Central and peripheral dual neuromodulation strategy in pain management of zoster-associated pain：a retrospective cohort study

Central and peripheral dual neuromodulation strategy in pain management of zoster-associated pain：a retrospective cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Central and peripheral dual neuromodulation strategy in pain management of zoster-associated pain：a retrospective cohort study Xuelian Li, Huaxiang Zhang, Xu Zhang, Ke Ma, Yan Lv, Tao Song, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4608493/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Oct, 2024 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Spinal cord stimulation (SCS) has shown effectiveness in relieving zoster-associated pain (ZAP), but some patients still experience moderate or severe pain after SCS treatment. This study aims to evaluate the impact of SCS combined with dorsal root ganglion (DRG) pulsed radiofrequency (PRF) as a dual neuromodulation strategy on the prognosis of ZAP.The clinical records of patients diagnosed with ZAP who underwent SCS (SCS group) or SCS combined with PRF (SCS + PRF group) at The Third Xiangya Hospital, Central South University, were retrospectively analyzed to compare the effectiveness of the two treatment approaches for ZAP. Outcome measures included changes in Visual Analog Scale (VAS) scores before and after neuromodulation treatment, response rates, and incidence of progression to postherpetic neuralgia (PHN).13 SCS patients and 15 SCS + PRF patients were analyzed. Admission VAS scores were similar (P = 0.934). Upon discharge, no significant differences in VAS or response rates were observed (P > 0.05). However, at 6-month follow-up, the SCS + PRF group had lower VAS scores (1.53 ± 1.06 vs. 3.23 ± 1.50, P < 0.001) and a lower proportion of residual moderate pain (P = 0.041). None in the SCS + PRF group progressed to PHN in the acute/subacute phases, differing significantly from the SCS group (P = 0.038).Therefore,SCS combined with DRG PRF is feasible and effective in the treatment of ZAP. This dual neuromodulation strategy may be a more appropriate regimen for the treatment of ZAP. Health sciences/Diseases Health sciences/Medical research Health sciences/Neurology neuromodulation pulsed radiofrequency spinal cord stimulation zoster-associated pain Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Herpes zoster (HZ) is a neurocutaneous disease caused by the varicella-zoster virus (VZV), with 80% of patients experiencing pain. Zoster-associated pain (ZAP) can be divided into three phases based on duration: the acute phase occurs within one month of the onset of herpes; the subacute phase is from one to three months; and postherpetic neuralgia (PHN) is pain that lasts for more than three months [1] . Data show that about 10-20% of patients will develop PHN after skin lesion healing, with the risk being higher in the elderly [2,3] . Once PHN occurs, the disease may last for months or even years and can lead to serious complications, such as secondary bacterial infection, disseminated rash, encephalitis, and herpes zoster ophthalmicus [4] . Patients often experience anxiety, depression, and sleep disorders, causing a significant burden on their mental health, family, and social economy. Effective treatment of ZAP has become a major focus and challenge in clinical practice [5] . The treatment of ZAP includes medications such as antivirals, tricyclic antidepressants, antiepileptic drugs, opioids, and local analgesics [6,7] . For refractory cases that do not respond to conventional drug treatment, invasive interventional treatments such as nerve block, dorsal root ganglion (DRG) pulsed radiofrequency (PRF), and spinal cord stimulation (SCS) are often required [8-10] . SCS, a widely used interventional therapy for chronic pain, has been proven to effectively alleviate neuropathic pain, including ZAP [11] . In SCS, electrodes are placed in the epidural space of the spinal canal at the segments corresponding to the herpes zoster skin lesion. These electrodes are connected to a pulse generator that generates and outputs a continuous current between the cathode and anode, covering the patient's pain area [12] . However, for patients with severe pain, SCS may not be fully effective, and some patients continue to experience moderate or severe pain after discharge. A recent study showed that 41.7% of ZAP patients treated with SCS had less than 50% pain reduction at discharge [13] . Another review summarized the long-term follow-up of various types of SCS in the treatment of PHN, noting that 32.1% of patients still had unsatisfactory pain relief [14] . Addressing residual pain after SCS treatment of ZAP remains an important clinical challenge. DRG PRF is a type of peripheral neuromodulation technology that uses radio waves to generate electric fields, producing brief electrical stimulation and intermittent alternating pulse currents at the tip of the radiofrequency needle to regulate neural activity and provide pain relief [15,16] . DRG PRF has been shown to be an effective option for chronic refractory neuropathic pain and has been successfully applied to treat various types of neuropathic pain, including ZAP [17-19] . To address the problem of inadequate pain relief, multimodal analgesia is often used in clinical practice. The generation mechanism of ZAP involves both central and peripheral levels [20,21] .However, there is no research report on the effectiveness of neuromodulation therapy for ZAP at these two levels. This study aims to analyze the efficacy and safety of this dual nerve stimulation therapy for ZAP and to recommend a more effective treatment strategy for the comprehensive management of ZAP in clinical practice. Methods Participants This study followed the International Conference on Harmonisation of Good Clinical Practice guidelines and the Declaration of Helsinki (2008).With the approval of the Ethics Committee of the Third Xiangya Hospital of Central South University (No. 23863) to waive the requirement for signed informed consent, a retrospective medical record analysis was conducted on patients with ZAP who were hospitalized in the Department of Pain at The Third Xiangya Hospital, Central South University, from October 2019 to October 2023. Inclusion criteria were as follows: age over 18 years, meeting the diagnostic criteria for ZAP, lesions affecting the cervical, thoracic, or lumbar segments, inability to control pain with conventional treatments, and undergoing either SCS treatment or a combination of SCS and PRF treatment. Exclusion criteria included: insufficient medical records (lack of baseline data or follow-up records at 6 months post-treatment), experiencing other significant medical conditions during the follow-up period, and receiving other interventional therapies during the follow-up period. Patients who received only SCS treatment were defined as the SCS group, while those who received both SCS and PRF treatments were classified as the SCS+PRF group. According to the course of the disease, acute pain was defined as pain occurring within 1 month, pain persisting for more than 3 months was considered as PHN, and subacute pain was defined as lasting between 1 to 3 months [1] . Surgery Spinal cord stimulation The surgical procedure for SCS has been detailed previously [22] . Briefly, the target spinal segment for electrode implantation was determined based on the affected pain area, and the electrode position was confirmed by intraoperative fluoroscopy. The patient was placed in a prone position, and after local anesthesia, an epidural puncture was performed with a 14G Tuohy needle. The core was removed once the needle entered the epidural space, and an 8-contact lead (3873; Medtronic, Minneapolis, MN, USA) was inserted through the cannula. The lead was advanced under fluoroscopic anteroposterior view, and a sensory test was conducted to ensure that the electrical stimulation covered the patient's pain area. Patients were asked to remain in bed for 2 days to avoid potential lead migration. Those with lead displacement and dislocation were excluded from the study. The stimulation frequency was set to 50 Hz, and the pulse width was 500 μs. The electrical stimulation voltage was adjusted according to the degree of pain. Stimulation leads were removed within 2 weeks after surgery to prevent infection. DRG PRF PRF treatment was performed about one week after SCS. As described [23] , for DRG PRF, the patient was placed prone on the operating table with a comfortable pillow under their chest. The needle was guided into the thoracic paraspinal space using B-scan ultrasound (Fujifilm Sonosite, Bothell, WA, USA). The needle tip was fine-tuned based on the ultrasound probe scan to the target segment. X-ray imaging confirmed that the needle tip was directly below the lateral border of the pedicle in the anteroposterior view and in the superior quadrant dorsal to the foramina in the lateral view (Fig 1). The internal needle was replaced by a pulsed radiofrequency electrode, connected to a standard clinical specification radiofrequency generator (Beiqi, R-2000BA1, Beijing, China). The position of the needle tip was controlled by sensory and motor nerve stimulation