Finding predictors for successful opioid response in cancer patients: An analysis of data from four randomized controlled trials.

CONTEXT: There is no consensus on which "strong" (or step 3 WHO analgesic ladder) opioid to prescribe to a particular patient with cancer-related pain. A better understanding of opioid and patient characteristics on treatment response will contribute to a more personalized opioid treatment. OBJECTIVES: Assessment of potential predictors for successful opioid treatment response in patients with cancer pain. METHODS: An international partnership between four cancer pain research groups resulted in a combined individual-level database from four relevant randomized controlled trials (RCTs; n = 881). Together, these RCTs investigated the short-term (1 week) and medium-term (4 or 5 weeks) treatment responses for morphine, buprenorphine, methadone, oxycodone, and fentanyl. Candidate predictors for treatment response were sex, age, pain type, pain duration, depression, anxiety, Karnofsky performance score, opioid type, and use of anti-neuropathic drug. RESULTS: Opioid type and pain type were found statistically significant predictors of short-term treatment success. Sex, age, pain type, anxiety, and opioid type were statistically, significantly associated with medium-term treatment success. However, these models showed low discriminative power. CONCLUSION: Fentanyl and methadone, and mixed pain were found to be statistically significant predictors of treatment success in patients with cancer-related pain. With the predictors currently assessed our data did not allow for the creation of a clinical prediction model with good discriminative power. Additional - unrevealed - predictors are necessary to develop a future prediction model.

Development and external validation of a predictive multivariable model for last-weeks survival of advanced cancer patients in the palliative home care setting (PACS).

PURPOSE: Various prognostic indexes have been proposed to improve physicians' ability to predict survival time in advanced cancer patients, admitted to palliative care (PC) with a survival probably to a few weeks of life, but no optimal score has been identified. The study aims therefore to develop and externally validate a new multivariable predictive model in this setting. METHODS: We developed a model to predict short-term overall survival in cancer patients on the basis of clinical factors collected at PC admission. The model was developed on 1020 cancer patients prospectively enrolled to home palliative care at VIDAS Milan, Italy, between May 2018 and February 2020 and followed-up to June 2020, and validated in two separate samples of 544 home care and 247 hospice patients. RESULTS: Among 68 clinical factors considered, five predictors were included in the predictive model, i.e., rattle, heart rate, anorexia, liver failure, and the Karnofsky performance status. Patient's survival probability at 5, 15, 30 and 45 days was estimated. The predictive model showed a good calibration and moderate discrimination (area under the receiver operating characteristic curve between 0.72 and 0.79) in the home care validation set, but model calibration was suboptimal in hospice patients. CONCLUSIONS: The new multivariable predictive model for palliative cancer patients' survival (PACS model) includes clinical parameters routinely at patient's admission to PC and can be easily used to facilitate immediate and appropriate short-term clinical decisions for PC cancer patients in the home setting.

[STOPPFrail version 2: a tool for deprescription in medicine, validated in Italian language.] / Strumenti a supporto della deprescrizione in medicina: la versione italiana dello STOPPFrail2.

OBJECTIVE: Deprescribing, i.e. the suspension of drugs whose existing or potential harms outweigh the benefits in the context of care for the individual patient, is an increasingly frequently encountered topic in various congresses today. This issue becomes predominant especially in patients with chronic pathologies with a life expectancy of less than a year, in whom the goal of the treatments passes from healing to caring. Currently there are few validated deprescribing tools, one of these is certainly the STOPPFrail, currently available in its second version. Therefore, we decided to provide for the translation into Italian, to make the description for the elderly patient with limited life expectation more applicable. METHODS: For the translation, we used the method expressed by the European organisation for research and treatment of cancer (Eortc), using forward-backward translation and a Pilot Testing to verify the clarity and comprehensibility of the translation itself. RESULTS: We interviewed 15 experts, of whom 13 responded and completed the evaluation, without bringing to light any unclear sections or sources of misunderstanding. CONCLUSIONS: STOPPFrail2 can be a valid deprescribing tool in the elderly with limited life expectancy; the Italian version can help the physicians in the therapeutic appropriateness in this time of life where it is necessary to focus on the quality of life and on the ethical aspect of the choices, as well as being of help in a "cost-opportunity" logic.

