in placebo-controlled trials in patients with non-cancer pain and opioid-induced constipation, including those with an inadequate response to laxatives, and was well tolerated in a long-term safety study. As a PEGylated naloxone derivative, naloxegol is associated with significant improvements in spontaneous bowel movements, while maintaining levels of opioid-related analgesia (a result of its reduced ability to cross the blood-brain barrier). Naloxegol is a useful option in the treatment of opioid-induced constipation.

Topics: Analgesics, Opioid; Constipation; Humans; Morphinans; Narcotic Antagonists; Polyethylene Glycols; Randomized Controlled Trials as Topic; Receptors, Opioid, mu

Treatment of opioid-induced constipation (OIC) is becoming a relevant clinical challenge as most of the treatments demonstrated to be more effective than placebo in treating OIC have safety issues limiting a broad clinical application. Naloxegol is the first orally administered, peripherally acting, µ opioid receptor antagonist approved by the FDA and EMA specifically for the treatment of noncancer patients with OIC. This review summarizes the results of the studies regarding the effects of naloxegol in OIC. Pharmacodynamic studies have demonstrated that naloxegol was able to inhibit gastrointestinal opioid effects while preserving central analgesic actions. Phase II and phase III studies in patients with noncancer OIC have confirmed the efficacy of naloxegol to inhibit OIC, and the most consistent efficacy was seen with the 25-mg dose once daily. Side effects were mainly gastrointestinal in origin (and usually transient and mild) and there were no signs of opioid withdrawal in the studies. Safety and tolerability were shown in a long-term safety study. Considering its efficacy, safety, route of administration and the limitations of most of the other available treatments, naloxegol has the potential to become the first-line treatment for noncancer patients with OIC.

Topics: Administration, Oral; Analgesics, Opioid; Constipation; Humans; Morphinans; Narcotic Antagonists; Polyethylene Glycols; Receptors, Opioid, mu

Topics: Analgesics, Opioid; Animals; Clinical Trials as Topic; Constipation; Gastrointestinal Diseases; Humans; Morphinans; Narcotic Antagonists; Polyethylene Glycols

▼Naloxegol (Moventig-AstraZeneca) is a peripherally acting mu-opioid receptor antagonist licensed for the treatment of opioid-induced constipation in adults who have had an inadequate response to laxative treatment. It was launched in the United Kingdom in October 2015. Here, we review the evidence for naloxegol and consider its place in the management of opioid-induced constipation.

Topics: Analgesics, Opioid; Constipation; Humans; Morphinans; Narcotic Antagonists; Polyethylene Glycols

With increasing chronic opioid use, opioid-induced constipation (OIC) is a rapidly increasing clinical challenge. Naloxegol, an orally administered, peripherally-acting, µ-opioid receptor antagonist, was developed for the treatment of OIC. This drug profile summarizes published information and presentations at meetings on the effects of naloxegol in OIC. In animal studies, naloxegol was able to inhibit gastrointestinal opioid effects while preserving central analgesic actions and human pharmacodynamic studies were in agreement with such mode of action. Phase II and Phase III studies in patients with non-cancer OIC confirmed the efficacy of naloxegol to inhibit OIC, and the most consistent efficacy was seen with the 25 mg dose once daily. There were no signs of opioid withdrawal in these studies. Side effects were mainly gastrointestinal in origin, and usually transient and mild. A long-term safety study showed no new adverse events. The US FDA and EMA are currently evaluating the use of naloxegol in OIC.

