As in various medical domains, creating new treatments for neuropathic pain is challenging because rodent models don’t always translate to clinical success. Neuropathic pain features ongoing pain, often with burning or shock-like sensations, and pain hypersensitivity (hyperalgesia and allodynia), frequently to mechanical stimuli, indicating neural transmission sensitization.
We conducted a systematic literature review (PubMed-Medline, Cochrane, WoS, ClinicalTrials) and a semi-quantitative meta-analysis of human pain models that induce central sensitization, creating hyperalgesia around a real or simulated injury.
From 1569 reports, we identified and analyzed 269 studies using over a dozen human sensitization models. Five models (intradermal or topical capsaicin, low- or high-frequency electrical stimulation, thermode-induced heat-injury) reliably induced secondary hyperalgesia to pinprick and were implemented in multiple labs. These models were less effective at inducing dynamic mechanical allodynia. Hypersensitivity prevalence was rarely reported, creating reporting bias. In four models, pharmacological profiles mirrored clinical conditions, potentially informing new drug development.
Intradermal capsaicin, applied topically, affects nerve fibers in the skin.
While no “optimal” central sensitization model exists, the validated and accessible human procedures can guide preclinical researchers on potential biomarkers, reducing the gap between basic and clinical data.
Mimicking pathological pain aspects in humans has significant potential for understanding pathophysiology and providing animal research with translatable drug development biomarkers. Human surrogate models have shown excellent predictive validity: responding to clinically active medications and not to clinically inactive medications, even those effective in animals but failing clinically. Therefore, they should inform basic research for new drug development.
Electrical stimulation can be used to stimulate nerve endings that might be causing pain.
