Palliative Care Needs Assessment in the Population Living in Mayotte: SPMAYOTTE, a Qualitative Study Conducted with 62 Patients, Caregivers and Healthcare Professionals.

BACKGROUND/AIM: Mayotte is a French island in the Indian Ocean. There is no palliative care structure in this territory. The island and its population have specific characteristics: insularity, poverty, coexistence of modern and traditional medicine, importance of religion (Islam) and the presence of many foreigners without health insurance. The aim of this study is to determine the palliative care needs of the Mayotte population and propose the establishment of an appropriate service. METHODS: A qualitative study was conducted in Mayotte using interviews with patients and their caregivers, and focus groups were conducted with healthcare professionals involved in their care. Patients requiring palliative care were identified and recruited from the hospital or the patient's home by healthcare professionals. RESULTS: A total of 62 people participated in the study between May and June 2019. The needs expressed were analysed and then grouped into categories: access to medical care (especially at home), management of physical symptoms (analgesia) and psychological symptoms, organisation of care (coordination between healthcare professionals) and training of healthcare professionals (pain management, palliative care, interculturality and translation), taking into account cultural and religious aspects. Regarding the foreign population, the categories were: improving access to healthcare, access to the social protection system and daily living conditions (transport, food and accommodation). CONCLUSIONS: The specific needs of the population, assessed through the study, have led to an original proposal, which differs from the usual structures of palliative care in France.

Quelle démarche méthodologique afin d'aboutir à une offre pertinente de soins palliatifs à Mayotte ?

OBJECTIVE: The department of Mayotte is lagging far behind in terms of access to palliative care. We present the methodological approach for assessing the palliative care needs of the population, which led us to make a proposal for a care offer adapted to the local context. METHOD: The main principles of a public health methodology for health needs assessment were followed. The researchers carried out an overall analysis of the situation based on several axes: bibliographical research, collection of quantitative data, qualitative study, interviews with local experts and institutional decision-makers. A summary report of the results was presented to those working in the field at the end of the study in order to support proposals for the creation of a suitable palliative care offer. RESULTS: In view of the paucity of epidemiological data, the qualitative study was decisive in assessing needs. Exchanges with institutional decision-makers enabled a deeper understanding of local specificities and improved the relationship between local actors leading to the emergence of a co-construction process. In December 2019, a palliative care offer resulting from the study’s proposals was funded. CONCLUSION: Our methodology was based on regular exchanges in the field and enabled us to encourage the emergence of a decisive element for the success of the project: the support of carers and institutional decision-makers. This co-construction between the partners allowed interactivity between the different categories of actors involved and reinforced the quality of the work and the emergence of a collective intelligence (study SP Mayotte).

NEO6860, modality-selective TRPV1 antagonist: a randomized, controlled, proof-of-concept trial in patients with osteoarthritis knee pain.

INTRODUCTION: NEO6860 is a TRPV1 antagonist when activated by capsaicin but not by heat or pH, developed to relieve pain without the adverse events reported with non-modality-selective TRPV1 antagonists. OBJECTIVE: The primary Objective of this study was to evaluate the analgesic efficacy and safety of NEO6860 after 1 day oral dosing in patients with Kellgren-Lawrence stage I, II or III osteoarthritis of the knee. METHOD: This randomized, double-blinded, 3-period crossover, phase II study compared 1 day (2 doses) of NEO6860 (500 mg twice a day), placebo, and naproxen in 54 patients with osteoarthritis knee pain. Primary endpoint was reduction in pain intensity (PI) on Numerical Rating Scale after exercise, using the staircase test, 8 hours after dose. RESULTS: Level of PI, compared with baseline, was numerically lower during NEO6860 and naproxen periods vs placebo at 3 and 24 hours, but not at 8 hours after first dose. A statistically significant effect for naproxen and a trend for NEO6860 were observed at 3 and 24 hours. Least square means' (95% confidence interval) change in PI at 24 hours was -0.67 (-1.09 to -0.26), -0.97 (-1.39 to -0.55), -0.29 (-0.71 to 0.13) for NEO6860, naproxen, and placebo, respectively. NEO6860 exposure was ∼1.6 times higher compared with previous phase I. In this study, NEO6860 safety profile was less favorable than naproxen or placebo. Possibly NEO6860-related adverse events included: feel hot, headache, nausea, dizziness, fatigue, hypoaesthesia, and increased blood pressure. CONCLUSION: In this exploratory study, NEO6860 did not statistically significantly outperform placebo but showed an analgesic trend, without impacting body temperature and heat pain perception. Further studies are warranted to explore the potential of NEO6860 in other pain indications. We intent to optimize the dose and evaluate analgesic synergism with other mechanism.

