Association of opioid use with survival in patients with cancer treated with immune checkpoint inhibitors: it is time for evidence-based behaviors.

Cancer is a leading cause of morbidity and mortality worldwide, with pain experienced by most patients undergoing cancer treatment. Opioids are the recommended treatment for cancer pain management, but recent studies suggest a negative association between opioid use and survival rates among patients undergoing immunotherapy. However, conclusions cannot be drawn regarding causality from these observational data. Immunotherapy, which boosts the body's immune system to fight cancer cells, has emerged as a promising treatment option for all types of cancer. Immune checkpoint inhibitors (ICIs) can activate the anticancer function of exhausted T cells and have shown remarkable survival benefits in patients with multiple malignancies. However, a recent systematic review and meta-analysis suggested that the use of opioids during ICI treatment has an adverse effect on patient prognosis, while the use of NSAIDs is not significantly associated with the prognosis in patients treated with ICIs. These reviews have major limitations due to the retrospective nature of the studies and the multiple factors that can influence the phenomenon. Therefore, caution is required when interpreting results from retrospective data on drug interactions. The findings of this study are alarming and potentially harmful to patients with cancer suffering from pain or other symptoms requiring opioid drugs.

Medicinal Cannabis: Extended Stability of Cannabis Extracts Produced Using a New Ethanol-based Extraction Method.

Cannabis as a therapeutic agent is increasing in popularity all around the globe, particularly in Western countries, and its potential is now well assessed. On the other hand, each country has its own regulation for the preparation of cannabis macerated oils; in Italy, there are only a few preparation methods allowed. With this work, we aim to perform a stability study of cannabis oils produced with a novel method for the extraction of cannabinoids from cannabis inflorescence. Three different varieties of cannabis were used, with and without the adding of tocopherol acetate as an antioxidant. Cannabinoids were extracted using ethanol at room temperature; then, the solvent was evaporated under reduced pressure and the preparations reconstituted with olive oil. In this work, we assessed the stability of both cannabinoids and terpenes in these formulas over 8 months. Cannabinoid stability was assessed by monitoring the concentrations of THC and CBD, while terpene stability was assessed by monitoring ß-Caryophyllene and α-Humulene concentrations. Stability of the extracts was not influenced by the presence of tocopherol acetate, though refrigeration seems to be detrimental for a long storage of products, especially regarding THC concentrations. The improvements offered by this method reside in the flexibility in controlling the concentration of the extract and the ability to produce highly concentrated oils, alongside the possibility to produce standardized oils despite the variability of the starting plant material.

Strategies to build and maintain competence in pain management: Insights from a SIAARTI survey on educational needs among Italian anesthesiologists.

PURPOSE: Fulfilling educational needs in pain management should be a lifelong process, even involving physicians board certified in pain medicine such as the anesthesiologists/pain therapists. The aim of the study was to investigate Italian anesthesiologists' self-perceived competency, confidence, and interest to attend educational programs in relation to their seniority in pain management. METHODS: SIAARTI members were sent an online questionnaire addressing the following items: education, skills (both soft and hard skills), technical expertise and engaged to participate between December 2020 and January 2021. Participants rated their competence based on the following range (no knowledge, knowledge, competence) while their agreement to attend educational courses was assessed using a 5-point Likert-type scale. RESULTS: Less than one in four participants declare to be dedicated to pain medicine activity with greater proportion among older (over 61 years) compared to younger ones (31-40 years). Regarding cancer and chronic noncancer pain a positive gradient of self-perceived competence has been observed in relation to seniority. In contrast, no gradient of self-perceived competence was reported about musculoskeletal and low back pain. Participants self-perceived competent in both opioid use and prevention of opioid-related adverse event while feeling less competent when managing drugs with abuse potential. The lowest competence has been observed in pediatric pain along with the lowest interest to attend educational courses. Participants were much and very much interested to education regarding cancer, noncancer, musculoskeletal, and low back pain, invasive analgesic procedures but less regarding items for which they declared less competence, such as use of pain scales, pain management in children, and use of drugs with abuse potential. CONCLUSION: This work provides first evidence of a summative assessment of competency and related educational needs' profile of anesthesiologists/pain therapists thus paving the way for developing a nationwide educational program to improve chronic pain care in Italy.

