The neuropathic chameleon: we are hot on the scent

A common chronic pain condition, neuropathic pain arises from a lesion or disease affecting the somatosensory or neural tissue and is characterized by a combination of negative (eg, numbness) and positive (eg, burning pain) sensory symptoms that significantly affect the quality of life. Common comorbidities such as depression and sleep disruption contribute to a substantial disease burden, which is further exacerbated by the apparent lack of effective therapeutic options. Current treatment options frequently achieve only partial, insufficient pain relief or may be completely ineffective in a considerable number of patients. The development of new drugs has thus far achieved moderate success, with many clinical trials failing to meet their primary endpoints; thus, a substantial unmet clinical need persists. One reason for this therapeutic deadlock is the considerable heterogeneity of neuropathic pain, driven by diverse pathophysiological mechanisms that vary between patients regardless of the underlying disease etiology. Accordingly, reclassification efforts follow a mechanism-based approach that reflects pathophysiological pain generators rather than disease etiology. Although diagnosis remains anchored in lesion- or disease-based criteria and structured clinical assessment, treatment development increasingly benefits from mechanism-informed phenotyping. A priori stratification based on individual mechanisms may help identify treatment responders, but implementation requires surrogate markers, as no biomarkers for pain mechanisms currently exist. In this article, we discuss candidate predictive markers and surrogate markers, focusing on sensory symptoms and signs assessed through patient-reported outcome measures and sensory testing, and their integration into future clinical trials.