Overcoming barriers to opioid-induced constipation management in cancer patients.

PURPOSE: Opioid-induced constipation (OIC) is a common adverse effect of opioid therapy. We aim to identify the main barriers hindering clinical recommendations implementation and propose consensus solutions to improve OIC control in cancer patients. METHODS: Following collaborative and prioritization techniques, a scientific committee generated statements addressing possible barriers to optimal OIC management (related to patients, health providers and health care system), and potential interventions to overcome these barriers. An expert panel of 36 oncologists assessed the statements to reach a consensus. RESULTS: The survey consisted of 70 statements. Consensus was reached on 12/45 items related to barriers (26.6%) and on 19/25 items about corrective interventions (76%). The panel considered that patients are unaware of the existence of a specific OIC treatment, and their information sources are highly variable and unreliable. Regarding health providers, the panel considered that the oncologists prioritize symptoms such as diarrhea, pain, anxiety, or other treatment toxicities, over constipation. Work overload and bureaucratic requirements were the main barriers related to health care system. Regarding potential interventions, best-rated proposals included specific training programs development for primary care physicians and nurses, and multiplatform informative resources development for patients and caregivers, including precisely written instructions about OIC recognition and management. Oncologists assessed positively measures aiming to improve coordination between primary care physicians and oncologists, and nursing consultations implementation. The panel considered useful the OIC treatment algorithms simplification. CONCLUSIONS: The expert panel identified the main barriers to optimal OIC management and suggested some feasible approaches to overcome these barriers.

Procedural pain in patients with cancer: a Delphi expert management consensus.

OBJECTIVES: Diagnosis, treatment and care of cancer often involve procedures that may be distressing and potentially painful for patients. The PROCEDIO Study aimed to generate expert-based recommendations on the management of moderate to severe procedural pain in inpatients and outpatients with cancer. METHODS: Using a two-round Delphi method, experts from pain and palliative care units, medical and radiation oncology and haematology departments expressed their agreement on 24 statements using a 9-point Likert scale, which were classified as appropriate (median 7-9), uncertain (4-6) or inappropriate (1-3). Consensus was achieved if at least two-thirds of the panel scored within the range containing the median. RESULTS: With an overall agreement on the current definition of procedural pain, participants suggested a wider description based on evidence and their clinical experience. A strong consensus was achieved regarding the need for a comprehensive pre-procedural pain assessment and experts emphasised that healthcare professionals involved in procedural pain management should be adequately trained. Most panellists (98.2%) agreed that pharmacological treatment should be chosen considering the duration of the procedure. Transmucosal fentanyl (96.5%) and morphine (71.7%) were recommended as the most appropriate drugs. Oral and nasal transmucosal fentanyl were agreed as the most suitable for both outpatients and inpatients, while consensus was reached for intravenous and subcutaneous morphine for inpatients. CONCLUSIONS: These results provide updated expert-based recommendations on the definition, prevention and treatment of moderate to severe procedural pain, which could inform specialists involved in pain management of patients with cancer.

One-year efficacy and safety of naloxegol on symptoms and quality of life related to opioid-induced constipation in patients with cancer: KYONAL study.

OBJECTIVES: Naloxegol is a peripherally acting µ-opioid receptor antagonist (PAMORA) for treatment of opioid-induced constipation (OIC). The main objective was to analyse the long-term efficacy, quality of life (QOL) and safety of naloxegol in patients with cancer in a real-world study. METHODS: This one-year prospective study included patients older than 18 years, with active oncological disease who were under treatment with opioids for pain control and Karnofsky≥50 and OIC with inadequate response to treatment with laxative (s). All the patients received treatment with naloxegol according to clinical criteria. The main efficacy objectives were measured by the patient assessment of constipation QOL questionnaire (PAC-QOL), the PAC symptoms (PAC-SYM), the response rate at day 15, and months 1-3-6-12, and global QOL (EuroQoL-5D-5L). RESULTS: A total of 126 patients (58.7% males) with a mean age of 61.5 years (95% CI 59.4 to 63.7) were included. PAC-SYM and PAC-QOL total score and all their dimensions improved from baseline (p<0.0001). At 12 months, 77.8% of the patients were responders to naloxegol treatment. Global QOL was conserved from baseline. A total of 28 adverse reactions, mainly gastrointestinal were observed in 15.1% of the patients (19/126), being 75% (21) mild, 17.9% (5) moderate and 7.1% (2) severe. Most adverse reactions (67.9%) appeared the first 15 days of treatment. CONCLUSION: The results of this first long-term and real-world-data study in patients with cancer, showed the sustained efficacy and safety of naloxegol for the treatment of OIC in this group of patients.

