Zoster-Related Pain (ZRP) is pain caused by Varicella-Zoster Virus (VZV) infection that significantly affects the quality of life of patients (1). More than 90% of the world's population is infected with VZV during childhood, and as specific immunity wanes, the virus can reactivate, leading to herpes zoster and associated pain (2). ZRP is categorized into Acute Herpes Zoster-Related Pain (AHZRP), Subacute Herpes Zoster-Related Pain and Chronic Herpes Zoster-Related Pain (CHZRP). AHZRP is characterized by a sharp stabbing and burning sensation, often described by patients as a “cutting” or “electric shock” pain, limited to the area of the attack and distributed along the affected nerve roots, usually starting a few days before the rash appears. The pain is confined to the area of the attack and distributed along the affected nerve roots, usually starting a few days before the rash appears (3). CHZRP, called postherpetic neuralgia (PHN), can last for months or even years and is characterized by allodynia, persistent burning sensation, intense itching, hyperalgesia, and tactile hypersensitivity, which complicates the management of PHN (1). Visual analog scale (VAS), numeric rating scale (NRS), verbal rating scale (VRS) and facial expression pain scale (FPS) are mostly used to assess pain intensity.

During an acute episode of herpes zoster, the goal of treatment is to control symptoms and prevent complications, and commonly used treatments include antiviral therapies, corticosteroids, and analgesics. Antiviral drugs (e.g., acyclovir, valacyclovir, and famciclovir) accelerate rash healing and reduce pain levels by inhibiting VZV replication and shortening the viral shedding period (4, 5). However, the antiviral effect is significantly reduced if the rash is not treated promptly within 72 hours of rash appearance. Corticosteroids may be used in combination with antivirals to reduce acute pain, but should not be used alone and do not reduce the incidence of PHN (6). Acute pain usually requires additional analgesics, NSAIDs are often insufficiently effective, and opioids may be considered (7). Treatment of PHN is extremely challenging, and in addition to traditional medications, first- and second-line pharmacological therapies (e.g., tricyclic antidepressants, 5-hydroxytryptamine-norepinephrine reuptake inhibitors, pregabalin, gabapentin, and tramadol, among others) are recognized as having grade A evidence of pain relief (8, 9). Effects remain limited (8, 9). Even when multiple oral medications are combined, pain relief is often incomplete, highlighting the complexity of PHN management.

ZRP causes significant suffering to patients, and conventional oral drug therapy has limitations and adverse effects. Antiviral drugs (e.g., acyclovir, vasiclovir) inhibit VZV but do not reduce the incidence of PHN, and can also cause nausea, neurotoxicity, and renal damage (10). Opioids, on the other hand, carry the risk of addiction and respiratory depression, and corticosteroids may lead to metabolic disorders and mood swings, and are usually only indicated for those with severe symptoms or without contraindications (11). Therefore, finding more effective and safer treatments has become a focus of research. In this paper, we review the research progress of non-oral drug treatment of ZRP, focusing on summarizing its action, safety and mechanism to provide clinical reference.

Histopathologic studies in patients with PHN have shown that infiltration of lymphocytes occurs in the posterior horn of the spinal cord during subacute and chronic inflammatory processes, suggesting that inflammation may play an important role in the development and progression of PHN (12). In addition, the concentration of interleukin-8 (IL-8) in the cerebrospinal fluid of patients with PHN is significantly elevated, and studies have confirmed that IL-8 is associated with pain triggered by inflammatory responses (13).PHN causes intense spinal inflammation that persists for several years before gradually resolving, and the concentration of IL-8 is inversely correlated with the duration of PHN before treatment (14). Given the potent anti-inflammatory effects of corticosteroids, it is able to reduce nerve damage and thus alleviate the pain of PHN (15). Intrathecal injection of methylprednisolone further supports its potential anti-inflammatory effect by reducing IL-8 concentrations (14). A randomized controlled trial comparing intrathecal midazolam and epidural methylprednisolone showed that epidural methylprednisolone had a long-term analgesic effect in lumbosacral dermatomal PHN (16). In addition, in a study by Dureja G P et al, a single dose of intrathecal midazolam combined with epidural methylprednisolone reduced AHZAP but did not prevent PHN (17). Another matched cohort study of 427 participants also showed that corticosteroids helped to relieve the acute phase of infection but were not effective in preventing PHN (18). A small randomized controlled study found no significant difference in patients with postherpetic neuralgia with intrathecal injection of methylprednisolone acetate compared to controls (19). The effectiveness of epidural or intrathecal cortisol hormone injections for ZRP remains controversial. In addition, the side effects of epidural injection of cortisol hormone, such as chemical meningitis, transverse myelitis, cauda equina syndrome, lumbar radiculitis, intractable headache, and urinary retention should not be ignored (20). Therefore, although epidural anesthetics and steroids can alleviate PHN (15), more clinicians are needed to weigh the benefits of this treatment.