before proceeding. DRG PRF treatment was set at 2 Hz (20 ms pulse width) three times for 240 s. Impedance was maintained at less than 300Ω throughout the procedure. Clinical outcomes and follow-up The primary data analyzed included changes in the intensity of patients' pain, evaluated using the Visual Analog Scale (VAS), which ranges from 0 ("no pain") to 10 ("the worst pain imaginable"). Preoperative information included age, gender, duration of disease, and baseline VAS score upon admission. Postoperative data included VAS scores at discharge, VAS scores 6 months after surgery, whether patients in the acute and subacute phases progressed to PHN, and the occurrence of treatment-related complications (including pneumothorax, bleeding, infection, nerve injury, and electrode displacement). During postoperative follow-up, a reduction in VAS score of 50% or more compared to the baseline score upon admission was defined as a responder [13] . Statistical analysis Prism 9.0 software (GraphPad, San Diego, CA, USA) was used for statistical analysis. Continuous variables were expressed as mean ± standard deviation. Two-way analysis of variance with repeated measures and post-hoc multiple pairwise comparison using Sidak's test was employed to assess changes in pain scores between the two groups over time. Differences in response rates were compared using χ 2 tests (including possible χ 2 -corrected tests and Fisher's exact test). A P value of less than 0.05 was considered statistically significant. Results A total of 39 patient medical records were reviewed. Four patients had missing data for the 6-month postoperative follow-up, three patients lacked sufficient preoperative medical records, three patients underwent other interventional procedures, and one patient reported other significant medical conditions during follow-up. The medical records of these patients were excluded from the analysis. Finally, the medical records of 28 patients were analyzed. Thirteen patients received SCS treatment during hospitalization (SCS group), and the other fifteen patients received both SCS and PRF treatment (SCS+PRF group) (Fig 2). Demographics The demographic and clinical characteristics of the enrolled patients are summarized in Table 1. The mean age of patients in the SCS group was 70.92±9.74 years, while in the SCS+PRF group, it was 68.53±6.45 years, with no statistically significant difference (P=0.476). There were no significant differences in gender distribution, duration of illness, hospital stay, or electrode implantation between the two groups. Among the participants, 71.43% (20/28) had acute or subacute herpetic lesions with a disease duration of less than 3 months. Additionally, 8 patients were diagnosed with PHN. All enrolled patients had failed to achieve pain control with conventional treatments before undergoing neuromodulation therapy. Table 1 .General characteristics of patients. Group SCS SCS+PRF p value N 13 15 Age (years) 70.92±9.74 68.53±6.45 0.476 Sex (male/female) 5/8 8/7 0.450 Duration (n, %) 0.769 3 months 2(23%) 6(40%) VAS Baseline 7.23±0.83 7.47±1.19 0.934 Discharge 2.62±1.33 2.60±1.06 ＞0.99 6 months postoperative 3.23±1.50 1.53±1.06 ＜0.001 Responders at discharge(n, %) 0.583 Responders 11(84.62%) 14(93.33%) Nonresponders 2(15.38%) 1(6.77%) Responders at 6 months postoperative(n, %) 0.029 Responders 7(53.85%) 14(93.33%) Nonresponders 6(46.15%) 1(6.77%) Long-term analgesic effect The baseline VAS upon admission showed no significant difference between the SCS and SCS+PRF groups (P=0.934). Following treatment, both groups exhibited significant pain relief at discharge, with VAS scores of 2.62±1.33 and 2.60±1.06 for the SCS and SCS+PRF groups, respectively, showing no significant statistical difference (P＞0.99). At the 6-month follow-up, both groups demonstrated effective long-term pain relief. The VAS score of the SCS+PRF group (1.53±1.06) was significantly lower than that of the SCS group (3.23±1.50) (P<0.001) (Table 1). Additionally, the response rates at discharge were 84.62% and 93.33% for the SCS and SCS+PRF groups, respectively, with no significant difference (P=0.583) (Table 1). However, at the 6-month follow-up, the response rate in the SCS+PRF group remained at 93.33%, significantly higher than the 53.85% observed in the SCS group (P=0.029) (Table 1). Furthermore, at the 6-month follow-up, 6.67% of the SCS+PRF group still had moderate pain (Fig 3B), which was significantly lower than the 38.4% in the SCS group (Fig 3A) (P=0.041). These findings suggest the superior long-term efficacy of the dual-modulation therapy. Prevention of PHN We conducted efficacy analyses on patients in the acute and subacute phases (non-PHN) of ZAP and found no significant differences in preoperative and discharge VAS scores between the acute and subacute patient groups in both the SCS and SCS+PRF groups (all P>0.05). However, at the 6-month follow-up, the VAS scores in the SCS+PRF group were significantly lower than those in the SCS group (P<0.001) (Fig 4A). Furthermore, at 6 months post-operation, 45.45% (5/11) of patients in the SCS group in the acute and subacute phases had VAS scores higher than 3, whereas no patients in the SCS+PRF group had VAS scores exceeding 3, indicating a significant difference (P=0.038) (Fig 4B). These findings suggest that central and peripheral dual modulation therapy may help prevent the development of PHN in patients in the acute and subacute phases of ZAP. Safety No complications related to the treatment regimens used (including pneumothorax, bleeding, infection, nerve injury, or stimulation lead migration) were observed during hospitalization or follow-up. Discussion Patients with ZAP often suffer from severe and persistent neuropathic pain, and there is no widely accepted optimal treatment in clinical practice. For refractory ZAP, clinicians aim to provide adequate pain relief, prevent recurrence, and enhance the patient's quality of life. Drug therapy alone often has limited effectiveness and comes with various side effects [24,25] . Neuromodulation therapy plays an important role in managing ZAP when conventional therapies are ineffective [26] . Here, we present preliminary evidence suggesting that a dual neuromodulation approach, combining peripheral nerve stimulation with central stimulation, is an effective option for pain management in patients with ZAP. We observed that the dual stimulation strategy of central and peripheral neuromodulation significantly relieved severe pain in patients with ZAP. At the final follow-up, patients in the SCS+PRF group showed a significant reduction in VAS scores and a notably lower proportion of residual moderate pain compared to the SCS group. This indicates that combining SCS with DRG PRF provides superior long-term pain relief. Moreover, among patients with subacute pain, the dual stimulation protocol effectively prevented the progression to PHN compared to single central stimulation alone. This finding aligns with current trends in pain management, suggesting that multimodal and multitarget therapeutic approaches often yield better outcomes [27] . The multifaceted pathogenesis of ZAP involves sensitization of central and peripheral nerves and abnormal ion channel expression [20,21] . SCS may function by selectively activating large, rapidly conducting fibers and influencing pain signal transmission at the spinal cord level [28] . DRG PRF, on the other hand, can block pain signal transmission by directly acting on peripheral nerves [15,16] . This dual stimulation strategy addresses pain signal processing at both central and peripheral levels, enhancing therapeutic effects. ZAP originates from VZV latent in peripheral ganglia, evolving from peripheral sensitization to central sensitization over time, with the two mechanisms influencing each other [27,29,30] . We describe this phenomenon of layered and integrated sensitization as the "layer-integrate" sensitization theory (LIST). The dual stimulation strategy of SCS combined with DRG PRF offers comprehensive pain management at both central and peripheral levels. Neuromodulation therapy is a key component of multimodal analgesia for refractory neuropathic pain [9] . A review summarized that SCS combined with conventional medical management reduces chronic pain intensity, decreases the dose of analgesics needed, and improves long-term quality of life and physical function [31] . A recent study indicated that the efficacy of combined DRG and SCS stimulation in treating chronic focal neuropathic pain was 78.9% [32] . Ji et al. also reported that, after 6 months of PRF combined with nerve block for ZAP, only 16.67% of patients had an unsatisfactory prognosis [33] . These findings consistently suggest that integrated management may be a better approach for treating refractory neuropathic pain. Research on dual neuromodulation therapy for patients with ZAP is still extremely limited. Ma et al. found that a dual stimulation regimen of peripheral nerve electrical stimulation combined with PRF in the trigeminal ganglion achieved better clinical outcomes compared with peripheral nerve electrical stimulation alone in the management of herpes zoster ophthalmicus [34] . Additionally, Wang et al. reported the analgesic effect of