The Effect of Esketamine Combined with Pulsed Radiofrequency on Neuropathic Pain in Herpes Zoster Patients: A Randomised Clinical Trial

Abstract

Introduction

Zoster-related neuralgia (ZRN) remains challenging to treat with current analgesics and interventional therapies. Esketamine, an N-methyl-D-aspartate receptor antagonist, offers potent analgesic effects. This study evaluated the efficacy and safety of low-dose esketamine combined with pulsed radiofrequency (PRF) for ZRN.

Methods

In this randomized controlled trial, 60 patients with ZRN scheduled for PRF were assigned to receive either continuous esketamine (0.02 mg/kg/h for 48 h) or saline alongside standard PRF and anticonvulsants. Pain (NRS, ID-pain), anxiety (HAMA), depression (HAMD-24), sleep quality (PSQI), and dissociative symptoms (CADSS) were assessed at baseline (T0), 48 h post-treatment (T1), 48 h post-treatment (T1), 1 week (T2), 2 weeks (T3), 1 month (T4), and 3 months (T5) post-treatment. Vital signs, CADSS scores (measuring dissociative symptoms), and other relevant clinical data were recorded at pre-medication (t0), 1 h (t1), 12 h (t2), 24 h (t3), and 48 h (t4) post-medication.

Results

Sixty patients completed the study. The esketamine group showed significantly lower NRS and ID-pain scores at all post-treatment time points (P < 0.01). HAMD-24 and PSQI scores were significantly improved from 48 h through 12 weeks (P < 0.05), while HAMA scores improved significantly from 1 week onward (P < 0.05). No significant differences in CADSS scores or adverse events were observed between groups.

Conclusion

Low-dose esketamine combined with PRF provides effective pain relief and improves mood and sleep quality in ZRN patients with a favorable safety profile.

Trial Registration

ChiCTR2400093061.

Key Summary Points

Why carry out this study?

This study addressed zoster-related neuralgia (ZRN), a common neuropathic pain in older adults where first-line oral therapies often fail

It hypothesized that adding low-dose esketamine to pulsed radiofrequency (PRF) and anticonvulsants would improve pain, mood, and sleep without increasing dissociative side effects

What was learned from the study?

The combination therapy (ES group) significantly lowered pain scores (NRS) from 48 h to 3 months compared with controls (P < 0.01)

The ES group also showed significant improvements in anxiety (HAMA), depression (HAMD-24), and sleep quality (PSQI) from 48 h to 3 months (P < 0.05)

Low-dose esketamine is an effective, opioid-sparing adjunctive therapy for ZRN, targeting both sensory and affective dimensions without raising dissociative symptoms

Introduction

Zoster-related neuralgia (ZRN) is a neuropathic pain condition caused by varicella-zoster virus infection, characterized by severe pain in the dermatomal distribution of the affected nerves. According to epidemiological data, the global incidence of herpes zoster in the general population ranges from 4 to 5.5 cases per 1000 person-years. The incidence of postherpetic neuralgia (PHN) is approximately 18% in patients over 50 years of age, reaching as high as 33% in those aged > 80 years [1,2]. The clinical manifestations are primarily characterized by spontaneous burning pain alternating with electric shock-like neuralgia. The management of ZRN presents a significant therapeutic challenge, and enhancing treatment efficacy remains a central focus of current research. First-line oral pharmacotherapies, including anticonvulsants and antidepressants, often yield unsatisfactory results or are poorly tolerated because of their adverse effect profiles. Furthermore, the therapeutic outcomes of minimally invasive interventional procedures, such as pulsed radiofrequency (PRF) and short-term spinal cord stimulation implantation, require further improvement [3,4].

Ketamine was discovered in 1962 and is primarily known as an NMDA receptor antagonist that provides dose-dependent analgesic, sedative, and anaesthetic effects. Ketamine acts on NMDA, serotonergic, dopaminergic, adrenergic, cholinergic, and opioid receptors, resulting in diverse and potentially beneficial effects across a range of clinical settings. Ketamine is a water and lipid-soluble N-methyl-d-aspartic acid (NMDA) receptor antagonist that has been widely used to provide cataleptic, amnesic, analgesic, and anaesthetic effects. Ketamine has been used to treat both acute and chronic pain at doses that provide light sedative effects or at entirely subanaesthetic doses. Ketamine provides analgesic effects similar to morphine but without the pronounced respiratory depression [5].