Palliative medicine favourably influences end-of-life cancer care intensity: a large retrospective database study.

OBJECTIVES: Hospice and home palliative care have been associated to a reduction of aggressive treatments in the end-of-life, but data in the Italian context are scanty. Therefore, we aim to investigate the role of palliative care on indicators of end-of-life intensity of care among patients with cancer in Lombardy, the largest Italian region. METHODS: Within a retrospective study using the healthcare utilisation databases of Lombardy, Italy, we selected all residents who died in 2019 with a diagnosis of cancer. We considered as exposure variables admission to palliative care and time at palliative care admission, and as indicators of aggressive care hospitalisations, diagnostic/therapeutic procedures, in-hospital death, emergency department visits and chemotherapy over a time window of 30 days before death; chemotherapy in the last 14 days was also considered. RESULTS: Our cohort included 26 539 individuals; of these, 14 320 (54%) were admitted to palliative care before death. Individuals who were admitted to palliative care had an odds ratio (OR) of 0.27 for one hospitalisation, 0.14 for ≥2 hospitalisations, 0.25 for hospital stay ≥12 days, 0.38 for minor diagnostic/therapeutic procedures, 0.18 for major diagnostic/therapeutic procedures, 0.02 for in-hospital death, 0.35 for one emergency department visit, 0.29 for ≥2 emergency department visits and 0.66 for chemotherapy use in the last 30 days; the OR was 0.56 for chemotherapy use in the last 14 days. CONCLUSIONS: This large real-world analysis confirms and further support the importance of palliative care assistance for patients with cancer in the end- of- life; this is associated to a significant reduction in unnecessary treatments.

[Palliative Care in Lombardy Region: analysis of the care offer in 2019.] / Le cure palliative in Lombardia: analisi dell'offerta assistenziale nel 2019.

OBJECTIVE: The Lombardy Region has one of the most widespread and advanced models of Palliative Care (PC) in the country. However, there is a relative lack of updated data referring to the activity of the Lombardy PC network. METHODS: This work aims to describe the activity carried out in the two main PC care settings (home care and hospice) in 2019 through the analysis of the data sent by each Unit to the Lombardy Region. Data were analysed on a regional basis and considering the 8 Health Protection Agencies (ATS) separately. RESULTS: In 2019, PC activity was provided by 114 home care units (1.14/100,000 inhabitants) and 70 hospice for a total of 812 beds (8.1 beds/100,000 inhabitants). Overall, 25,514 patients were assisted for a total of 29,892 care pathway. 77.6% of the patients assisted were oncologic and about 67% of the patients who died of cancer in Lombardy were intercepted by CP. 54.4% of patients were taken care of in home care, although with a significant difference between cancer patients (58%) and non-cancer patients (42%). In home care, average activation time was 2.8 days and in 81% of cases the assistance was activated within 24-48 hours; in hospice, average activation time was 3.5 days, with 60% of admissions within 24 hours and over 30% with waiting time ≥3 days. The median duration of home palliative care was approximately 21 days (average 40.5), that in hospice was 9 days (average 17.2). In the home care pathways, the prevalent outcome was the death of the patient at home (64%) and hospitalization in hospice (17.2%), while 86% of hospitalizations in hospice ended with death. CONCLUSIONS: This accurate report of the Lombardy PC activity indicates that PC satisfy various qualitative indicators of structural and care process identified by national regulations. However, PC still remain predominantly intended for cancer patients, with relatively short duration of care, particularly in the hospice setting.

Early Diagnosis of Delirium in Palliative Care Patients Decreases Mortality and Necessity of Palliative Sedation: Results of a Prospective Observational Study.