Topics: Analgesics, Opioid; Animals; Constipation; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Morphinans; Narcotic Antagonists; Polyethylene Glycols

To determine patient preference for treating opioid-induced constipation (OIC) using naloxegol or polyethylene glycol (PEG) 3350 in patients receiving opioids for noncancer pain.. This crossover study included two 2-week active treatment periods, each preceded by a 1-week washout period (NCT03060512). Individuals with baseline Bowel Function Index scores ≥30 were randomized to 1 of 2 treatment sequences (naloxegol/PEG 3350 or PEG 3350/naloxegol). Patient preference (primary end point) was measured at the end of the second treatment period.. Of 276 patients randomized, 246 completed both treatment periods and reported preference (per protocol). Similar proportions of patients reported overall preference for naloxegol (50.4%) or PEG 3350 (48.0%; P = 0.92); 1.6% reported no preference. Medication characteristics influencing preference were similar for both treatments, except convenience and working quickly, which were strong influences of preference for higher proportions of patients preferring naloxegol (69.9% and 39.0%, respectively) vs those preferring PEG 3350 (29.9% and 27.4%, respectively). Patients aged <50 years or receiving laxatives within the previous 2 weeks generally preferred naloxegol. Changes from baseline in overall Bowel Function Index and Patient Global Impression of Change scores were similar between treatments, but analyses according to treatment preference revealed clinical improvement aligned with reported preference. Safety profiles were generally consistent with known medication profiles.. Almost equal proportions of patients with OIC reported similar preference for daily naloxegol or PEG 3350 treatment, and their preference was generally supported by clinically relevant and measurable improvements in OIC symptoms.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Constipation; Cross-Over Studies; Defecation; Dose-Response Relationship, Drug; Electrolytes; Female; Follow-Up Studies; Humans; Laxatives; Male; Middle Aged; Morphinans; Patient Preference; Polyethylene Glycols; Prospective Studies; Treatment Outcome; Young Adult

To summarize results from pain and opioid use assessments with naloxegol in adults with opioid-induced constipation (OIC) and chronic noncancer pain.. Two phase 3 randomized, double-blind, 12-week studies evaluated the efficacy and safety of oral naloxegol (12.5 or 25 mg daily) in adults (18 to < 85 years) with confirmed OIC and chronic noncancer pain: KODIAC-04 (NCT01309841) and KODIAC-05 (NCT01323790). Pain level was assessed daily (11-point numeric rating scale [NRS]; 0 = no pain, 10 = worst imaginable pain). Changes from baseline in mean weekly pain scores and opioid dose (weeks 1 through 12) were analyzed using mixed-model repeated measures.. At baseline, mean daily NRS average pain scores ranged from 4.5 to 4.8 for all groups in KODIAC-04 (N = 652) and were 4.6 for each group in KODIAC-05 (N = 700). Respective mean ± SD changes from baseline average pain for placebo, naloxegol 12.5 mg, and naloxegol 25 mg were -0.2 ± 1.07, -0.3 ± 1.05 (P = 0.773 vs. placebo), and 0.2 ± 0.95 (P = 0.837 vs. placebo; KODIAC-04) and -0.1 ± 0.94, -0.1 ± 0.87 (P = 0.744), and 0.0 ± 1.18 (P = 0.572; KODIAC-05). At baseline, mean daily opioid doses ranged from 135.6 to 143.2 morphine equivalent units (MEUs)/day in KODIAC-04, and from 119.9 to 151.7 MEUs/day in KODIAC-05. Respective mean ± SD changes from baseline dose were -1.8 ± 30.19, -2.3 ± 20.52 (P = 0.724 vs. placebo), and 0.4 ± 13.01 (P = 0.188 vs. placebo; KODIAC-04) and -0.3 ± 17.14, -1.3 ± 17.11 (P = 0.669 vs. placebo), and 0.1 ± 8.54 (P = 0.863 vs. placebo; KODIAC-05). Changes in maintenance opioid dose were few; reasons for such changes were similar across treatment groups.. Centrally mediated opioid analgesia was maintained during treatment with naloxegol in patients with noncancer pain and OIC.