As a traditional N-methyl-d-aspartate (NMDA) receptor antagonist, ketamine exerts central effects including sensory inhibition, dissociation, analgesia, and amnesia by shortening the open time of NMDA receptor ion channels and reducing their opening frequency. Ketamine has been used for the treatment of ZRN; however, it is not well tolerated [6]. It may induce central adverse reactions such as hallucinations, dizziness, delirium, nightmares, and somnolence [5]. Esketamine, the pure dextrorotatory enantiomer of ketamine, exhibits higher potency, faster clearance, and a shorter recovery time while also providing multimodal analgesia for patients [7,8]. As one of the multimodal analgesic agents, it effectively alleviates acute postoperative and cancer-related pain while also improving mood and exerting multifaceted antidepressant effects [9]. However, evidence regarding its efficacy in neuropathic pain remains very limited. Preclinical studies have confirmed that esketamine alleviates pain by inhibiting microglial calcium-activated potassium channels. Low-dose esketamine has been shown to increase the mechanical pain threshold (assessed by Von Frey filaments) and thermal pain threshold in rats with chronic constriction injury (CCI) of the sciatic nerve, demonstrating superior efficacy compared with Selective Serotonin Reuptake Inhibitor (SSRIs) [10]. We hypothesized that esketamine may provide more effective relief for neuropathic pain in patients with ZRN. Therefore, this study enrolled hospitalized patients with ZRN to investigate the efficacy and safety of esketamine combined with pulsed radiofrequency therapy, aiming to lay the foundation for its clinical application. The introduction initially focused primarily on NMDA receptor antagonism. However, as Sleigh et al. [11] noted, ketamine's pharmacology extends beyond NMDA blockade to include cholinergic, aminergic, and opioid systems, which play a modulatory role in its effects.

Methods

Study Design

This single-centre, patient- and assessor-blinded, randomized controlled trial was conducted at the First Affiliated Hospital of Zhejiang University School of Medicine. The trial was registered on November 27, 2024, with www.chictr.org.cn (registration no. ChiCTR2400093061). The Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine (Chairperson Prof. Youming Li) approved the study protocol (approval no. 2024-080) on July 16, 2024. The study adhered to the Declaration of Helsinki and the CONSORT guidelines, and written informed consent was obtained from all participants. Throughout the study, all patient-identifiable data were anonymized.

Patients

The study was conducted among inpatients in the Department of Pain Management at this hospital from July 2024 to January 2025. Participants were eligible for inclusion only if they met all of the following criteria: (1) age 18–80 years, regardless of sex; (2) clinically diagnosed with zoster-related neuralgia, disease duration ≤ 6 months, and scheduled to undergo dorsal root ganglion pulsed radiofrequency treatment; (3) worst pain Numeric Rating Scale (NRS) score ≥ 4 within 24 h prior to admission despite taking pregabalin 150 mg/day (orgabapentin 1200 mg/day); (4) possessing competence to consent, voluntarily providing written informed consent, and being able to cooperate with all assessments and follow-up visits.

Participants were excluded if they presented with any of the following criteria: (1) severe cardiac, hepatic, or renal dysfunction, or malignant tumours; (2) pregnancy or lactation, or psychiatric disorders; (3) previous receipt of dorsal root ganglion radiofrequency treatment at the same site or presence of contraindications to the procedure; (4) contraindications to esketamine use, including uncontrolled hypertension, hyperthyroidism, and glaucoma; (5) use of ketamine or its analogs within the preceding 3 months. All enrolled patients provided written informed consent.

Randomization and Blinding

Using a simple randomization method, participants were allocated in a 1:1 ratio to either the esketamine group or the control group. The randomization sequence was generated with SAS version 9.4, and the assignments were concealed in sequentially numbered, opaque envelopes. An independent researcher performed the randomization to ensure that participants, outcome assessors, and statisticians remained blinded to group allocation throughout the study.

