An observational post-authorization safety study (PASS) of naloxegol drug utilization in four European countries.

PURPOSE: Naloxegol has been shown to be an efficient alternative to treat opioid-induced constipation (OIC). This study aimed at describing the characteristics of naloxegol users and assessing patterns of naloxegol use and associated factors. METHODS: This drug utilization cohort study used observational registry data on patients newly prescribed naloxegol in four European countries. Patient characteristics and patterns of naloxegol use and associated factors were described. RESULTS: A total of 17 254 naloxegol users were identified across the countries. Their median age was 56-71 years, and each country had a majority of women (ranging 57.5%-62.9%). Multiple comorbidities, including cancer, were common. Natural opium alkaloids and osmotically acting laxatives (excluding saline) were the most frequently used opioids and laxatives. Overall prior use of opioids ranged from 91.9% to 99.6% and overall prior use of laxatives ranged from 69.9% to 92.4%. Up to 77.7% had prior use of medications with interaction potential, and up to 44.5% used them concurrently with naloxegol. Naloxegol was discontinued by 55.1%-90.9% of users, typically during the first 30 days. Approximately 10%-30% switched to or augmented the treatment with another constipation medication or restarted naloxegol after discontinuation. Augmentation with another constipation medication was relatively common, suggesting that naloxegol was used for multifactorial constipation. CONCLUSION: The present study reflects real-world clinical use of naloxegol, including in vulnerable patient groups. Some naloxegol users lacked laxative or regular opioid use within six months before index date or used naloxegol concomitantly with medications presenting an interaction potential.

Efficacy and safety of sinomenine for diabetic kidney diseases: A meta-analysis.

BACKGROUND: In traditional Chinese medicine, Sinomenii Caulis contains Sinomenine (SIN), one of the major active ingredients. According to some studies, SIN can reduce proteinuria and provides clinical effectiveness rates in diabetic kidney disease (DKD) patients, however, the evidence is not strong and mechanisms of action are unclear. The efficacy and safety of SIN in treating DKD were evaluated by meta-analysis, and the potential mechanism of SIN therapy for DKD was initially explored by network pharmacology. METHODS: PubMed, Cochrane Library, Embase, Web of Science, CNKI, Wanfang, VIP, and SinoMed databases were comprehensively searched until March 28, 2022. Randomized controlled trials on DKD treated with SIN were selected. The main results were clinical effective rate and the secondary results were the decrease in 24-hour urine total protein (24-hour UTP), serum creatinine, adverse reactions, etc. Drug combinations and disease stages were analyzed in subgroups. Sensitivity analysis was performed for 24-hour UTP. The potential target genes and pathways of SIN in treating DKD were studied using protein-protein interactions, gene ontology, and the Kyoto Genome Encyclopedia and Genomes enrichment analysis. RESULTS: The meta-analysis included 7 randomized controlled trials. SIN treatment had a higher clinical effectiveness rate than conventional treatment (relative risk = 1.53, 95% confidence interval [1.30; 1.80], Z = 5.14, P < .0001); the decrease in 24-hour UTP, treatment group was higher than control group (standardized mean difference = -1.12, 95% confidence interval [-1.71; -0.52], Z = -3.69, P = .0002); In the experimental group, adverse reactions were more common than in the control group. SIN mainly affected 5 target genes, NFκB-1, TNF, interleukin 6, interleukin 1ß and signal transducer and activator of transcription 3, and IL-17, AGE-RAGE signaling pathways, lipids, and atherosclerosis were all controlled to achieve therapeutic effects. CONCLUSION: SIN is an effective and safe drug for treating DKD, enhancing clinical efficacy, and reducing proteinuria. The main potential mechanism is anti-inflammatory.

Factors associated with non-response to naldemedine for opioid-induced constipation in cancer patients: A subgroup analysis.

