Low-dose methadone added to another opioid for cancer pain: a multicentre prospective study.

CONTEXT: The use of methadone for cancer pain management is gaining wider acceptance. However, switching to methadone treatment can still pose challenges. Consequently, there is ongoing development of its use in low doses in combination with other opioids, despite a lack of clinical evidence regarding its efficacy and safety. OBJECTIVES: This study aimed to evaluate the efficacy and tolerability of low-dose methadone in combination with another opioid in patients with moderate-to-severe cancer-related pain in a clinical setting. PATIENTS AND METHODS: This was a prospective, open-label study conducted in 19 pain and/or palliative care centres treating patients with cancer-related pain. Pain intensity, patients' global impression of change, and adverse effects were assessed on day 7 and day 14. The main outcome measure was the proportion of responders. RESULTS: The study included 92 patients. The daily dose of methadone was 3 [3-6] mg at baseline, 9 [4-10] mg on day 7 and 10 [6-15] mg on day 14. The NRS pain ratings significantly decreased from 7 [6-8] at baseline to 5 [3-6] on visit 2 (p < .0001) and 4 [3-6] on visit 3 (p < .0001). Similarly, the VRS pain ratings decreased from 3 [3-3] at baseline to 2 [2-3] on visit 2 (p = 0.026) and 2 [1-3] (p < 0.001) on visit 3. At Visits 1 and 2, half of the patients were considered Responders. Of those responders, 73.5% were High-Responders at Visit 1 and 58.7% were High-Responders at Visit 2. No adverse events related to the risk of QT prolongation, overdose, or drug interactions were reported. CONCLUSION: For patients experiencing moderate to severe cancer-related pain despite initial opioid treatment, our study found that low-dose methadone, when used in combination with another opioid, was both safe and effective. This supports the use of methadone as an adjunct to opioid-based treatment for cancer pain.

Dissecting and modeling photic and melanopsin effects to predict sleep disturbances induced by irregular light exposure in mice.

Artificial lighting, day-length changes, shift work, and transmeridian travel all lead to sleep-wake disturbances. The nychthemeral sleep-wake cycle (SWc) is known to be controlled by output from the central circadian clock in the suprachiasmatic nuclei (SCN), which is entrained to the light-dark cycle. Additionally, via intrinsically photosensitive retinal ganglion cells containing the photopigment melanopsin (Opn4), short-term light-dark alternations exert direct and acute influences on sleep and waking. However, the extent to which longer exposures typically experienced across the 24-h day exert such an effect has never been clarified or quantified, as disentangling sustained direct light effects (SDLE) from circadian effects is difficult. Recording sleep in mice lacking a circadian pacemaker, either through transgenesis (Syt10cre/creBmal1fl/- ) or SCN lesioning and/or melanopsin-based phototransduction (Opn4-/- ), we uncovered, contrary to prevailing assumptions, that the contribution of SDLE is as important as circadian-driven input in determining SWc amplitude. Specifically, SDLE were primarily mediated (>80%) through melanopsin, of which half were then relayed through the SCN, revealing an ancillary purpose for this structure, independent of its clock function in organizing SWc. Based on these findings, we designed a model to estimate the effect of atypical light-dark cycles on SWc. This model predicted SWc amplitude in mice exposed to simulated transequatorial or transmeridian paradigms. Taken together, we demonstrate this SDLE is a crucial mechanism influencing behavior on par with the circadian system. In a broader context, these findings mandate considering SDLE, in addition to circadian drive, for coping with health consequences of atypical light exposure in our society.

Legalisation of euthanasia and assisted suicide: advanced cancer patient opinions - cross-sectional multicentre study.

OBJECTIVES: The French government voted a new law in February 2016 called the Claeys-Leonetti Law, which established the right to deep and continuous sedation, confirmed the ban on euthanasia and ruled out physician-assisted suicide. The aim of this work was to gather the opinion of patients on continuous sedation and the legalisation of medical assistance in dying and to explore determinants associated with favourable and unfavourable opinions. METHODS: This was a French national prospective multicentre study between 2016 and 2020. RESULTS: 331 patients with incurable cancer suffering from locally advanced or metastatic cancer in 14 palliative care units were interviewed. 48.6% of participants expressed a favourable opinion about physician-assisted suicide and 27.2% an unfavourable opinion about its legalisation. Regarding euthanasia, 52% of patients were in favour of its legalisation. In univariate analysis, the only factor determining opinion was belief in God. CONCLUSIONS: While most healthy French people are in favour of legalising euthanasia, only half of palliative care patients expressed this opinion. Medical palliative care specialists were largely opposed to euthanasia. The only determining factor identified was a cultural factor that was independent of the other studied variables. This common factor was found in other studies conducted on cohorts from other countries. This study contributes to the knowledge and thinking about the impact of patients' personal beliefs and values regarding their opinions about euthanasia and assisted suicide. TRIAL REGISTRATION NUMBER: NCT03664856.

