Effects of Esketamine Infusion by Patient-Controlled Intravenous Analgesia in Patients With Zoster-Associated Pain: A Retrospective Study

Introduction

Zoster-associated pain (ZAP) is a chronic neuropathic pain resulting from the reactivation of the varicella-zoster virus [1]. Early diagnosis and prompt treatment are essential for managing ZAP and preventing the development of postherpetic neuralgia (PHN) [2]. While current treatment strategies, such as medications, minimally invasive interventions, and neural modulation techniques, can relieve persistent symptoms, the incidence of PHN still remains high, ranging from 5% to over 30%. Given the multifactorial nature of the disease, combination therapies tailored to individual patients are likely to be more effective in comprehensive ZAP treatment [3,4].

Central sensitization, an activity-dependent amplification of nociceptive signaling within the central nervous system, has been consistently observed in patients with ZAP whose condition progresses to PHN [5–7]. Preclinical work indicates that sustained nociceptive input upregulates spinal N-methyl-D-aspartate receptors (NMDARs) and increases glutamatergic tone, thereby contributing to central sensitization [8,9]. Whether early pharmacological blockade of NMDARs can prevent or reverse central sensitization in humans and ultimately reduce PHN incidence remains hypothetical, as randomized data are lacking.

Esketamine, initially identified as an intravenous (IV) anesthetic used during the perioperative period, exhibits affinity for opioid receptors and NMDARs [10]. In rodent models of neuropathic pain, systemic esketamine acutely suppresses hyperalgesia and reduces wind-up of spinal wide dynamic-range neurons [11–13]. Clinical evidence is limited to 1 small case series by Huang et al, who reported that short-term esketamine use decreased the frequency and severity of breakthrough zoster pain [14]. Whether these effects translate into sustained benefit or lower PHN incidence remains untested.

Pulsed radiofrequency (PRF) applied to the affected dorsal root ganglion is thought to interrupt peripheral nociceptive drive with minimal neuronal damage and is widely used for subacute ZAP treatment [15]. Combining PRF with an NMDAR antagonist may offer an additive or synergistic effect: PRF reduces peripheral input, while esketamine limits the spinal hyper-excitability that underlies central sensitization [16]. In this study, we compared the effects of normal saline and esketamine for patient-controlled IV analgesia with PRF in patients with ZAP during the subacute stage. To assess the maintenance effects of esketamine, we evaluated numeric rating scale (NRS) scores, Pittsburgh Sleep Quality Index (PSQI) scores, Central Sensitization Index (CSI) scores, postoperative analgesic (tramadol and pregabalin) consumption, PHN incidence, and adverse events during treatment. The aim of this study was to explore the potential effects of esketamine on nerve function regulation and pain relief in patients with ZAP, thereby improving their quality of life.

Material and Methods

STUDY DESIGN AND PARTICIPANTS:

This was a non-randomized, retrospective study. We reviewed consecutive medical records of patients with ZAP treated at Ningbo Medical Center Lihuili Hospital between January 1, 2024, and September 1, 2024. The inclusion criteria were as follows: patients with herpes zoster herpes zoster lasting between 30 and 90 days, aged between 50 and 80 years, with a NRS pain score of ≥4, and herpes zoster affecting the neck, thoracic, or lumbar ganglion. Exclusion criteria included the use of hormones or immunosuppressants, coagulation abnormalities, spinal tumors, fractures, and infection at the injection site. This study was approved by the Ethics Committee of Ningbo Medical Center Lihuili Hospital (approval No. KY2025SL027-01) and conducted in accordance with the Declaration of Helsinki.

GROUPING:

Patients were allocated to 1 of 2 analgesic strategies (group ES and group C) according to the attending physician’s clinical preference and patient willingness. No randomization or blinding was performed. Group ES received esketamine-based patient-controlled IV analgesia (Figure 1). Esketamine (100 mg diluted in 100 mL saline, 1 mg/mL) was administered for IV analgesia via a pump, with a continuous background infusion of 2 mL/h and patient-controlled boluses of 0.5 mL, a lockout interval of 15 minutes, and treatment duration of 5 days. Group C received identical-volume saline patient-controlled IV analgesia. Rescue antiemetics or laxatives were administered when needed. If the NRS score exceeded 4, an additional 50 mg tramadol was given as a rescue analgesic measure.