dual neuromodulation in the dorsal root ganglia in a patient with extremely painful ZAP [35] . They performed dual nerve stimulation on a single level of the peripheral nervous system. Our study supported the efficacy of dual electrical stimulation in treating refractory ZAP at both the central and peripheral nervous system levels. This suggests that neuromodulation of both the peripheral and central nervous systems may have significant advantages in the comprehensive treatment of ZAP. Our study has several limitations. Firstly, as a retrospective study, the data is sourced from existing medical records, which may introduce certain biases due to variations in data recording by different doctors. Secondly, the single-center nature of the study resulted in a small sample size. Finally, long-term follow-up results are not yet available. Despite these limitations, our results preliminarily demonstrate the excellent effect of this central and peripheral hierarchical and integrated neuromodulation for pain management. Therefore, it is necessary to conduct multi-center, large sample-size randomized controlled clinical trials to verify the efficacy of SCS combined with DRG PRF dual stimulation in the treatment of ZAP in the future. This will help explore the best neuromodulation scheme for treating ZAP. Conclusions SCS combined with DRG PRF is feasible and effective for treating ZAP. This new central and peripheral dual nerve stimulation strategy may be a more appropriate regimen for ZAP treatment. Declarations Data Availability The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Funding This research was funded by the National Natural Science Foundation of China (82271512 to DH). Authors’ contributions KM, YL, TS, and DH: conceptualization, investigation, supervision, project administration, and funding acquisition. XL HZ and XZ: methodology. XL and GG: formal analysis. XZ and GG: data curation. XL HZ and GG: original draft preparation. DH: writing review and editing. All authors have read and agreed to the published version of the manuscript. Competing interests Te authors declare no competing interests. Compliance with Ethics Guidelines The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of The Third Xiangya Hospital, Central South University (No. 23863). This trial was registered on ClinicalTrials.gov with the following number: ChiCTR2400084515. References Wang, X. X., Zhang, Y. & Fan, B. F. Predicting Postherpetic Neuralgia in Patients with Herpes Zoster by Machine Learning: A Retrospective Study. Pain and therapy 9 , 627-635, doi:10.1007/s40122-020-00196-y (2020). Kawai, K., Gebremeskel, B. G. & Acosta, C. J. Systematic review of incidence and complications of herpes zoster: towards a global perspective. BMJ open 4 , e004833, doi:10.1136/bmjopen-2014-004833 (2014). Gross, G. E. et al. S2k guidelines for the diagnosis and treatment of herpes zoster and postherpetic neuralgia. Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG 18 , 55-78, doi:10.1111/ddg.14013 (2020). Johnson, R. W. et al. The impact of herpes zoster and post-herpetic neuralgia on quality-of-life. BMC medicine 8 , 37, doi:10.1186/1741-7015-8-37 (2010). Johnson, R. W. et al. Herpes zoster epidemiology, management, and disease and economic burden in Europe: a multidisciplinary perspective. Therapeutic advances in vaccines 3 , 109-120, doi:10.1177/2051013615599151 (2015). Patil, A., Goldust, M. & Wollina, U. Herpes zoster: A Review of Clinical Manifestations and Management. Viruses 14 , doi:10.3390/v14020192 (2022). Tang, J., Zhang, Y., Liu, C., Zeng, A. & Song, L. Therapeutic Strategies for Postherpetic Neuralgia: Mechanisms, Treatments, and Perspectives. Current pain and headache reports 27 , 307-319, doi:10.1007/s11916-023-01146-x (2023). Li, D. et al. Combined therapy of pulsed radiofrequency and nerve block in postherpetic neuralgia patients: a randomized clinical trial. PeerJ 6 , e4852, doi:10.7717/peerj.4852 (2018). Han, R. et al. Clinical Efficacy of Short-Term Peripheral Nerve Stimulation in Management of Facial Pain Associated With Herpes Zoster Ophthalmicus. Front Neurosci 14 , 574713, doi:10.3389/fnins.2020.574713 (2020). Ni, Y. et al. Implantable Peripheral Nerve Stimulation for Trigeminal Neuropathic Pain: A Systematic Review and Meta-Analysis. Neuromodulation 24 , 983-991, doi:10.1111/ner.13421 (2021). Sdrulla, A. D., Guan, Y. & Raja, S. N. Spinal Cord Stimulation: Clinical Efficacy and Potential Mechanisms. Pain practice : the official journal of World Institute of Pain 18 , 1048-1067, doi:10.1111/papr.12692 (2018). Liu, B. et al. Clinical Study of Spinal Cord Stimulation and Pulsed Radiofrequency for Management of Herpes Zoster-Related Pain Persisting Beyond Acute Phase in Elderly Patients. Pain physician 23 , 263-270 (2020). Chen, L. et al. Correlation between spinal cord stimulation analgesia and cortical dynamics in pain management. Annals of clinical and translational neurology 11 , 57-66, doi:10.1002/acn3.51932 (2024). Isagulyan, E. et al. The Effectiveness of Various Types of Electrical Stimulation of the Spinal Cord for Chronic Pain in Patients with Postherpetic Neuralgia: A Literature Review. Pain research & management 2023 , 6015680, doi:10.1155/2023/6015680 (2023). Wu, C. Y. et al. Efficacy of Pulsed Radiofrequency in Herpetic Neuralgia: A Meta-Analysis of Randomized Controlled Trials. The Clinical journal of pain 36 , 887-895, doi:10.1097/ajp.0000000000000867 (2020). Yang, L. et al. Clinical Outcome of Pulsed-Radiofrequency Combined With Transforaminal Epidural Steroid Injection for Lumbosacral Radicular Pain Caused by Distinct Etiology. Front Neurosci 15 , 683298, doi:10.3389/fnins.2021.683298 (2021). Chang, M. C. Efficacy of Pulsed Radiofrequency Stimulation in Patients with Peripheral Neuropathic Pain: A Narrative Review. Pain physician 21 , E225-e234 (2018). Esposito, M. F., Malayil, R., Hanes, M. & Deer, T. Unique Characteristics of the Dorsal Root Ganglion as a Target for Neuromodulation. Pain Med 20 , S23-s30, doi:10.1093/pm/pnz012 (2019). Sun, C. L. et al. High-voltage, Long-duration Pulsed Radiofrequency to the Dorsal Root Ganglion Provides Improved Pain Relief for Herpes Zoster Neuralgia in the Subacute Stage. Pain physician 26 , E155-e162 (2023). Fields, H. L., Rowbotham, M. & Baron, R. Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiology of disease 5 , 209-227, doi:10.1006/nbdi.1998.0204 (1998). Campbell, J. N. & Meyer, R. A. Mechanisms of neuropathic pain. Neuron 52 , 77-92, doi:10.1016/j.neuron.2006.09.021 (2006). Zhou, H. et al. Effect of Implantable Electrical Nerve Stimulation on Cortical Dynamics in Patients With Herpes Zoster-Related Pain: A Prospective Pilot Study. Frontiers in bioengineering and biotechnology 10 , 862353, doi:10.3389/fbioe.2022.862353 (2022). Huang, X. et al. Efficacy and safety of pulsed radiofrequency modulation of thoracic dorsal root ganglion or intercostal nerve on postherpetic neuralgia in aged patients: a retrospective study. BMC neurology 21 , 233, doi:10.1186/s12883-021-02286-6 (2021). Beydoun, A. Postherpetic neuralgia: role of gabapentin and other treatment modalities. Epilepsia 40 Suppl 6 , S51-56; discussion S73-54, doi:10.1111/j.1528-1157.1999.tb00933.x (1999). Onakpoya, I. J., Thomas, E. T., Lee, J. J., Goldacre, B. & Heneghan, C. J. Benefits and harms of pregabalin in the management of neuropathic pain: a rapid review and meta-analysis of randomised clinical trials. BMJ open 9 , e023600, doi:10.1136/bmjopen-2018-023600 (2019). Lin, C. S., Lin, Y. C., Lao, H. C. & Chen, C. C. Interventional Treatments for Postherpetic Neuralgia: A Systematic Review. Pain physician 22 , 209-228 (2019). Rui, M., Ni, H., Xie, K., Xu, L. & Yao, M. Progress in Radiofrequency Therapy for Zoster-Associated Pain About Parameters, Modes, Targets, and Combined Therapy: A Narrative Review. Pain and therapy 13 , 23-32, doi:10.1007/s40122-023-00561-7 (2024). Melzack, R. & Wall, P. D. Pain mechanisms: a new theory. Science (New York, N.Y.) 150 , 971-979, doi:10.1126/science.150.3699.971 (1965). Baron, R. & Saguer, M. Postherpetic neuralgia. Are C-nociceptors involved in signalling and maintenance of tactile allodynia? Brain : a journal of neurology 116 ( Pt 6) , 1477-1496, doi:10.1093/brain/116.6.1477 (1993). Hashizume, K. [Herpes zoster and post-herpetic neuralgia]. Nihon rinsho. Japanese journal of clinical medicine 59 , 1738-1742 (2001). Zhou, M. et al. Comparison of clinical outcomes associated with spinal cord stimulation (SCS) or conventional medical management (CMM) for chronic pain: a systematic review and meta-analysis. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society 32 , 2029-2041, doi:10.1007/s00586-023-07716-2 (2023). Mullins, C. F. et al. Effectiveness of combined dorsal root ganglion and spinal cord stimulation: a retrospective, single-centre case series for chronic focal neuropathic pain. Pain Med 25 , 116-124, doi:10.1093/pm/pnad128 (2024). Ji, M., Yao, P., Han, Z. & Zhu, D. Pulsed Radiofrequency Combined With Methylene Blue Paravertebral Nerve Block Effectively Treats Thoracic Postherpetic Neuralgia. Frontiers in neurology 13 , 811298, doi:10.3389/fneur.2022.811298 (2022). Ma, J., Wan, Y., Yang, L., Huang, D. & Zhou, H. Dual-neuromodulation strategy in pain management of herpes zoster ophthalmicus: retrospective cohort study and literature review. Annals of medicine 55 , 2288826, doi:10.1080/07853890.2023.2288826 (2023). Wang, Q. et al. A new dual function dorsal root ganglion stimulation in pain management: a technical note and case report. Therapeutic advances in chronic disease 14 , 20406223231206224, doi:10.1177/20406223231206224 (2023). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 21 Oct, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 09 Sep, 2024 Reviews received at journal 06 Sep, 2024 Reviewers agreed at journal 27 Aug, 2024 Reviewers agreed at journal 27 Aug, 2024 Reviewers agreed at journal 22 Jul, 2024 Reviewers agreed at journal 13 Jul, 2024 Reviewers invited by journal 23 Jun, 2024 Editor assigned by journal 23 Jun, 2024 Editor invited by journal 21 Jun, 2024 Submission checks completed at journal 21 Jun, 2024 First submitted to journal 19 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4608493","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":325109611,"identity":"695528c5-9043-4aa6-a805-d10f19504763","order_by":0,"name":"Xuelian Li","email":"","orcid":"","institution":"Department of Pain, The Third Xiangya Hospital and Institute of Pain Medicine, Central South University","correspondingAuthor":false,"prefix":"","firstName":"Xuelian","middleName":"","lastName":"Li","suffix":""},{"id":325109612,"identity":"00d86309-37ef-4dcb-839c-0b4502781abb","order_by":1,"name":"Huaxiang Zhang","email":"","orcid":"","institution":"Department of Pain, The Third Xiangya Hospital and Institute of Pain Medicine, Central South University","correspondingAuthor":false,"prefix":"","firstName":"Huaxiang","middleName":"","lastName":"Zhang","suffix":""},{"id":325109613,"identity":"63ac667e-3553-42cc-8acd-cc80c2a2a396","order_by":2,"name":"Xu Zhang","email":"","orcid":"","institution":"Department of Pain, The Third Xiangya Hospital and Institute of Pain Medicine, Central South University","correspondingAuthor":false,"prefix":"","firstName":"Xu","middleName":"","lastName":"Zhang","suffix":""},{"id":325109614,"identity":"93776aa3-b64d-4428-bcd3-8d6bc9b8a830","order_by":3,"name":"Ke Ma","email":"","orcid":"","institution":"Department of Pain, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ke","middleName":"","lastName":"Ma","suffix":""},{"id":325109615,"identity":"af0ca712-4f7c-4122-87e1-75b394920ac2","order_by":4,"name":"Yan Lv","email":"","orcid":"","institution":"Department of Pain, Xijing Hospital, Air Force Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Lv","suffix":""},{"id":325109616,"identity":"16b56665-b926-4266-bd0c-2078fcd9977b","order_by":5,"name":"Tao Song","email":"","orcid":"","institution":"Department of Pain, The First Hospital of China Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tao","middleName":"","lastName":"Song","suffix":""},{"id":325109617,"identity":"8795a767-3dbb-4b37-88b3-f9f2c5bf6b43","order_by":6,"name":"Gangwen Guo","email":"","orcid":"","institution":"Department of Pain, The Third Xiangya Hospital and Institute of Pain Medicine, Central South University","correspondingAuthor":false,"prefix":"","firstName":"Gangwen","middleName":"","lastName":"Guo","suffix":""},{"id":325109618,"identity":"6286e61d-0b12-4364-9cff-b6cbb5a17a4c","order_by":7,"name":"Dong Huang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABH0lEQVRIiWNgGAWjYBACAzDJBsTszQcOfKhg4GFgYGx8+IEoLTzHEg/OOAPSwtxsLEGUFgkf5cO8bSAee5sADx4t5hLJzx5+KbPJk4/gYTjMO++wjDkDYxuDBIOdnG4Ddi2WM9LMjWXOpRUb3u49cHDutsM8lg2MbQ8KGJKNzQ7gcNiNBDNpybbDiRvnnEs48HZbGo/BAcZ2AwmGA4nbcGpJ/wbRMiPH4ADvHLCWNgkevFpyzCQ/ArXMl8gxOMjbYEOEljNvyqQZzqUlbuA5lnBwxjEbHstmRmAgG+Dxy/H0bZI/ymwS57c3H/7woUbC3py9/eHDDxV2cri0gAAzKBYMYAoMmMEkbuUgwPgDSMg3wLTgVzwKRsEoGAUjEAAAZ5JlWFb//a8AAAAASUVORK5CYII=","orcid":"","institution":"Department of Pain, The Third Xiangya Hospital and Institute of Pain Medicine, Central South University","correspondingAuthor":true,"prefix":"","firstName":"Dong","middleName":"","lastName":"Huang","suffix":""}],"badges":[],"createdAt":"2024-06-20 01:59:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4608493/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4608493/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-75890-4","type":"published","date":"2024-10-21T15:57:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60601020,"identity":"8ae05c73-a63b-4669-be78-ccbfbe0544c9","added_by":"auto","created_at":"2024-07-18 16:03:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":791679,"visible":true,"origin":"","legend":"\u003cp\u003ePRF cannulas were accurately located in the intervertebral foramens confirmed by the guidance of C-arm fluoroscopy. (A)Anterior-posterior.(B) lateral view.\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4608493/v1/1c26de5c587816f5bb8a81ea.png"},{"id":60601021,"identity":"7b4bc310-81b0-4cc0-913c-99c8ef5998e2","added_by":"auto","created_at":"2024-07-18 16:03:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":107584,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram for patient selection..\u003c/p\u003e","description":"","filename":"figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4608493/v1/7bd24f2fad019314f60e89e5.png"},{"id":60602281,"identity":"e5081194-7c03-4117-9bc1-45dcc14574eb","added_by":"auto","created_at":"2024-07-18 16:11:55","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1364408,"visible":true,"origin":"","legend":"\u003cp\u003e6 months postoperation, the proportion of patients with different degrees of pain in the two groups was compared. (A) 6 months postoperation, 38.46% of the patients in the SCS group had moderate pain. (B)6 months postoperation, 6.67% of the patients in the SCS+PRF group had moderate pain. χ2 test,P=0.041.\u003c/p\u003e","description":"","filename":"figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4608493/v1/60711487f2ef0b71b4d6a60a.png"},{"id":60601022,"identity":"ba3f0453-aa08-4a53-a6e2-f6ed4046133d","added_by":"auto","created_at":"2024-07-18 16:03:56","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1234189,"visible":true,"origin":"","legend":"\u003cp\u003eAnalysis of the therapeutic effects of patients with acute and subacute in ZAP.(A)Changes of VAS scores at baseline, discharge and 6 months postoperative in Non-PHN patients.Two-way analysis of variance with repeated measures and post-hocmultiple pairwise comparison Sidak's testing was used to assess the alteration of pain scores between two groups over time.***P＜0.001.(B)Numbers of Non-PHN progressing to PHN at 6 months postoperative.χ2 test,P=0.038.\u003c/p\u003e","description":"","filename":"figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4608493/v1/8667c01c6c6c86bae5219d7c.png"},{"id":67681845,"identity":"de377c8e-3ae3-4d0f-b261-30527f2e621f","added_by":"auto","created_at":"2024-10-28 16:10:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5274462,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4608493/v1/f4ed896b-0051-470b-b945-086da3e3c114.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Central and peripheral dual neuromodulation strategy in pain management of zoster-associated pain：a retrospective cohort study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHerpes zoster (HZ) is a neurocutaneous disease caused by the varicella-zoster virus (VZV), with 80% of patients experiencing pain. Zoster-associated pain (ZAP) can be divided into three phases based on duration: the acute phase occurs within one month of the onset of herpes; the subacute phase is from one to three months; and postherpetic neuralgia (PHN) is pain that lasts for more than three months\u003csup\u003e[1]\u003c/sup\u003e. Data show that about 10-20% of patients will develop PHN after skin lesion healing, with the risk being higher in the elderly\u003csup\u003e[2,3]\u003c/sup\u003e. Once PHN occurs, the disease may last for months or even years and can lead to serious complications, such as secondary bacterial infection, disseminated rash, encephalitis, and herpes zoster ophthalmicus\u003csup\u003e[4]\u003c/sup\u003e. Patients often experience anxiety, depression, and sleep disorders, causing a significant burden on their mental health, family, and social economy. Effective treatment of ZAP has become a major focus and challenge in clinical practice\u003csup\u003e[5]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe treatment of ZAP includes medications such as antivirals, tricyclic antidepressants, antiepileptic drugs, opioids, and local analgesics\u003csup\u003e[6,7]\u003c/sup\u003e. For refractory cases that do not respond to conventional drug treatment, invasive interventional treatments such as nerve block, dorsal root ganglion (DRG) pulsed radiofrequency (PRF), and spinal cord stimulation (SCS) are often required\u003csup\u003e[8-10]\u003c/sup\u003e. SCS, a widely used interventional therapy for chronic pain, has been proven to effectively alleviate neuropathic pain, including ZAP\u003csup\u003e[11]\u003c/sup\u003e. In SCS, electrodes are placed in the epidural space of the spinal canal at the segments corresponding to the herpes zoster skin lesion. These electrodes are connected to a pulse generator that generates and outputs a continuous current between the cathode and anode, covering the patient\u0026apos;s pain area\u003csup\u003e[12]\u003c/sup\u003e. However, for patients with severe pain, SCS may not be fully effective, and some patients continue to experience moderate or severe pain after discharge. A recent study showed that 41.7% of ZAP patients treated with SCS had less than 50% pain reduction at discharge\u003csup\u003e[13]\u003c/sup\u003e. Another review summarized the long-term follow-up of various types of SCS in the treatment of PHN, noting that 32.1% of patients still had unsatisfactory pain relief\u003csup\u003e[14]\u003c/sup\u003e. Addressing residual pain after SCS treatment of ZAP remains an important clinical challenge.