Effects of Perioperative Intranasal Dexmedetomidine Spray on Clinical Outcomes of Pulsed Radiofrequency in Patients with Zoster-Associated Pain: A Randomized Controlled Trial

Abstract

Objective

To investigate the effects of perioperative intranasal dexmedetomidine spray on hemodynamic stability, postoperative analgesia and sleep quality in patients with zoster-associated pain (ZAP) undergoing pulsed radiofrequency (PRF), and assess its clinical efficacy and safety.

Methods

A single-center, randomized, double-blind, parallel-controlled trial was conducted. Sixty-eight ZAP patients receiving dorsal root ganglion PRF were randomly assigned (1:1) to the dexmedetomidine (Dex) group or control group. The Dex group received intranasal dexmedetomidine 40 μg 30 min preoperatively, followed by 40 μg twice daily for 3 postoperative days; the control group received equal-volume normal saline at matched time points. Perioperative mean arterial pressure (MAP) and heart rate (HR) were recorded. Pain intensity (VAS) and sleep quality (PSQI) were assessed at baseline and on postoperative days 1, 3, 7 and 14. The primary outcome was change in MAP from baseline to PRF treatment stage. Linear mixed-effects models were used for longitudinal analyses.

Results

Baseline characteristics were comparable between groups (all P>0.05). The Dex group showed significantly smaller MAP and HR fluctuations during puncture, nerve stimulation and PRF treatment (group × time interaction, all P<0.001). VAS and PSQI scores were markedly lower in the Dex group at all postoperative time points (all P<0.001 after Bonferroni correction). No severe adverse events occurred; mild-to-moderate transient bradycardia and hypotension in the Dex group required no specific intervention.

Conclusion

Perioperative intranasal dexmedetomidine spray effectively stabilizes perioperative hemodynamics, improves postoperative analgesia and sleep quality in ZAP patients undergoing PRF, with no serious safety signals observed in this study population. It provides evidence for optimized perioperative management strategies in this population.

Trial Registration

Chinese Clinical Trial Registry, ChiCTR2500098608, first posted 11/03/2025.

Introduction

Zoster-associated pain (ZAP) is a type of neuropathic pain caused by peripheral and central sensitization resulting from reactivation of varicella-zoster virus, and ranks among the most common refractory neuropathic pains in clinical practice.¹ ZAP can be staged by time since rash onset: acute zoster pain (< 4 weeks), subacute ZAP (4–12 weeks), and postherpetic neuralgia (PHN, > 12 weeks). Statistics indicate that 5–20% of patients with herpes zoster progress to PHN. The incidence and severity of PHN increase with age: 20% of patients aged 60–65 years with acute herpes zoster develop secondary PHN, while this proportion exceeds 30% in patients older than 80 years.²

Pulsed radiofrequency (PRF) technology generates an electric field effect by intermittently emitting high-frequency currents, which modulates nerve cell membrane potential and ion channel function, inhibits nociceptive signal transmission, and facilitates repair of damaged nerves. Featuring minimal invasiveness, reversibility, preservation of intact neural structures and repeatable operation, PRF is a well-established interventional treatment option for ZAP patients who fail first-line pharmacotherapy, and is recommended for subacute ZAP and established PHN in multiple clinical practice guidelines.³

At present, benzodiazepines and opioids are commonly used for sedation and analgesia during the perioperative period of PRF in clinical settings. However, these drugs carry multiple adverse reactions including respiratory depression, postoperative somnolence, nausea and vomiting, urinary retention, and addiction. Moreover, they cannot simultaneously maintain perioperative circulatory stability or achieve long-term improvements in postoperative pain and sleep. Dexmedetomidine is a highly selective α₂-adrenergic receptor agonist with dose-dependent sedative, analgesic, anxiolytic, and anti-sympathomimetic effects, and it presents negligible risk of respiratory depression, making it an ideal agent for perioperative sedation and analgesia.⁴ Existing studies on dexmedetomidine applied during PRF mainly focus on the sedative efficacy of single intraoperative intravenous administration, whereas systematic research evaluating a protocol combining preoperative single intranasal spray with continuous postoperative intranasal dexmedetomidine spray in ZAP patients remains scarce. Existing evidence indicates that the first 72 hours after interventional surgery for neuropathic pain is a critical window for exacerbation of peripheral and central sensitization. Sustained administration of α₂-adrenoceptor agonists during this period can inhibit the sensitization process, thereby prolonging analgesic duration and improving sleep quality.⁵ Therefore, this study adopted a perioperative regimen of a single preoperative dose combined with 3 consecutive days of postoperative administration.

