Translational issues in precision medicine in neuropathic pain

Abstract

Neuropathic pain remains poorly treated, with most new drugs falling through the translational gap. The traditional model of bench-to-bedside research has relied on identifying new mechanisms/targets in animal models and then developing clinical applications. Several have advocated bridging the translational gap by beginning with clinical observations and backtranslating to animal models for further investigation of mechanisms. There is good evidence that phenotyping of patients through quantitative sensory testing can lead to improved treatment selection and hence improved patient outcomes. This practice has been widely adopted in clinical investigations, but its application in preclinical research is not mainstream. In this review, we retrospectively examine our historical rodent data sets with the aim of reconsidering drug effects on sensory neuronal endpoints, their alignment with clinical observations, and how these might guide future clinical studies. RÉSUMÉLa douleur neuropathique reste mal traitée, alors que la plupart des nouveaux médicaments ne réussissent pas à franchir le fossé translationnel. Le modèle traditionnel de la recherche, du laboratoire au chevet du patient, repose sur l'identification de nouveaux mécanismes ou cibles dans des modèles animaux, suivie du développement d'applications cliniques. Certains préconisent de combler le fossé de la recherche translationnelle en commençant par des observations cliniques et en les transposant ensuite sur des modèles animaux afin d'approfondir l'étude des mécanismes. Il est bien établi que le phénotypage des patients par des tests sensoriels quantitatifs peut conduire à une meilleure sélection des traitements et, par conséquent, à de meilleurs résultats pour les patients. Ces pratiques ont été largement adoptées dans les enquêtes cliniques, mais leur application dans la recherche préclinique n'est pas généralisée. Dans cette revue, nous examinons rétrospectivement nos ensembles de données historiques sur les rongeurs dans le but de reconsidérer les effets des médicaments sur les paramètres neuronaux sensoriels, leur alignement avec les observations cliniques et la manière dont celles-ci pourraient orienter les études cliniques futures.

Targeted Therapy for Orofacial Pain: A Novel Perspective for Precision Medicine

“…New drugs fail to be implemented in clinical practice due to the translational gap from traditional animal models to clinical application. Although there has been a persistent desire to focus on precision medicine as a method of treating the condition’s underlying cause, it is exceptionally rare for a disorder to originate from just a single gene mutation [ 63 ]. In pain, more frequently, mutations are characterized in sodium channels.…”

“…Despite several novel blockers targeting these sodium channels, the translation of these laboratory results to practical day-to-day use in humans is not generally available [ 64 ]. The major reason for the translational gap is failure in clinical studies due to inappropriate endpoint selection for validation [ 63 ]. For example, 5HT3-antagonist when used for neuropathy patients showed positive results when ongoing pain [ 65 ] was evaluated, whereas it showed negative results when dynamic pain was evaluated [ 66 ].…”

Exploiting Injury-Induced Peripheral Opioid Receptor Changes in Novel Analgesic Development for Chronic Pain

“…The models do, however, allow for examination of features that may relate to symptoms experienced in some patients. Back translating from human to animal by identifying patient phenotypes based on QST or other biomarkers has been suggested as a “precision medicine” method to improve preclinical pain model selection ( 38 ). Absent better models, this approach seems completely reasonable.…”

Developmental mechanisms of CPSP: Clinical observations and translational laboratory evaluations

“… 23 Delayed emergence of neuropathic pain has also been reported following traumatic or surgical nerve injury in children. 35 , 86 , 94 The potential for preclinical studies to also link specific sensory modalities and mechanisms to efficacy of pharmacological interventions has been highlighted 95 and warrants further assessment at different developmental stages. In addition, more complex behavioral tasks in adult rodents have evaluated alterations in motivational–affective response (e.g., conditioned place preference, social interaction, anxiety) and cognitive function (e.g., memory and attention) 95–98 and have identified long-term effects following surgical injury in early life (increased anxiety, impaired attentional performance and learning 99 ).…”