Rapid and Impressive Response to a Combined Treatment with Single-Dose Tocilizumab and NIV in a Patient with COVID-19 Pneumonia/ARDS.

Treatment of acute respiratory distress syndrome (ARDS) due to COVID-19 pneumonia (CARDS) represents a clinical challenge, requiring often invasive mechanical ventilation (IMV). Since the pathogenesis of CARDS it probably involves a direct viral attack to pulmonary and endothelium cells, and immune-mediated inflammation with dysfunctional coagulation, it was suggested to interfere with interleukin-6 (IL-6) activity by using the IL-6 receptor monoclonal antibody tocilizumab (TCZ). We reported the case of a 54-year-old 100 kg male COVID-19 patient (BMI 29) with severe respiratory insufficiency featuring dyspnea and hypoxia (SpO2 89% on room; PaO2 53 mmHg). Despite treatment with antiviral and non-invasive ventilation (NIV), after 24 h there was a progressive worsening of clinical conditions with higher fever (40 °C), increased dyspnea, and hypoxia (PaO2/FiO2 or P/F ratio of 150). The patient was at the limit to be sedated and intubated for IMV. He was treated with tocilizumab (8 mg/Kg i.v., single shot 800 mg) and NIV in the prone positioning. After only 96 h, the clinical, laboratory, and imaging findings showed incredible improvement. There was an important gain in oxygenation (P/F 300), a decrease of C-reactive protein values, and a decrease of the fever. Both the neutrophil-to-lymphocyte ratio (NLR) and the derived NLR ratio dropped down to 44%. Chest imaging confirmed the favorable response. This case suggested that for CARDS management efforts are needed for reducing its underlying inflammatory processes. Through a multiprofessional approach, the combination of IL-6-targeting therapies with calibrated ventilatory strategies may represent a winning strategy for improving outcomes.

The use of low doses of a sublingual fentanyl formulation for breakthrough pain in patients receiving low doses of opioids.

OBJECTIVE: The aim of this study was to prospectively assess the efficacy and safety of low doses of sublingual fentanyl (SLF) for the treatment of breakthrough pain (BTP) in cancer patients in patients who were receiving low opioid doses for background analgesia. METHODS: A sample of cancer patients presenting BTP episodes and receiving stable low doses of opioids for background pain (less than 60 mg of oral morphine equivalents) was selected to assess the efficacy and safety of low doses of SLF (67 µg). For each patient, data from four consecutive episodes were collected. For each episode, changes in pain intensity and adverse effects when pain got severe (T0), and 5, 10, and 15 min after SLF administration (T5-T30) were recorded. The occurrence of serious effects occurring within 2 h of SLF administration were also considered. RESULTS: Fifty-one patients were recruited for the study. The mean age was 66.8 (SD 12.9). A mean of 3.3 episodes/patient were recorded. Four patients did not have episodes of BTP. 147 episodes were evaluated. Six episodes (4.1 %) required a rescue medication at T30. Pain intensity significantly decreased at T5, T10, T15 and T30 (p < 0.0005 in all cases). A high percentage of patients had a pain reduction of more than 33 and 50 % at T5, T10, T15 and T30. Adverse effects were mild and generally already present, due to basal opioid treatment or disease. No serious adverse effects were observed for the subsequent 2 h. CONCLUSION: This study suggests that SLF given in low doses in patients receiving lower doses of opioids for background analgesia is safe and effective in clinical practice.

Breakthrough Cancer Pain: Ten Commandments.

The term "breakthrough cancer pain" (BTcP) was introduced about 25 years ago. Peaks of pain intensity reported in patients with cancer had been invariably examined in the past years, providing relevant information for a better knowledge of this phenomenon and its treatment. The aim of this critical review was to provide the golden rules, namely, the 10 commandments, for a correct diagnostic pathway of BTcP and a consequent personalized pharmacological treatment. These are as follows: 1) assessment of background analgesia, 2) drugs used for background analgesia, 3) BTcP is a frequent phenomenon, 4) characteristics of BTcP, 5) diagnosis of BTcP, 6) continuous assessment, 7) tailored pharmacological treatment of BTcP, 8) selection of BTcP medication, 9) dosing BTcP medications, and 10) education. These steps may help clinicians to recognize and treat BTcP adequately.