INTRODUCTION: Delirium in end-of-life patients is reported to be between 13% and 42% and up to 80% in the terminal phase. It is a serious clinical situation, often a cause of death due to the frequent ineffectiveness of treatments. This study aimed to assess whether and how much precocity of diagnosis, hitherto little considered, could affect the outcomes and prognosis of delirium in palliative care settings. METHODS: Patients consecutively admitted to a palliative care unit (PCU) between October 2018 and December 2019, cared for both in hospice and home programs, were analyzed. All patients were subjected to a careful procedure aimed at recognizing the onset of delirium. The first step was the detection of prodromal "sentinel" symptoms related to incoming delirium. PCU staff and family members/caregivers were trained to observe the patients and immediately identify the appearance of even one symptom. The final diagnosis was performed with the 4AT (4 A's test). Patients were then included in the categories of "early" or "slow" diagnosis (cut-off: four hours) depending on the time between sentinel symptom observation and the final diagnosis of delirium. RESULTS: Among 503 admitted patients, 95 developed delirium. Confusion was the most frequent sentinel symptom (49.5%). The early diagnosis was more frequent in hospice than in home care (p-value<0.0001). Delirium was positively resolved in 43 patients, of which 25 with an early diagnosis (p-value=0.038). Time to resolution was shorter in the case of early diagnosis (7.1 vs. 13.7 hours in hospice patients; p-value=0.018). Palliative sedation was performed on 25 patients, but only 8 of them had an early diagnosis. CONCLUSION: Time of diagnosis was important in determining the clinical outcomes of patients in charge of PCU who experienced delirium. The early diagnosis reduced both mortality and the necessity of palliative sedation.

Living systematic review to assess the analgesic undertreatment in cancer patients.

BACKGROUND AND AIMS: This living and systematic review aimed to provide an updated summary of the available evidence on pain undertreatment prevalence in patients with cancer; correlations with some potential determinants and confounders were also carried out. MATERIALS AND METHODS: We updated a systematic review published on 2014, including observational and experimental studies reporting the use of the pain management index (PMI) in adults with cancer and pain, from 2014 to 2020. We conducted searches in PubMed/MEDLINE, Embase, and Google Scholar. We performed univariate and multivariable regression analyses to describe the relationship between PMI and a list of potential explanatory variables. RESULTS: Twenty new papers were identified, yielding a total sample size of 66 studies. The proportion of patients classified as undertreated according to the year of study publication shows a higher decrease from 1994 to 2013 (-13% as relative change) than the most recent years 2014-2020 (-11%). The quality of the included studies has increased over the years (from 80% to 93%). At the multivariable analysis, a statistically significant relationship was confirmed between undertreatment and the year of the publication of the study and with a low-medium economic level of the countries, where the studies were conducted. DISCUSSION: Despite the improvement when compared to the period 1994-2000, still about 40% of the cases identified received an analgesic treatment inadequate to the intensity of pain, according to the PMI. Despite its intrinsic limitations, PMI continues to be widely used, and it could allow a continuous monitoring of pain management across a different mix of studies and patients.

Efficacy and Safety of Peripherally Acting µ-Opioid Receptor Antagonist (PAMORAs) for the Management of Patients With Opioid-Induced Constipation: A Systematic Review.

In treating chronic and acute pain, opioids are widely used. Although they do provide analgesia, their usage does come with adverse events (AEs). One of the most burdensome is opioid-induced bowel dysfunction, and more specifically opioid-induced constipation (OIC). The pathogenesis of these AEs is well known as the consequence of the action of opioids on m-receptors in the enteric nervous system. In recent years, medicines counteracting this specific action at the receptors have been registered for clinical use: the peripherally acting µ-opioid receptor antagonists (PAMORAs). The knowledge of their comparative efficacy and tolerability is very important for physicians and patients in opioid therapy. This systematic review of the existing literature on PAMORAs aimed to study the relative clinical advantages and disadvantages. The most important data banks, including "PubMed," "Embase," "CT.gov," "ICTRP" and "CINAHL" were used to find the published material on PAMORAs. The selected publications were examined to systematically analyze the efficacy and safety of the four existing PAMORAs. All of the medications are superior to placebo in reducing OIC. There are few published data on alvimopan used to treat OIC, and it is only indicated for the treatment of post-abdominal surgery ileus. Methylnaltrexone is studied mainly in its subcutaneous (SC) formulation. When used in its oral formulation, it seems more rapid than naloxegol and placebo in the reduction of OIC. Naldemedine is able to produce more spontaneous bowel movements (SBMs) when compared to alvimopan and naloxegol. Tolerability was found to be similar for all of them. In particular, they affect the gastrointestinal tract (GI), with flatulence and diarrhea, especially at high dosages. For some of them, nasopharyngitis and abdominal pain were observed as treatment adverse effects (TEAs). Several cardiovascular TEAs were reported after methylnaltrexone use, but it is not clear whether they were consequences of the drug or related to the general conditions of the patients. Considering the existing data, naloxegol and naldemedine seem to be the best choices, with a higher number of spontaneous bowel movements following naldemedine administration.