BTX-A injection, an emerging therapy for ZRP treatment, has shown significant pain relief (21, 22). The mechanism of action may include reducing neurogenic inflammation and preventing peripheral sensitization (23). Studies have shown that BTX-A inhibits the release of neurotransmitters such as acetylcholine, glutamate, substance P, and calcitonin gene-related peptide, thereby reducing neuropathic pain (24). Based on these theories, BTX-A is gradually being used in ZRP. Recent randomized controlled trials have shown that BTX-A injections resulted in significant reductions in VAS scores in painful areas, prolonged sleep, and reduced opioid use (25–27). In one study, all 13 patients with PHN had a decrease in their VAS scores after receiving BTX-A injections for 2 weeks (28). A preliminary study by Freund and Schwartz showed a decrease in VAS scores from 8/10 to 5/10 in 7 patients with PHN, although the lack of a control group failed to draw definitive conclusions (29). In addition, an 80-year-old patient experienced significant pain relief with multiple BTX-A injections for 52 days after conventional treatment failed (30). Despite the favorable efficacy of BTX-A, it may also lead to adverse effects such as local muscle weakness, discomfort at the injection site, and systemic allergic reactions (31). Therefore, when BTX-A is applied to treat PHN, the health status of the patient should be adequately assessed and monitored after treatment to reduce the risk of adverse reactions. In conclusion, although BTX-A has demonstrated positive effects in ZRP treatment, rigorous evaluation before injection remains crucial.

PRP is activated by calcium chloride and thrombin to release a variety of growth factors that support nerve repair and serve as a clinical adjunctive therapeutic tool (32). The pathogenesis of ZRP is related to inflammation and nerve damage caused by viral replication, and inflammation can sustain damage to peripheral and central neurons and enhance pain sensitivity (33). Therefore, controlling the inflammatory response to promote nerve repair is key to the treatment of ZRP. Growth factors in PRP modulate inflammation and promote tissue regeneration (34–36). It also increases the secretion of platelet microbial protein (PMP), which significantly reduces inflammation (37). In addition, IGF-1 and VEGF factors in PRP promote spinal cord axon proliferation and restore innervation (38) Studies have shown that PRP is associated with the proliferation and neurophysiological activity of rat chervon cells, which play an important role in the maintenance and regeneration of peripheral nerves (39). Thus, PRP may exhibit ZRP therapeutic potential by reducing inflammation and promoting nerve regeneration in peripheral nerves. Studies on PRP in ZRP prevention and treatment are still limited. Zhou Z et al. (40) showed that in the observation group, an ultrasound-guided local paravertebral nerve puncture technique was used to inject 1 ml of PRP into each nerve segment. The results showed that the NRS score in the observation group was significantly lower than that in the control group, which was accompanied by improved sleep quality, reduced drug use, and shorter time for herpes to dry up and scab over. In addition, the incidence of dizziness, drowsiness, ataxia and PHN in the observation group was also significantly reduced. Despite the positive results of PRP in ZRP treatment, localized adverse effects such as pain, swelling and bruising at the injection site may occur, and individual patients may be at risk of systemic allergy or infection. Overall, PRP has a high safety profile, but clinical application requires proper evaluation and monitoring to identify potential adverse reactions.