BACKGROUND: Opioid-induced constipation (OIC) is one of the most common adverse events of opioid therapy and can severely reduce quality of life (QOL). Naldemedine is the orally available peripheral-acting µ-opioid receptor antagonist approved for OIC treatment. However in daily clinical practice, some cancer patients show insufficient control of OIC even while receiving naldemedine. OBJECTIVE: To identify factors associated with non-response to naldemedine in cancer patients. METHODS: This study retrospectively analyzed 127 cancer patients prescribed naldemedine at Seirei Hamamatsu General Hospital in Japan between November 2016 and June 2021. For the regression analysis of factors associated with OIC, variables were extracted manually from electronic medical records. Naldemedine had been prescribed by the attending physician after the presence of OIC had been defined with reference to Rome IV diagnostic criteria. Naldemedine was evaluated as "effective" in cases where the number of defecations increased at least once in the first 3 days after starting naldemedine. Multivariate logistic regression analysis was performed to identify factors associated with non-response to naldemedine. The data used were from the group of patients who received naldemedine in our previous study. RESULTS: Factors significantly associated with non-response to naldemedine included chemotherapy with taxanes within 1 month of evaluation of naldemedine effect (odds ratio [OR] = 0.063; 95% confidence interval [CI] = 0.007-0.568), and addition of or switching to naldemedine due to insufficient efficacy of prior laxatives (OR = 0.352, 95% CI = 0.129-0.966). CONCLUSION: The identification of factors associated with non-response to naldemedine prescribed for OIC may help improve QOL among cancer patients.

Synthesis of unnatural morphinan compounds to induce itch-like behaviors in mice: Towards the development of MRGPRX2 selective ligands.

Mas-related G protein-coupled receptor X2 (MRGPRX2) mediates the itch response in neurons and is involved in atopic dermatitis (AD)-associated inflammation and itch. Potent and MRGPRX2-selective ligands are essential to an understanding of the detailed function of the receptor and to develop new therapeutic agents for its related diseases. (+)-TAN-67 (1), the enantiomer of the δ-opioid receptor (DOR) selective ligand (-)-TAN-67 (1), has been reported to activate MRGPRX2, although (+)-1 also interacts with DOR, which prevents investigators from interrogating the function of MRGPRX2. Here, we have succeeded in developing a novel unnatural morphinan compound (+)-2a by a transformation based on the structure of (+)-1, which removes the DOR binding affinity. (+)-2a activated both human MRGPRX2 and the mouse orthologue Mrgprb2 in in vitro experiments and induced itch-like behaviors in mice to the same extent as (+)-1. The (+)-2a-induced itch response in mice was suppressed by administration of the tripeptide QWF, an MRGPRX2/Mrgprb2 antagonist, or the antipruritic drug nalfurafine. Together, (+)-2a serves as a useful tool to elucidate the itch-related function/action of MRGPRX2 and its mouse orthologue Mrgprb2.

Assessment of potentially abuse-related events in two phase 3 studies of NKTR-181, a novel opioid analgesic, using the MADDERS® system (Misuse, Abuse, and Diversion Drug Event Reporting System).

Objective: To prospectively evaluate the abuse potential of NKTR-181, a novel opioid analgesic, in two phase 3 clinical trials using a newly developed reporting system: the Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS®).Methods: SUMMIT-07 was an enriched enrollment randomized withdrawal study that examined the safety and efficacy of NKTR-181 across 12 weeks in opioid-naïve subjects with chronic low back pain. SUMMIT-LTS was a 52 week open-label study in opioid-naïve and experienced subjects with chronic low back pain or noncancer pain rolled over from SUMMIT-07 or enrolled de novo. System evaluations were triggered by adverse events of interest and drug accountability discrepancies signaling potentially abuse-related events. Each event was assigned a primary classification and supplementary classification(s) by investigators and by a blinded, independent committee of substance abuse experts (adjudicators). At the final study visit, investigators administered a survey to subjects to identify overlooked events of interest.Results: Seventy-nine (6.6%) of 1189 subjects were associated with 86 events in SUMMIT-07 and 51 (8.0%) of 638 subjects were associated with 59 events in SUMMIT-LTS. Most events were attributed to "Withdrawal" and, primarily in SUMMIT-07, "Therapeutic Error" (unintentional overuse) or "Misuse" (intentional overuse for a therapeutic purpose) of study medication. Adjudicators identified five possible "Abuse" events (three NKTR-181, two placebo) in SUMMIT-07 and four possible "Abuse" events (all NKTR-181) in SUMMIT-LTS.Conclusions: The MADDERS® system discerns potentially abuse-related events and identified low rates of withdrawal and a low risk of abuse potential, diversion or addiction associated with NKTR-181 in phase 3 trials.

