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Elodie Martin,1 Marc Sorel,2 Véronique Morel,3 Fabienne Marcaillou,4 Pascale Picard,4 Noémie Delage,4 Florence Tiberghien,5 Marie-Christine Crosmary,6 Mitra Najjar,6 Renato Colamarino,6 Christelle Créach,7,8 Béatrice Lietar,7 Géraldine Brumauld de Montgazon,9 Anne Margot-Duclot,10 Marie-Anne Loriot,11,12 Céline Narjoz,11,12 Céline Lambert,13 Bruno Pereira,13 Gisèle Pickering1,31Université Clermont Auvergne, Pharmacologie Fondamentale Et Clinique de la Douleur, Neuro-Dol, Inserm 1107, F-63000 Clermont-Ferrand, France; 2Centre D’evaluation et de Traitement de la Douleur/soins Palliatifs, Nemours, France; 3CHU Clermont-Ferrand, Centre de Pharmacologie Clinique/Centre d’investigation Clinique Inserm 1405, F-63003 Clermont-Ferrand cedex, France; 4Centre d’Evaluation et de Traitement de la Douleur, CHU de Clermont-Ferrand, France; 5Centre d’evaluation et de Traitement de la Douleur/soins Palliatifs, CHU Jean Minjoz, Besançon, France; 6Centre d’evaluation et de Traitement de la Douleur, CH Jacques Lacarin Vichy, France; 7Centre d’evaluation et de Traitement de la Douleur, CHU de Saint-etienne, France; 8Inserm U1028 & Umr 5292, Centre de Neurosciences de Lyon, Université Lyon & Jean-monnet De Saint-etienne, France; 9Centre d’evaluation et de Traitement de la Douleur/soins Palliatifs, CH La Rochelle, France; 10Centre d’evaluation et de Traitement de la Douleur, Fondation A de Rothschild, Paris, France; 11Service de biochimie, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France; 12Inserm UMR-S 1147, Université Paris Descartes, Paris, France; 13CHU Clermont-Ferrand, Délégation Recherche Clinique & Innovation - Villa annexe IFSI, 58 Rue Montalembert, F-63003 Clermont-Ferrand cedex, FrancePurpose: Intravenous ketamine is often prescribed in severe neuropathic pain. Oral N-methyl-D-aspartate receptor (NMDAR) antagonists might prolong pain relief, reducing the frequency of ketamine infusions and hospital admissions. This clinical trial aimed at assessing whether oral dextromethorphan or memantine might prolong pain relief after intravenous ketamine.Patients and methods: A multicenter randomized controlled clinical trial included 60 patients after ketamine infusion for refractory neuropathic pain. Dextromethorphan (90 mg/day), memantine (20 mg/day) or placebo was given for 12 weeks (n=20 each) after ketamine infusion. The primary endpoint was pain intensity at one month. Secondary endpoints included pain, sleep, anxiety, depression, cognitive function and quality of life evaluations up to 12 weeks.Results: At 1 month, dextromethorphan maintained ketamine pain relief (Numeric Pain Scale: 4.01±1.87 to 4.05±2.61, p=0.53) and diminished pain paroxysms (p=0.03) while pain intensity increased significantly with memantine and placebo (p=0.04). At 3 months, pain remained lower than at inclusion (p=0.001) and was not significantly different in the three groups. Significant benefits were observed on cognitive-affective domains and quality of life for dextromethorphan and memantine (p

Gisèle Pickering,1–3 Elodie Martin,1,3 Florence Tiberghien,4 Claire Delorme,5 Gérard Mick6,7 1Centre de Pharmacologie Clinique, CHU Clermont-Ferrand, 2Inserm, CIC 1405, Neurodol 1107, 3Laboratoire de Pharmacologie, Faculté de Médecine, Clermont Université, Clermont-Ferrand, 4Centre d’Evaluation et de Traitement de la Douleur, CHU Jean Minjoz, Besançon, 5Centre d’Evaluation et Traitement de la Douleur, Bayeux, 6Unité d’Evaluation et Traitement de la Douleur, Voiron, 7Laboratoire AGEIS, Université Grenoble Alpes, Grenoble, France Background: Pain localization is one of the hallmarks for the choice of first-line treatment in neuropathic pain. This literature review has been conducted to provide an overview of the current knowledge regarding the etiology and pathophysiology of localized neuropathic pain (LNP), its assessment and the existing topical pharmacological treatments. Materials and methods: Literature review was performed using Medline from 2010 to December 2016, and all studies involving LNP and treatments were examined. A multidisciplinary expert panel of five pain specialists in this article reports a consensus on topical approaches that may be recommended to alleviate LNP and on their advantages in clinical practice. Results: Successive international recommendations have included topical 5% lidocaine and 8% capsaicin for LNP treatment. The expert panel considers that these compounds can be a first-line treatment for LNP, especially in elderly patients and patients with comorbidities and polypharmacy. Regulatory LNP indications should cover the whole range of LNP and not be restricted to specific etiologies or sites. Precautions for the use of plasters must be followed cautiously. Conclusion: Although there is a real need for more randomized controlled trials for both drugs, publications clearly demonstrate excellent risk/benefit ratios, safety, tolerance and continued efficacy throughout long-term treatment. A major advantage of both plasters is that they have proven efficacy and may reduce the risk of adverse events such as cognitive impairment, confusion, somnolence, dizziness and constipation that are often associated with systemic neuropathic pain treatment and reduce the quality of life. Topical modalities also may be used in combination with other drugs and analgesics with limited drug–drug interactions. Keywords: neuropathic pain, topical, localized, medicated plaster, patch, review