Study Procedures and Interventions

This study employed a randomized grouping method. Patients with ZRN scheduled to receive pulsed radiofrequency and anticonvulsant medication (pregabalin or an equivalent dose of gabapentin)were divided into two groups: (1) the combination treatment with esketamine group (ES group): received 1 mg/kg esketamine (Hengrui Medicine, H20143314) diluted in 50 ml normal saline, administered via continuous pump infusion at 0.02 mg/kg/h (1 ml/h) for 48 h; (2) the group without esketamine treatment (CON group): received an equivalent volume of normal saline (1 ml/h) via pump infusion for 48 h. For both groups, a physician (Dong Wang) prescribed the medication based on random group allocation using the envelope method. The prescription was given to an informed registered nurse who prepared the medication. The prepared medication was then handed to another nurse, who was blinded to the group allocation, for patient identity verification and infusion administration. Vital signs (heart rate, blood pressure, oxygen saturation, respiratory rate) were monitored throughout the procedure, and adverse reactions, including dissociative symptoms (assessed using the CADSS scale), were evaluated. A 30-min observation period followed the infusion to ensure safety. A standardized monitoring protocol was maintained during the treatment period to ensure data comparability. Another physician (Gi Gai) recorded the number of breakthrough pain episodes and the amount of rescue medication required during the 48-h infusion period. Follow-up assessment pain scores, sleep quality, and anxiety/depression scores were recorded at 1 week, 2 weeks, 1 month, and 3 months after treatment. The infusion lasted for 48 h around the time of the procedure, and follow-up lasted for 3 months.

Medication Adjustment and Rescue Measures

The medication regimen was adjusted based on the patient's pain intensity: for NRS > 7, oxycodone sustained-release tablets (10 mg Q12h or dose escalation) were administered; for NRS 4–7, the dose of pregabalin or gabapentin was increased. If the NRS remained > 7 after treatment, rescue medication with tramadol 100 mg intramuscularly or morphine 5 mg was given (dose conversion: acetaminophen oxycodone 5 mg = oxycodone 5 mg; oxycodone = twice the dose of morphine; 8 mg gabapentin ≈ 1 mg pregabalin). The number of breakthrough pain episodes and the total amount of rescue medication (tramadol or equivalent morphine dose) used during the 48-h period were recorded.

Dorsal Root Ganglion Pulsed Radiofrequency Procedure

Pulsed radiofrequency treatment for all patients was performed by the same senior attending physician within 48 h of medication administration. Based on the rash distribution and the affected sensory dermatome, CT-guided puncture was used to position the electrode near the dorsal root ganglion. Sensory and motor testing was conducted after electrode connection to confirm correct placement. Subsequently, pulsed radiofrequency treatment was administered (parameters: 2 Hz, 20 ms, 42 °C, 600 s).

Safety outcomes including the incidence, type, and treatment-relatedness of adverse events (AEs) and serious adverse events (SAEs) were prespecified, with AEs monitored via active questioning, clinical observation, and spontaneous reporting, assessed by study physicians, recorded in case report forms, and reported to the ethics committee and regulatory authorities, while participants were discharged 1 day after radiofrequency treatment and followed up for 3 months to evaluate short-term efficacy and delayed AEs.

Data Collection

Patient general data were collected at baseline. Patient-reported measurements (NRS, ID-pain, PSQI) were collected via self-report with standardized instructions, while clinician-administered scales (HAMA, HAMD-24, CADSS, RSS) were completed by trained physicians. NRS, ID-pain, HAMA, HAMD-24, and PSQI were recorded before treatment (T0), 48 h (T1), 1 week (T2), 2 weeks (T3), 1 month (T4), and 3 months (T5) post-treatment. Vital signs, CADSS, and RSS were recorded before medication (t0), 1 h (t1), 12 h (t2), 24 h (t3), and 48 h (t4) after medication.

Outcome Measures

The primary outcome measure was the NRS score at 48 h post-medication. Secondary outcome measures included changes in the Hamilton Anxiety Rating Scale (HAMA) score, the 24-item Hamilton Depression Rating Scale (HAMD-24) score, and the Pittsburgh Sleep Quality Index (PSQI) score. Vital signs and dissociative symptom scores (assessed using the Clinician-Administered Dissociative States Scale, CADSS) were recorded at baseline (t0), 1 h (t1), 12 h (t2), 24 h (t3), and 48 h (t4) after medication initiation.