Factors for Timely Identification of Possible Occurrence of Delirium in Palliative Care: A Prospective Observational Study.

Delirium occurs in 50-80% of end-of-life patients but is often misdiagnosed. Identification of clinical factors potentially associated with delirium onset can lead to a correct early diagnosis. To this aim, we conducted a prospective cohort study on patients from an Italian palliative care unit (PCU) admitted in 2018-2019. We evaluated the presence of several clinical factors at patient admission and compared their presence in patients who developed delirium and in those who did not develop it during follow-up. Among 503 enrolled patients, after a median follow-up time of 16 days (interquartile range 6-40 days), 95 (18.9%) developed delirium. Hazard ratios (HR) and corresponding 95% confidence intervals were computed using Cox proportional hazard models. In univariate analyses, factors significantly more frequent in patients with delirium were care in hospice, compromised performance status, kidney disease, fever, renal failure, hypoxia, dehydration, drowsiness, poor well-being, breathlessness, and "around the clock" therapy with psychoactive drugs, particularly haloperidol. In multivariate analyses, setting of care (HR 2.28 for hospice versus home care, 95% CI 1.45-3.60; p < 0.001), presence of breathlessness (HR 1.71, 95% CI 1.03-2.83, p = 0.037), and administration of psychoactive drugs, particularly haloperidol (HR 2.17 for haloperidol, 95% CI 1.11-4.22 and 1.53 for other drugs, 95% CI 0.94-2.48; p = 0.048) were significantly associated with the risk of developing delirium. The study indicates that some clinical factors are associated with the probability of delirium onset. Their evaluation in PC patients could help healthcare professionals to identify the development of delirium in those patients in a timely manner.

Influence of Physical Activity on Pain, Depression and Quality of Life of Patients in Palliative Care: A Proof-of-Concept Study.

INTRODUCTION: Palliative care not only focuses on physical ailments associated with the disease, but also considers the psychological, social and spiritual needs of the patients. The aim of this study is to assess the impact of physical activity on palliative care patients, with special regard to the subjective assessment of severity of total pain and quality of life. MATERIALS AND METHODS: The study was conducted on 92 palliative care patients either in a hospice or at home. The tool used to assess the patients was an original questionnaire focusing on the area of their independence and motor abilities. The study attempted to understand whether an appropriate physical activity and the instruction of palliative care patients and their families in the field of independence would improve the quality of life and reduce the intensity of total pain in the patients. RESULTS: All of the patients were at an advanced stage of cancer. The survey at time "0", conducted before the start of the instructions for patients and their relatives, showed that a majority of patients (47, 51.09%) often experienced limitations during the performance of daily activities. In the fourth visit, conducted one week after the fourth educational session, there was a significant increase in patients who did not experience any limitations in performing their daily activities or experienced them just sometimes. CONCLUSIONS: The ultimate effect of the proposed educational program on physical activity was an increase in the quality of life, a reduction in pain and a mood improvement. These results would need confirmation with more extensive studies.

Use of preventive drugs during the last year of life in older adults with cancer or chronic progressive diseases.

PURPOSE: To evaluate the prescription of preventive medications with questionable usefulness in community dwelling elderly adults with cancer or chronic progressive diseases during the last year of life. METHODS: Through the utilization of the healthcare databases of the Lombardy region, Italy, we identified two retrospective cohorts of patients aged 65 years or more, who died in 2018 and had a diagnosis of either a solid cancer (N = 19 367) or a chronic progressive disease (N = 27 819). We estimated prescription of eight major classes of preventive drugs 1 year and 1 month before death; continuation or initiation of preventive drug use during the last month of life was also investigated. RESULTS: Over the last year of life, in both oncologic and non-oncologic patients, we observed a modest decrease in the prescription of blood glucose-lowering drugs, anti-hypertensives, lipid-modifying agents, and bisphosphonates, and a slight increase in the prescription of vitamins, minerals, antianemic drugs, and antithrombotic agents (among oncologic patients only). One month before death, the prescription of preventive drugs was still common, particularly for anti-hypertensives, antithrombotics, and antianemics, with more than 60% of patients continuing to be prescribed most preventive drugs and an over 10% starting a therapy with an antithrombotic, an antianemic, or a vitamin or mineral supplement. CONCLUSION: These findings support the need for an appropriate drug review and improvement in the quality of drug prescription for vulnerable populations at the end-of-life.