[The advanced practice nurse in a supportive care department: The missing link?] / L'infirmière en pratique avancée au sein d'un service de soins de support : le chainon manquant ?

INTRODUCTION: Cancer has become a chronic disease thanks to therapeutic evolutions and justifies the early integration of supportive care in the management. The Advanced Practice Nurse (APN) was created to respond to the increase in the number of patients followed in the long term. The objective of this study is to identify the place and expected missions of an APN within a multidisciplinary supportive care team. MATERIAL AND METHOD: A qualitative study by semi-directed interview using a previously developed interview grid was carried out with 14 health professionals (doctors, nurses and health managers) working in a supportive care service in three Cancer Centres. RESULTS: The role expected by the participants is based on the optimisation of patients' follow-up, the integration of supportive care into the care pathway, the improvement of the relationship with the town, and the development of nursing leadership in the establishment. At the same time, the potential arrival of an APN as a change agent in a supportive care service is a source of fears. DISCUSSION: The APN seems to be a real link in the institutional organisations facilitating the link between the professionals of the institution and with the professionals of the territory. The identification of the origins of the fears expressed should enable work to be done to facilitate the integration of the APN into specific support care services, particularly for patients in palliative situations.

[End-of-life care pathways of patients followed in palliative care in Strasbourg: A retrospective study]. / Parcours de soins en fin de vie des patients suivis en soins palliatifs à Strasbourg : étude rétrospective.

OBJECTIVES: The goal of palliative care is to relieve suffering and provide the best possible quality of life for patients and their families. We looked for individual factors related to a poor-quality end-of-life pathway in patients followed in palliative care. METHODS: We included all the patients followed in palliative care in Strasbourg deceased from October to December of 2020. We retrospectively collected data about these patients, their first contact with palliative care, their care pathway, and their death. Multivariate analysis was undertaken. RESULTS: In total, 116 patients were included. Seventy-nine of them had cancer. At the end of life, people living in an institution were less likely to be admitted to the emergency department (OR=0.06), as were non-communicative patients (OR=0.08). Patients expressing a wish to die at home were less likely to be admitted to and die in an intensive care unit (OR=0.1). Isolated patients and non-communicative patients appeared protected from aggressive treatment (chemotherapy/immunotherapy, dialysis, orotracheal intubation, cardiopulmonary resuscitation) during the last month of life (OR=0.1, OR=0.05). DISCUSSION: Our study suggests a profile of patients less exposed to invasive or unreasonable care at the end of life. It leads us to pay particular attention to young subjects, with family, living at home. In our population followed in palliative care, exposure to aggressive care at the end of life appeared to be very low compared to that observed in similar studies with other populations.

Critically ill cancer patient's resuscitation: a Belgian/French societies' consensus conference.

To respond to the legitimate questions raised by the application of invasive methods of monitoring and life-support techniques in cancer patients admitted in the ICU, the European Lung Cancer Working Party and the Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique, set up a consensus conference. The methodology involved a systematic literature review, experts' opinion and a final consensus conference about nine predefined questions1. Which triage criteria, in terms of complications and considering the underlying neoplastic disease and possible therapeutic limitations, should be used to guide admission of cancer patient to intensive care units?2. Which ventilatory support [High Flow Oxygenation, Non-invasive Ventilation (NIV), Invasive Mechanical Ventilation (IMV), Extra-Corporeal Membrane Oxygenation (ECMO)] should be used, for which complications and in which environment?3. Which support should be used for extra-renal purification, in which conditions and environment?4. Which haemodynamic support should be used, for which complications, and in which environment?5. Which benefit of cardiopulmonary resuscitation in cancer patients and for which complications?6. Which intensive monitoring in the context of oncologic treatment (surgery, anti-cancer treatment …)?7. What specific considerations should be taken into account in the intensive care unit?8. Based on which criteria, in terms of benefit and complications and taking into account the neoplastic disease, patients hospitalized in an intensive care unit (or equivalent) should receive cellular elements derived from the blood (red blood cells, white blood cells and platelets)?9. Which training is required for critical care doctors in charge of cancer patients?