Safety, Pharmacokinetics, and Pharmacodynamics Study in Healthy Subjects of Oral NEO6860, a Modality Selective Transient Receptor Potential Vanilloid Subtype 1 Antagonist.

Most previous transient receptor potential vanilloid subtype 1 (TRPV1) antagonist programs have been put on hold, mainly because of on-target adverse events: hyperthermia and impaired noxious heat sensation. NEO6860 is a TRPV1 antagonist, blocking capsaicin activation of the target, with little or no effect against pH or heat activation. The hypothesis is that this pharmacological profile will translate into analgesia without undesired effects on the body temperature or heat-pain threshold. This phase I, double blind, placebo controlled, ascending dose study, included 64 subjects. Pharmacodynamics (intradermal capsaicin test) was explored. The study was comprised of 6 dose levels (50, 100, 200, 400, 800, and 1,200 mg) and 2 doses of 500 mg, 12 hours apart. NEO6860 was rapidly absorbed and systemic exposure increases were less than dose proportional. Median time of maximum observed plasma concentration values ranged from 2 to 3 hours. The mean apparent plasma terminal elimination half-life was between 4 and 8 hours. No significant food-effect or gender-effect was observed. The most frequently reported events were feeling hot, headache, paresthesia, nausea, and dizziness. Single oral doses of up to 800 mg and two 500-mg doses administered 12 hours apart of NEO6860 were well tolerated in this study. Unlike other TRPV1 antagonists, no clinically significant increase in temperature or heat pain threshold/tolerance was noted despite thorough and specific monitoring of these parameters. At all doses, most subjects reported a sensation of "feeling hot," with a rapid onset and transient. NEO6860 showed an improvement in the pharmacodynamics parameters (evoked pain and secondary hyperalgesia) at 3 and 8 hours post NEO6860 dosing. PERSPECTIVE: This first in human study on NEO6860, showed that an antagonist of TRPV1, blocking only the activation by capsaicin has been identified. This finding paves the way for the development of a new powerful analgesic for many pain conditions, without the fear of the side effects observed with previous TRPV1 antagonists.

Opioid receptor random mutagenesis reveals a mechanism for G protein-coupled receptor activation.

The high resolution structure of rhodopsin has greatly enhanced current understanding of G protein-coupled receptor (GPCR) structure in the off-state, but the activation process remains to be clarified. We investigated molecular mechanisms of delta-opioid receptor activation without a preconceived structural hypothesis. Using random mutagenesis of the entire receptor, we identified 30 activating point mutations. Three-dimensional modeling revealed an activation path originating from the third extracellular loop and propagating through tightly packed helices III, VI and VII down to a VI-VII cytoplasmic switch. N- and C-terminal determinants also influence receptor activity. Findings for this therapeutically important receptor may apply to other GPCRs that respond to diffusible ligands.

Proenkephalin A gene products activate a new family of sensory neuron--specific GPCRs.

Several peptide fragments are produced by proteolytic cleavage of the opioid peptide precursor proenkephalin A, and among these are a number of enkephalin fragments, in particular bovine adrenal medulla peptide 22 (BAM22). These peptide products have been implicated in diverse biological functions, including analgesia. We have cloned a newly identified family of 'orphan' G protein--coupled receptors (GPCRs) and demonstrate that BAM22 and a number of its fragments bind to and activate these receptors with nanomolar affinities. This family of GPCRs is uniquely localized in the human and rat small sensory neuron, and we called this family the sensory neuron--specific G protein--coupled receptors (SNSRs). Receptors of the SNSR family are distinct from the traditional opioid receptors in their insensitivity to the classical opioid antagonist naloxone and poor activation by opioid ligands. The unique localization of SNSRs and their activation by proenkephalin A peptide fragments indicate a possible function for SNSRs in sensory neuron regulation and in the modulation of nociception.