Breakthrough pain and its treatment: critical review and recommendations of IOPS (Italian Oncologic Pain Survey) expert group.

Controversies exist about the definition and epidemiology of breakthrough cancer pain (BTcP), the pharmacological treatment options, drug dosing, and how to select the medications for BTcP among the new fentanyl products. Existing data were critically evaluated to provide recommendations by an expert group. An algorithm to diagnose BTcP should be used followed by a careful assessment. Fentanyl products provide efficacy and rapidity of action to counteract the temporal pattern of BTcP. The doses of opioids used for background pain should guide the choice of the doses of fentanyl products. The choice of fentanyl products should be based on individual clinical conditions.

Limitation in monitoring depth of anesthesia: a case report.

Although we describe a clinical situation that most likely occurs in hundreds of operatory rooms in the world, we report this case as provocation. It concerns an unexpected awakening from an appropriate depth of anesthesia, although the BIS monitor showed a BIS index of less than 50 for a prolonged period before and after the event. Approximately 30 min after induction of anesthesia, the patient had a hypothetic sudden arousal of consciousness, with spontaneous movements, facial muscle activation, intolerance to the tracheal tube, and tearing. After immediate intravenous administration of midazolam (4 mg), the patient returned to a depth of anesthesia status, and surgery was completed uneventfully. The patient had no recall of the event when questioned during the episode, at emergence, or at 24 h, 36 h, and 7 days after surgery. Were these events spinal reflexes to pain or stimulation although the cortex was still anesthetized? Maybe this is the more rational explanation. Was the patient awake but not aware? Is it possible that our patient experienced only a transient arousal from consciousness, and that he did not have recall because the arousal time was short and we blocked memory consolidation? The latter hypothesis provides an opportunity to discuss the evidence that at the moment there is no device to assess the depth of anesthesia. We also focus on the possibility of interfering with memory processing under anesthesia.

Long-term efficacy and tolerability of intranasal fentanyl in the treatment of breakthrough cancer pain.

PURPOSE: The aim of the present study was to assess the long-term tolerability and efficacy of intranasal fentanyl (INFS) in opioid-tolerant patients with breakthrough cancer pain (BTP). PATIENTS AND METHODS: A 6 months, observational, prospective, cohort study design was employed to follow advanced cancer patients with BTP receiving INFS under routine clinical practice. Eligible adult cancer patients suffering from BTP had been prescribed INFS at effective doses. Data were collected at T0 and at month intervals for six months. The principal outcomes were the evaluation of possible serious adverse effects with prolonged use of INFS, the efficacy of BTP treatment with INFS, the quality of sleep, the rate of INFS discontinuation, and reasons for that. RESULTS: Seventy-five patients were surveyed. Thirty-four patients (45.3 %) had a follow-up at 3 months, and twelve patients (16 %) were followed up at 6 months. The mean opioid doses, expressed as oral morphine equivalents, ranged 111-180 mg/day, while the mean INFS doses were 87-119 µg. Adverse effects were reported in a minority of patients and were considered to be associated with opioid therapy used for background pain. The quality of sleep significantly improved during the first 3-4 months. Finally, efficacy based on a general impression regarding the efficacy of INFS was good-excellent in most patients and statistically improved in time up to the third month. CONCLUSION: The long-term use of INFS in advanced cancer patients is effective and safe. No serious adverse effects were found up to six months of assessment. The level of quality of sleep and patients' satisfaction was relatively good, considering the advanced stage of disease.

Role of Nutrition in the Management of Patients with Chronic Musculoskeletal Pain.