Statistical Analysis

Statistical analysis was performed using SPSS software (version 27.0, IBM Corp.). Continuous variables with a normal distribution were expressed as mean ± standard deviation ($\overline{x}$ ± SD). Continuous variables with a non-normal distribution were expressed as median and interquartile range. Categorical variables were presented as percentages. For the primary outcome (NRS score at 48 h post-medication), the Mann-Whitney U test was used for between-group comparison because the data were expected to be non-normally distributed. For longitudinal data, the generalized estimating equation (GEE) with an exchangeable correlation structure was employed to analyse the effects of group, time, and their interaction on repeated-measures continuous variables. When a significant group × time interaction was detected in the GEE model, post hoc pairwise comparisons across multiple time points were performed using Bonferroni correction to adjust for the risk of type I error. Comparisons of categorical variables were conducted using the Pearson chi-square test or Fisher's exact test. Normally distributed continuous variables between two independent groups were analysed using the independent samples t test, while the Mann-Whitney U test was used for non-normally distributed continuous variables and ordinal variables.

All analyses followed the intention-to-treat (ITT) principle, and missing data were handled using multiple imputation. Sensitivity analyses were conducted in the per-protocol population, defined as participants who adhered to their assigned intervention and completed the prespecified primary outcome assessments. A two-sided P value < 0.05 was considered statistically significant for main effects, and the Bonferroni-adjusted significance level was applied for post hoc comparisons.

Sample Size Calculation

The sample size was calculated based on the NRS score at 48 h post-medication as the primary outcome. According to the literature, the control group had a score of 2.85 ± 1.08, and the experimental group was expected to show a reduction of 1.1 points (α = 0.05, 90% power). PASS 15.0.5 software indicated a requirement of 24 patients per group. Considering a 20% dropout rate during long-term follow-up, 30 patients per group were ultimately required, for a total of 60 patients. Methods for handling missing data: multiple imputation will be used for variables with a missing rate of approximately 15%; for variables with a missing rate > 20%, after evaluation, priority will be given to either deleting the variable or applying a "dummy variable + simple imputation" strategy.

Results

Flow diagram (Fig. 1).

Fig. 1.

Flow diagram

Patient Characteristics

There were no statistically significant differences in baseline general clinical data between the two groups, including age, sex, body mass index (BMI), duration of herpes zoster, pain location and laterality, and comorbidities (e.g., hypertension, diabetes) (P > 0.05) (Table 1).

Table 1.

Comparison of the general conditions of the two groups

	CON	ES	P
Age(years, $\overline{x}$ ± s)	64.03 ± 11.25	63.7 ± 6.85	0.890
Weight(kg, $\overline{x}$ ± s)	63.18 ± 10.89	63.68 ± 13.51	0.875
Height(cm, $\overline{x}$ ± s)	161.03 ± 7.42	161.83 ± 8.86	0.706
BMI(kg/m2, $\overline{x}$ ± s)	24.5 ± 2.85	24.16 ± 4.61	0.733
Sex			0.592
Male	10(33.3%)	12(40%)
Female	20(66.7%)	18(60%)
Pain location			0.841
Head and face	8	6
Neck	4	2
Chest	12	14
Lumbosacral region	4	5
Lower limb	2	3
Disease duration (days)	44.80 ± 38.95	46.80 ± 33.05	0.524
Left/right			0.121
Left	13	19
Right	17	11
Hypertension			0.893
Yes	18	19
No	12	11
Diabetes mellitus			0.129
Yes	28	24
No	2	6
NRS	6.33 ± 1.32	6.43 ± 1.30	0.769
HAMD-24	15.27 ± 6.34	15.67 ± 6.15	0.805
HAMA	8.43 ± 3.30	8.33 ± 3.37	0.908
PSQI	8.13 ± 2.46	7.53 ± 2.05	0.309

CON group without esketamine treatment, ES group with esketamine combination treatment, BMI body mass index, $\overline{x}$ ± s mean ± standard deviation, NRS Numeric Rating Scale, HAMD-24 24-item Hamilton Depression Rating Scale, HAMA Hamilton Anxiety Rating Scale, PSQI Pittsburgh Sleep Quality Index

Comparison of Pain Scores Between the Two Groups After Treatment

In patients with zoster-related neuralgia receiving pulsed radiofrequency and anticonvulsant therapy, pain scores gradually decreased over time regardless of whether esketamine was administered in combination. However, the combination therapy demonstrated superior analgesic efficacy.