PULSED RADIOFREQUENCY:

After patient-controlled IV analgesia, a computed tomography (CT)-guided PRF procedure was arranged after using esketamine or saline for 2 days. PRF was performed on the target site according to the distribution of nerves, with the procedure being guided by CT images [17]. The needle was inserted into the appropriate dorsal root ganglion based on physician assessment. Sensory and motor stimulation tests were conducted using the radiofrequency instrument (Boston Scientific, USA). The sensory test was performed at voltages of 0.1 to 0.5 V and a frequency of 50 Hz, while the motor test was performed at voltages of 0.1 to 0.5 V and a frequency of 2 Hz. The PRF parameters were set as follows: 42°C electrode tip temperature, 2-Hz pulse frequency, 20-ms pulse width, and a 180-second duration, performed 3 times consecutively.

DATA COLLECTION:

Baseline characteristics of patients, including age, sex, height, weight, pain duration, comorbidities, and location of herpes zoster, were recorded.

OUTCOMES:

The primary outcome was NRS scores at baseline and 1, 4, 12, and 24 weeks after treatment. Secondary outcomes were PSQI scores (0–21), weekly tramadol and pregabalin consumption, PHN rate (NRS ≥3), CSI scores (0–100), and adverse events.

The PSQI, a widely used tool to assess sleep quality, consists of 19 self-reported items, with a total score ranging from 0 to 21. The PSQI evaluates various sleep parameters, including sleep duration, sleep disturbances, latency, habitual sleep efficiency, and daytime dysfunction [18]. PSQI scores were measured at 1, 4, 12, and 24 weeks after treatment.

PHN is defined as pain with an NRS score 3 or higher that persists for 3 or more months after the onset of herpes zoster rash [19]. The incidence of PHN was assessed at 3 months after rash onset.

The CSI is a 25-item questionnaire used to evaluate the presence and severity of central sensitization. Scores range from 0 to 100, with higher scores indicating a higher degree of central sensitization. The CSI includes questions on pain intensity, pain locations, sleep disturbances, fatigue, and the presence of other symptoms, such as dizziness and memory problems [20]. CSI scores were measured at 12 and 24 weeks following treatment.

STATISTICAL ANALYSIS:

As this was a feasibility study, no formal sample size calculation was required. The sample size of 110 was determined by the total number of patients we could recruit during the period available. Statistical analyses were performed using IBM SPSS Statistics Version 26.0, and GraphPad Prism 10.0 was used for chart generation. For baseline characteristics of patients, categorical data are presented as frequencies and percentages and analyzed using the chi-square test or Fisher exact test; numerical data with a normal distribution are presented as mean±standard deviation, and group comparison was performed using the t test. For data with a skewed distribution, results were expressed as median (interquartile range), and group comparisons were made using the Mann-Whitney U test. The outcomes were analyzed using the Friedman test to assess changes over time within each group. For the primary outcome, a P value of <0.05 was considered statistically significant. For each secondary outcome, the Bonferroni correction was applied to adjust for multiple comparisons, and a P value of <0.01 was considered statistically significant. Missing data, including patients lost to follow-up, were handled using a complete-case approach, and only available data were included in the analyses. The potential effect of missing data on study results was assessed and reported where appropriate.

Results

BASELINE CHARACTERISTICS OF PATIENTS:

In brief, 110 patients were screened for research, with 24 patients excluded due to 13 patients with insufficient medical records, 6 patients lost to follow-up, and 5 patients with trigeminal neuralgia. Finally, data obtained from group ES (n=44) and group C (n=42) were available for analysis. The diagram of patient enrollment is shown in Figure 2. The baseline characteristics of all participants are shown in Table 1. There were no significant differences in terms of age (t=1.013, P=0.314), gender (χ2=0.059, P=0.808), weight (t=0.353, P=0.725), height (t=0.846, P=0. 400), pain duration (t=0.014, P=0.989), comorbidities or location of herpes zoster (χ2=0.044, P=0.978) between the patients in group ES and group C (P>0.05).