Chronic musculoskeletal pain (CMP), defined as persistent discomfort in musculoskeletal tissues persisting for over 3 months, afflicts an estimated 1.71 billion people globally, leading to significant functional impairments and psychological distress, thereby detrimentally affecting individuals' quality of life. The objective of this narrative review is to elucidate the complex relationship among dietary habits, sarcopenia, and gut microbiota composition, with an eye toward enhancing patient management and outcomes. Given the burgeoning interest in the influence of diet on CMP, a detailed examination of the current literature is warranted. Nutritional intake is a critical determinant of the gut microbiota profile, which, in turn, is linked to musculature integrity and performance, potentially leading to sarcopenia. The development of sarcopenia can aggravate CMP owing to diminished muscular strength and functionality. Additionally, disruptions in the gut microbiota may directly modulate nociception, intensifying CMP manifestations. Thus, nutritional optimization emerges as a viable approach to CMP management. Emphasizing a diet conducive to a healthy gut microbiome could forestall or mitigate sarcopenia, thereby attenuating CMP intensity. Nevertheless, the domain calls for further empirical exploration to unravel the nuances of these interactions and to forge efficacious dietary strategies for individuals with CMP. Beyond mere analgesia, comprehensive patient care for CMP requires acknowledgment of the complex and multifactorial nature of pain and its foundational elements. Embracing an integrative treatment model allows healthcare practitioners to promise better patient prognoses, enriched life quality, and a decrease in the sustained healthcare costs associated with CMP.

Chronic musculoskeletal pain (CMP) is long-lasting pain in the bones, muscles, and joints, and it's a common problem affecting over 1.7 billion people worldwide. This kind of pain can really disrupt someone's daily life, making it hard to do everyday things and causing a lot of stress. This review is like a deep dive into how eating habits, muscle loss, and the tiny organisms living in our guts all connect to this pain. As we are becoming more curious about how food affects CMP, it's important to look closely at what we already know. What we eat can change the tiny bugs in our guts, which has a big impact on our muscles. If our muscles get weak and shrink (a condition called sarcopenia), it can make CMP worse because weak muscles cannot support our bodies well. Also, if the balance of bugs in our gut is off, it might even make us feel pain more intensely. So, changing what we eat might be a good way to tackle CMP. Eating foods that keep our gut bugs happy might help prevent muscle loss and reduce pain. But we still need to do more research to understand this better and to figure out the best foods to eat for this purpose. Treating CMP is not just about getting rid of the pain; it's about looking at the whole picture and all the things that contribute to the pain. By considering everything ­ from our diet to our muscles to our gut bugs ­ doctors can help improve the lives of people with CMP, making them more comfortable and possibly reducing medical costs in the long run.

Cannabinoids for Cancer-related Pain Management: An Update on Therapeutic Applications and Future Perspectives.

Pain is a debilitating phenomenon that dramatically impairs the quality of life of patients. Many chronic conditions, including cancer, are associated with chronic pain. Despite pharmacological efforts that have been conducted, many patients suffering from cancer pain remain without treatment. To date, opioids are considered the preferred therapeutic choice for cancer-related pain management. Unfortunately, opioid treatment causes side effects and inefficiently relieves patients from pain, therefore alternative therapies have been considered, including Cannabis Sativa and cannabinoids. Accumulating evidence has highlighted that an increasing number of patients are choosing to use cannabis and cannabinoids for the management of their soothing and non-palliative cancer pain and other cancer-related symptoms. However, their clinical application must be supported by convincing and reproducible clinical trials. In this review, we provide an update on cannabinoid use for cancer pain management. Moreover, we tried to turn a light on the potential use of cannabis as a possible therapeutic option for cancer-related pain relief.

Fentanyl in cancer pain management: avoiding hasty judgments and discerning its potential benefits.

Cancer pain is an important challenge in treatment and requires a rapid onset of action for its control. In particular, breakthrough cancer pain (BTcP) should be adequately controlled with a stable dose of a short-acting oral opioid. Fentanyl is a synthetic, highly selective opioid with many advantageous chemical properties, including high lipophilicity and distinct pharmacokinetic properties. It is recommended for pain management in a variety of settings, including acute pain, chronic pain and BTcP. To date, its variously designed formulations allow non-invasive administration; amongst others, sublingual fentanyl has proven useful in the management of BTcP and in improving the quality of life of patients with cancer. This review provides an update on the management of BTcP with fentanyl, with consideration of safety, as it remains an important tool in the treatment of cancer pain.

Phytocannabinoids in Triple Negative Breast Cancer Treatment: Current Knowledge and Future Insights.