The primary outcome of this study was the NRS score at 48 h post-intervention. The Shapiro-Wilk test indicated that the NRS scores in both groups were not normally distributed; therefore, the Mann-Whitney U test was used to compare the treatment efficacy between the two groups. The results showed that the median NRS scores were 2 in the ES group and 3 in the CON group, a statistically significant difference (U = 166.5, P < 0.001). The Hodges-Lehmann estimator revealed a median pseudo-median difference of 1 (95% CI 1–2) (Fig. 2).

Fig. 2.

Comparison of pain scores between the two groups after treatment. Baseline (T0), 48 h post-treatment (T1), 1 week (T2), 2 weeks (T3), 1 month (T4), and 3 months (T5) post-treatment. **P < 0.01; ***P < 0.001

Using the NRS score at time point T0 as a covariate for adjustment, a generalized estimating equation (GEE) analysis was performed to evaluate the effect of the two treatment methods on NRS scores. The results showed no significant interaction between group and time (Wald χ² = 2.630, P = 0.622); thus, only the main effects were analysed. After adjusting for the effect of time, the difference in NRS scores between the two groups was statistically significant (Wald χ² = 23.945, P < 0.001). The marginal mean NRS score in the ES group was 1.18 points lower (95% CI 0.72–1.63) than in the CON group. After adjusting for the effect of group, the difference in NRS scores across different time points was statistically significant (Wald χ² = 74.643, P < 0.001). NRS scores in both groups gradually decreased after treatment; compared with T1, the marginal mean NRS scores at T2, T3, T4, and T5 decreased by 0.200, 0.483, 1.050, and 1.350, respectively.

Comparison of Emotional State and Sleep Quality Between the Two Groups After Treatment

In patients with zoster-related neuralgia receiving pulsed radiofrequency and anticonvulsant therapy, emotional state and sleep quality gradually improved over time, regardless of whether esketamine was administered in combination. However, the combination therapy demonstrated superior efficacy in improving these outcomes.

Using the HAMA score at time point T0 as a covariate for adjustment, a generalized estimating equation (GEE) analysis was performed to evaluate the effect of the two treatment methods on HAMA scores. The results showed no significant interaction between group and time (Wald χ² = 8.936, P = 0.063); thus, the main effects were analysed. After adjusting for the effect of time, the difference in HAMA scores between the two groups was statistically significant (Wald χ² = 18.724, P < 0.001). The marginal mean HAMA score in the ES group was 2.24 points lower (95% CI 1.23—3.25, P < 0.001) than in the CON group. After adjusting for the effect of group, the difference in HAMA scores across different time points was statistically significant (Wald χ² = 34.288, P < 0.001). HAMA scores gradually decreased over time; compared with T1, the marginal mean HAMA scores at T2, T3, T4, and T5 decreased by 0.83, 1.383, 1.650, and 1.267, respectively.

Using the HAMD score at time point T0 as a covariate for adjustment, a generalized estimating equation (GEE) analysis was performed to evaluate the effect of the two treatment methods on HAMD scores. The results showed no significant interaction between group and time (Wald χ² = 8.298, P = 0.081); thus, the main effects were analysed. After adjusting for the effect of time, the difference in HAMD scores between the two groups was statistically significant (Wald χ² = 30.452, P < 0.001). The marginal mean HAMD score in the ES group was 4.60 points lower (95% CI 1.33–3.09, P < 0.001) than in the CON group. After adjusting for the effect of group, the difference in HAMD scores across different time points was statistically significant (Wald χ² = 46.315, P < 0.001). HAMD scores gradually decreased over time; compared with T1, the marginal mean HAMD scores at T2, T3, T4, and T5 decreased by 2.100, 2.767, 3.417, and 4.117, respectively.