COMPARISON OF NRS SCORES:

As shown in Figure 3, both groups showed a significant decrease in NRS scores at 1, 4, 12 and 24 weeks after treatment compared with baseline (P<0.001). In practice, group ES showed a lower NRS score than group C at 1 week (Z=2.075, P=0.038) and 4 weeks (Z=2.117, P=0.034) after treatment (Table 2). There were no statistically significant differences between the 2 groups at other time points (P>0.05).

COMPARISON OF PSQI SCORES:

The scores of PSQI in the 2 groups were significantly lower at 1, 4, 12, and 24 weeks after treatment when compared with pre-treatment (P<0.001). The PSQI scores were lower in group ES than in group C at 1 week (Z=4.224, P<0.001) and 4 weeks (Z=5.775, P<0.001) after treatment, consistent with the NRS score (Figure 4).

COMPARISON OF ANALGESIC CONSUMPTION:

As shown in Table 3, the 2 groups showed a similar consumption of tramadol at 1 week (Z=2.017, P=0.044), 4 weeks (Z=2.046, P=0.041), 12 weeks (Z=1.996, P=0.046,), and 24 weeks (Z=2.034, P=0.042) after treatment. Interestingly, the consumption of pregabalin was also similar between the 2 groups at 1 week (Z=0.176, P=0.860,), 4 weeks (Z=0.023, P=0.982), 12 weeks (Z=0.586, P=0.558), and 24 weeks (Z=0.206, P=0.837) after treatment.

COMPARISON OF PHN RATES:

At 3 months after treatment, the PHN rate was 25.00% in group ES, comparable with 42.86% in group C (χ²=3.066, P=0.08). There was no statistically significant difference between the 2 groups.

COMPARISON OF CSI SCORES:

As shown in Table 4, the CSI scores were comparable in group ES and group C at 12 weeks (t=2.591, P=0.011) and 24 weeks (t=2.135, P=0.036) after treatment.

COMPARISON OF ADVERSE EFFECTS:

During treatment, group ES had a higher incidence of adverse events than did group C, including dizziness (52.27% vs 14.29%), nausea (61.36% vs 11.90%), and vomiting (34.09% vs 7.14%). In contrast, group C showed higher rates of rebound pain (28.57% vs 9.09%) and constipation (30.95% vs 9.09%), indicating a tendency for these adverse events in the control group (Table 5).

Discussion

In this retrospective trial, we found that during the subacute stage of ZAP, esketamine at 1 mg/mL resulted in lower NRS and PSQI scores within 4 weeks, compared with the control group. However, analgesic consumption, PHN incidence, and CSI scores did not differ between groups at 12 or 24 weeks. Thus, esketamine may provide short-term benefits in terms of pain intensity and sleep quality; however, its effect on PHN prevention or central sensitization was not demonstrated in this study.

Studies have shown that NMDARs are expressed on both the peripheral and central neurons, contributing to sustained excitability of neuronal synapses and the development of central sensitization [21]. Hyperactivity of glutamatergic NMDARs in the spinal cord has been implicated as a key mechanism in chronic pain [22]. Esketamine, a non-competitive NMDAR antagonist, has shown promise in neuropathic pain models [23,24]. Huang et al observed sustained relief of breakthrough zoster pain with 2 mg/mL [14]. However, Wang et al found that 1 mg/mL improved mood but not pain scores in patients with PHN [25]. These discrepancies highlight that dose, timing, and phenotype may all influence outcomes. In the present study, the early analgesic and sleep benefits did not translate into lower analgesic consumption or reduced PHN and central sensitization rates, underscoring the need for prospective dose–response trials.

To expand the application of esketamine, we focused on patients in the subacute stage of ZAP, the most common window for pain clinic visits. PRF is already established as effective for ZAP and reduces peripheral input, while esketamine limits spinal hyper-excitability underlying central sensitization; the combination of both may yield stronger analgesic effects [26,27]. In our study, we used esketamine at 1 mg/mL rather than at 2 mg/mL to minimize potential adverse effects, such as dizziness, nausea, and vomiting, observed in our preliminary experiments. Consistent with previous studies [28], the results of this study further confirm that compared with PRF alone, the combination of esketamine and PRF can lead to better improvements in neurological function but with a higher incidence of adverse effects. In fact, when compared with the relief from pain and improvement in neurological function, the mild nausea and vomiting were deemed tolerable by most participants in this study. In addition, based on 58 months of post-approval data from the United States, real-world esketamine use in nearly 1.5 million treatment sessions showed expected adverse events, rare serious events, low suicide rates, and infrequent abuse/misuse, with no new safety signals beyond the established clinical safety profile [29].