This single-center, randomized, double-blind parallel controlled clinical trial was designed to clarify the stabilizing effect of perioperative intranasal dexmedetomidine spray on perioperative hemodynamics, as well as its efficacy in alleviating postoperative pain and improving sleep quality in ZAP patients receiving PRF. The study also verifies the clinical safety of this administration regimen, aiming to provide high-level evidence-based medical support for standardized perioperative management of ZAP patients undergoing PRF.

Methods

Study Design

This double-blind, randomized controlled clinical trial was conducted at The First Affiliated Hospital of Wannan Medical University. The study protocol was approved by the Medical Research Ethics Committee of The First Affiliated Hospital of Wannan Medical University (Approval No. 2024LunShenYan200) and registered with the Chinese Clinical Trial Registry (http://www.chictr.org.cn, Registration No. ChiCTR2500098608) on March 11, 2025, prior to subject recruitment. All participants provided written informed consent. This study report was prepared in strict accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines.

Inclusion Criteria

① Meeting the diagnostic criteria for ZAP; skin lesions distributed in the innervation areas of spinal nerves or the trigeminal nerve, with a disease course ranging from 1 week to 6 months after rash onset;② Aged 18–80 years, regardless of gender;③ Visual Analogue Scale (VAS) score≥4 points; inadequate response to standardized pharmacological treatment; scheduled to receive CT/DSA-guided pulsed radiofrequency ablation of the target nerve;④ American Society of Anesthesiologists (ASA) physical status classification I–III;⑤ Clear consciousness, able to complete questionnaire assessments, perioperative monitoring, and full‑course follow-up;⑥ Voluntary participation in the study with signed written informed consent.

Exclusion Criteria

① Those allergic to dexmedetomidine, nasal spray excipients, local anesthetics, or other study‑related medications;② Patients with severe failure of vital organs including the heart, liver, kidneys and lungs, or with severe arrhythmia and atrioventricular block (Grade II or above);③ Patients with a baseline mean arterial pressure (MAP)< 70 mmHg, heart rate (HR) < 55 beats per minute, or uncontrolled severe hypertension;④ Pregnant or breastfeeding women;⑤ Patients with mental disorders, cognitive dysfunction, or a history of alcohol/drug dependence who cannot cooperate with the study procedures;⑥Those with a previous history of target nerve surgery, intracranial/spinal space‑occupying lesions, or severe cervical/lumbar spinal deformities;⑦ Patients who have used α2‑adrenergic receptor agonists, sedative‑hypnotics, or opioids within the previous two weeks, or who cannot discontinue such medications;⑧ Individuals with severe nasal mucosal damage, rhinitis, or sinusitis that prevents nasal administration;⑨ Patients currently participating in other clinical trials.

Randomisation and Blinding

Randomization

An independent statistician who was not involved in patient enrollment, clinical procedures, outcome assessment, or statistical analysis generated a 1:1 random allocation sequence using a random number table Allocation concealment was achieved with opaque sealed envelopes. Eligible patients opened the envelopes in sequential order upon enrollment to determine their assigned group.

Blinding

This study adopted quadruple blinding for patients, surgeons, outcome assessors, and statistical analysts. Study medications were prepared by independent pharmacists from the hospital pharmacy according to the random sequence. The investigational product (dexmedetomidine nasal spray) and the placebo (normal saline nasal spray) were identical in packaging, appearance, and spray volume; only the subject number was labeled, with no distinguishing information regarding group allocation. Medications were dispensed to participants by dedicated staff according to the subject numbers. All personnel involved in clinical procedures, assessments, and data analysis remained unaware of the group assignments throughout the trial. Unblinding was performed only after data collection was completed and the database was locked.

Emergency Unblinding

In the event of a serious adverse event where group information is urgently required to guide clinical rescue, emergency unblinding may be performed with the approval of the principal investigator. The reason and time of unblinding are fully documented and reported to the ethics committee; the participant remains in the safety analysis set in accordance with the intention-to-treat principle, and all adverse events are fully recorded and reported.

Intervention

Dex Group

Preoperative administration: At 30 min before PRF, intranasal dexmedetomidine spray (Jiangsu Hengrui Medicine Co., Ltd., specification: 2 mL:200 μg) was administered bilaterally, with one spray per nostril, yielding a total dose of 40 μg.