\u003c/p\u003e\n\u003cp\u003eDRG PRF is a type of peripheral neuromodulation technology that uses radio waves to generate electric fields, producing brief electrical stimulation and intermittent alternating pulse currents at the tip of the radiofrequency needle to regulate neural activity and provide pain relief\u003csup\u003e[15,16]\u003c/sup\u003e. DRG PRF has been shown to be an effective option for chronic refractory neuropathic pain and has been successfully applied to treat various types of neuropathic pain, including ZAP\u003csup\u003e[17-19]\u003c/sup\u003e. To address the problem of inadequate pain relief, multimodal analgesia is often used in clinical practice. The generation mechanism of ZAP involves both central and peripheral levels\u003csup\u003e[20,21]\u003c/sup\u003e.However, there is no research report on the effectiveness of neuromodulation therapy for ZAP at these two levels. This study aims to analyze the efficacy and safety of this dual nerve stimulation therapy for ZAP and to recommend a more effective treatment strategy for the comprehensive management of ZAP in clinical practice.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study followed the International Conference on Harmonisation of Good Clinical Practice guidelines and the Declaration of Helsinki (2008).With the approval of the Ethics Committee of the Third Xiangya Hospital of Central South University (No. 23863) to waive the requirement for signed informed consent,\u0026nbsp;a retrospective medical record analysis was conducted on patients with ZAP who were hospitalized in the Department of Pain at The Third Xiangya Hospital, Central South University, from October 2019 to October 2023. Inclusion criteria were as follows: age over 18 years, meeting the diagnostic criteria for ZAP, lesions affecting the cervical, thoracic, or lumbar segments, inability to control pain with conventional treatments, and undergoing either SCS treatment or a combination of SCS and PRF treatment. Exclusion criteria included: insufficient medical records (lack of baseline data or follow-up records at 6 months post-treatment), experiencing other significant medical conditions during the follow-up period, and receiving other interventional therapies during the follow-up period.\u003c/p\u003e\n\u003cp\u003ePatients who received only SCS treatment were defined as the SCS group, while those who received both SCS and PRF treatments were classified as the SCS+PRF group. According to the course of the disease, acute pain was defined as pain occurring within 1 month, pain persisting for more than 3 months was considered as PHN, and subacute pain was defined as lasting between 1 to 3 months\u003csup\u003e[1]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurgery\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSpinal cord stimulation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe surgical procedure for SCS has been detailed previously\u003csup\u003e[22]\u003c/sup\u003e. Briefly, the target spinal segment for electrode implantation was determined based on the affected pain area, and the electrode position was confirmed by intraoperative fluoroscopy. The patient was placed in a prone position, and after local anesthesia, an epidural puncture was performed with a 14G Tuohy needle. The core was removed once the needle entered the epidural space, and an 8-contact lead (3873; Medtronic, Minneapolis, MN, USA) was inserted through the cannula. The lead was advanced under fluoroscopic anteroposterior view, and a sensory test was conducted to ensure that the electrical stimulation covered the patient\u0026apos;s pain area. Patients were asked to remain in bed for 2 days to avoid potential lead migration. Those with lead displacement and dislocation were excluded from the study. The stimulation frequency was set to 50 Hz, and the pulse width was 500 \u0026mu;s. The electrical stimulation voltage was adjusted according to the degree of pain. Stimulation leads were removed within 2 weeks after surgery to prevent infection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDRG PRF\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePRF treatment was performed about one week after SCS. As described\u003csup\u003e[23]\u003c/sup\u003e, for DRG PRF, the patient was placed prone on the operating table with a comfortable pillow under their chest. The needle was guided into the thoracic paraspinal space using B-scan ultrasound (Fujifilm Sonosite, Bothell, WA, USA). The needle tip was fine-tuned based on the ultrasound probe scan to the target segment. X-ray imaging confirmed that the needle tip was directly below the lateral border of the pedicle in the anteroposterior view and in the superior quadrant dorsal to the foramina in the lateral view (Fig 1). The internal needle was replaced by a pulsed radiofrequency electrode, connected to a standard clinical specification radiofrequency generator (Beiqi, R-2000BA1, Beijing, China). The position of the needle tip was controlled by sensory and motor nerve stimulation before proceeding. DRG PRF treatment was set at 2 Hz (20 ms pulse width) three times for 240 s. Impedance was maintained at less than 300\u0026Omega; throughout the procedure.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical outcomes and follow-up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary data analyzed included changes in the intensity of patients\u0026apos; pain, evaluated using the Visual Analog Scale (VAS), which ranges from 0 (\u0026quot;no pain\u0026quot;) to 10 (\u0026quot;the worst pain imaginable\u0026quot;). Preoperative information included age, gender, duration of disease, and baseline VAS score upon admission. Postoperative data included VAS scores at discharge, VAS scores 6 months after surgery, whether patients in the acute and subacute phases progressed to PHN, and the occurrence of treatment-related complications (including pneumothorax, bleeding, infection, nerve injury, and electrode displacement). During postoperative follow-up, a reduction in VAS score of 50% or more compared to the baseline score upon admission was defined as a responder\u003csup\u003e[13]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrism 9.0 software (GraphPad, San Diego, CA, USA) was used for statistical analysis. Continuous variables were expressed as mean \u0026plusmn; standard deviation. Two-way analysis of variance with repeated measures and post-hoc multiple pairwise comparison using Sidak\u0026apos;s test was employed to assess changes in pain scores between the two groups over time. Differences in response rates were compared using \u0026chi;\u003csup\u003e2\u003c/sup\u003e tests (including possible \u0026chi;\u003csup\u003e2\u003c/sup\u003e-corrected tests and Fisher\u0026apos;s exact test). A P value of less than 0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 39 patient medical records were reviewed. Four patients had missing data for the 6-month postoperative follow-up, three patients lacked sufficient preoperative medical records, three patients underwent other interventional procedures, and one patient reported other significant medical conditions during follow-up. The medical records of these patients were excluded from the analysis. Finally, the medical records of 28 patients were analyzed. Thirteen patients received SCS treatment during hospitalization (SCS group), and the other fifteen patients received both SCS and PRF treatment (SCS+PRF group) (Fig 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDemographics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe demographic and clinical characteristics of the enrolled patients are summarized in Table 1. The mean age of patients in the SCS group was 70.92\u0026plusmn;9.74 years, while in the SCS+PRF group, it was 68.53\u0026plusmn;6.45 years, with no statistically significant difference (P=0.476). There were no significant differences in gender distribution, duration of illness, hospital stay, or electrode implantation between the two groups. Among the participants, 71.43% (20/28) had acute or subacute herpetic lesions with a disease duration of less than 3 months. Additionally, 8 patients were diagnosed with PHN. All enrolled patients had failed to achieve pain control with conventional treatments before undergoing neuromodulation therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e.General characteristics of patients.