Comparison of combination therapy with methotrexate and sinomenine or leflunomide for active rheumatoid arthritis: A randomized controlled clinical trial.

BACKGROUND: A combination of conventional disease-modifying anti-rheumatic drugs improves the treatment of rheumatoid arthritis but with high side-effects. Methotrexate (MTX) combination therapy that with high therapeutic efficacy and low toxicity is in demand in many countries to replace the use of expensive biological agents. STUDY DESIGN: This study was an open-label, 24-week, parallel randomized controlled trial conducted between November 2015 and December 2017. METHODS: Patients were randomly assigned at a 3:2 ratio to receive MTX combined with sinomenine (SIN) at a dose of 120 mg twice daily, or leflunomide (LEF) at a dose of 20 mg once daily. Efficacy and safety were assessed at weeks 4, 12 and 24. The primary efficacy endpoint was the proportion of patients achieving an American College of Rheumatology (ACR)50 response and a European League Against Rheumatism (EULAR) good response at week 24. RESULTS: A total of 101/120 (84.2%) patients completed 24 weeks of observation. In the intention-to-treat (ITT) analysis, 65.3% of patients treated with MTX + SIN showed improved disease activity as determined by the ACR50 response at week 24 compared to 69.6% of patients treated with MTX + LEF. A similar insignificant pattern was found for the ACR20 and ACR70 responses, as well as the clinical disease activity index, EULAR response, and remission and low disease activity rates between these two treatment groups. The per-protocol analysis showed results consistent with those of the ITT analysis. Notably, significant reductions in gastrointestinal adverse reactions and liver toxicity were found in patients treated with MTX + SIN compared to patients treated with MTX + LEF (p < 0.05). CONCLUSION: Considering the balance of efficacy and toxicity, the current study provides evidence that MTX + SIN combination therapy is probably one of the choices for treating patients with active rheumatoid arthritis in addition to MTX + LEF combination therapy.

Efficacy and safety of naloxegol for opioid-induced constipation assessed by specific opioid medication, opioid dose, and duration of opioid use.

OBJECTIVE: Efficacy and safety of naloxegol, a peripherally acting µ-opioid receptor antagonist that significantly reduces opioid-induced constipation (OIC), were assessed for patient subgroups defined post hoc by baseline maintenance opioid characteristics. DESIGN: Post hoc, pooled analysis of data from two 12-week, randomized, double-blind, placebo-controlled, phase 3 studies. SETTING: Two hundred fifty-seven outpatient centers in the United States and Europe. PATIENTS: Patients with noncancer pain and OIC. INTERVENTIONS: Naloxegol (12.5 or 25 mg daily) or placebo. MAIN OUTCOMES MEASURES: The primary efficacy endpoint was the proportion of patients meeting response criteria at 12 weeks: at least three spontaneous bowel movements (SBMs)/wk and an increase from baseline of at least one SBM for ≥9 of 12 weeks and ≥3 of the last 4 weeks. No adjustments were made for multiplicity; all p values are descriptive. RESULTS: This analysis included 1,337 patients. Increases in the proportion of patients who achieved response at 12 weeks were observed with naloxegol 25 mg versus placebo in patients taking maintenance oxycodone, hydrocodone, morphine, or fentanyl (p ≤ 0.038); patients taking either ≥120 or <120 morphine-equivalent units at baseline (p ≤ 0.032); and patients treated with their current opioid for >6 months (p ≤ 0.035). Efficacy results were less robust with naloxegol 12.5 mg versus placebo. Adverse event incidences were generally comparable across treatment groups, regardless of opioid dose or duration of therapy but were numerically higher with some specific baseline opioids. CONCLUSION: In this post hoc, exploratory analysis, naloxegol 25 mg showed similar efficacy in treating OIC regardless of maintenance opioid type, dose, or duration of opioid use at baseline.