Topics: Administration, Oral; Adult; Aged; Analgesics, Opioid; Chronic Pain; Constipation; Double-Blind Method; Female; Humans; Male; Middle Aged; Morphinans; Narcotic Antagonists; Polyethylene Glycols

Opioid treatment interferes with anal sphincter function and its regulation during defecation. This may result in straining, incomplete evacuation, and contribute to opioid-induced bowel dysfunction (OIBD). Employing an experimental model of oxycodone-induced OIBD, we hypothesized that co-administration of the peripherally acting μ-opioid antagonist naloxegol would improve anal sphincter function in comparison to placebo.. In a double-blind randomized crossover trial, 24 healthy males were assigned to a six-day treatment of oral oxycodone 15 mg twice daily in combination with either oral naloxegol 25 mg once daily or placebo. At baseline and at day 6, anal resting pressure and the recto-anal inhibitory reflex (RAIR) were evaluated using manometry and rectal balloon distension. Furthermore, the functional lumen imaging probe was used to measure distensibility of the anal canal. Gastrointestinal symptoms were assessed with the Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire and the Bristol Stool Form Scale.. During oxycodone treatment, naloxegol improved RAIR-induced sphincter relaxation by 15% (-45.9 vs -38.8 mm Hg; P < 0.01). No differences in anal resting pressure and anal canal distensibility were found between treatments (all P > 0.5). Naloxegol improved PAC-SYM symptoms (mean score over days; 2.6 vs 4.5, P < 0.001) and improved stool consistency scores (mean score over days; 3.3 vs 2.9, P < 0.01).. In this experimental model of OIBD, naloxegol improved the RAIR and reduced gastrointestinal symptoms. Hence, in contrast to conventional laxatives, naloxegol may regulate opioid-induced anal sphincter dysfunction and facilitate the defecation process.

Topics: Administration, Oral; Adult; Anal Canal; Analgesics, Opioid; Constipation; Cross-Over Studies; Defecation; Denmark; Double-Blind Method; Humans; Male; Middle Aged; Morphinans; Narcotic Antagonists; Oxycodone; Polyethylene Glycols; Pressure; Time Factors; Treatment Outcome; Young Adult

Naloxegol is approved for the treatment of opioid-induced constipation (OIC) in adults with chronic noncancer pain. Population exposure-response models were developed using data from a phase II study comprising 185 adults with OIC. The weekly probability of response defined as having ≥3/week spontaneous bowel movements (SBMs) and ≥1 SBM/week increase over baseline was characterized by a longitudinal mixed-effects logistic regression dose-response model, and the probability of time to discontinuation was modeled with a Weibull distribution function. The predicted probability of SBM in a given week increased with increasing naloxegol dose. The model predicted that 12.5, 25, and 37.5 mg doses would produce median response rates of 40%, 50%, and 60%, and dropout rates of 13.3%, 16.7%, and 23.3%, respectively. The large overlap of predicted difference of the response rate between placebo and the 25 or 37.5 mg doses suggested little utility of using a 37.5 mg dose in phase III studies.

Topics: Algorithms; Analgesics, Opioid; Chronic Pain; Constipation; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Models, Statistical; Morphinans; Narcotic Antagonists; Polyethylene Glycols; Regression Analysis

Opioid-induced constipation (OIC) is the most common side effect of opioid treatment. Treatment for OIC typically involves a laxative. However, some patients have an inadequate response to these (laxative inadequate responders, or LIR). This has led to the development of treatments such as naloxegol. This analysis estimates the impact of naloxegol on the health state utility of LIR patients, examines if this utility impact is driven by the change in OIC status, and estimates the utility impact of relief of OIC.. The analysis was conducted using data from two 12-week randomized controlled trials, KODIAC 4 (ClinicalTrials.gov identifier, NCT01309841) and KODIAC 5 (ClinicalTrials.gov identifier, NCT01323790), plus KODIAC 7 (ClinicalTrials.gov identifier, NCT01395524), a 12-week extension to KODIAC 4. All were designed to assess the efficacy and safety of oral naloxegol (12.5 and 25 mg) compared to placebo. Health state utility data were collected through the EuroQol-five dimensions questionnaire (EQ-5D-3L). Descriptive analysis was undertaken to estimate how EQ-5D utility scores and EQ-5D domain responses varied with treatment, OIC status, and over time. A repeated measure mixed-effects model was used to predict the change from baseline in health state utility score over time.. Compared with placebo, LIR patients treated with naloxegol 25 mg reported a 0.08 improvement in the EQ-5D overall score after 12 weeks of treatment. The analyses also suggest that change in OIC status is a key driver of the impact of OIC treatment on health state utility. When other factors are controlled, relieving OIC is associated with a 0.05 improvement in health state utility, although treatment with naloxegol is associated with an improvement in health state utility over and above the improvement in OIC status.. These analyses suggest that treatment with naloxegol improves patients' health state utility; driven predominantly by the relief of patients' constipation.. AstraZeneca.