Efficacy of naloxegol on symptoms and quality of life related to opioid-induced constipation in patients with cancer: a 3-month follow-up analysis.

OBJECTIVES: Opioid-induced constipation (OIC) can affect up to 63% of all patients with cancer. The objectives of this study were to assess quality of life as well as efficacy and safety of naloxegol, in patients with cancer with OIC. METHODS: An observational study was made of a cohort of patients with cancer and with OIC exhibiting an inadequate response to laxatives and treated with naloxegol. The sample consisted of adult outpatients with a Karnofsky performance status score ≥50. The Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL) and the Patient Assessment of Constipation Symptoms (PAC-SYM) were applied for 3 months. RESULTS: A total of 126 patients (58.2% males) with a mean age of 61.3 years (range 34-89) were included. Clinically relevant improvements (>0.5 points) were recorded in the PAC-QOL and PAC-SYM questionnaires (p<0.0001) from 15 days of treatment. The number of days a week with complete spontaneous bowel movements increased significantly (p<0.0001) from 2.4 to 4.6 on day 15, 4.7 after 1 month and 5 after 3 months. Pain control significantly improved (p<0.0001) during follow-up. A total of 13.5% of the patients (17/126) presented some gastrointestinal adverse reaction, mostly of mild (62.5%) or moderate intensity (25%). CONCLUSIONS: Clinically relevant improvements in OIC-related quality of life, number of bowel movements and constipation-related symptoms were recorded as early as after 15 days of treatment with naloxegol in patients with cancer and OIC, with a good safety profile.

Real-life management of patients with breakthrough cancer pain caused by bone metastases in Spain.

Purpose: We aimed to explore the characteristics, and real-life therapeutic management of patients with breakthrough cancer pain (BTcP) caused by bone metastases in Spain, and to evaluate physicians' opinion of and satisfaction with prescribed BTcP therapy. Participants and methods: For the purposes of this study, an ad-hoc questionnaire was developed consisting of two domains: a) organizational aspects and care standards; b) clinical and treatment variables of bone metastatic BTcP patients. In addition, physicians' satisfaction with their prescribed BTcP therapy was assessed. Specialists collected data from up to five patients receiving treatment for BTcP caused by bone metastasis, all patients gave their consent to participate prior to inclusion. Results: A total of 103 cancer pain specialists (radiation oncologists [38.8%], pain specialists [33.0%], and palliative care (PC) specialists [21.4%]) were polled, and data on 386 BTcP patients with bone metastatic disease were collected. Only 33% of the specialists had implemented specific protocols for BTcP management, and 19.4% had established referral protocols for this group of patients. Half of all participants (50.5%) address quality of life and quality of care in their patients; however, only 27.0% did so from the patient's perspective, as they should do. Most patients had multiple metastases and were prescribed rapid-onset fentanyl preparations (71.2%), followed by immediate-release morphine (9.3%) for the treatment of BTcP. Rapid-onset fentanyl was prescribed more often in PC units (79.0%) than in pain units (75.9%) and radiation oncology units (61.1%) (p<0.01). Furthermore, most physicians (71.8%) were satisfied with the BTcP therapy prescribed. Conclusions: Our results demonstrate the need for routine assessment of quality of life in patients with bone BTcP. These findings also underscore the necessity for a multidisciplinary therapeutic strategy for breakthrough pain in clinical practice in Spain.

Expert consensus on the management of breakthrough cancer pain in older patients. A Delphi study.