PRF is a minimally invasive, targeted therapeutic technique that controls heat below 42°C (64) by pulsed current to avoid nerve damage (65) and is commonly used to alleviate PHN (66). It has been found that patients with ZRP have degenerative changes in class C fibers, which may lead to reorganization of pain signaling pathways in the central nervous system, activation of fiber reflexes, and lowering of the pain threshold, which in turn exacerbates neuropathic pain (67). The potential mechanism of PRF is that a rapidly changing electric field acts on the neuronal cell membranes, inducing electrolyte conduction and depolarization, which reduces pain and protects the nerves (64). Currently, PRF is mainly used in the treatment of pain in dorsal root ganglia, spinal ganglia and sympathetic ganglia. A randomized triple-blind controlled trial showed that PRF was superior to local anesthetic drug injections in the treatment of radicular pain and reduced TNF-α concentrations and CD3⁺ counts in cerebrospinal fluid (68). Another retrospective study showed that patients' VAS scores, Pittsburgh Sleep Quality Index (PSQI) and 36-item Brief Health Survey (SF-36) scores were significantly lower after single vs. two PRF treatments, and that the overall effectiveness rate was higher in the two-treatment group than in the single-treatment group. In addition, several reports have confirmed the effectiveness of PRF in controlling pain in patients with PHN and acute herpes zoster (69–71). PRF likewise provides significant relief of recalcitrant ZRP pain (69, 72). Studies have shown that VAS scores 6 months after PRF were significantly lower than those of the control group, and SF-36 scores improved significantly on all functional and mental health measures (69). A meta-analysis also showed that PRF significantly relieved ZRP pain and was associated with only minor adverse events, such as localized symptoms and transient bradycardia (73). In summary, PRF is a minimally invasive, targeted treatment technique that avoids nerve damage by controlling heat, can both effectively relieve ZRP, and shows good efficacy and relatively few adverse events.

The mechanism of SCS in the treatment of ZRP is unclear, but the rationale for spinal cord electrical stimulation in pain modulation is supported by the “gate control” theory, in which neural signaling is regulated by the dorsal horn of the spinal cord (74). SCS may reduce neuropathic pain by affecting the levels of γ-aminobutyric acid and adenosine in the dorsal horn (75). This method uses electrical current to stimulate spinal cord nerve fibers by implanting electrodes at specific locations in the spinal cord, altering the transmission and perception of pain signals (76) and modulating nerve fiber excitability for further pain relief (77). Several studies have demonstrated that SCS is an effective treatment for recalcitrant PHN (78–80). Early application of SCS significantly relieves PHN pain (81), with relief rates ranging from 27% to 82% (82). Small randomized controlled double-blind trials have shown that both PRF and SCS are effective alternative therapies for acute/subacute herpes zoster-related pain, but SCS achieves more significant pain relief and quality-of-life improvement than PRF (83). A longitudinal study of 28 patients by Harke H and Gretenkort P et al. demonstrated that 23 patients with postherpetic neuralgia and 4 acute patients with chronic pain improved after electrical stimulation (78). In addition, temporary SCS also reduced subacute herpetic pain and prevented the development of chronic pain (84, 85). A retrospective study showed that among 32 ZRP patients treated with SCS, VAS scores decreased significantly, 18 patients (39.1%) achieved complete pain relief, and no serious adverse effects were observed throughout the follow-up period (86). SCS therapy consists primarily of short-term spinal cord stimulation (stSCS) and permanent spinal cord stimulation. The effectiveness of temporary electrodes needs to be tested initially before implanting permanent electrodes. If temporary SCS is effective, permanent electrodes can be implanted after several weeks (87). Although permanent SCS can provide long-term analgesia, its application faces the complexity of patient selection and high cost. In contrast, stSCS has received increasing attention due to its simplicity, low cost and high efficiency. Compared with conventional SCS, temporary SCS is less costly and less invasive (88). A Japanese study showed that temporary SCS was effective in reducing PHN and preventing its occurrence (77). In addition, SCS combined with microsurgical posterior rhizotomy also improves the treatment outcome of PHN (82). However, SCS still has some drawbacks such as e.g., dislocated electrodes, broken wires or malfunctioning stimulators. In addition, patients may feel abnormal, tingling or numbness. In summary, despite the potential application of SCS in ZRP therapy, patients should be adequately evaluated preoperatively and monitored postoperatively during implementation, and further research and clinical practice will help to explore the potential of SCS in ZRP therapy and provide more effective pain management programs for patients.