Using the PSQI score at time point T0 as a covariate for adjustment, a generalized estimating equation (GEE) analysis was performed to evaluate the effect of the two treatment methods on PSQI scores. The results showed no significant interaction between group and time (Wald χ² = 4.185, P = 0.382); thus, the main effects were analysed. After adjusting for the effect of time, the difference in PSQI scores between the two groups was statistically significant (Wald χ² = 23.654, P < 0.001). The marginal mean PSQI score in the ES group was 1.82 points lower (95% CI 1.09—2.55, P < 0.001) than in the CON group. After adjusting for the effect of group, the difference in PSQI scores across different time points was statistically significant (Wald χ² = 52.772, P < 0.001). PSQI scores gradually decreased over time; compared with T1, the marginal mean PSQI scores at T2, T3, T4, and T5 decreased by 0.967, 1.483, 2.350, and 2.550, respectively (Fig. 3).

Fig. 3.

Comparison of emotional state and sleep quality before and after treatment among the two groups. A comparison between the ES group and the control group at 48 h (T1), 1-week (T2), 2-weeks (T3), 1-month (T4), and 3-months (T5) post-treatment. *P < 0.05; **P < 0.01; ***P < 0.001

Comparison of Pregabalin Dosage and Rescue Medication Between the Two Groups

Compared with the CON group, the ES group showed a significantly lower pregabalin dosage at 48 h post-treatment (T1) (167.50 ± 37.80 mg vs. 202.50 ± 81.57 mg in the CON group, P < 0.05). By T3, the dosage in the ES group (102.50 ± 77.50 mg) was further reduced compared with the CON group (P < 0.001). Additionally, the ES group experienced significantly fewer episodes of breakthrough pain within 48 h (P < 0.001) and required significantly less rescue morphine (P < 0.05) (Fig. 4).

Fig. 4.

Comparison between the two groups regarding pregabalin dosage (A), number of breakthrough pain episodes within 48 h of medication (B), equivalent morphine rescue dose (C), and number of patients requiring repeat radiofrequency during follow-up (D). *P < 0.05; **P < 0.01

Comparison of Vital Signs, Dissociative Symptom Scores, and Adverse Reactions Between the Two Groups During the 48-h Infusion Period

Compared with the CON group, there was no statistically significant difference in CADSS scores in the ES group during the 48-h period (P > 0.05). No significant differences were observed between the two groups in mean arterial pressure, oxygen saturation, or respiratory rate (all P > 0.05). Heart rate was significantly lower in the ES group than in the CON group only at time point t4 (P < 0.05). In the CON group, no significant changes were observed in any of the indicators compared with baseline (all P > 0.05) (Fig. 5).

Fig. 5.

Dissociative symptom scores (CADSS) assessed at baseline (t0), 1 h (t1), 12 h (t2), 24 h (t3), and 48 h (t4) after medication initiation. *P < 0.05; **P < 0.01

Adverse Reactions

The overall incidence of adverse reactions was five cases (16.7%) in the ES group, including one case each of agitation/delirium, nausea/vomiting, nightmares, headache/dizziness, and elevated blood pressure. In the CON group, the overall incidence of adverse reactions was three cases (10%), including one case each of agitation/delirium, nausea/vomiting, and headache/dizziness. The chi-square test showed no significant difference in the overall incidence of adverse reactions between the two groups (P = 0.313).