Difficulties in providing palliative care in identified palliative care beds: An exploratory survey.

AIM: Identified Palliative Care Beds (Lits Identifiés Soins Palliatifs - LISPs) is a French specificity. Primarily created to integrate palliative care culture into conventional hospital units, the relevance of this measure became a controversial issue. Nowadays, hospital teams continue to frequently encounter complex situations regarding medical care for palliative patients. To the best of our knowledge, there is only one study, a quantitative one, bridging the gap about that subject. It showed failure in practicing palliative care work around LISP. Our study is based on a qualitative method that complements the quantitative study. It aimed to describe difficulties that limit palliative care practices in managing adult patients in LISP. METHOD: This qualitative exploratory survey was conducted with a sample of health service professionals (n=20), from senior physicians to caregivers. Each semi-structured interview included open questions regarding their experiences, feelings and difficulties with palliative care practices on LISP. It also included closed questions concerning interviewee's demographics and career course. The data for this research were submitted to a two-stage analysis: first, a global review of each interview was performed to identify trends. Then, a detailed breakdown, question by question, was implemented. RESULTS: From a quantitative perspective, the interviews revealed 305 difficulties, indicating the gaps and barriers limiting the implementation of a palliative approach in these services. From a qualitative perspective, five topics raised our attention by their recurrence in discourses: (1) partial knowledge about palliative care definition and legislation mostly due to a lack of training; (2) need for time; (3) need for human resources; (4) need for communication; (5) hard time in transitioning from curative to palliative care. PERSPECTIVE: This survey gives the opportunity to understand health service professionals' difficulties in practicing palliative care in conventional medical services. It raises the central issue of the pricing reform on the health institutes activity. It also provides angles of inquiry to improve LISP effectiveness. This qualitative and descriptive study was designed to explore difficulties in practicing palliative care around LISP. Nevertheless, according to the size of the sample, results will need to be confirmed by a more extensive qualitative survey.

Light therapy with boxes or glasses to counteract effects of acute sleep deprivation.

Sleep deprivation, in the context of shift work, is an increasing major public health issue. We aimed to determine whether early light administration can counteract sleep deprivation effects, and to compare LED-glasses with a traditional light therapy box. This cross-over design study included 18 individuals exposed to light therapy for 30 minutes at 5 am after one night of complete sleep deprivation, to mimic the night shift condition. Individuals were randomly exposed to 10,000 Lux light box, 2,000 Lux LED blue-enriched glasses, and control (ambient dim-light at 8 lux). Alertness, cognition and mood were assessed throughout the night and following morning. Five women and 13 men (mean 24.78 year old) presented with a progressive and increasing alteration of alertness, cognition, and mood during each sleep deprivation. A rebound was observed at 8 am resulting from the circadian drive overriding cumulative sleep homeostatic effects. Morning light significantly improved sleepiness and sustained attention from 5 to 7 am. These effects were comparable between devices and significantly different from control. Both devices were overall well and similarly tolerated. Early morning light therapy in the condition of sleep loss may have broad practical applications to improve sleepiness, sustained attention and subsequent risk of accidents.

Anxiolytics targeting GABAA receptors: Insights on etifoxine.

OBJECTIVES: Anxiety and adjustment disorders are among the most prevalent mental health conditions. This review focuses on γ-aminobutyric acid receptor type A (GABAAR)-mediated anxiolysis, describing the action of both endogenous and exogenous modulators of GABAAR. Future directions and innovative strategies to alleviate anxiety symptoms are discussed, with a particular emphasis on etifoxine. METHODS: We used available data from the recent literature to update the mode of action of anxiolytics. We focussed our search on anxiolytics acting at GABAARs, as well as on the pharmacological properties of formerly and currently prescribed anxiolytics. RESULTS: Considering the adverse effects of current treatments aimed at increasing inhibitory controls, optimisation of existing pharmacotherapies is of crucial importance. Among the alternative compounds targeting the GABAergic system, translocator protein (TSPO) ligands, such as etifoxine (EFX), which promote endogenous neurosteroidogenesis, are emerging as promising candidates for anxiety relief. In several papers comparing the efficacy of benzodiazepines and EFX, EFX showed interesting properties with limited side effects. Indeed, neurosteroids are potent GABAAR modulators with highly underrated anxiolytic properties. CONCLUSIONS: Novel therapeutic strategies have been emerging following the recognition of neurosteroids as potent anxiolytics. Featured at the top of the list for well-tolerated anxiety relief, TSPO ligands such as etifoxine appear promising.