Topics: Adult; Aged; Analgesics, Opioid; Constipation; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Morphinans; Narcotic Antagonists; Polyethylene Glycols; Quality of Life

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 (OIC) is a common adverse effect associated with opioid use. Naloxegol is a PEGylated derivative of naloxone in clinical development as a once-daily oral treatment of OIC.. A thorough QT/QTc study was conducted, according to International Conference on Harmonisation E14 guidelines, to characterize the effect of naloxegol on cardiac repolarization.. In this randomized, positive- and placebo-controlled crossover study, healthy men received a single dose of naloxegol 25 mg (therapeutic dose), naloxegol 150 mg (supratherapeutic dose), moxifloxacin 400 mg (positive control), or placebo in 1 of 4 sequences (Williams Latin square design). The washout time between treatment periods was at least 5 days. Digital 12-lead ECGs were recorded at baseline and at 10 time points over 24 hours after dosing in each treatment period. QT intervals were corrected for heart rate using the Fridericia formula (QTcF) and the Bazett formula (QTcB).. A total of 52 subjects were enrolled (mean age, 28 years), and 45 received all 4 treatments. The placebo-corrected, baseline-adjusted, mean increases in QTcF with naloxegol 25 and 150 mg were both <5 msec at each time point, and all upper limits of the 2-sided 90% CI were <10 msec. Similar findings were observed using QTcB; the upper limits of the 2-sided 90% CI were <10 msec at all time points after dosing with naloxegol 25 or 150 mg. With moxifloxacin 400 mg, mean QTcF was increased by a maximum of 11.1 msec (90% CI, 9.3-12.9 msec), supporting assay sensitivity.. Naloxegol at 25 and 150 mg was not associated with QT/QTc interval prolongation in these healthy men, and at the proposed therapeutic dose of 25 mg/d, naloxegol is not expected to have a clinically relevant effect on cardiac repolarization in patients with OIC. ClinicalTrials.gov identifier: NCT01325415.

Topics: Adult; Aza Compounds; Constipation; Cross-Sectional Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Fluoroquinolones; Healthy Volunteers; Heart; Heart Rate; Humans; Male; Middle Aged; Morphinans; Moxifloxacin; Naloxone; Narcotic Antagonists; Polyethylene Glycols; Quinolines; Young Adult

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 is a common problem in critically ill children requiring sedation. Naloxegol is an oral U.S. Food and Drug Administration (FDA)-approved peripherally acting mu-opioid receptor antagonist for chronic opioid-induced constipation use in adults, but data on its use in children are lacking. We performed a retrospective analysis of critically ill children that had received naloxegol for opioid-induced constipation at our institution. Of the 45 patients studied, mean stool frequency increased significantly from 0.63 ± 0.12 stools per day to 1.71 ± 0.13 stools per day after starting naloxegol (95% confidence interval [CI]: [0.75, 1.4],

Topics: Adult; Analgesics, Opioid; Child; Constipation; Critical Illness; Humans; Intensive Care Units, Pediatric; Opioid-Induced Constipation; Polyethylene Glycols; Retrospective Studies