Triple negative breast cancer (TNBC) represents an aggressive subtype of breast cancer, which is deficient in estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Thus, TNBC cells are unable to respond to the conventional hormonal therapies, making chemotherapy the only therapeutic choice. Patients with TNBC develop metastasis and recurrence over time and have reduced survival compared to patients with other subtypes of breast cancer. Therefore, there is a need for innovative therapies. Data emerged from pre-clinical studies, highlighted various antitumor activities of plant-derived Cannabis sativa and synthetic cannabinoids (CBs), including delta-9-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD). On the contrary, some studies indicated that CBs might also promote tumor progression. At present, clinical studies on the effects of CBs from Cannabis sativa in cancer patients are few. In the present study, we reviewed known and possible interactions between cannabinoids and TNBC therapies.

High-rate breakthrough cancer pain and tumour characteristics - literature review and case series.

Cancer pain requires careful comprehensive patient evaluation and an appropriate and personalized clinical approach by a trained multidisciplinary team. The proper assessment of breakthrough cancer pain (BTcP) is part of an all-inclusive multidimensional evaluation of the patient. The aim of this narrative review is to explore the relationship between high-rate BTcP, which strongly impacts health- related quality of life and tumour characteristics, in the face of novel approaches that should provide guidance for future clinical practice. The presentation of short, emblematic clinical reports also promotes knowledge of BTcP, which, despite the availability of numerous therapeutic approaches, remains underdiagnosed and undertreated. This article is part of the Management of breakthrough cancer pain Special Issue: https://www.drugsincontext.com/special_issues/management-of-breakthrough-cancer-pain.

Investigating Functional Impairment in Chronic Low Back Pain: A Qualitative Study from the Patients and Specialists' Perspectives.

Prompt and appropriate treatment of chronic low back pain (cLBP) is of the utmost importance for preventing relevant disability, high burden of disease, and increasing costs for the healthcare system. Recently, the concept of functional impairment has been associated with any type of chronic pain, and mounting attention has been paid to extending the aims of treatment beyond mere pain remission, including restoration of working capacity, everyday functioning, mobility, and quality of life. Nevertheless, a shared definition of functionality is still lacking. Notably, different specialists involved in the treatment of cLBP such as general practitioners, orthopedists, pain therapists, and physiatrists, and patients themselves have different opinions on what "functional impairment" actually means. On these premises, a qualitative interview study was performed to investigate how the concept of "functionality" is interpreted by different specialists involved in the management of cLBP, and by patients. Overall, all different specialists agreed that functionality should be assessed in clinical practice. However, in spite of several instruments available for evaluating functionality, no homogeneity of behavior is observable.

Implementation of a Hybrid Care Model for Telemedicine-based Cancer Pain Management at the Cancer Center of Naples, Italy: A Cohort Study.

BACKGROUND/AIM: Telemedicine, the remote delivery of healthcare services, represents a great opportunity for cancer pain management. A care model of telemedicine that combines remote visits and hospital access could be an effective and safe strategy for pain management of cancer patients. PATIENTS AND METHODS: A retrospective study was conducted using the dataset of the telemedicine program at the Istituto Nazionale Tumori of Naples, Italy for assessing the efficacy of a telehealth-based model of care. Demographic, clinical, and process variables were investigated. RESULTS: A total of 226 cases and 489 visits were included in the analysis. The mean age of patients was 63.4 years (SD=12.4 years), and no sex differences were observed. Approximately 55% of patients were ECOG-PS ≤2 and 87% suffered from metastatic disease. More than half of the patients were treated with high doses of opioids. Each patient had a mean of 2 remote visits and half of the patients had more than 1 telehealth consultation. The dropout ratio was 5.3%. Most visits (n=472) were conducted on patients in the Campania Region, Italy. The maximum covered distance from the Cancer Center and the patients' location was 555.22 Km. A significant difference in the overall number of visits (p=0.006) and the number of pro-capita remote visits (p=0.010) was found, in favor of the group of patients treated before the end of the Covid-19 emergency in Italy, compared to those treated after the pandemic. CONCLUSION: Despite various positive outcomes, the analysis highlights several weaknesses, such as the need to assist patients with advanced and non-advanced disease located outside the regional territory. Overall, the telehealth processes should be adapted to post-pandemic scenarios towards their implementation in routine clinical practice.

