Pharmacological Influences on the R2 Blink Reflex Response in Healthy Participants: A Systematic Review

The R2 blink reflex (BR) is a polysynaptic brainstem-mediated response that can be activated by innocuous and noxious electrocutaneous stimulation of the supraorbital nerve and has been used as a biomarker across pharmacological studies. Whilst standard patch electrodes activate both the tactile (R1) and nociceptive (R2) components of the blink reflex, concentric electrodes preferentially evoke a nociceptive-specific response (NBR) by isolating the R2 component. This preregistered systematic review (CRD420251014203) aims to assess the pharmacological modulation of nociceptive R2 responses as measured by both standard patch and concentric electrodes in healthy participants. Following PRISMA guidelines, systematic searches of PubMed, Cochrane and Ovid identified studies examining R2 responses in healthy adults receiving a pharmacological intervention. Data were extracted on study design, drug category, stimulation electrode, dosage and outcome measures. Nine studies met inclusion criteria, which included eight distinct drug classes. Limited effects on the R2 response were found for opioids, selective serotonin receptor agonists, nonsteroidal anti-inflammatory drugs and ketamine. In contrast, α2-adrenoreceptor modulators, benzodiazepines, nitrous oxide and selective adenosine A1 receptor agonists demonstrated effects. The stimulation electrode used did not affect the impact of intervention on nociceptive R2 responses where comparable studies were available. These findings indicate that nociceptive R2 components of the BR, whether evoked using standard or concentric electrodes, exhibit comparable sensitivity to pharmacological modulation. Future research should further delineate the contributions of local and descending modulatory systems to nociceptive-specific and tactile processing within trigeminofacial circuits.