The pathophysiology of ZRP encompasses both central and peripheral mechanisms, resulting in complex and varied treatment. Peripheral electrical nerve stimulation, as a highly targeted and less invasive form of neuromodulation, is commonly used to treat patients with intractable neuropathic pain. This technique modulates nerve fiber excitability through continuous stimulation of peripheral nerves and alters pain signaling pathways to relieve pain (89). The results of several small studies have shown that patients treated with peripheral neuromodulation significantly reduced their pain symptoms over a follow-up period of more than 6 months (90–92). These studies support the potential value of peripheral nerve electrical stimulation in improving chronic pain management.Studies by Green A L et al. have shown that deep brain electrical stimulation of the gray matter around the contralateral ventricles and the ventral posterolateral part of the thalamus can significantly reduce the symptoms of post-herpes zoster neuralgia (PHN).In this study, a patient with sensory impairment on the right side of the face caused by herpes zoster infection experienced pain for up to 10 years. After a period of 6 months of electrical stimulation treatment, the final follow-up VAS score was 0/10, showing a significant therapeutic effect (93).

In addition, a retrospective study showed that transcutaneous electrical nerve stimulation has a positive effect in preventing the development of PHN.The work of Stepanović A and other investigators confirmed the effectiveness of transcutaneous electrical nerve stimulation in reducing the incidence of subacute herpetic neuralgia (94). According to a report by Kolšek et al, transcutaneous electrical nerve stimulation was more effective in reducing and preventing PHN compared to conventional antiviral drugs, suggesting the importance of this method in clinical application (95). Meanwhile, another study noted that the combination of transcutaneous electrical nerve stimulation combined with methylcobalamin demonstrated a favorable analgesic effect on PHN (96).

Significant progress has been made in the treatment of ZRP with the continued advancement of non-oral drug therapy techniques. However, when selecting an appropriate treatment regimen, the safety and relevance of the treatment must be prioritized. Current research suggests that nonoral treatments such as subcutaneous injection of botulinum toxin A or tretinoin, transcutaneous electrical nerve stimulation, peripheral nerve stimulation, and stellate ganglion block may be the preferred option for those patients who do not respond well to oral medications. In addition, there are significant differences in the pathomechanisms of acute pain and postherpetic neuralgia that occur during active herpes zoster. Acute pain is usually associated with an active inflammatory response, whereas PHN is associated with chronic pain mechanisms such as nerve remodeling and increased central sensitization. Therefore, the patient's pain type should be specifically analyzed when developing a treatment plan. Therapies such as paravertebral blocks and pulsed radiofrequency have also shown some potential in acute herpes zoster pain, however, if the pain is severely persistent, spinal cord electrical stimulation should be considered at this time.

In addition, these minimally invasive interventional techniques have a wide range of applications not only in ZAP, but also for the effective treatment of other pathologic neuropathic pain. For example, SCS and peripheral nerve stimulation have shown significant pain relief in patients with diabetic neuropathy. SGB and PRF techniques also play an important role in complex regional pain syndromes by blocking sympathetic nerves and modulating neural activity to alleviate chronic pain.PVB and ENB are also widely used in postoperative pain control, effectively reducing patients' pain sensations and opioid requirements. In addition, PRF and PVB are able to relieve radicular pain caused by disc herniation by targeting the nerves. In summary, although these approaches can provide pain relief for patients, they need to be implemented with caution, especially when considering the destructive nature of dorsal root ganglia and the potential adverse events of intrathecal methylprednisolone injections. Therefore, larger, multicenter clinical trials are urgently needed to clarify the exact efficacy and side effects of these minimally invasive interventional techniques and to explore their applicability and mechanisms in the management of other virus-induced neuropathies.