Postoperative administration: Administration was initiated immediately after patients returned to the ward following PRF. The spray was delivered bilaterally twice daily (morning and evening), one spray per nostril, with a total dose of 40 μg per time point, for three consecutive days.

Control Group

Preoperative administration: At 30 min before PRF, normal saline nasal spray was administered bilaterally, one spray per nostril, with a total volume of 0.2 mL.

Postoperative administration: Administration was initiated immediately after patients returned to the ward following PRF. The saline spray was delivered bilaterally twice daily (morning and evening), one spray per nostril, with a total volume of 0.2 mL per time point, for three consecutive days.

PRF Procedure

All patients received standardized PRF therapy under C-arm fluoroscopic guidance, performed by a single senior interventional pain physician with >10 years of PRF experience. A 22-gauge radiofrequency needle with a 5 mm active tip (Baylis Medical, Montreal, Canada) was advanced via a standard puncture approach. Needle tip position was confirmed by anteroposterior and lateral fluoroscopic views, followed by injection of 0.5 mL iohexol (300 mgI/mL) to verify extravascular periganglionic spread.

Sensory stimulation (50 Hz, 0.3–0.5 V) was applied to reproduce concordant paresthesia in the target dermatome; motor stimulation (2 Hz, 1.0–2.0 V) confirmed absence of motor response. Successful localization was defined as reproduction of typical pain at sensory threshold < 0.5 V, with no motor response at 2 V. Impedance was maintained at 300–600 Ω.

Treatment parameters: frequency 2 Hz, pulse width 20 ms, voltage 45 V, maximum temperature limit 42 °C, 120 s per cycle, 2 cycles total. 1 mL of 1% lidocaine was administered prior to PRF initiation.

All acute ZAP patients had completed a 7-day course of valacyclovir prior to PRF. All patients received oral pregabalin 150 mg preoperatively and continued 150 mg twice daily throughout follow-up. All patients remained alert and communicative during nerve stimulation localization, consistent with light sedation. Oral celecoxib 200 mg was used as rescue analgesia for VAS ≥ 4 points, with total consumption documented. All patients received a standardized intraoperative fluid management regimen (crystalloid 5 mL·kg⁻¹·h⁻¹), and no vasoactive medications were administered perioperatively.

Outcome Measurements

1. Primary outcome: Change in mean arterial pressure (ΔMAP) from baseline (T0) to PRF treatment stage (T4).

2. Hemodynamic parameters: MAP and HR at T0 (baseline), T1 (15 min post-drug), T2 (puncture), T3 (nerve stimulation), T4 (RF treatment), T5 (procedure end).

3. Pain intensity: VAS at baseline and postoperative days 1, 3, 7, 14; total rescue analgesic consumption.

4. Sleep quality: Pittsburgh Sleep Quality Index (PSQI). Baseline used standard 1-month recall; postoperative assessments used a validated modified short-interval version (“since surgery” for days 1/3; “past 7 days” for days 7/14).

5. Adverse events: incidence, severity and management of all adverse events.

Sample Size

The primary outcome was ΔMAP from baseline to T4. Based on Chen et al (2022),⁶ control group MAP fluctuation was 15.2±6.3 mmHg vs 8.5±4.2 mmHg in the dexmedetomidine group. Sample size was calculated with PASS 15.0 using a two-sided independent-samples t-test (α=0.05, power=0.9), requiring 27 patients per group. With 10% dropout allowance, 30 patients per group were enrolled. We note this calculation does not fully reflect the repeated-measures final analysis.

Statistical Analyses

Data analysis was performed using SPSS 26.0 statistical software in strict accordance with the CONSORT guidelines for clinical trial reporting. For quantitative data conforming to a normal distribution, results were presented as mean±standard deviation (xˉ±s). The primary analysis followed the intention-to-treat (ITT) principle; per-protocol (PP) analysis served as sensitivity analysis. Normality was verified via Shapiro–Wilk test and Q-Q plots. For longitudinal outcomes (MAP, HR, VAS, PSQI), linear mixed-effects models (LMM) with REML estimation were used, including fixed effects for group, time and group × time interaction, and random intercepts for patients. Post hoc pairwise comparisons used Bonferroni correction. Between-group mean differences (MD), 95% CIs and Cohen’s d effect sizes were reported. Categorical data were compared with χ²-test or Fisher’s exact test. The significance level was set at α= 0.05, and a P value < 0.05 was considered statistically significant.