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"494\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"44.84848484848485%\"\u003e\n \u003cp\u003eGroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.393939393939394%\"\u003e\n \u003cp\u003eSCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.595959595959595%\"\u003e\n \u003cp\u003eSCS+PRF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.161616161616163%\"\u003e\n \u003cp\u003ep\u0026nbsp;value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e70.92\u0026plusmn;9.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e68.53\u0026plusmn;6.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.476\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSex (male/female)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8/7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.450\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDuration (n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.769\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026lt;1 month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2(8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0(0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; 1\u0026ndash;3 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9(69%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9(60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026gt;3 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2(23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6(40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eVAS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.23\u0026plusmn;0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.47\u0026plusmn;1.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.934\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Discharge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.62\u0026plusmn;1.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.60\u0026plusmn;1.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e＞0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;6 months postoperative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.23\u0026plusmn;1.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.53\u0026plusmn;1.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e＜0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eResponders at discharge(n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.583\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Responders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11(84.62%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14(93.33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Nonresponders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2(15.38%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1(6.77%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eResponders at 6 months postoperative(n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.029\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Responders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7(53.85%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14(93.33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Nonresponders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6(46.15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1(6.77%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLong-term analgesic effect\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe baseline VAS upon admission showed no significant difference between the SCS and SCS+PRF groups (P=0.934). Following treatment, both groups exhibited significant pain relief at discharge, with VAS scores of 2.62\u0026plusmn;1.33 and 2.60\u0026plusmn;1.06 for the SCS and SCS+PRF groups, respectively, showing no significant statistical difference (P＞0.99). At the 6-month follow-up, both groups demonstrated effective long-term pain relief. The VAS score of the SCS+PRF group (1.53\u0026plusmn;1.06) was significantly lower than that of the SCS group (3.23\u0026plusmn;1.50) (P\u0026lt;0.001) (Table 1). Additionally, the response rates at discharge were 84.62% and 93.33% for the SCS and SCS+PRF groups, respectively, with no significant difference (P=0.583) (Table 1). However, at the 6-month follow-up, the response rate in the SCS+PRF group remained at 93.33%, significantly higher than the 53.85% observed in the SCS group (P=0.029) (Table 1). Furthermore, at the 6-month follow-up, 6.67% of the SCS+PRF group still had moderate pain (Fig 3B), which was significantly lower than the 38.4% in the SCS group (Fig 3A) (P=0.041). These findings suggest the superior long-term efficacy of the dual-modulation therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrevention of PHN\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted efficacy analyses on patients in the acute and subacute phases (non-PHN) of ZAP and found no significant differences in preoperative and discharge VAS scores between the acute and subacute patient groups in both the SCS and SCS+PRF groups (all P\u0026gt;0.05). However, at the 6-month follow-up, the VAS scores in the SCS+PRF group were significantly lower than those in the SCS group (P\u0026lt;0.001) (Fig 4A). Furthermore, at 6 months post-operation, 45.45% (5/11) of patients in the SCS group in the acute and subacute phases had VAS scores higher than 3, whereas no patients in the SCS+PRF group had VAS scores exceeding 3, indicating a significant difference (P=0.038) (Fig 4B). These findings suggest that central and peripheral dual modulation therapy may help prevent the development of PHN in patients in the acute and subacute phases of ZAP.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo complications related to the treatment regimens used (including pneumothorax, bleeding, infection, nerve injury, or stimulation lead migration) were observed during hospitalization or follow-up.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePatients with ZAP often suffer from severe and persistent neuropathic pain, and there is no widely accepted optimal treatment in clinical practice. For refractory ZAP, clinicians aim to provide adequate pain relief, prevent recurrence, and enhance the patient\u0026apos;s quality of life. Drug therapy alone often has limited effectiveness and comes with various side effects\u003csup\u003e[24,25]\u003c/sup\u003e. Neuromodulation therapy plays an important role in managing ZAP when conventional therapies are ineffective\u003csup\u003e[26]\u003c/sup\u003e. Here, we present preliminary evidence suggesting that a dual neuromodulation approach, combining peripheral nerve stimulation with central stimulation, is an effective option for pain management in patients with ZAP.\u003c/p\u003e\n\u003cp\u003eWe observed that the dual stimulation strategy of central and peripheral neuromodulation significantly relieved severe pain in patients with ZAP. At the final follow-up, patients in the SCS+PRF group showed a significant reduction in VAS scores and a notably lower proportion of residual moderate pain compared to the SCS group. This indicates that combining SCS with DRG PRF provides superior long-term pain relief. Moreover, among patients with subacute pain, the dual stimulation protocol effectively prevented the progression to PHN compared to single central stimulation alone. This finding aligns with current trends in pain management, suggesting that multimodal and multitarget therapeutic approaches often yield better outcomes\u003csup\u003e[27]\u003c/sup\u003e. The multifaceted pathogenesis of ZAP involves sensitization of central and peripheral nerves and abnormal ion channel expression\u003csup\u003e[20,21]\u003c/sup\u003e. SCS may function by selectively activating large, rapidly conducting fibers and influencing pain signal transmission at the spinal cord level\u003csup\u003e[28]\u003c/sup\u003e. DRG PRF, on the other hand, can block pain signal transmission by directly acting on peripheral nerves\u003csup\u003e[15,16]\u003c/sup\u003e. This dual stimulation strategy addresses pain signal processing at both central and peripheral levels, enhancing therapeutic effects. ZAP originates from VZV latent in peripheral ganglia, evolving from peripheral sensitization to central sensitization over time, with the two mechanisms influencing each other\u003csup\u003e[27,29,30]\u003c/sup\u003e. We describe this phenomenon of layered and integrated sensitization as the \u0026quot;layer-integrate\u0026quot; sensitization theory (LIST). The dual stimulation strategy of SCS combined with DRG PRF offers comprehensive pain management at both central and peripheral levels.