Artificial Intelligence for Automatic Pain Assessment: Research Methods and Perspectives.

Although proper pain evaluation is mandatory for establishing the appropriate therapy, self-reported pain level assessment has several limitations. Data-driven artificial intelligence (AI) methods can be employed for research on automatic pain assessment (APA). The goal is the development of objective, standardized, and generalizable instruments useful for pain assessment in different clinical contexts. The purpose of this article is to discuss the state of the art of research and perspectives on APA applications in both research and clinical scenarios. Principles of AI functioning will be addressed. For narrative purposes, AI-based methods are grouped into behavioral-based approaches and neurophysiology-based pain detection methods. Since pain is generally accompanied by spontaneous facial behaviors, several approaches for APA are based on image classification and feature extraction. Language features through natural language strategies, body postures, and respiratory-derived elements are other investigated behavioral-based approaches. Neurophysiology-based pain detection is obtained through electroencephalography, electromyography, electrodermal activity, and other biosignals. Recent approaches involve multimode strategies by combining behaviors with neurophysiological findings. Concerning methods, early studies were conducted by machine learning algorithms such as support vector machine, decision tree, and random forest classifiers. More recently, artificial neural networks such as convolutional and recurrent neural network algorithms are implemented, even in combination. Collaboration programs involving clinicians and computer scientists must be aimed at structuring and processing robust datasets that can be used in various settings, from acute to different chronic pain conditions. Finally, it is crucial to apply the concepts of explainability and ethics when examining AI applications for pain research and management.

Utilizing an artificial intelligence framework (conditional generative adversarial network) to enhance telemedicine strategies for cancer pain management.

BACKGROUND: The utilization of artificial intelligence (AI) in healthcare has significant potential to revolutionize the delivery of medical services, particularly in the field of telemedicine. In this article, we investigate the capabilities of a specific deep learning model, a generative adversarial network (GAN), and explore its potential for enhancing the telemedicine approach to cancer pain management. MATERIALS AND METHODS: We implemented a structured dataset comprising demographic and clinical variables from 226 patients and 489 telemedicine visits for cancer pain management. The deep learning model, specifically a conditional GAN, was employed to generate synthetic samples that closely resemble real individuals in terms of their characteristics. Subsequently, four machine learning (ML) algorithms were used to assess the variables associated with a higher number of remote visits. RESULTS: The generated dataset exhibits a distribution comparable to the reference dataset for all considered variables, including age, number of visits, tumor type, performance status, characteristics of metastasis, opioid dosage, and type of pain. Among the algorithms tested, random forest demonstrated the highest performance in predicting a higher number of remote visits, achieving an accuracy of 0.8 on the test data. The simulations based on ML indicated that individuals who are younger than 45 years old, and those experiencing breakthrough cancer pain, may require an increased number of telemedicine-based clinical evaluations. CONCLUSION: As the advancement of healthcare processes relies on scientific evidence, AI techniques such as GANs can play a vital role in bridging knowledge gaps and accelerating the integration of telemedicine into clinical practice. Nonetheless, it is crucial to carefully address the limitations of these approaches.

Pathophysiology and Therapeutic Perspectives for Chemotherapy-induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) develops as a challenging nerve-damaging adverse effect of anticancer drugs used in chemotherapy. The disorder may require a chemotherapy dose reduction and a cessation of administration of chemotherapeutic drugs. Its principal sensory symptoms include, tingling, and numbness in the hands and feet. Severe pain can be encompassed among clinical manifestations. CIPN affects dramatically the patient's quality of life (QoL). Pain and sensory symptoms may occur for months, or even years after the termination of chemotherapeutic drugs. Although many pharmacological and non-pharmacological therapeutic approaches have been tested to overcome these symptoms, there is currently no standardized treatment for CIPN. According to current guidelines, Duloxetine is the only recommended agent for painful neuropathic symptoms. Therefore, finding effective therapies for CIPN is mandatory. The aim of this review was to dissect CIPN, the target and immunotherapy-based approaches to this disorder, as well as to offer new insights for new therapeutic perspectives.