Discussion

This randomized controlled clinical study investigated the efficacy of esketamine combination therapy in patients with ZRN. Compared with the group that did not receive esketamine, the group receiving esketamine combination therapy demonstrated significantly reduced pain at 48 h, 1 week, 2 weeks, 1 month, and 3 months post-treatment. Furthermore, there was no significant increase in adverse reactions such as agitation/delirium, nausea/vomiting, dissociative symptoms, or nightmares. This is the first finding demonstrating that, compared with the group not receiving esketamine, the esketamine combination group exhibited significantly lower NRS scores at 48 h post-treatment in patients with zoster-related neuralgia. This finding aligns with the results of existing literature on the analgesic efficacy of esketamine [5,6]. This indicates that esketamine can effectively alleviate pain in patients with ZRN [7]. Furthermore, the esketamine treatment group showed greater improvements in the Hamilton Anxiety Rating Scale (HAMA) and the 24-item Hamilton Depression Rating Scale (HAMD-24) scores compared with the group not receiving esketamine. This may be related to esketamine's modulatory effect on NMDA receptors, as its antidepressant efficacy has been well established in psychiatric treatment. The results of this study demonstrate that patients' emotional state improved significantly as early as 1 week after combination therapy with esketamine, suggesting its advantage in rapid mood regulation.This finding is consistent with the conclusions of a recent meta-analysis, which indicated that NMDA antagonists can shorten the onset time for mood improvement in patients with chronic pain [9]. Furthermore, in the largest multicentre study to date on the antidepressant efficacy of esketamine, a single low dose was shown to reduce the incidence of postpartum depression at 42 days by approximately three-quarters [12]. The Pittsburgh Sleep Quality Index (PSQI) scores in the esketamine treatment group were also significantly lower than those in the group not receiving esketamine after treatment, confirming that esketamine may positively affect sleep quality in patients with ZRN, which is of great significance for enhancing patients' quality of life.

The present study found that, compared with the group not receiving esketamine, the esketamine combination group had significantly lower NRS scores at all post-treatment time points. During the 48-h continuous infusion period in this study, the number of breakthrough pain episodes and the equivalent morphine rescue dose were also significantly reduced (P < 0.05), confirming that esketamine combined with conventional pulsed radiofrequency and anticonvulsant therapy can significantly reduce pain intensity in patients with ZRN. Previous studies have demonstrated that esketamine has favorable analgesic effects and can reduce opioid consumption [13,14]. In one study involving patients with post-craniotomy headache, esketamine treatment even resulted in a 40% reduction in opioid consumption [15]. Therefore, esketamine is widely used for both acute and chronic postoperative pain. Esketamine can be used to treat chronic pain conditions, such as neuropathic pain and complex regional pain syndrome, with therapeutic effects lasting up to 12 weeks.

Esketamine is a non-competitive NMDA receptor antagonist with anesthetic, analgesic, and antidepressant properties. Literature suggests that the adverse effects of esketamine are dose-dependent and primarily include dissociative symptoms, dizziness, nausea, elevated blood pressure, and hallucinations. Therefore, determining the appropriate esketamine dosage was also a key issue in this study. In recent years, the use of first-line medications for zoster-related neuralgia has become increasingly standardized, including calcium channel modulators, tricyclic antidepressants, and 5% lidocaine patches [16,17]. However, the efficacy of pharmacological treatment regimens remains suboptimal, with associated risks of adverse effects [18]. To balance analgesic efficacy with the risk of adverse reactions, selecting an appropriate dose and duration of esketamine administration for analgesia is critical. The literature indicates that perioperative analgesic regimens with esketamine vary considerably depending on the type of surgery, individual patient characteristics, and specific protocols. Key considerations include determining the optimal dosage, infusion duration, and strategies to optimize the combination regimen. This study employed a low dose of esketamine to mitigate the risk of potential psychotomimetic side effects while achieving desired effects (such as analgesia, anxiolysis, and antidepressant effects) and avoiding associated adverse reactions. According to expert guidance on the clinical application of esketamine, which references clinical studies on ketamine for complex regional pain syndrome, a single dose of esketamine should not exceed 0.2 mg/kg. A low dose of esketamine (0.25 mg/kg) can effectively inhibit long-term potentiation of synapses induced by painful stimuli, thereby preventing the development of chronic pain. Due to the pharmacokinetic properties of esketamine, characterized by relatively rapid metabolism, a single administration fails to produce long-lasting analgesic effects. Therefore, most postoperative analgesia and chronic pain treatment protocols employ a continuous infusion of esketamine at a concentration of 0.25 mg/ml over a 48-h period [19]. Alternatively, outpatient intermittent protocols use a continuous infusion of 0.05 mg/kg/h for 6 h, administered twice weekly for 6 consecutive weeks [16]. Alternatively, inpatient protocols may involve a single continuous infusion of 0.2 mg/kg over a 3-h period [20,21]. The current study protocol, involving a continuous infusion of esketamine at 1 ml/kg over 48 h, is generally consistent with the widely used low-dose esketamine continuous infusion regimens reported in the literature [21,22]. The dosage and duration of esketamine administration used in this study are consistent with those reported in previous research. Furthermore, as a combination therapy, Thomas, Zuzana et al. [23] have recommended esketamine for chronic pain conditions such as complex regional pain syndrome and fibromyalgia, noting its significant short-term analgesic effects.