The objective of this clinical case report is to highlight unusual adverse effects brought on by naloxegol therapy in a patient with underlying psychiatric illness. The patient is a 68-year-old female, with a psychiatric history of bipolar disorder, who presented for chronic pain management and opioid-induced constipation. After failing other therapies, she was trialed on naloxegol on three separate occasions. She experienced mood lability with symptoms including agitation, confusion, irritability, hysteria and unprompted crying spells on each occasion. Notably, the drug manufacturer does not describe mood lability, nor the profound psychiatric manifestations outlined in our case report, as side effects of Naloxegol. Clinicians may consider judicious prescription of naloxegol when treating opioid-induced constipation in patients with pre-existing psychiatric co-morbidities.. Lay abstract Our case report describes a patient with a history of pre-existing psychiatric illness and chronic pain treated with opioids who experienced unusual psychiatric side effects with naloxegol treatment. Naloxegol is used in patients who suffer from constipation from treatment with long-term opioids, often after not responding to the first-line treatment, which is stool-softeners and laxatives. Our patient, a 68-year-old female with bipolar disorder, tried naloxegol multiple times and each time experienced side effects that resolved after stopping the medication. Her symptoms included agitation, confusion, irritability, hysteria and unprompted crying spells. The drug manufacturer states that the most common side effects are gastrointestinal, such as diarrhea and nausea, but does not mention these types of psychiatric symptoms as possible side effects.

Topics: Aged; Analgesics, Opioid; Constipation; Female; Humans; Morphinans; Narcotic Antagonists; Opioid-Induced Constipation; Polyethylene Glycols

Naloxegol is a new peripherally acting mu-opioid receptor antagonist to treat opioid-induced constipation with supposedly no effect on opioid analgesia. We present a patient with cancer-related pain who developed acute opioid withdrawal symptoms due to an interaction between the opioid antagonist naloxone and naloxegol. He was treated with oxycodone sustained release because of poor pain control. For opioid-related constipation, he had been receiving naloxegol. He complained about worsening pain and constipation and oxycodone was switched to oxycodone/naloxone. Shortly after intake, he experienced acute severe agitation, anxiety, sweating, tachycardia, disorientation and yawning without improvement after intravenous midazolam. Only after intravenous morphine administration, symptoms were controlled. He was switched back to the previous oxycodone dose without naloxone, with naloxegol being maintained. In the light of this case we suggest to avoid the use of naloxone and naloxegol in combination, or at least, to use it with extreme caution and monitorisation of tolerance.

Topics: Analgesics, Opioid; Constipation; Humans; Male; Morphinans; Naloxone; Narcotic Antagonists; Oxycodone; Polyethylene Glycols; Substance Withdrawal Syndrome

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

Naloxegol, an oral once-daily peripherally acting mu-opioid receptor antagonist, is indicated for the treatment of opioid-induced constipation (OIC) with inadequate response to laxative(s), in cancer and non-cancer patients. This study mainly aimed to assess in real-life conditions the efficacy and safety of naloxegol in cancer pain patients and the evolution of their quality of life.. A non-interventional, 4-week follow-up study was conducted in 24 French oncology and pain centers between 2018 and 2019. Eligible patients were aged ≥ 18 years, treated with opioids for cancer pain, and started naloxegol for OIC with inadequate response to laxatives. The rate of the response to naloxegol (primary criterion) was assessed at W4. The evolution of quality of life was measured using the Patient Assessment of Constipation Quality of Life (PAC-QOL).. A total of 124 patients were included (mean age, 62 ± 12 years; ECOG ≤ 2, 79%; primary cancer, lung 18%, breast 16%, prostate 11%, head and neck 9%, digestive 9%…; metastatic stage, 80%). At inclusion, the median opioid dosage was 60 mg of oral morphine or equivalent. At W4, the response rate was 73.4% (95% CI [63.7-83.2%]), and 62.9% (95% CI [51.5-74.2%]) of patients had a clinically relevant change in quality of life (decrease in PAC-QOL score ≥ 0.5 point). Adverse events related to naloxegol were reported in 8% of patients (7% with gastrointestinal events; one serious diarrhea).. This real-world study shows that naloxegol is effective and well tolerated in cancer pain patients with OIC and that their quality of life improves under treatment.

