A meta-analysis of naldemedine for the treatment of opioid-induced constipation

Introduction: Opioid-induced constipation (OIC) is a common adverse effect in patients under long-term opioid therapy. Naldemedine is a novel peripherally acting μ-opioid receptor antagonists being developed for the treatment of OIC without affecting central analgesia. This meta-analysis is to assess the current evidence for efficacy and safety of naldemedine for the treatment of OIC.

Areas covered: We searched through MEDLINE, EMBASE, Web of Science and Cochrane Library, ‘ISRCTN Register’ and‘ClinicalTrials.gov’ (up to Aug 2018). Our final review included five randomized clinical trials (1751 participants in total), three trials observed naldemedine for the treatment of OIC in non-cancer patients and two trials in cancer patients. A Random Effects model was used for all comparisons. Subgroup analyses for the following subgroups were carried out: naldemedine 0.1 mg; 0.2 mg; 0.4 mg; cancer patients; non-cancer patients.

Expert opinion: Naldemedine improved the proportion of responders and spontaneous bowel movements frequency. The incidence of serious adverse effects (AEs) in naldemedine group was higher than placebo, especially in cancer patient subgroup. The AEs occurred in participants with naldemedine were mild to moderate and well tolerated during treatment. The results of this network meta-analysis will guide the future researchers in evaluating naldemedine for the treatment of OIC.     

Investigational opioid antagonists for treating opioid-induced bowel dysfunction

Introduction: Opioids have been highlighted for their role in pain relief among cancer and non-cancer patients. Novel agents have been investigated to reduce opioid-induced constipation (OIC) as the main adverse effect that may lead to treatment discontinuation. Development of peripherally acting mu-opioid receptor antagonists (PAMORA) has resulted in a novel approach to preserve the efficacy of pain control along with less OIC.

Areas covered: Clinical evidence for investigational PAMORAs was reviewed and clinical trials on investigational agents to reduce OIC were included. TD-1211 is currently being evaluated in Phase II clinical trial. Oxycodone-naltrexone and ADL-5945 went through Phase III clinical trials, but have been discontinued.

Expert opinion: There is a substantial need to develop agents with specific pharmacokinetic properties to meet the needs of patients with underlying diseases. Holding the efficacy of a medicine with the highest selectivity on targeted receptors and the least adverse effects is the main approach in upcoming investigations to improve patients’ quality of life (QoL). Novel agents to reduce opioid-induced bowel dysfunction (OIBD) that do not reverse peripherally mediated pain analgesia are of great interest. Direct comparison of available agents in this field is lacking in the literature.     

Prolonged-release oxycodone/naloxone in the treatment of neuropathic pain – results from a large observational study

Objectives: Opioids have shown consistent efficacy in neuropathic pain, but opioid-induced bowel dysfunction is a relevant problem. In controlled clinical trials, a fixed-dose combination of prolonged-release (PR) oxycodone/PR naloxone was superior to oxycodone alone in bowel function, while providing effective analgesia. The present report is an analysis of its efficacy and safety in a subgroup of patients with severe chronic neuropathic pain who were treated in a large observational study under real-life conditions.

Research design and methods: Dosed according to pain severity, 1488 patients with chronic severe neuropathic pain received PR oxycodone/PR naloxone for up to 4 weeks. Variables included pain severity, patient-reported bowel function (Bowel Function Index; BFI) and quality of life.

Results: During treatment with PR oxycodone/PR naloxone, mean pain intensity decreased in opioid-naive and opioid-pretreated patients. After 4 weeks on treatment, mean BFI scores were reduced from 41.6 ± 31.6 at the initiation visit to 16.5 ± 19.6 (p < 0.001), reflecting normal bowel function. Quality of life was improved by 47%.

Conclusions: Treatment of severe neuropathic pain with PR oxycodone/PR naloxone provided effective analgesia with the added benefit of favorable effects on bowel function and quality of life.     