Results

Patient Characteristics

Patients undergoing PRF therapy from April 2025 to June 2026 were assessed for eligibility. During the study period, 79 patients were screened; 11 excluded, 68 randomized (34 per group). 4 patients withdrew before intervention; 4 more were lost to follow-up after day 3. Primary ITT analysis included all 68 randomized patients; 60 patients completed per protocol. (Figure 1). The main comorbidities of ASA class III patients in both groups were essential hypertension, type 2 diabetes mellitus, coronary heart disease, and chronic obstructive pulmonary disease. There were no statistically significant between-group differences in the prevalence of each comorbidity (all P > 0.05), indicating good baseline balance. Baseline demographic and clinical characteristics were well balanced between groups (Table 1).

Figure 1.

CONSORT diagram demonstrating enrollment, randomization, and analysis of all study subjects.

Table 1.

Demographics and Baseline Characteristics of Trial Participants

Variable	Dex Group (n = 30)	Control Group (n = 30)	P value
Age, years	67.93±7.85	67.36±7.79	0.7801
Weight, kg	63.80±8.93	61.33±9.77	0.3118
Gender, F/M	15/15	16/14	0.7961
ASA, I/II/III	2/15/13	6/11/13	0.8501
MAP,mmHg	108.26±11.05	110.16±10.06	0.4890
HR,bpm	84.23±6.06	81.8±5.18	0.1004
VAS Score	6.63±0.83	6.60±0.79	0.8920
PSQI Score	16.53±1.56	16.60±1.52	0.1670
Pain duration,weeks	7.2 ± 4.1	6.9±3.8	0.772
Time since rash onset,weeks	8.1±3.9	7.8 ± 3.6	0.759
Disease stage
Thoracic, n (%)	18(60)	19(63.3)	0.791
Lumbar, n (%)	9(30.0)	8(26.7)	0.775
Trigeminal, n (%)	3(10.0)	3(10.0)	1.000
Comorbidities
Hypertension, n (%)	13(43.3)	16(53.3)	0.438
T2DM, n (%)	8(26.7)	8(26.7)	1.000
CHD, n (%)	6(20.0)	3(10.0)	0.471
COPD, n (%)	3(10.0)	1(3.3)	0.612

Abbreviations: Dex, dexmedetomidine; ASA, American Society of Anesthesiologists; MAP, mean arterial pressure; HR, heart rate; bpm, beats per minute; VAS, Visual Analogue Scale; PSQI, Pittsburgh Sleep Quality Index; T2DM, Type 2 diabetes mellitus; CHD, Coronary heart disease; COPD, Chronic obstructive pulmonary disease.

Perioperative Hemodynamic Changes

Baseline MAP and HR did not differ between groups. LMM revealed significant group × time interactions for both MAP (P < 0.001) and HR (P < 0.001).

For the primary outcome (ΔMAP at T4), the Dex group had a significantly smaller increase in MAP (MD = −27.73 mmHg, 95% CI: −34.66 to −20.80, P < 0.001). MAP and HR at T2–T4 remained significantly lower in the Dex group after Bonferroni correction (Figures 2 and 3).

Figure 2.

Perioperative changes of mean arterial pressure in the two groups. Linear mixed-effects model showed a significant group × time interaction effect (P < 0.001). **** P < 0.0001 vs control group at the same time point.T0: Preoperative baseline; T1: 15 min after drug administration; T2: Needle puncture; T3: Nerve stimulation; T4: Radiofrequency treatment; T5: End of procedure.

Figure 3.

Perioperative heart rate changes between the two groups. Linear mixed-effects model showed a significant group × time interaction effect (P < 0.001). **** P < 0.0001 vs control group at the same time point. T0: Preoperative baseline; T1: 15 min after drug administration; T2: Needle puncture; T3: Nerve stimulation; T4: Radiofrequency treatment; T5: End of procedure.

The difference in total intraoperative fluid volume between the two groups was not statistically significant (173.33 ± 25.37 vs 171.66 ± 25.20, P = 0.799), excluding the confounding effects of fluid management and vasoactive medications on hemodynamic outcomes.

Postoperative Pain Intensity

Baseline VAS scores were comparable (6.63 ± 0.83 vs 6.60 ± 0.79, P = 0.892). LMM showed a significant group × time interaction (P < 0.001).

The Dex group had significantly lower VAS scores at all postoperative time points (all P < 0.001, Table 2).

Table 2.