Nutraceuticals and Exercise against Muscle Wasting during Cancer Cachexia.

Cancer cachexia (CC) is a debilitating multifactorial syndrome, involving progressive deterioration and functional impairment of skeletal muscles. It affects about 80% of patients with advanced cancer and causes premature death. No causal therapy is available against CC. In the last few decades, our understanding of the mechanisms contributing to muscle wasting during cancer has markedly increased. Both inflammation and oxidative stress (OS) alter anabolic and catabolic signaling pathways mostly culminating with muscle depletion. Several preclinical studies have emphasized the beneficial roles of several classes of nutraceuticals and modes of physical exercise, but their efficacy in CC patients remains scant. The route of nutraceutical administration is critical to increase its bioavailability and achieve the desired anti-cachexia effects. Accumulating evidence suggests that a single therapy may not be enough, and a bimodal intervention (nutraceuticals plus exercise) may be a more effective treatment for CC. This review focuses on the current state of the field on the role of inflammation and OS in the pathogenesis of muscle atrophy during CC, and how nutraceuticals and physical activity may act synergistically to limit muscle wasting and dysfunction.

Impact of Palliative Care in Evaluating and Relieving Symptoms in Patients with Advanced Cancer. Results from the DEMETRA Study.

Background: Cancer patients experience multiple symptoms throughout the course of the disease. We aimed to provide a comprehensive analysis of the symptom burden in patients with advanced cancer at admission to specialist palliative care (PC) services and seven days later to estimate the immediate impact of PC intervention. Patient and methods: The analysis was based on an observational, prospective, multicenter study (named DEMETRA) conducted in Italy on new patients accessing network specialist PC centers during the period May 2017-November 2017. The prevalence and intensity of symptoms were assessed at baseline and after seven days using three tools including the Edmonton Symptom Assessment System (ESAS). Results: Five PC centers recruited 865 cancer patients. Thirty-three different symptoms were observed at the baseline, the most frequent being asthenia (84.9%) and poor well-being (71%). The intensity of the most frequent symptoms according to ESAS ranged from 5.5 for asthenia to 3.9 for nausea. The presence and intensity of physical symptoms increased with increasing levels of anxiety and depression. After seven days, prevalence of nausea and breathlessness as well as intensity of almost all symptoms significantly decreased. Conclusions: The study confirmed the considerable symptom burden of patients with advanced cancer. PC intervention has significantly reduced the severity of symptoms, despite the patients' advanced disease and short survival.

Pain and Frailty in Hospitalized Older Adults.

INTRODUCTION: Pain and frailty are prevalent conditions in the older population. Many chronic diseases are likely involved in their origin, and both have a negative impact on quality of life. However, few studies have analysed their association. METHODS: In light of this knowledge gap, 3577 acutely hospitalized patients 65 years or older enrolled in the REPOSI register, an Italian network of internal medicine and geriatric hospital wards, were assessed to calculate the frailty index (FI). The impact of pain and some of its characteristics on the degree of frailty was evaluated using an ordinal logistic regression model after adjusting for age and gender. RESULTS: The prevalence of pain was 24.7%, and among patients with pain, 42.9% was regarded as chronic pain. Chronic pain was associated with severe frailty (OR = 1.69, 95% CI 1.38-2.07). Somatic pain (OR = 1.59, 95% CI 1.23-2.07) and widespread pain (OR = 1.60, 95% CI 0.93-2.78) were associated with frailty. Osteoarthritis was the most common cause of chronic pain, diagnosed in 157 patients (33.5%). Polymyalgia, rheumatoid arthritis and other musculoskeletal diseases causing chronic pain were associated with a lower degree of frailty than osteoarthritis (OR = 0.49, 95%CI 0.28-0.85). CONCLUSIONS: Chronic and somatic pain negatively affect the degree of frailty. The duration and type of pain, as well as the underlying diseases associated with chronic pain, should be evaluated to improve the hospital management of frail older people.