OBJECTIVES: We aimed to generate expert-based recommendations on the management of breakthrough cancer pain (BTcP) in older patients with cancer. MATERIAL AND METHODS: A two-round multidisciplinary Delphi study. Specialists rated their agreement with a set of statements using a nine-point Likert scale (one = totally disagree and nine = totally agree). Statements were classified as appropriate (median ranged from seven to nine), irrelevant (median ranged from four to six) or inappropriate (median ranged from one to three). Consensus was established when at least two thirds of the panel scored within any of the ranges. RESULTS: A total of 64 specialists from pain units (44.4%), palliative care units (25.4%), medical oncology (19.1%), geriatric medicine (7.9%) and others (3.2%), participated in two consultation rounds. Specialists agreed that effective coordination between the different specialties and levels of care is essential for proper management of BTcP. Most participants (81.3%) supported the assessment of frailty and resolved (96.8%) that frailty status is a better indicator of patient needs than biological age. Participants agreed (75.8%) in the application of the Davies algorithm for diagnosis of BTcP in older patients. A strong consensus was achieved regarding which pharmacological treatment (transmucosal fentanyl) and dosing method (start low and go slow) are the most suitable for the older population. No agreement was reached on how interventionist techniques should be integrated into the therapeutic strategy for BTcP. CONCLUSIONS: The present Delphi has generated a set of recommendations that will help healthcare professionals in the management of BTcP in older patients.

Observational Study Evaluating the Economic Impact of Breakthrough Pain in Cancer Patients in Clinical Practice in Spain: The IMDI Study.

INTRODUCTION: Breakthrough pain (BTP) has great repercussions on the quality of life, and on the use of health resources. The scope of BTP costs in cancer patients is unknown. The purpose of this study was to evaluate the economic cost of BTP in patients with cancer and the relationship with their quality of life. METHODS: A 1-month observational prospective cost-of-illness study was designed. The patients recorded the consumption of health resources and drugs related to BTP in a diary. The current symptoms in Edmonton Symptoms Assessment Scale (ESAS) and their quality of life (EORTC QLQ-C30, version 3) were assessed. The direct medical and non-medical costs fixed and variable and the indirect costs of the patient and the caregivers were evaluated. Factors related to cost and quality of life were identified using linear generalized models (LGM) type gamma and logistic link. Participants were oncologic patients with BTP, older than 18 years, with controlled basal pain. RESULTS: Eight Spanish pain units, eight palliative care units, and one oncology department included 152 patients. One hundred patients (65.8%) were male and the mean age was 66.8 years (95% CI 64.8-68.8). The total cost per patient was 2941.60 euros per month: 88% direct medical costs, 5% non-medical direct costs, and 7% indirect costs due to lost productivity. A better score in EORTC QLQ-30 quality of life was associated with a reduction in overall costs. CONCLUSIONS: The study showed the results of the first real-life prospective study evaluating the cost of illness of BTP in cancer patients demonstrating that the presence of breakthrough pain in a cancer patient causes a very significant increase in healthcare costs. FUNDING: Kyowa Kirin Farmacéutica, S.L.U.

Evaluation of the quality of care of elderly patients with chronic and breakthrough pain treated with opioids: SAND study.

OBJECTIVE: The objective of this study was to evaluate the quality of care of elderly patients with treatment for chronic pain (CP) and breakthrough pain (BTP). METHODS: A cross-sectional observational study was conducted in 20 pain units, selecting patients aged 70 years or older with baseline controlled CP in treatment with opioids and a diagnosis of BTP. Patients were classified as first episode of BTP or patient in follow-up. The patients completed the SF-12 quality of life questionnaire, Brief Pain Inventory, Lattinen Index, and Edmonton Symptoms Assessment Scale. The patient's satisfaction with the treatment was evaluated through a visual analogue scale (VAS). RESULTS: A total of 199 patients were included with 67.7% women (132). There were 28.5% (55) attending the first visit for BTP and 71.5% (138) were on follow-up visits. On the physical component of the SF-12, 95% had a score below the mean for the Spanish general population and 44% had a score below the mean on the mental component. Worse scores were observed for women in the bodily pain dimension (p = .032) and in the overall physical component (p = .045). There were 62.9% (112) patients satisfied with the treatment for BTP. In the multivariate analysis, SF-12 physical component scores (p = .017) and patient's satisfaction with BTP treatment was better in follow-up visits (p = .031). CONCLUSIONS: All clinical parameters compared between first visit for the treatment of BTP and follow-up visits were improved, so the quality of care was also considered improved. Elderly women and non-oncologic patients were observed to be the population with worse symptom control.

The Neandertals of northeastern Iberia: new remains from the Cova del Gegant (Sitges, Barcelona).