The opioid crisis: a 21st century pain.

The opioid pain market is a lucrative one, but is experiencing significant challenges in the U.S. as the country grapples with prescription opioid addiction, overdose and fatalities. The situation has been declared a national Public Health Emergency and the Food and Drug Administration (FDA) has introduced several measures intended to reduce opioid abuse. The development of abuse-deterrent prescription opioids is one such measure, but although abuse-deterrent formulations of opioids reduce drug liking and abuse, concerns have been highlighted by an Institute of Clinical and Economic Review (ICER) report regarding the insufficiency of currently available data to determine the effects of these formulations at the population level. However, the low abuse liability but effective analgesic efficacy reported for drugs such as NKTR-181 and difelikefalin highlight the potential of novel abuse-deterrent opioids.

Cardiovascular Safety of the Selective µ-Opioid Receptor Antagonist Naloxegol: A Novel Therapy for Opioid-Induced Constipation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

The impact of naloxegol on anal sphincter function - Using a human experimental model of opioid-induced bowel dysfunction.

BACKGROUND AND AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Naloxegol for managing opioid-induced constipation.

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.

Agranulocytosis Induced by Sinomenine Hydrochloride.

BACKGROUND Sinomenine hydrochloride is an alkaloid that is extracted from the Chinese herbal plant Sinomenium acutum, and is used as a herbal medicine in the treatment or rheumatic disease. This report is the first to describe a case of sinomenine hydrochloride-induced agranulocytosis. CASE REPORT A 44-year-old woman with systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) was treated with sinomenine hydrochloride and developed agranulocytosis with a neutrophil count of 0.01×10^9/L. She subsequently developed an opportunistic bacterial infection. Bone marrow aspiration showed a severe reduction in the proportion of mature granulocytes. The patient discontinued sinomenine hydrochloride therapy and was treated with granulocyte colony-stimulating factor (G-CSF) and antibiotics. The patient showed a return to normal granulocyte levels within ten days of discontinuing treatment with sinomenine hydrochloride. CONCLUSIONS The findings of this case report show that monitoring of bone marrow function and granulocyte levels should be performed during treatment with sinomenine hydrochloride.

Suppressing mPGES-1 expression by sinomenine ameliorates inflammation and arthritis.

Recently, microsomal prostaglandin E synthase 1 (mPGES-1) has attracted much attention from pharmacologists as a promising strategy and an attractive target for treating various types of diseases including rheumatoid arthritis (RA), which could preserve the anti-inflammatory effect while reducing the adverse effects often occur during administration of non-steroidal anti-inflammatory drugs (NSAIDs). Here, we report that sinomenine (SIN) decreased prostaglandin (PG)E2 levels without affecting prostacyclin (PG)I2 and thromboxane (TX)A2 synthesis via selective inhibiting mPGES-1 expression, a possible reason of low risk of cardiovascular event compared with NSAIDs. In addition, mPGES-1 protein expression was down-regulated by SIN treatment in the inflamed paw tissues both in carrageenan-induced edema model in rats and the collagen-II induced arthritis (CIA) model in DBA mice. More interestingly, SIN suppressed the last step of mPGES-1 gene expression by decreasing the DNA binding ability of NF-κB, paving a new way for drug discovery.

Long-term efficacy and safety of nalfurafine hydrochloride on pruritus in chronic liver disease patients: Patient-reported outcome based analyses.