夏黄颗粒治疗慢传输型便秘的实验研究

目的 采用吗啡致小鼠慢传输型便秘模型,评价夏黄颗粒的治疗作用,并对其通便作用进行实验研究。方法 采用连续sc 2.5 mg/kg盐酸吗啡45 d致小鼠慢传输型便秘模型,观察夏黄颗粒的通便作用;采用1次性ip 5 mg/kg盐酸吗啡致小鼠小肠推进、胃排空抑制模型,观察夏黄颗粒对胃肠抑制的拮抗作用;采用测定小鼠小肠湿、干质量法,观察夏黄颗粒对肠水分吸收的作用;采用顺铂致大鼠异嗜模型,观察夏黄颗粒的止吐作用;采用吗啡致豚鼠离体回肠、结肠痉挛模型,观察夏黄颗粒的作用及机制。结果 与模型组比较,小鼠给药5 d,夏黄颗粒14.95、7.48 g生药/kg能显著增加慢传输型便秘小鼠的24 h排便量（P<0.05、0.01）,继续给药至7 d,14.95、7.48 g生药/kg能显著增加小肠推进率、14.95 g生药/kg显著升高血清P物质含量（P<0.05、0.01）;给药1次,14.95、7.48 g生药/kg剂量组能显著增加小鼠小肠推进率、加快胃排空（P<0.01）,14.95 g生药/kg显著增加小鼠小肠含水量（P<0.01）;大鼠给药3 d,10.35 g生药/kg剂量组能显著降低大鼠异嗜高岭土质量（P<0.05）;给药1次,2.49、1.25 mg生药/mL（浴槽终浓度）能显著降低吗啡所致痉挛性回肠的肠张力（P<0.01）,2.49、1.25、0.62 mg生药/mL（浴槽终浓度）能显著降低吗啡所致痉挛性结肠的肠张力（P<0.05、0.01）。结论 夏黄颗粒对吗啡所致慢传输型便秘有显著的治疗作用,具有显著的通便、解痉、促进胃肠运动、肠吸收及止吐作用。     

Reliability and validity of the Bowel Function Index for evaluating opioid-induced constipation: translation,cultural adaptation and validation of the Portuguese version (BFI-P)

Objective: The Bowel Function Index (BFI) is a simple and sound bowel function and opioid-induced constipation (OIC) screening tool. We aimed to develop the translation and cultural adaptation of this measure (BFI-P) and to assess its reliability and validity for the Portuguese language and a chronic pain population.

Methods: The BFI-P was created after a process including translation, back translation and cultural adaptation. Participants (n?=?226) were recruited in a chronic pain clinic and were assessed at baseline and after one week. Internal consistency, test–retest reliability, responsiveness, construct (convergent and known groups) and factorial validity were assessed.

Results: Test–retest reliability had an intra-class correlation of 0.605 for BFI mean score. Internal consistency of BFI had Cronbach’s alpha of 0.865. The construct validity of BFI-P was shown to be excellent and the exploratory factor analysis confirmed its unidimensional structure. The responsiveness of BFI-P was excellent, with a suggested 17–19 point and 8–12 point change in score constituting a clinically relevant change in constipation for patients with and without previous constipation, respectively.

Conclusions: This study had some limitations, namely, the criterion validity of BFI-P was not directly assessed; and the absence of a direct criterion for OIC precluded the assessment of the criterion based responsiveness of BFI-P. Nevertheless, BFI may importantly contribute to better OIC screening and its Portuguese version (BFI-P) has been shown to have excellent reliability, internal consistency, validity and responsiveness. Further suggestions regarding statistically and clinically important change cut-offs for this instrument are presented.     

Evaluating naloxegol for the treatment of opioid-induced constipation

ABSTRACT

Introduction

Due to the increased use of opioids for pain and their abuse globally, the rate of restrictive side effects is elevating. Opioid-induced constipation (OIC) is probably the most widespread, underdiagnosed, and yet common adverse effect. Naloxegol, as an opioid antagonist, is associated with beneficial impacts in OIC. Indeed, blocking mu (μ)-opioid receptors in the gastrointestinal tract (GI) may lead to neutralization of the GI adverse events of opioids.     

Pharmacologic treatment of opioid-induced constipation

Opioids are potent analgesics for treating moderate to severe pain, but their use is associated with a number of adverse effects, especially opioid-induced constipation (OIC). If the centrally mediated analgesia of opioids could be separated from their peripherally mediated gastrointestinal effects, by a peripherally acting opioid receptor antagonist, opioid-induced bowel dysfunction could be prevented or reversed. There has been considerable interest in peripherally acting opioid antagonists or other compounds to treat OIC. Subcutaneous methylnaltrexone is the first approved therapeutic agent for treatment of OIC, and studies have been conducted using the oral formulation. This editorial contains a brief overview of other selected compounds to treat OIC. Other potential uses of peripherally acting opioid antagonist in clinical practice are also discussed.     

Study description and baseline characteristics of the population enrolled in a multinational,observational study of teriparatide in postmenopausal women with osteoporosis: the Asia and Latin America Fracture Observational Study (ALAFOS)

Objective: To describe the study design and baseline patient characteristics of the Asia and Latin America Fracture Observational Study (ALAFOS) to better understand the profile of patients receiving teriparatide during the course of routine clinical practice in Asia, Latin America, the Middle East and Russia.

Methods: Prospective, observational, non-interventional study in postmenopausal women with osteoporosis who are prescribed teriparatide for up to 24?months, according to local medical standards, with a 12?month post-treatment follow-up.

Measures: Demographics, risk factors for osteoporosis and fractures, history of fracture, prior osteoporosis medications, comorbidities, physical function, back pain and quality of life (QoL).