Clinical Care Conditions and Needs of Palliative Care Patients from Five Italian Regions: Preliminary Data of the DEMETRA Project.

In order to plan the right palliative care for patients and their families, it is essential to have detailed information about patients' needs. To gain insight into these needs, we analyzed five Italian local palliative care networks and assessed the clinical care conditions of patients facing the complexities of advanced and chronic disease. A longitudinal, observational, noninterventional study was carried out in five Italian regions from May 2017 to November 2018. Patients who accessed the palliative care networks were monitored for 12 months. Sociodemographic, clinical, and symptom information was collected with several tools, including the Necesidades Paliativas CCOMS-ICO (NECPAL) tool, the Edmonton Symptom Assessment System (ESAS), and interRAI Palliative Care (interRAI-PC). There were 1013 patients in the study. The majority (51.7%) were recruited at home palliative care units. Cancer was the most frequent diagnosis (85.4%), and most patients had at least one comorbidity (58.8%). Cancer patients reported emotional stress with severe symptoms (38.7% vs. 24.3% in noncancer patients; p = 0.001) and were less likely to have clinical frailty (13.3% vs. 43.9%; p < 0.001). Our study confirms that many patients face the last few months of life with comorbidities or extreme frailty. This study contributes to increasing the general knowledge on palliative care needs in a high-income country.

The Complex Balance between Analgesic Efficacy, Change of Dose and Safety Profile Over Time, in Cancer Patients Treated with Opioids: Providing the Clinicians with an Evaluation Tool.

BACKGROUND: Scanty data exist on the integration between the analgesic effect of opioids, dose changes, and adverse events in cancer patients. METHODS: To provide further information on this issue, we analysed data on 498 advanced-stage cancer patients treated with strong opioids. At baseline and three visits (at days 7, 14, and 21), pain intensity, oral morphine-equivalent daily dose, and the prevalence of major adverse events were measured. The proportion of responders (pain intensity decrease ≥30% from baseline) and non-responders, as well as of patients with low or high dose escalation, was calculated. RESULTS: Pain intensity strongly decreased from baseline (pain intensity difference -4.0 at day 7 and -4.2 at day 21) in responders, while it was quite stable in non-responders (pain intensity difference -0.8 at day 7 and -0.9 at day 21). In low dose escalation patients (82.4% at final visit), daily dose changed from 52.3 to 65.3 mg; in high dose escalation patients (17.6%), it varied from 94.1 to 146.7 mg. Among responders, high dose escalation patients experienced significantly more frequent adverse events compared to low or high dose escalation patients, while no differences were observed in non-responders. CONCLUSIONS: The response to opioids results from the combination of three clinical aspects, which are strongly interrelated. These results provide some thoughts to help clinical evaluations and therapeutic decisions regarding opioid use.

Identification of genetic polymorphisms modulating nausea and vomiting in two series of opioid-treated cancer patients.

Nausea and vomiting are often associated with opioid analgesia in cancer patients; however, only a subset of patients develop such side effects. Here, we tested the hypothesis that the occurrence of nausea and vomiting is modulated by the genetic background of the patients. Whole exome sequencing of DNA pools from patients with either low (n = 937) or high (n = 557) nausea and vomiting intensity, recruited in the European Pharmacogenetic Opioid Study, revealed a preliminary association of 53 polymorphisms. PCR-based genotyping of 45 of these polymorphisms in the individual patients of the same series confirmed the association for six SNPs in AIM1L, CLCC1, MUC16, PDE3A, POM121L2, and ZNF165 genes. Genotyping of the same 45 polymorphisms in 264 patients of the Italian CERP study, also treated with opioids for cancer pain, instead confirmed the association for two SNPs in ZNF568 and PDE3A genes. Only one SNP, rs12305038 in PDE3A, was confirmed in both series, although with opposite effects of the minor allele on the investigated phenotype. Overall, our findings suggest that genetic factors are indeed associated with nausea and vomiting in opioid-treated cancer patients, but the role of individual polymorphisms may be weak.