Topics: Aged; Analgesics, Opioid; Cancer Pain; Constipation; Follow-Up Studies; Humans; Male; Middle Aged; Morphinans; Neoplasms; Opioid-Induced Constipation; Polyethylene Glycols; Quality of Life

Topics: Analgesics, Opioid; Constipation; Humans; Morphinans; Patient Preference; Polyethylene Glycols; Prospective Studies

Oncologic patients on opioid therapy due to pain may have several side effects, including respiratory depression (in about 1% of cases), pruritus (up to 10% of cases), nausea (in 25-32% of cases), sedation (in 20- 60% of cases); but the most far-reaching side effect (up to 95% of cases) that can occur is constipation. The socalled "opioid-induced constipation" (OIC) can develop at the start of opioid therapy and can last as long as continued use. The OIC is a real change in intestinal habits that occurs when opioid treatment is started; it is noted with a reduced frequency of episodes of defecation, with a development or worsening of the effort to defecation, with a feeling of incomplete emptying and a perception on the part of the patient to live in a stressful way the act of defecation. Also because of this, the OIC can induce to tolerate the dose of opioids routinely causing inadequate pain management. Continuous therapy with opioids lasting at least two weeks and resistance to the treatment of constipation with osmotic laxatives for more than three days in patients with terminal disease (Nota 90 AIFA) allow the prescription of naloxegol, a PEGylated derivative of the naloxone. Naloxegol belongs to the PAMORA family (peripheral mu-opioid receptor antagonists) which does not generally cross the blood-brain barrier and therefore does not interfere with the central nervous system-mediated analgesic efficacy. The reported clinical case tends to show how the use of the drug under examination (naloxegol) solves the problem of the OIC in a oncologic patient, improving her quality of life.

Topics: Analgesics, Opioid; Cancer Pain; Constipation; Female; Humans; Middle Aged; Morphinans; Narcotic Antagonists; Polyethylene Glycols; Quality of Life

Topics: Analgesics, Opioid; Constipation; Humans; Morphinans; Patient Preference; Polyethylene Glycols; Prospective Studies

Naloxegol is a novel selective, peripherally acting μ-opioid receptor antagonist for treating opioid-induced constipation (OIC) in patients with chronic pain syndromes. We analyzed the cardiovascular (CV) safety of naloxegol based on data from its development program prior to approval by the US Food and Drug Administration in 2015.. Comprehensive CV safety analyses were performed in 4 clinical studies of naloxegol (12.5 and/or 25 mg) in patients with noncancer pain and OIC: two 12-week, double-blind, randomized studies; a 12-week, double-blind, extension study; and a 52-week, randomized, open-label study versus usual care. Evaluations of baseline CV risk were obtained from medical histories and clinical findings at the time of study initiation.. Across the 4 studies (N = 2135), 68% of patients had ≥1 CV risk factor and 41% had a history of CV disease, diabetes, or ≥2 other CV risk factors. There were no increases in blood pressure, heart rate, or the rate-pressure product with naloxegol versus placebo. The rates of major adverse cardiovascular events (MACE) per 100 patient-years of exposure were 1.13 (95% confidence interval [CI], 0.31-2.89) for placebo/usual care and 0.75 (95% CI, 0.24-1.75) for naloxegol. The relative risk of MACE for all doses of naloxegol versus placebo was 0.67 (95% CI, 0.14-3.36).. These data demonstrate that naloxegol has a CV safety profile comparable to placebo/usual care in patients with OIC. Although the observed number of events was low, the data show no CV signal in patients with OIC treated with naloxegol.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Cardiovascular System; Chronic Pain; Clinical Trials, Phase III as Topic; Constipation; Defecation; Evidence-Based Medicine; Female; Humans; Male; Middle Aged; Morphinans; Narcotic Antagonists; Polyethylene Glycols; Randomized Controlled Trials as Topic; Receptors, Opioid, mu; Recovery of Function; Risk Assessment; Risk Factors; Signal Transduction; Treatment Outcome; Young Adult

Opioid-induced constipation (OIC) is a common gastrointestinal adverse effect of opioids, which can severely affect compliance and adherence to pain medication regimens and quality of life. Naloxegol has demonstrated efficacy against OIC in several studies involving patients with nonmalignant chronic pain. Here we report efficacy and tolerability of naloxegol in a 68-year-old patient with metastatic lung cancer and severe pain, treated with opioids, who presented with OIC resistant to traditional measures. Addition of naloxegol produced rapid improvement in his OIC symptoms and no apparent adverse effects while taking extended-release morphine 130 mg orally every 12 hours.