\u003c/p\u003e\n\u003cp\u003eNeuromodulation therapy is a key component of multimodal analgesia for refractory neuropathic pain\u003csup\u003e[9]\u003c/sup\u003e. A review summarized that SCS combined with conventional medical management reduces chronic pain intensity, decreases the dose of analgesics needed, and improves long-term quality of life and physical function\u0026nbsp;\u003csup\u003e[31]\u003c/sup\u003e. A recent study indicated that the efficacy of combined DRG and SCS stimulation in treating chronic focal neuropathic pain was 78.9%\u003csup\u003e[32]\u003c/sup\u003e. Ji et al. also reported that, after 6 months of PRF combined with nerve block for ZAP, only 16.67% of patients had an unsatisfactory prognosis\u003csup\u003e[33]\u003c/sup\u003e. These findings consistently suggest that integrated management may be a better approach for treating refractory neuropathic pain. Research on dual neuromodulation therapy for patients with ZAP is still extremely limited. Ma et al. found that a dual stimulation regimen of peripheral nerve electrical stimulation combined with PRF in the trigeminal ganglion achieved better clinical outcomes compared with peripheral nerve electrical stimulation alone in the management of herpes zoster ophthalmicus\u003csup\u003e[34]\u003c/sup\u003e. Additionally, Wang et al. reported the analgesic effect of dual neuromodulation in the dorsal root ganglia in a patient with extremely painful ZAP\u0026nbsp;\u003csup\u003e[35]\u003c/sup\u003e. They performed dual nerve stimulation on a single level of the peripheral nervous system. Our study supported the efficacy of dual electrical stimulation in treating refractory ZAP at both the central and peripheral nervous system levels. This suggests that neuromodulation of both the peripheral and central nervous systems may have significant advantages in the comprehensive treatment of ZAP.\u003c/p\u003e\n\u003cp\u003eOur study has several limitations. Firstly, as a retrospective study, the data is sourced from existing medical records, which may introduce certain biases due to variations in data recording by different doctors. Secondly, the single-center nature of the study resulted in a small sample size. Finally, long-term follow-up results are not yet available. Despite these limitations, our results preliminarily demonstrate the excellent effect of this central and peripheral hierarchical and integrated neuromodulation for pain management. Therefore, it is necessary to conduct multi-center, large sample-size randomized controlled clinical trials to verify the efficacy of SCS combined with DRG PRF dual stimulation in the treatment of ZAP in the future. This will help explore the best neuromodulation scheme for treating ZAP.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eSCS combined with DRG PRF is feasible and effective for treating ZAP. This new central and peripheral dual nerve stimulation strategy may be a more appropriate regimen for ZAP treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was funded by the National Natural Science Foundation of China (82271512 to DH).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKM, YL, TS, and DH: conceptualization, investigation, supervision, project administration, and funding acquisition. XL HZ and XZ: methodology. XL and GG: formal analysis. XZ and GG: data curation. XL HZ and GG: original draft preparation. DH: writing review and editing. All authors have read and agreed to the published version of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTe authors declare no competing interests.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with Ethics Guidelines\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of The Third Xiangya Hospital, Central South University (No. 23863). This trial was registered on ClinicalTrials.gov with the following number: ChiCTR2400084515.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWang, X. X., Zhang, Y. \u0026amp; Fan, B. F. Predicting Postherpetic Neuralgia in Patients with Herpes Zoster by Machine Learning: A Retrospective Study. \u003cem\u003ePain and therapy\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, 627-635, doi:10.1007/s40122-020-00196-y (2020).\u003c/li\u003e\n\u003cli\u003eKawai, K., Gebremeskel, B. G. \u0026amp; Acosta, C. J. Systematic review of incidence and complications of herpes zoster: towards a global perspective. \u003cem\u003eBMJ open\u003c/em\u003e \u003cstrong\u003e4\u003c/strong\u003e, e004833, doi:10.1136/bmjopen-2014-004833 (2014).\u003c/li\u003e\n\u003cli\u003eGross, G. E.\u003cem\u003e et al.\u003c/em\u003e S2k guidelines for the diagnosis and treatment of herpes zoster and postherpetic neuralgia. \u003cem\u003eJournal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG\u003c/em\u003e \u003cstrong\u003e18\u003c/strong\u003e, 55-78, doi:10.1111/ddg.14013 (2020).\u003c/li\u003e\n\u003cli\u003eJohnson, R. W.\u003cem\u003e et al.\u003c/em\u003e The impact of herpes zoster and post-herpetic neuralgia on quality-of-life. \u003cem\u003eBMC medicine\u003c/em\u003e \u003cstrong\u003e8\u003c/strong\u003e, 37, doi:10.1186/1741-7015-8-37 (2010).\u003c/li\u003e\n\u003cli\u003eJohnson, R. W.\u003cem\u003e et al.\u003c/em\u003e Herpes zoster epidemiology, management, and disease and economic burden in Europe: a multidisciplinary perspective. \u003cem\u003eTherapeutic advances in vaccines\u003c/em\u003e \u003cstrong\u003e3\u003c/strong\u003e, 109-120, doi:10.1177/2051013615599151 (2015).\u003c/li\u003e\n\u003cli\u003ePatil, A., Goldust, M. \u0026amp; Wollina, U. Herpes zoster: A Review of Clinical Manifestations and Management. \u003cem\u003eViruses\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, doi:10.3390/v14020192 (2022).\u003c/li\u003e\n\u003cli\u003eTang, J., Zhang, Y., Liu, C., Zeng, A. \u0026amp; Song, L. Therapeutic Strategies for Postherpetic Neuralgia: Mechanisms, Treatments, and Perspectives. \u003cem\u003eCurrent pain and headache reports\u003c/em\u003e \u003cstrong\u003e27\u003c/strong\u003e, 307-319, doi:10.1007/s11916-023-01146-x (2023).\u003c/li\u003e\n\u003cli\u003eLi, D.\u003cem\u003e et al.\u003c/em\u003e Combined therapy of pulsed radiofrequency and nerve block in postherpetic neuralgia patients: a randomized clinical trial. \u003cem\u003ePeerJ\u003c/em\u003e \u003cstrong\u003e6\u003c/strong\u003e, e4852, doi:10.7717/peerj.4852 (2018).\u003c/li\u003e\n\u003cli\u003eHan, R.\u003cem\u003e et al.\u003c/em\u003e Clinical Efficacy of Short-Term Peripheral Nerve Stimulation in Management of Facial Pain Associated With Herpes Zoster Ophthalmicus. \u003cem\u003eFront Neurosci\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, 574713, doi:10.3389/fnins.2020.574713 (2020).\u003c/li\u003e\n\u003cli\u003eNi, Y.\u003cem\u003e et al.\u003c/em\u003e Implantable Peripheral Nerve Stimulation for Trigeminal Neuropathic Pain: A Systematic Review and Meta-Analysis. \u003cem\u003eNeuromodulation\u003c/em\u003e \u003cstrong\u003e24\u003c/strong\u003e, 983-991, doi:10.1111/ner.13421 (2021).\u003c/li\u003e\n\u003cli\u003eSdrulla, A. D., Guan, Y. \u0026amp; Raja, S. N. Spinal Cord Stimulation: Clinical Efficacy and Potential Mechanisms. \u003cem\u003ePain practice : the official journal of World Institute of Pain\u003c/em\u003e \u003cstrong\u003e18\u003c/strong\u003e, 1048-1067, doi:10.1111/papr.12692 (2018).\u003c/li\u003e\n\u003cli\u003eLiu, B.\u003cem\u003e et al.\u003c/em\u003e Clinical Study of Spinal Cord Stimulation and Pulsed Radiofrequency for Management of Herpes Zoster-Related Pain Persisting Beyond Acute Phase in Elderly Patients. \u003cem\u003ePain physician\u003c/em\u003e \u003cstrong\u003e23\u003c/strong\u003e, 263-270 (2020).\u003c/li\u003e\n\u003cli\u003eChen, L.\u003cem\u003e et al.\u003c/em\u003e Correlation between spinal cord stimulation analgesia and cortical dynamics in pain management. \u003cem\u003eAnnals of clinical and translational neurology\u003c/em\u003e \u003cstrong\u003e11\u003c/strong\u003e, 57-66, doi:10.1002/acn3.51932 (2024).\u003c/li\u003e\n\u003cli\u003eIsagulyan, E.\u003cem\u003e et al.\u003c/em\u003e The Effectiveness of Various Types of Electrical Stimulation of the Spinal Cord for Chronic Pain in Patients with Postherpetic Neuralgia: A Literature Review. \u003cem\u003ePain research \u0026amp; management\u003c/em\u003e \u003cstrong\u003e2023\u003c/strong\u003e, 6015680, doi:10.1155/2023/6015680 (2023).\u003c/li\u003e\n\u003cli\u003eWu, C. Y.\u003cem\u003e et al.\u003c/em\u003e Efficacy of Pulsed Radiofrequency in Herpetic Neuralgia: A Meta-Analysis of Randomized Controlled Trials. \u003cem\u003eThe Clinical journal of pain\u003c/em\u003e \u003cstrong\u003e36\u003c/strong\u003e, 887-895, doi:10.1097/ajp.0000000000000867 (2020).\u003c/li\u003e\n\u003cli\u003eYang, L.\u003cem\u003e et al.\u003c/em\u003e Clinical Outcome of Pulsed-Radiofrequency Combined With Transforaminal Epidural Steroid Injection for Lumbosacral Radicular Pain Caused by Distinct Etiology. \u003cem\u003eFront Neurosci\u003c/em\u003e \u003cstrong\u003e15\u003c/strong\u003e, 683298, doi:10.3389/fnins.2021.683298 (2021).\u003c/li\u003e\n\u003cli\u003eChang, M. C. Efficacy of Pulsed Radiofrequency Stimulation in Patients with Peripheral Neuropathic Pain: A Narrative Review. \u003cem\u003ePain physician\u003c/em\u003e \u003cstrong\u003e21\u003c/strong\u003e, E225-e234 (2018).\u003c/li\u003e\n\u003cli\u003eEsposito, M. F., Malayil, R., Hanes, M. \u0026amp; Deer, T. Unique Characteristics of the Dorsal Root Ganglion as a Target for Neuromodulation. \u003cem\u003ePain Med\u003c/em\u003e \u003cstrong\u003e20\u003c/strong\u003e, S23-s30, doi:10.1093/pm/pnz012 (2019).\u003c/li\u003e\n\u003cli\u003eSun, C. L.\u003cem\u003e et al.\u003c/em\u003e High-voltage, Long-duration Pulsed Radiofrequency to the Dorsal Root Ganglion Provides Improved Pain Relief for Herpes Zoster Neuralgia in the Subacute Stage. \u003cem\u003ePain physician\u003c/em\u003e \u003cstrong\u003e26\u003c/strong\u003e, E155-e162 (2023).\u003c/li\u003e\n\u003cli\u003eFields, H. L., Rowbotham, M. \u0026amp; Baron, R. Postherpetic neuralgia: irritable nociceptors and deafferentation. \u003cem\u003eNeurobiology of disease\u003c/em\u003e \u003cstrong\u003e5\u003c/strong\u003e, 209-227, doi:10.1006/nbdi.1998.0204 (1998).