Results: In total 3031 postmenopausal women (mean age 72.5?years) recruited at 152 sites in 20 countries were analyzed; 62.9% had a history of fragility fracture after age 40 (33.0% of patients with spinal, 14.2% with hip fractures). The mean (SD) bone mineral density T-scores at baseline were ?3.06 (1.40) and ?2.60 (1.05) at the lumbar spine and femoral neck, respectively. At entry, 43.7% of patients were naïve to prior osteoporosis treatments; 40.5% of patients reported ≥1 fall in the past year. The median (Q1; Q3) EuroQoL Visual Analog Scale (EQ-VAS) for perceived overall health status was 60 (50; 80). The mean (SD) worst back pain Numeric Rating Scale in the last 24?hours was 4.6 (3.3).

Conclusions: Our data indicates that patients who were prescribed teriparatide in the ALAFOS participant countries had severe osteoporosis, high prevalence of fractures, disabling back pain and poor QoL. The frequency of patients receiving prior osteoporosis medications was lower than in previous observational studies conducted in other locations.     

观察性药物流行病学研究的P值相关问题探讨

目的探索观察性药物流行病学研究中P值相关的常见问题。方法通过文献研究结合专家经验等途径进行叙述性综述。结果在观察性药物流行病学研究中,P值的常见问题包括容易被错误解读与被人为操纵、基于P值是否小于0.05进行一刀切来判断结论是否具有统计学意义等,这些常见问题极容易损害药物流行病学研究结论的可重复性与真实有效性。结论药物流行病学研究容易出现P值的相关问题。通过综合提高对P值等基本概念的教育水平等多渠道,规范科学研究和临床实践,结合多方的联动努力,才能减缓当前P值不当使用的窘况,提高观察性药物流行病学研究结论的真实有效性与可重复性。     

Gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer: a prospective observational study

Pancreatic cancer has one of the worst prognosis of any malignant disease. Systemic therapy is often administered because the disease is usually detected at advanced stages. Gemcitabine (Gemzar?, Eli Lilly & Co.) has proven activity in the treatment of pancreatic cancer. Gemcitabine 1000 mg/m² was given on days 1, 8 and 15, every 4 weeks. A total of 100 chemonaive patients with locally advanced or metastatic pancreatic cancer were enrolled; 32 and 68% had stage III and IV disease, respectively. The average number of administered cycles was 3.5 (range: 1 – 12). The overall response rate was 13%, with 13 partial responders. The median time to progression was 13.5 weeks (range: 3 – 56; 95% CI = 12 – 14). The median survival was 32 weeks (range: 4 – 104; 95% CI = 27 – 36). Clinical benefit response was acheived for 26 patients (26%). Grade 3/4 haematological toxicities occurred infrequently (anaemia: 5%; neutropenia: 8% and thrombocytopenia: 3% of patients). Grade 3/4 non-haematological toxicities were not observed. There were no treatment-related deaths. Gemcitabine treatment of patients with locally advanced or metastatic pancreatic cancer is effective and well-tolerated.     

Adverse drug reaction profile of nanoparticle versus conventional formulation of paclitaxel: An observational study

Objectives:

Conventional polyethoxylated castor oil (PCO)-based paclitaxel is associated with major adverse drug reactions (ADRs). Nanoxel, a nanoparticle-based formulation, may improve its tolerability by removing the need for PCO vehicle, and also permit its use in a higher dose. We conducted intensive monitoring of the ADR profile of Nanoxel in comparison with conventional paclitaxel in a public tertiary care set-up.

Materials and Methods:

ADR data were collected from 10 patients receiving Nanoxel and 10 age-matched controls receiving conventional paclitaxel in this longitudinal observational study, conducted in a medical oncology ward over 18 months. Severity was graded as per US National Cancer Institute Common Terminology Criteria for Adverse Events.

Results:

The groups had comparable demography at baseline. The median disease duration and per cycle median dose of paclitaxel were greater in the Nanoxel arm. Total 119 ADRs were noted with Nanoxel and 123 with conventional paclitaxel. Of these, 25 (21.0%, 95% CI 13.69–28.33%) in the Nanoxel and 20 (16.2%, 95% CI 9.74–22.78%) in paclitaxel group were of grade 3/4 severity. Common events included myalgia, nausea, anemia, paresthesia, alopecia, diarrhea, and vomiting with Nanoxel, and paresthesia, anemia, myalgia, anorexia, alopecia, vomiting, diarrhea, stomatitis, and nausea with paclitaxel. Of the less common events (<5%), grade 2 or 3 arthralgia was seen exclusively with Nanoxel while motor neuropathy with muscular weakness was more frequent and severe with conventional paclitaxel. Hypersensitivity reactions were not encountered in either arm, although no antiallergy premedication was employed for Nanoxel.

Conclusions:

Despite its ADR profile being statistically comparable to conventional paclitaxel, this observational study suggests that Nanoxel tolerability could be better, considering that a significantly higher dose was employed. This hypothesis needs confirmation through an interventional study.