The present study describes a new juvenile hominin mandible and teeth and a new juvenile humerus from level V of the GP2 gallery of Cova del Gegant (Spain). The mandible (Gegant-5) preserves a portion of the right mandibular corpus from the M1 distally to the socket for the dc mesially, and the age at death is estimated as 4.5-5.0 years. Gegant-5 shows a single mental foramen located under the dm1/dm2 interdental septum, a relatively posterior placement compared with recent hominins of a similar developmental age. The mental foramen in Gegant-5 is also placed within the lower half of the mandibular corpus, as in the previously described late adolescent/adult mandible (Gegant-1) from this same Middle Paleolithic site. The Gegant-5 canine shows pronounced marginal ridges, a distal accessory ridge, and a pronounced distolingual tubercle. The P3 shows a lingually-displaced protoconid cusp tip and a distal accessory ridge. The P4 shows a slightly asymmetrical crown outline, a continuous transverse crest, a mesially placed metaconid cusp tip, a slight distal accessory ridge, and an accessory lingual cusp. The M1 shows a Y5 pattern of cusp contact and a well-developed and deep anterior fovea bounded posteriorly by a continuous midtrigonid crest. Gegant-4 is the distal portion of a left humerus from a juvenile estimated to be between 5 and 7 years old at death. The specimen shows thick cortical bone. Although fragmentary, the constellation of morphological and metric features indicates Neandertal affinities for these specimens. Their spatial proximity at the site and similar ages at death suggest these remains may represent a single individual. The addition of these new specimens brings the total number of Neandertal remains from the Cova del Gegant to five, and this site documents the clearest evidence for Neandertal fossils associated with Middle Paleolithic stone tools in this region of the Iberian Peninsula.

Environmental enrichment promotes neurogenesis and changes the extracellular concentrations of glutamate and GABA in the hippocampus of aged rats.

The aim of the present study was to investigate the effects of environmental enrichment on the neurogenesis and the extracellular concentrations of glutamate and GABA in the hippocampus of freely moving young and aged rats. Male Wistar rats of 2 (young) and 25 (old) months of age were housed during 8 weeks in an enriched environment; control rats were kept in individual plastic cages during that same period of time. Rats were injected intraperitoneally with bromodeoxyuridine (BrdU; 40 mg/kg; 7 days) during the fourth week of the housing period to detect neurogenesis in the dentate gyrus (DG) of the hippocampus. Rats were sacrified 6 weeks after the last injection of BrdU. During the last week of housing, rats were tested in the water maze for the evaluation of spatial learning. After the housing period, rats were stereotaxically implanted with guide-cannulas to accommodate microdialysis probes in the CA3 area of the hippocampus and the extracellular concentrations of glutamate and GABA were determined. Aged rats showed a decrease in the number of BrdU positive cells in the dentate gyrus compared to young rats. However, neurogenesis in the dentate gyrus of both young and old rats was increased in animals housed in an enriched environment. Microdialysis experiments in the CA3 area of the hippocampus showed that enriched housing conditions increased basal extracellular concentrations of glutamate in aged rats. Perfusion of KCl 100 mM produced a higher increase of extracellular glutamate and GABA in aged rats but not in young rats housed in an enriched environment compared to control rats. These results suggest that enriched housing conditions change both neurogenesis in the dentate gyrus and glutamate and GABA levels in the CA3 area of the hippocampus of aged rats.

Selective impairment of hippocampal neurogenesis by chronic alcoholism: protective effects of an antioxidant.

A major pathogenic mechanism of chronic alcoholism involves oxidative burden to liver and other cell types. We show that adult neurogenesis within the dentate gyrus of the hippocampus is selectively impaired in a rat model of alcoholism, and that it can be completely prevented by the antioxidant ebselen. Rats fed for 6 weeks with a liquid diet containing moderate doses of ethanol had a 66.3% decrease in the number of new neurons and a 227-279% increase in cell death in the dentate gyrus as compared with paired controls. Neurogenesis within the olfactory bulb was not affected by alcohol. Our studies indicate that alcohol abuse, even for a short duration, results in the death of newly formed neurons within the adult brain and that the underlying mechanism is related to oxidative or nitrosative stress. Moreover, these findings suggest that the impaired neurogenesis may be a mechanism mediating cognitive deficits observed in alcoholism.