Topics: Aged; Analgesics, Opioid; Cancer Pain; Constipation; Humans; Lung Neoplasms; Male; Morphinans; Morphine; Narcotic Antagonists; Polyethylene Glycols; Quality of Life

Opioid-induced bowel dysfunction wich comprises several other gastrointestinal complaints; could be highly debilitating, thus significantly deteriorating patients' quality of life. In particular, opioid-induced constipation (OIC) is the most frequent symptom. Therefore patients with haematological malignances need special attention of these disabling symptoms, which should be prevented by a correct evaluation of diet, age, intestinal habits, history of prior bowel disorders as well as constipating effects of other concomitant medication. However the occurrence of OIC during treatment with opioids requires pharmacological interventions. If these measures are not sufficient to regulate intestinal functions, required to pharmacological interventions, can be used osmotic laxatives. New emerging approved agents such as naloxone pegylate (naloxegol) indicated for the treatment of opioid-induced constipation in adult patients who have had an inadequate response to osmotic laxatives for more than 3 days in patients on opioids for at least 2 weeks. Here we report the case of patient treated with this new molecule both to test its efficacy and to dispel any doubt about the possibility of worsening of pain control linked to the use of this new molecule.

Topics: Aged; Analgesics, Opioid; Cancer Pain; Constipation; Hematologic Neoplasms; Humans; Laxatives; Male; Morphinans; Narcotic Antagonists; Polyethylene Glycols; Quality of Life

Naloxegol is an oral peripherally acting μ-opioid receptor antagonist approved for the treatment of opioid-induced constipation. Sensitive, robust, bioanalytical methods were required to quantitate naloxegol in human biological matrices as part of the clinical development program.. Analytical plasma samples were prepared using Solid Phase Extraction (SPE) coupled with concentration. The method's linearity was established at 0.1-50 ng/ml with up to 100-fold dilution. Urine samples were analyzed directly postdilution; dialysate samples were extracted by supported liquid extraction. Sensitive liquid chromatography/mass spectrometry (LC-MS/MS) assays were developed and validated, and demonstrated acceptable precision, accuracy and selectivity for naloxegol in the appropriate matrices.. Methods for quantifying naloxegol in human biological matrices have been successfully validated.

Topics: Analgesics, Opioid; Chromatography, Liquid; Constipation; Humans; Limit of Detection; Morphinans; Narcotic Antagonists; Polyethylene Glycols; Receptors, Opioid, mu; Solid Phase Extraction; Tandem Mass Spectrometry

Topics: Adult; Advance Care Planning; Aged; Antiemetics; Baclofen; Benzodiazepines; Constipation; Depressive Disorder, Major; Dyspnea; Female; Hiccup; Humans; Male; Methylphenidate; Middle Aged; Morphinans; Morphine; Nausea; Olanzapine; Palliative Medicine; Polyethylene Glycols; Prochlorperazine; Pruritus; Sertraline; Terminal Care; Walkers

Naloxegol is a peripherally acting mu-opioid receptor antagonist for opioid-induced constipation in adults with chronic noncancer pain. This drug's once-daily oral formulation can be used as monotherapy and helps to decrease the constipating effects of opioid therapy; however, it has been associated with abdominal pain.

Topics: Abdominal Pain; Adult; Analgesics, Opioid; Chronic Pain; Constipation; Female; Humans; Male; Morphinans; Narcotic Antagonists; Polyethylene Glycols; Receptors, Opioid, mu