Lack of Efficacy: When Opioids Do Not Achieve Analgesia from the Beginning of Treatment in Cancer Patients.

INTRODUCTION: Opioids are often used to relieve moderate to severe pain, but their analgesic response may vary. We focused on the absolute lack of analgesic response immediately after beginning opioid treatment, quantifying the proportion of patients with unchanged or worse pain on day 3 (defined as early non-responders (ENRs)) and day 7. METHODS: This is a post-hoc analysis from a randomized controlled trial involving 498 cancer patients with pain, starting to receive WHO step III opioids. On days 1, 3 and 7 pain intensity (PI) was measured. RESULTS: On day 3, 68 (13.7%) patients were ENRs, 53 no change and 15 greater PI compared to baseline. The relationships between pain and clinical characteristics showed no significant differences between ENRs and Early responders (ERs), except for PI at baseline, which was significantly lower in ENRs. ENRs on day 3 were re-assessed on day 7 to explore the patterns of analgesic response: 31.7% of patients remained NRs, 48.3% had become responders, and 20.0% were poor responders. Adverse drug reactions were similar in ERs and ENRs at each visit. DISCUSSION: The complete lack of early response to opioids in cancer patients is clinically important and more frequent than expected. Better definition of the mechanism will allow better pain management in cancer and non-cancer patients.

Oral prolonged-release Oxycodone-Naloxone: analgesic response, safety profile, and factors influencing the response in advanced cancer patients.

BACKGROUND: Oxycodone-Naloxone (OXN) aims to reduce opioid-related constipation while being successfully analgesic. METHODS: We evaluated the analgesic response, prevalence, and severity of side effects in 176 cancer patients with moderate to severe pain and treated with OXN. Patients were followed for 28 days and evaluated every seven. Pain intensity, changes of therapy, and adverse drug reactions were recorded at each visit. The primary efficacy endpoint was the proportion of responders (≥30% reduction of pain intensity from baseline to final) and final average pain score ≤4 on a 0-10 scale. RESULTS: Average and worst pain intensity, and breakthrough pain (BTP) prevalence decreased over time and 81.3% of patients were responders. The starting daily dose of OXN was raised from 25.1±13.0 mg to 44.1±29.9 mg, and dose escalation >5%/day was observed in 19.4% of patients; 40.8-46.2% and 11.0-17.0% experienced any and severe grade of constipation during the follow-up visit, respectively. Digestive system tumor, thyroid endocrinopathies, psychological irritability, and BTP increased the risk of analgesic non-response. CONCLUSIONS: OXN had strong analgesic effect in moderate to severe cancer pain patients: the safety profile is in line with the common adverse effects of opioids and severe constipation was uncommon. This article is protected by copyright. All rights reserved.

The Burden of Opioid Adverse Events and the Influence on Cancer Patients' Symptomatology.

CONTEXT: Opioids are frequently used for the treatment of moderate-to-severe pain and their use may produce a number of unwanted adverse events (AEs). OBJECTIVES: The objective of this study was to understand the burden of opioid-induced AEs in cancer patients with pain after the introduction of strong opioids (WHO Step III). METHODS: This is a cohort study derived from a randomized controlled trial involving 498 cancer patients with pain who received strong opioids. During 28-day follow-up, we analyzed frequency, intensity, and changes over time of the main opioid-induced AEs; the influence of previous pain therapy on AEs; and the relationships between the presence of AEs and analgesic response. RESULTS: After starting strong opioids, dry mouth, nausea, and vomiting immediately increased and persisted over time, constipation continued to increase, while drowsiness and confusion tended to decrease. Patients previously treated with weak opioids had more frequent and severe AEs. While at all observation points the percentage of patients without AEs was 37%-39%, considering all the five scheduled visits, from Day 3 to Day 28, 17% of patients never experienced any AEs, while 48% of patients had four or more concomitant AEs. Patients with no AEs experienced significantly lower pain intensity. CONCLUSION: Opioid introduction induces various AEs that persist over time and worse patients' symptomatology. Moreover, there seems to be a different expression of the opioid toxicity among patients, and a possible interaction between AEs and the analgesic response. The balance between the opioids analgesic effect and induced toxicity is fundamental in deciding the best management for pain in cancer patients.