For multidimensional efficacy evaluation, this study employed a continuous intravenous infusion of 1 mg/kg over 48 h, which aligns more closely with pharmacokinetic principles than traditional intermittent bolus regimens (e.g., a single 0.5 mg/kg bolus). Pharmacodynamic models indicate that maintaining steady-state plasma concentrations of esketamine within the range of 40–80 ng/ml can balance analgesic efficacy against the risk of dissociative symptoms [9, 24].

In this study, the overall incidence of adverse reactions was only 16.7%. The main adverse reactions included agitation, nausea/vomiting, and elevated blood pressure, all of which were transient and manageable. Most were mild agitation (3.33%) and blood pressure fluctuations (3.33%), with no occurrence of severe respiratory depression or hallucinations, indicating that this dosage of esketamine has a favorable safety profile. These findings support the use of short-term esketamine infusions as an effective adjuvant therapy. Although transient neuropsychiatric adverse events may occur, they do not require additional pharmacological intervention.

The findings of this study support the use of esketamine as an effective adjunctive treatment for zoster-related neuralgia, demonstrating significant benefits in pain management, emotional state, and sleep quality. However, further research is needed to address the limitations of this study and to further explore optimal clinical application strategies for esketamine. Such studies will help optimize the clinical use of esketamine and provide more effective pain management options for patients with ZRN. Adding esketamine to radiofrequency plus anticonvulsant therapy improved clinical outcomes compared with radiofrequency plus anticonvulsant alone.

Limitations

This study was conducted at a single centre, which may introduce selection bias. Furthermore, the rescue medication and dose adjustments (e.g., pregabalin) differed between groups in this study, which may have affected pain outcomes, and this limitation should be noted. The management of zoster-related neuralgia represents a multidimensional clinical challenge. The severity of pain and the effectiveness of interventions not only depend on the choice of pharmacological regimen but also significantly correlate with the patient's psychological state (including mood disorders such as anxiety/depression), their cognitive expectations regarding treatment efficacy, the type of invasive therapeutic modality received, and individual-specific bio-psycho-social characteristics. Future research should aim to expand the sample size and conduct multicentre randomized controlled trials to enhance the reliability and generalizability of the findings.

Conclusions

This study supports the use of esketamine as an effective therapeutic agent for the treatment of zoster-related neuralgia, demonstrating potential for clinical translation and providing a new direction for future research and treatment strategies.

Author Contribution

Dong Wang, Qi Gai, Yanfeng Zhang, Zhe Yan, Bingwei Hu: experimental design and implementation, data collection and statistical analysis, manuscript conception, drafting, and revision; Zhiying Feng: project supervision, technical support, and manuscript guidance. Dong Wang, Qi Gai contributed equally as co-first authors of this article, and Zhiying Feng is the corresponding author. All authors have read and approved the final manuscript.

Funding

This study was supported by the China Red Cross Foundation Medical Empowerment Public Welfare Special Fund (grant no. CRCF-YXFN-202201070), Medical Science and Technology Project of Zhejiang Province (2024KY612). The journal’s Rapid Service Fee was funded by the authors.

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Conflict of Interest

Dong Wang, Qi Gai, Yanfeng Zhang, Zhe Yan, Bingwei Hu, and Zhiying Feng have nothing to disclose.

Ethical Approval

The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine (Chairperson: Prof. Youming Li) on July 16, 2024 (approval no. 2024-080). The study adhered to the Declaration of Helsinki and the CONSORT guidelines. Written informed consent was obtained from all participants. Throughout the study, all patient-identifiable data were anonymized.