Opioid-induced constipation (OIC) is the most common adverse effect reported in patients receiving opioids to manage pain. Initial treatment with laxatives provides inadequate response in some patients. Naloxegol is a peripherally acting µ-opioid receptor antagonist used to treat patients with inadequate response to laxative(s) (laxative inadequate responder [LIR]). A cost-effectiveness model was constructed from the UK payer perspective to compare oral naloxegol 25 mg with placebo in non-cancer LIR patients receiving opioids for chronic pain, and a scenario analysis of naloxegol 25 mg with rescue laxatives compared with placebo with rescue laxatives in the same patient population.. The model comprised a decision tree for the first 4 weeks of treatment, followed by a Markov model with a 4-week cycle length and the following states: 'OIC', 'non-OIC (on treatment)', 'non-OIC (untreated)' and 'death'. Two phase III trials with a follow-up period of 12 weeks provided data on treatment efficacy, transition probabilities, adverse event frequency and patient utility. Resource utilisation data were sourced from a UK-based burden of illness study and physician surveys. A UK National Health Service and Personal Social Service perspective was adopted; costs and health-related quality of life gains were discounted at a rate of 3.5 %. The model was run over a time horizon of 5 years, reflecting the average period of opioid use.. Naloxegol has an incremental cost-effectiveness ratio of £10,849 per quality-adjusted life-year gained versus placebo, and £11,179 when rescue laxatives are made available in both arms (2014 values). Model outcomes were only sensitive to variations in utility inputs. However, the probabilistic sensitivity analyses indicate that naloxegol has a 91 % probability of being cost effective at a £20,000 threshold when compared with placebo.. Naloxegol is likely a cost-effective treatment option for LIR patients with OIC. This assessment should be supported by further work on the utility of patients with OIC, including how utility varies with more granular measures of OIC.

Topics: Analgesics, Opioid; Chronic Pain; Constipation; Cost-Benefit Analysis; Decision Trees; Humans; Laxatives; Markov Chains; Models, Economic; Morphinans; Narcotic Antagonists; Polyethylene Glycols; Quality of Life; Quality-Adjusted Life Years; Receptors, Opioid, mu; United Kingdom

Naloxegol is a polyethylene glycol derivative of naloxone approved in the US as a once-daily oral treatment for opioid-induced constipation (OIC) in adults with chronic noncancer pain. Population exposure-response models were constructed based on data from two phase III studies comprising 1,331 adults with noncancer pain and OIC. In order to characterize the protocol-defined naloxegol responder rate, the number of daily spontaneous bowel movements (SBMs) was characterized by a longitudinal ordinal nonlinear mixed-effects logistic regression dose-response model, and the incidence of diary entry discontinuation was described by a time-to-event model. The mean number of SBMs per week increased with increasing naloxegol dose. The predicted placebo-adjusted responder rates (90% confidence interval) were 10.4% (4.6-13.4%) and 11.1% (4.8-14.4%) for naloxegol 12.5 and 25 mg/day, respectively. Model-predicted response to naloxegol was influenced by the baseline SBM frequency and characteristics of the opioid treatment.

Topics: Adult; Analgesics, Opioid; Chronic Pain; Clinical Trials, Phase III as Topic; Constipation; Defecation; Double-Blind Method; Female; Humans; Male; Medical Records; Middle Aged; Models, Statistical; Morphinans; Multicenter Studies as Topic; Narcotic Antagonists; Polyethylene Glycols; Randomized Controlled Trials as Topic; Treatment Outcome

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

Numerous factors, such as changes in gastrointestinal physiology, reduced mobility, decreased liquid and nutritional intake, and certain comorbidities, predispose older adults to constipation. Use of opioid medications further compounds this problem. Unlike other side effects associated with opioid use, patients do not develop tolerance to constipation and other opioid-induced bowel dysfunctions. Although opioid-induced constipation has a prevalence rate of 80% in this population, it remains highly undertreated. Despite this problem, there have been limited therapeutic options available for older adults suffering from opioid-induced constipation. On September 16, 2014, a new oral agent, naloxegol, a peripherally acting muopioid receptor antagonist (PAMORA), approved by the Food and Drug Administration, provides new hope for patients. This paper explores clinical complications associated with opioid-induced constipation in older adults, analyzes the efficacy and safety of laxatives and PAMORAs, and defines the future role of naloxegol in this vulnerable population.

Topics: Aged; Analgesics, Opioid; Constipation; Drug Approval; Humans; Laxatives; Morphinans; Narcotic Antagonists; Polyethylene Glycols; Prevalence; Receptors, Opioid, mu; United States; United States Food and Drug Administration

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