Nerve Stimulation Outperforms Single-Target Radiofrequency for Shingles Eye Pain

A retrospective cohort study of 269 patients has directly compared three neuromodulation techniques for the severe facial pain caused by herpes zoster ophthalmicus, a form of shingles that strikes the ophthalmic branch of the trigeminal nerve. The researchers, based at China–Japan Friendship Hospital in Beijing together with collaborators at Xuchang Central Hospital and Beijing University of Chinese Medicine, found that short-term peripheral nerve stimulation delivered more sustained pain relief than single-target pulsed radiofrequency of the supraorbital nerve, while a dual-target approach that additionally treated the stellate ganglion offered distinctive benefits for anxiety and sleep. The study, published in Frontiers in Neuroscience, is the first to compare all three strategies within a single cohort.

Herpes zoster ophthalmicus arises when latent varicella-zoster virus reactivates in the trigeminal ganglion, inflaming the ophthalmic division of the nerve. It accounts for roughly 8 percent of all shingles cases, and its incidence is rising. Beyond the periocular rash and burning pain, the condition can trigger conjunctivitis, uveitis, keratitis, and optic neuritis, with severe cases threatening vision. Previous research indicates that approximately 21 percent of these patients go on to develop postherpetic neuralgia, a chronic and notoriously difficult-to-treat pain condition, with the risk appearing higher in those with ocular complications such as keratitis or conjunctivitis. Older age, prodromal pain, and ocular inflammation may further increase the likelihood of chronification. Because persistent pain erodes sleep, mood, and quality of life, identifying the most effective interventional option carries considerable clinical weight.

The three techniques compared in the study work through distinct mechanisms. Short-term peripheral nerve stimulation, abbreviated st-PNS, involves threading an electrode under fluoroscopic guidance near the supraorbital and supratrochlear nerves, where it delivers continuous, adjustable electrical stimulation at 40 Hz for seven days. Supraorbital nerve pulsed radiofrequency, or SON-PRF, instead applies short pulses of an electric field at a controlled temperature of 42 degrees Celsius, modulating a single nerve without causing destructive thermal injury. The dual-target strategy, SON + SG-PRF, adds pulsed radiofrequency at the stellate ganglion, a collection of sympathetic nerve cell bodies in the neck at the level of the seventh cervical vertebra, aiming to address the sympathetic dysfunction and neuroinflammation thought to accompany the initiation and persistence of zoster-associated pain.

Between January 2023 and January 2026, the team screened 326 patients and enrolled 269 adults aged 50 or older with pain distributed in the ophthalmic division of the trigeminal nerve and a pretreatment pain score of at least 4 on the 0-to-10 Numerical Rating Scale. Patients themselves chose their treatment after clinicians explained the procedures, benefits, risks, and costs, and the investigators did not influence the selection. Eighty-four patients received st-PNS, 96 received SON-PRF, and 89 received the combined SON + SG-PRF procedure. All interventions were performed by the same pain medicine team, with the radiofrequency procedures guided by ultrasound. The groups were well matched at baseline: mean ages were close to 68 years in each arm, and baseline pain, anxiety, depression, and sleep scores were statistically indistinguishable.

Over 24 weeks of follow-up, pain scores fell in all three groups. In the primary analysis, which used baseline-adjusted linear mixed-effects models, the overall pain trajectory was significantly lower with st-PNS than with SON-PRF, with a Holm-adjusted p value of 0.005, and lower with SON + SG-PRF than with SON-PRF, at p = 0.028. The two stronger treatments did not differ significantly from each other. Clinical response, defined as at least a 50 percent reduction in pain score, was more frequent with st-PNS than with SON-PRF at every visit from week 2 through week 24; at weeks 12 and 24, response rates reached 89.3 percent versus 68.8 percent and 86.9 percent versus 65.6 percent, respectively. The advantage of SON + SG-PRF over SON-PRF appeared mainly at weeks 4 and 8, suggesting a more transient effect on response rates.

The pain findings held up under two propensity score-weighted sensitivity analyses, generalized overlap weighting and stabilized inverse probability of treatment weighting, designed to correct for measured differences in treatment selection. Both methods showed a significantly lower overall pain trajectory for st-PNS than for SON-PRF, and both preserved the equivalence between st-PNS and the dual-target approach. The weighting procedure achieved good covariate balance, with the maximum absolute standardized difference falling from 0.311 before weighting to 0.074 after overlap weighting, below the prespecified threshold of 0.10.