Comparison of Postoperative Pain Intensity and Sleep Quality Between the Two Groups

	Dex Group	Control Group	Cohen’s d	95% Confidence Interval		P-value
				Lower	Upper
VAS
PRO	6.63±0.03	6.60±0.24	0.033	−0.62	0.69	0.892
PO(1d)	2.50±0.68	3.80±0.76	−1.30	−1.78	−0.80	<0.0001
PO(3d)	2.80±0.55	4.20±0.48	−1.40	−1.76	−1.04	<0.0001
PO(7d)	2.63±0.49	3.73±0.52	−1.10	−1.45	−0.75	<0.0001
PO(14d)	2.43±0.50	3.20±0.71	−0.77	−1.19	−0.34	<0.0001
PSQI
PRO	16.53±1.56	16.60±1.52	−0.067	−1.13	0.99	0.868
PO(1d)	6.36±1.27	11.80±1.49	−5.43	−6.39	−4.48	<0.0001
PO(3d)	5.10±1.32	10.86±1.47	−5.77	−6.73	−4.80	<0.0001
PO(7d)	4.10±1.06	8.26±1.43	−4.17	−5.04	−3.29	<0.0001
PO(14d)	3.03±0.85	6.73±1.46	−3.70	−4.53	−2.87	<0.0001

Notes: Pain intensity and sleep quality were assessed using the Visual Analogue Scale (VAS) and the Pittsburgh Sleep Quality Index (PSQI), respectively, at preoperative baseline (PRO), postoperative day 1 [PO (1d)], postoperative day 3 [PO (3d)], postoperative day 7 [PO (7d)], and postoperative day 14 [PO (14d)].

Abbreviations: Dex, dexmedetomidine; VAS, Visual Analogue Scale; PSQI, Pittsburgh Sleep Quality Index; PRO, Preoperative; PO, postoperative.

Total celecoxib rescue doses were significantly lower in the Dex group (1.2 ± 0.8 vs 2.8 ± 1.1, MD = −1.6, 95% CI: −2.1 to −1.1, P < 0.001).

Postoperative Sleep Quality

Baseline PSQI scores were comparable (~16.5 points, severe sleep impairment). LMM showed a significant group × time interaction (P < 0.001).

The Dex group had significantly lower PSQI at all time points (all P < 0.001, Table 2). Between-group differences (3.70–5.76 points) exceeded the 3-point clinically meaningful threshold. Early improvements (day 1–3) partially reflect direct sedative effects of dexmedetomidine; sustained improvement at day 14 likely reflects genuine pain-related sleep restoration.

Adverse Events

No severe adverse events occurred. Bradycardia and hypotension were numerically more frequent in the Dex group but not statistically significant (Table 3). All events were transient and resolved spontaneously.

Table 3.

Comparison of the Incidence of Perioperative Adverse Events Between the Two Groups [n (%)]

	Adverse Events
	Bradycardia	Hypotension	Dry mouth	Nausea	Dizziness	Somnolence
Dex Group (n=30)	5(16.7)	2(6.7)	2(6.7)	2(6.7)	1(3.3)	3(10)
Control Group (n=30)	1(3.3)	1(3.3)	1(3.3)	3(10)	1(3.3)	1(3.3)
P value	0.1945	1.000	1.000	1.000	1.000	0.621

The study was not powered to detect differences in adverse event rates. No serious safety signals were identified in this small cohort.

Discussion

The core pathological alterations of ZAP consist of peripheral nerve injury and central sensitization induced by varicella-zoster virus invasion, accompanied by prominent sleep disturbance and abnormally elevated sympathetic tone in patients.⁷ PRF serves as a first-line interventional therapy for drug-refractory ZAP. Perioperative puncture stimulation, nerve localization and radiofrequency procedures readily trigger hemodynamic fluctuations. Sustained postoperative neuronal sensitization often leads to insufficient pain relief and poor sleep improvement, thereby compromising overall therapeutic efficacy.⁸ This is the first randomized controlled trial to evaluate a combined preoperative + 3-day postoperative intranasal dexmedetomidine regimen for ZAP patients undergoing PRF. The results demonstrate that this regimen stabilizes perioperative hemodynamics, reduces postoperative pain and improves sleep quality, with good tolerability, providing novel evidence-based references for standardized perioperative management of PRF in ZAP patients.