Persistent pain is a major risk factor for poor sleep, and the 2 domains interact reciprocally [30]. Sleep disturbance is one of the leading causes of neuropathic pain, making patients more likely to have undesirable prognoses [31]. Previous studies have reported that individuals with insomnia have a 62% higher risk of ZAP, compared with controls, indicating a close relationship between sleep quality and the development of herpes zoster [32,33]. Previous work showed that esketamine can improve early postoperative sleep [34,35]. The mechanism of esketamine in improving sleep quality can be explained by several factors. First, esketamine reduces analgesic consumption, which shortens the duration of rapid eye movement sleep, affecting the sleep-related neurotransmitter postoperatively [36]. Second, esketamine, as a rapid antidepressant, strongly influences depression and mood disorders [37]. Even low doses of esketamine can help avoid psychiatric symptoms, thereby improving sleep quality. Third, patients who undergo surgery often experience inflammatory storms that contribute to postoperative sleep disturbances, which can be alleviated by the anti-inflammatory effects of esketamine [38]. We also observed lower PSQI scores at 1 and 4 weeks, but values converged thereafter, and total analgesic consumption remained unchanged. Whether the transient sleep benefit is sufficient to affect long-term zoster recovery remains speculative.

The development and progression of PHN are influenced by peripheral and central sensitization. While nerve blocks and PRF attenuate peripheral input, central sensitization driven by spinal NMDAR overactivation remains a therapeutic target. Central sensitization refers to central pain or brain pain, whereby normal or subthreshold inputs trigger increased pain-sensitive neurons, causing hyperexcitability of the central nervous system by stimulating NMDARs in the dorsal horn of the spinal cord [6,39]. According to a systematic review, the estimated prevalence of central sensitization is approximately 30% among patients with PHN who experience more severe and persistent pain [40]. Unfortunately, patients with central sensitization experience worse outcomes regardless of medical treatment or surgical intervention. Blocking NMDARs, to some extent, alleviates this type of hyperpathia in patients with neuropathic pain [41]. Esketamine, regarded as a “resetting” pain switch, primarily modulates NMDAR activity to manage pain, thereby interrupting the formation of central sensitization and reducing the formation of pain memory. Since a positive feedback loop of pain has been established between the peripheral and central nervous systems [42], multidimensional approaches extending beyond conventional surgical interventions are necessary for patients with central sensitization. Although CSI scores were numerically lower with esketamine at 12 and 24 weeks, the difference never reached significance. This was consistent with the neutral findings for PHN rates and suggests that a single 1 mg/mL esketamine infusion does not produce durable modulation of central sensitization in ZAP. For chronic pain, a prospective study involving 60 patients with complex regional pain syndrome found that intermittent esketamine infusion achieved results comparable to that of continuous esketamine infusion after 12 weeks of follow-up [43], which was in line with the function of ketamine in neuropathic pain diseases [44]. Therefore, intermittent or higher-dose regimens deserve further investigation.

This study has some limitations. Due to its retrospective design, potential biases, including selection bias, are inherent. Patients were not randomly assigned to the treatment groups, which could have influenced the results. Furthermore, the absence of blinding introduces the potential for performance and detection bias. In this clinical trial, a small sample size of only 86 participants was included, which may have limited the statistical power and affected the generalizability of the long-term outcomes. Moreover, the potential effect of depression, a condition that esketamine is known to treat, was not assessed in this study, leading to an incomplete evaluation of esketamine’s effects. This omission is important since changes in depression status could influence pain and sleep quality outcomes. While this study provided valuable insights into the use of esketamine for ZAP, further intensive research is needed to better understand the long-term effects of esketamine on NRS scores, sleep quality, and central sensitization in larger, well-controlled, prospective studies.

Conclusions

In summary, our study suggests that esketamine was associated with improved pain intensity and sleep quality in the early phase after treatment yet did not reduce analgesic consumption, PHN incidence, or CSI scores within 24 weeks. Larger, randomized trials are required to clarify dose–response relationships and to identify patients who might derive sustained benefit from esketamine.