The emotional and sleep outcomes told a complementary story. Anxiety scores on the 7-item Generalized Anxiety Disorder scale fell in all groups, but the overall trajectory was lower with SON + SG-PRF than with SON-PRF, and lower with st-PNS as well; the difference remained significant after multiplicity adjustment across the three secondary outcomes. Sleep quality, measured with the Pittsburgh Sleep Quality Index, improved most in the dual-target group: its overall trajectory was significantly better than both other groups in the primary analysis and in both weighted analyses. Depressive symptoms on the 9-item Patient Health Questionnaire, by contrast, declined similarly in all three arms, with no significant group differences.

The authors interpret these patterns mechanistically. Short-term peripheral nerve stimulation continuously recruits large myelinated Aβ fibers, engaging inhibitory interneurons in the dorsal horn that gate the transmission of nociceptive Aδ and C-fiber signals, while also potentially involving autonomic, inflammatory, and endogenous pain-control pathways. Its longer treatment duration and adjustable current may repeatedly reinforce these gate-control mechanisms and promote activity-dependent synaptic plasticity. The linear electrode also covers both the supraorbital and supratrochlear nerve territories, whereas SON-PRF targets only the supraorbital nerve, potentially leaving pain driven by adjacent V1 branches incompletely treated. The dual-target benefit on anxiety and sleep may stem from the stellate ganglion’s role in sympathetic regulation: after nerve injury, sympathetic fibers can sprout abnormally within sensory ganglia, and norepinephrine release from these terminals can heighten sensory-neuron excitability. Reducing sympathetic output may dampen this amplification, and earlier clinical work has reported reduced norepinephrine and cortisol after stellate ganglion block alongside improvements in sleep duration and efficiency.

On the crucial question of whether any technique prevents postherpetic neuralgia, the study could not deliver a definitive answer. Among the 239 patients treated within 90 days of disease onset, postherpetic neuralgia, defined as pain of at least 3 on the rating scale persisting at week 12, occurred in 11.8 percent of the st-PNS group, 23.3 percent of the SON-PRF group, and 16.9 percent of the dual-target group. The overall comparison was not statistically significant, and all confidence intervals for the risk differences were wide and included zero. The authors caution that these numerical differences cannot be interpreted as evidence of a preventive effect.

Safety was reassuring across all arms. No serious treatment-related adverse events occurred during treatment or follow-up, with only two mild events recorded: a local hematoma at the puncture site in one st-PNS patient and upper-eyelid swelling in one SON-PRF patient. The authors acknowledge, however, the inherent limitations of a single-center retrospective design in which patients chose their own treatment, meaning that unmeasured factors such as disease severity and socioeconomic circumstances may have influenced outcomes despite the propensity score adjustments. The three interventions also differed in modality, duration, and anatomical coverage simultaneously, so the results reflect the overall effects of each treatment strategy rather than the isolated contribution of any single design element. Confirming the findings, particularly the putative effects on sympathetic function, will require large, multicenter, prospective randomized controlled trials incorporating autonomic, neuroendocrine, and inflammatory biomarkers.

Subject of Research: Comparison of neuromodulation techniques for herpes zoster ophthalmicus–associated pain

Article Title: Comparison of short-term peripheral nerve stimulation, single-target supraorbital nerve pulsed radiofrequency, and dual-target supraorbital nerve–stellate ganglion pulsed radiofrequency for herpes zoster ophthalmicus–associated pain: a retrospective cohort study

Article References: Liang, C., Liu, A., & Wang, W. (2026). Comparison of short-term peripheral nerve stimulation, single-target supraorbital nerve pulsed radiofrequency, and dual-target supraorbital nerve–stellate ganglion pulsed radiofrequency for herpes zoster ophthalmicus–associated pain: a retrospective cohort study. Frontiers in Neuroscience, 20, Article 1976324. https://doi.org/10.3389/fnins.2026.1976324

Image Credits: AI Generated

DOI: 10.3389/fnins.2026.1976324

Keywords: herpes zoster ophthalmicus, neuromodulation, peripheral nerve stimulation, pulsed radiofrequency, stellate ganglion, postherpetic neuralgia, zoster-associated pain, pain management, retrospective cohort study, trigeminal nerve, anxiety, sleep quality