Mice homozygous for the lpr gene show a marked lymphoproliferative syndrome. Most T cells which accumulate in their lymphoid organs belong to a fairly unusual subpopulation. Although being CD44+ T cells expressing neither CD4 nor CD8, they are CD3 T-cell receptor (TCR) αβ positive and express both Thy-1 and B220, the B-cell form of the CD45 marker. To support engraftment and development of transferred lpr lymphomyeloid cells, athymic recipients must be genetically lpr. While nude/beige (nubg) recipients do not allow the development of any lymphoproliferative syndrome, this is variable in nude/lpr (nulpr) recipients, and the genotypic origin of the proliferating lymphocytes in nulpr recipients is unclear. In this study, the surface phenotype of lymph node cells from nulpr recipients of lpr grafts ([lpr → nulpr] chimeras) was analysed by flow cytometry, and compared with various chimeras and parental (donor and recipient) strains as controls. Abnormal cells of the lpr type were not detectable either in [lpr → nubg] chimeras or in [wild → nubg] controls. Absence of lpr cells was also seen in neonatal lpr thymus-grafted nubg mice engrafted previously with lpr haematopoietic cells. In contrast, a substantial emergence of double-positive B220+ Thy-1+ cells occurred in [lpr → nulpr] chimeras, together with high levels of CD4+ cells, a substantial fraction of which might express B220. Finally, in thymus-grafted nulpr mice, the levels of B220+ Thy-1+ cells were as high as in Ipr mice and there was again an expansion of CD4+ (potentially B220+) cells. Abnormality of the nulpr haemopoietic environment was also shown by the low percentages of T cells, particularly CD8+ cells, in short-lived [wild →; nulpr] chimeras. Taken together, our results underline the differences between the nubg and nulpr environments. [ABSTRACT FROM AUTHOR]

The aetiology of the autoimmune and lymphoproliferative syndrome caused by the murine lpr (lymphoproliferation) mutation was studied by the adoptive transfer methodology using nonirradiated athymic and natural killer (NK)-deficient C57BL/6 nude beige mice (B6 nubg) as recipients. The [lpr→nubg] chimeras did not display the severe lymphoid organ aplasia shown by irradiated nonlpr recipients of lpr haematopoietic cells. However, nor did they either express the typical lpr phenotype features (hyperglobulinaemia, autoimmunity and lymphoid hyperplasia). Nevertheless, engraftment of lpr cells in the nubg recipients was shown by their much increased survival, the recovery of T-cell mitogen responsiveness in the spleen, and the presence of T-dependent immunoglobulin isotypes in their serum. The host of donor origin of serum immunoglobulin was studied by measuring IgG2a allotypes in the serum of [lpr→nubg] chimeras made with different lghcongenic mice. Interestingly, several months after grafting, the serum IgG2a was found to be mainly of lpr graft origin, suggesting that only lpr B cells could function in such chimeras. In conclusion, a lpr spleen cell graft reconstituted non-irradiated nubg recipients and induced neither a typical lpr syndrome nor a lpr-type graft-versus-host (GVH)-like disease. These features of the lpr syndrome are at variance with those of the phenotypically similar gld syndrome, since this mutation allows the transfer of a generalized lymphadenopathy disease by grafting gM spleen cells in nubg or irradiated recipients. Unlike the gld syndrome, the lpr gene might not only affect haematopoietic cells but also cells of the environment, which would interact in the same impaired process. [ABSTRACT FROM AUTHOR]