\u003c/li\u003e\n\u003cli\u003eCampbell, J. N. \u0026amp; Meyer, R. A. Mechanisms of neuropathic pain. \u003cem\u003eNeuron\u003c/em\u003e \u003cstrong\u003e52\u003c/strong\u003e, 77-92, doi:10.1016/j.neuron.2006.09.021 (2006).\u003c/li\u003e\n\u003cli\u003eZhou, H.\u003cem\u003e et al.\u003c/em\u003e Effect of Implantable Electrical Nerve Stimulation on Cortical Dynamics in Patients With Herpes Zoster-Related Pain: A Prospective Pilot Study. \u003cem\u003eFrontiers in bioengineering and biotechnology\u003c/em\u003e \u003cstrong\u003e10\u003c/strong\u003e, 862353, doi:10.3389/fbioe.2022.862353 (2022).\u003c/li\u003e\n\u003cli\u003eHuang, X.\u003cem\u003e et al.\u003c/em\u003e Efficacy and safety of pulsed radiofrequency modulation of thoracic dorsal root ganglion or intercostal nerve on postherpetic neuralgia in aged patients: a retrospective study. \u003cem\u003eBMC neurology\u003c/em\u003e \u003cstrong\u003e21\u003c/strong\u003e, 233, doi:10.1186/s12883-021-02286-6 (2021).\u003c/li\u003e\n\u003cli\u003eBeydoun, A. Postherpetic neuralgia: role of gabapentin and other treatment modalities. \u003cem\u003eEpilepsia\u003c/em\u003e \u003cstrong\u003e40 Suppl 6\u003c/strong\u003e, S51-56; discussion S73-54, doi:10.1111/j.1528-1157.1999.tb00933.x (1999).\u003c/li\u003e\n\u003cli\u003eOnakpoya, I. J., Thomas, E. T., Lee, J. J., Goldacre, B. \u0026amp; Heneghan, C. J. Benefits and harms of pregabalin in the management of neuropathic pain: a rapid review and meta-analysis of randomised clinical trials. \u003cem\u003eBMJ open\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, e023600, doi:10.1136/bmjopen-2018-023600 (2019).\u003c/li\u003e\n\u003cli\u003eLin, C. S., Lin, Y. C., Lao, H. C. \u0026amp; Chen, C. C. Interventional Treatments for Postherpetic Neuralgia: A Systematic Review. \u003cem\u003ePain physician\u003c/em\u003e \u003cstrong\u003e22\u003c/strong\u003e, 209-228 (2019).\u003c/li\u003e\n\u003cli\u003eRui, M., Ni, H., Xie, K., Xu, L. \u0026amp; Yao, M. Progress in Radiofrequency Therapy for Zoster-Associated Pain About Parameters, Modes, Targets, and Combined Therapy: A Narrative Review. \u003cem\u003ePain and therapy\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e, 23-32, doi:10.1007/s40122-023-00561-7 (2024).\u003c/li\u003e\n\u003cli\u003eMelzack, R. \u0026amp; Wall, P. D. Pain mechanisms: a new theory. \u003cem\u003eScience (New York, N.Y.)\u003c/em\u003e \u003cstrong\u003e150\u003c/strong\u003e, 971-979, doi:10.1126/science.150.3699.971 (1965).\u003c/li\u003e\n\u003cli\u003eBaron, R. \u0026amp; Saguer, M. Postherpetic neuralgia. Are C-nociceptors involved in signalling and maintenance of tactile allodynia? \u003cem\u003eBrain : a journal of neurology\u003c/em\u003e \u003cstrong\u003e116 ( Pt 6)\u003c/strong\u003e, 1477-1496, doi:10.1093/brain/116.6.1477 (1993).\u003c/li\u003e\n\u003cli\u003eHashizume, K. [Herpes zoster and post-herpetic neuralgia]. \u003cem\u003eNihon rinsho. Japanese journal of clinical medicine\u003c/em\u003e \u003cstrong\u003e59\u003c/strong\u003e, 1738-1742 (2001).\u003c/li\u003e\n\u003cli\u003eZhou, M.\u003cem\u003e et al.\u003c/em\u003e Comparison of clinical outcomes associated with spinal cord stimulation (SCS) or conventional medical management (CMM) for chronic pain: a systematic review and meta-analysis. \u003cem\u003eEuropean spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society\u003c/em\u003e \u003cstrong\u003e32\u003c/strong\u003e, 2029-2041, doi:10.1007/s00586-023-07716-2 (2023).\u003c/li\u003e\n\u003cli\u003eMullins, C. F.\u003cem\u003e et al.\u003c/em\u003e Effectiveness of combined dorsal root ganglion and spinal cord stimulation: a retrospective, single-centre case series for chronic focal neuropathic pain. \u003cem\u003ePain Med\u003c/em\u003e \u003cstrong\u003e25\u003c/strong\u003e, 116-124, doi:10.1093/pm/pnad128 (2024).\u003c/li\u003e\n\u003cli\u003eJi, M., Yao, P., Han, Z. \u0026amp; Zhu, D. Pulsed Radiofrequency Combined With Methylene Blue Paravertebral Nerve Block Effectively Treats Thoracic Postherpetic Neuralgia. \u003cem\u003eFrontiers in neurology\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e, 811298, doi:10.3389/fneur.2022.811298 (2022).\u003c/li\u003e\n\u003cli\u003eMa, J., Wan, Y., Yang, L., Huang, D. \u0026amp; Zhou, H. Dual-neuromodulation strategy in pain management of herpes zoster ophthalmicus: retrospective cohort study and literature review. \u003cem\u003eAnnals of medicine\u003c/em\u003e \u003cstrong\u003e55\u003c/strong\u003e, 2288826, doi:10.1080/07853890.2023.2288826 (2023).\u003c/li\u003e\n\u003cli\u003eWang, Q.\u003cem\u003e et al.\u003c/em\u003e A new dual function dorsal root ganglion stimulation in pain management: a technical note and case report. \u003cem\u003eTherapeutic advances in chronic disease\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, 20406223231206224, doi:10.1177/20406223231206224 (2023).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"neuromodulation, pulsed radiofrequency, spinal cord stimulation, zoster-associated pain","lastPublishedDoi":"10.21203/rs.3.rs-4608493/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4608493/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSpinal cord stimulation (SCS) has shown effectiveness in relieving zoster-associated pain (ZAP), but some patients still experience moderate or severe pain after SCS treatment. This study aims to evaluate the impact of SCS combined with dorsal root ganglion (DRG) pulsed radiofrequency (PRF) as a dual neuromodulation strategy on the prognosis of ZAP.The clinical records of patients diagnosed with ZAP who underwent SCS (SCS group) or SCS combined with PRF (SCS\u0026thinsp;+\u0026thinsp;PRF group) at The Third Xiangya Hospital, Central South University, were retrospectively analyzed to compare the effectiveness of the two treatment approaches for ZAP. Outcome measures included changes in Visual Analog Scale (VAS) scores before and after neuromodulation treatment, response rates, and incidence of progression to postherpetic neuralgia (PHN).13 SCS patients and 15 SCS\u0026thinsp;+\u0026thinsp;PRF patients were analyzed. Admission VAS scores were similar (P\u0026thinsp;=\u0026thinsp;0.934). Upon discharge, no significant differences in VAS or response rates were observed (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). However, at 6-month follow-up, the SCS\u0026thinsp;+\u0026thinsp;PRF group had lower VAS scores (1.53\u0026thinsp;\u0026plusmn;\u0026thinsp;1.06 vs. 3.23\u0026thinsp;\u0026plusmn;\u0026thinsp;1.50, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and a lower proportion of residual moderate pain (P\u0026thinsp;=\u0026thinsp;0.041). None in the SCS\u0026thinsp;+\u0026thinsp;PRF group progressed to PHN in the acute/subacute phases, differing significantly from the SCS group (P\u0026thinsp;=\u0026thinsp;0.038).Therefore,SCS combined with DRG PRF is feasible and effective in the treatment of ZAP. This dual neuromodulation strategy may be a more appropriate regimen for the treatment of ZAP.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e","manuscriptTitle":"Central and peripheral dual neuromodulation strategy in pain management of zoster-associated pain：a retrospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-18 16:03:51","doi":"10.21203/rs.3.rs-4608493/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-09-09T05:22:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-06T21:39:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"325361903880232132484073059108055518481","date":"2024-08-27T20:37:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"164685740004915866443595936164495788754","date":"2024-08-27T07:13:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"49631863139256716940391441680386720698","date":"2024-07-22T11:58:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"219469072825071282238186336987455218577","date":"2024-07-13T18:19:02+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-24T01:44:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-24T01:41:41+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-06-21T20:08:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-21T09:30:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-06-20T01:57:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7ef7b837-0392-4570-b5cf-0ddb992d00b1","owner":[],"postedDate":"July 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":34388618,"name":"Health sciences/Diseases"},{"id":34388619,"name":"Health sciences/Medical research"},{"id":34388620,"name":"Health sciences/Neurology"}],"tags":[],"updatedAt":"2024-10-28T16:01:30+00:00","versionOfRecord":{"articleIdentity":"rs-4608493","link":"https://doi.org/10.1038/s41598-024-75890-4","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-10-21 15:57:00","publishedOnDateReadable":"October 21st, 2024"},"versionCreatedAt":"2024-07-18 16:03:51","video":"","vorDoi":"10.1038/s41598-024-75890-4","vorDoiUrl":"https://doi.org/10.1038/s41598-024-75890-4","workflowStages":[]},"version":"v1","identity":"rs-4608493","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4608493","identity":"rs-4608493","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}