Intravenous Immunoglobulin Therapy Administered Early after Narcolepsy Type 1 Onset in Three Patients Evaluated by Clinical and Polysomnographic Follow-Up.

Narcolepsy type 1 is a rare disabling sleep disorder mainly characterized by excessive daytime sleepiness and cataplexy, an emotion-triggered sudden loss of muscle tone. Patients have a selective degeneration of hypocretin-producing neurons in the dorsolateral posterior hypothalamus with growing evidence supporting the hypothesis of an autoimmune mechanism. Few case studies that reported intravenous immunoglobulin therapy (IVIg) suggest the efficacy of IVIg when administered early after disease onset, but the results are controversial. In these retrospective case observations, IVIg cycles were initiated within one to four months after cataplexy onset in a twenty-seven-year-old man, a ten-year-old girl, and a seven-year-old boy, all three with early onset typical narcolepsy type 1. Efficacy of treatment (three IVIg cycles of 1 g/kg administered at four-week intervals) was evaluated based on clinical, polysomnographic, and multiple sleep latency test (mean latency and SOREM) follow-up. Two patients reported decreased cataplexy frequency and ameliorated daytime sleepiness, but no significant amelioration of polysomnographic parameters was observed. Given the possibility of spontaneous improvement of cataplexy frequency with self-behavioral adjustments, these observations would need to be confirmed by larger controlled studies. Based on the present study and current literature, proof of concept is still missing thus prohibiting the consideration of IVIg as an efficient treatment option.

Neonatal Pain, Still Searching for the Optimal Approach.

BACKGROUND: although neonatal pain management has seen huge improvements in the past years, many gaps between knowledge and practice still exist. OBJECTIVE: to give the reader the state of the art of actual pain management and treatment. METHODS: a literature review was done on the physiopathology of pain, sex differences in the perception of pain, epidemiology, non-pharmacological treatment and developmental care approach, pharmacological treatment with pharmacokinetics and pharmacodynamics approaches. CONCLUSION: despite an increasing knowledge in the field of neonatal pain, many gaps and questions remain, especially relative to the lack of assessment, prevention and treatment of painful procedures, appropriate drugs and dosing to support the well-being and the brain development of this highly vulnerable population.

Arvicanthis ansorgei, a Novel Model for the Study of Sleep and Waking in Diurnal Rodents.

STUDY OBJECTIVES: Sleep neurobiology studies use nocturnal species, mainly rats and mice. However, because their daily sleep/wake organization is inverted as compared to humans, a diurnal model for sleep studies is needed. To fill this gap, we phenotyped sleep and waking in Arvicanthis ansorgei, a diurnal rodent widely used for the study of circadian rhythms. DESIGN: Video-electroencephalogram (EEG), electromyogram (EMG), and electrooculogram (EOG) recordings. SETTING: Rodent sleep laboratory. PARTICIPANTS: Fourteen male Arvicanthis ansorgei, aged 3 mo. INTERVENTIONS: 12 h light (L):12 h dark (D) baseline condition, 24-h constant darkness, 6-h sleep deprivation. MEASUREMENTS AND RESULTS: Wake and rapid eye movement (REM) sleep showed similar electrophysiological characteristics as nocturnal rodents. On average, animals spent 12.9 h ± 0.4 awake per 24-h cycle, of which 6.88 h ± 0.3 was during the light period. NREM sleep accounted for 9.63 h ± 0.4, which of 5.13 h ± 0.2 during dark period, and REM sleep for 89.9 min ± 6.7, which of 52.8 min ± 4.4 during dark period. The time-course of sleep and waking across the 12 h light:12 h dark was overall inverted to that observed in rats or mice, though with larger amounts of crepuscular activity at light and dark transitions. A dominant crepuscular regulation of sleep and waking persisted under constant darkness, showing the lack of a strong circadian drive in the absence of clock reinforcement by external cues, such as a running wheel. Conservation of the homeostatic regulation was confirmed with the observation of higher delta power following sustained waking periods and a 6-h sleep deprivation, with subsequent decrease during recovery sleep. CONCLUSIONS: Arvicanthis ansorgei is a valid diurnal rodent model for studying the regulatory mechanisms of sleep and so represents a valuable tool for further understanding the nocturnality/diurnality switch.