BACKGROUND AND AIM: Among various symptoms accompanied with chronic liver disease, pruritus affects the quality of life of patients, causing physical and mental stress, and worsens hepatic function. Recently, κ-opioid receptor agonist, nalfurafine hydrochloride was approved to treat central pruritus in patients with liver disease in Japan. This study aimed to assess the long-term efficacy and safety of nalfurafine hydrochloride on pruritus in chronic liver disease patients. METHODS: A patient-reported outcome using questionnaire-based methods was used for 41 liver disease patients with or without pruritus symptoms. Nalfurafine hydrochloride (2.5 µg/day) was orally administered to 18 patients suffering from pruritus symptoms and whose current treatment was not effective. The same questionnaires and visual analogue scales (VAS) were repeatedly followed up for the patients for the entire follow-up period, and biochemical analyses were performed to evaluate the safety of the treatment. RESULTS: Pruritus completely disappeared in seven of 18 cases, and VAS scores showed a decreasing trend over time from the start of nalfurafine hydrochloride administration in all patients who received the medication. Among 11 patients who were followed up for more than 12 weeks, nine patients showed continuous improvement of symptoms, and this progress was still apparent at ≥20 weeks after starting administration (p < 0.0001). The medication was discontinued in four patients because of progression of primary disease, high cost, oral dryness, and anemia. No significant toxicity was observed on the serum biochemical analyses. CONCLUSIONS: Nalfurafine hydrochloride contributed to long-term suppression of pruritus without significant safety problems.

Novel Oral Therapies for Opioid-induced Bowel Dysfunction in Patients with Chronic Noncancer Pain.

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.

Nalfurafine hydrochloride, a selective κ opioid receptor agonist, has no reinforcing effect on intravenous self-administration in rhesus monkeys.

Nalfurafine hydrochloride [(E)-N-[17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6ß-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride; nalfurafine] is used in Japan as an antipruritic for the treatment of intractable pruritus in patients undergoing hemodialysis or with chronic liver disease. It is a potent and selective agonist at the κ opioid receptor, but also has weak and partial agonist activity at µ opioid receptors. Opioids, especially those acting at µ receptors, carry a risk of abuse. This is an important factor in the consideration of therapeutic risk vs. benefit in clinical use and the potential for misuse as a public health problem. It is therefore necessary to carefully evaluate the reinforcing effects of nalfurafine. To this end, we investigated intravenous self-administration of nalfurafine in rhesus monkeys. The number of self-administration of nalfurafine at doses of 0.0625, 0.125 and 0.25 µg/kg/infusion was not higher than that of saline in rhesus monkeys that frequently self-administered pentazocine (0.25 mg/kg/infusion). These results indicate that nalfurafine has no reinforcing effect in rhesus monkeys in the intravenous self-administration paradigm.

A 12-week extension study to assess the safety and tolerability of naloxegol in patients with noncancer pain and opioid-induced constipation.

OBJECTIVE: To compare the long-term safety and tolerability of naloxegol with placebo in patients with opioid-induced constipation (OIC) and noncancer pain. DESIGN: Twelve-week, multicenter, randomized, double-blind, parallel-group phase 3 extension study (KODIAC-07, NCT01395524). SETTING: Clinical investigation centers in the United States. PATIENTS: Adult outpatients (N = 302) with confirmed OIC who had completed a 12-week pivotal phase 3 study (KODIAC-04, NCT01309841). INTERVENTIONS: Daily oral administration of naloxegol (12.5 and 25 mg) or placebo. MAIN OUTCOME MEASURES: Adverse events (AEs), including treatment-related AEs, serious AEs, and AEs of special interest; changes from baseline to week 12 in pain scores, daily opioid dose, and symptoms and quality-of-life measurements. RESULTS: No important new AEs occurred during this extension study compared with KODIAC-04. AEs occurred more frequently with naloxegol 25 mg (41.2 percent) versus naloxegol 12.5 mg (34.0 percent) and placebo (33.0 percent). Treatment-emergent AEs occurring in >5 percent of patients in either naloxegol group during the treatment period were arthralgia (25 mg; 5.2 percent) and diarrhea (12.5 mg; 5.3 percent); two reported AEs attributable to opioid withdrawal syndrome in naloxegol groups were deemed unrelated to study medication. None of the gastrointestinal serious AEs was adjudicated as bowel perforation; one patient (naloxegol 12.5 mg) had an event adjudicated as a major cardiovascular event and was unrelated to study medication. Pain scores and daily opioid dose were unchanged, and improvements in symptoms and quality-of-life observed in KODIAC-04 were maintained throughout the extension study. CONCLUSION: Naloxegol was generally safe and well tolerated in this 12-week extension study in patients with noncancer pain and OIC.

Naloxegol: A Novel Therapy in the Management of Opioid-Induced Constipation.

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.