Although PRF is a minimally invasive interventional procedure, severe nociceptive stimulation and patient anxiety induced during paravertebral puncture, nerve stimulation localization and radiofrequency current delivery can trigger sympathetic excitation, resulting in abrupt hypertension and tachycardia. This is the first randomized controlled trial to evaluate a combined preoperative + 3-day postoperative intranasal dexmedetomidine regimen for ZAP patients undergoing PRF. The results demonstrate that this regimen stabilizes perioperative hemodynamics, reduces postoperative pain and improves sleep quality, with good tolerability. The subjects enrolled in this study were middle-aged and elderly patients over 50 years old, who generally suffered from decreased vascular elasticity and a high prevalence of underlying comorbidities. Severe perioperative hemodynamic fluctuations substantially raise the risk of cardiovascular and cerebrovascular adverse events. The results revealed that MAP and HR in the control group increased markedly relative to baseline at puncture (T2), nerve stimulation localization (T3) and radiofrequency therapy (T4). By contrast, the amplitude of circulatory parameter fluctuations at the above time points was significantly lower in the Dex group, indicating that intranasal dexmedetomidine administered 30 minutes preoperatively effectively inhibits procedure-related sympathetic stress responses.

Previous studies mostly focused on the circulatory stabilizing effects of intravenous dexmedetomidine during pain interventional procedures. Multiple clinical trials have confirmed that intraoperative intravenous dexmedetomidine infusion significantly reduces peak perioperative blood pressure and heart rate during interventions such as radiofrequency ablation of the trigeminal ganglion and dorsal root ganglion, and lowers the incidence of hypertensive crises.^6,9 Compared with intravenous administration, intranasal spray is directly absorbed via the abundant vascular plexus of the nasal mucosa, bypassing hepatic first-pass metabolism. It takes effect rapidly with a gentle rise in plasma drug concentration, avoiding transient hypertension followed by severe hypotension commonly seen after rapid intravenous bolus injection.¹⁰ Dexmedetomidine selectively activates central locus coeruleus α₂-adrenergic receptors to suppress sympathetic efferent output, enhance vagal tone and exert anxiolytic effects, mitigating stress responses via both pain and emotional pathways. This aligns with the stable perioperative hemodynamics observed in the Dex group of the present study. In addition, ZAP patients endure long-term chronic nociceptive stimulation and exhibit higher baseline sympathetic tone than the general population. Preoperative prophylactic administration downregulates sympathetic excitability in advance, facilitating superior perioperative circulatory control.

The present study found that postoperative VAS scores gradually declined over time in both groups, while VAS scores on postoperative days 1, 3, 7 and 14 were significantly lower in the Dex group than in the control group. This indicates that perioperative intranasal dexmedetomidine synergistically enhances the analgesic efficacy of PRF, with benefits persisting for two weeks postoperatively. The analgesic mechanism of PRF relies primarily on high-frequency electric fields acting on the dorsal root ganglion to modulate ion channel function on neuronal membranes, suppress abnormal neuronal discharges and facilitate nerve injury repair. Nevertheless, its capacity to reverse established central sensitization is limited, frequently resulting in inadequate early postoperative pain relief.

Dexmedetomidine exerts analgesic effects via multi-layered targets: peripherally, it inhibits depolarization of nociceptor terminals and reduces the release of inflammatory mediators; at the spinal level, it activates α₂ receptors in the spinal dorsal horn to block the transmission of nociceptive signals to the central nervous system; at the supraspinal level, it elicits central analgesia by activating the descending pain inhibitory pathway connecting the locus coeruleus and rostral ventromedial medulla.¹¹ Prior research predominantly investigated the immediate analgesic effects of single intraoperative dexmedetomidine dosing, whereas this study adopted a 3-day consecutive postoperative administration protocol covering the peak period of neuronal sensitization after PRF. Existing evidence confirms that the first 3 days following interventional surgery for neuropathic pain constitute a critical window for exacerbation of peripheral and central sensitization. Sustained dexmedetomidine administration suppresses NMDA receptor activation and astrocyte activation, halting the maintenance and progression of nociceptive sensitization to strengthen long-term analgesic effects.^12,13 Furthermore, patients in the Dex group achieved remarkable sleep improvement in this study. Sleep deprivation amplifies nociceptive sensitization by upregulating excitability of central pain pathways, thus sleep improvement and pain relief form a positive feedback loop that further augments analgesic benefits.

Sleep disturbance represents the most prevalent concomitant symptom in ZAP patients, with an incidence exceeding 70%. Pain causes difficulty falling asleep and nocturnal awakenings, while insufficient sleep in turn lowers pain thresholds and intensifies pain perception, creating a vicious cycle of pain-sleep disturbance-worsened pain.^14,15 Preoperative Pittsburgh Sleep Quality Index (PSQI) scores exceeded 16 points in all patients of both groups, suggestive of severe sleep impairment. Postoperative PSQI scores at all follow-up time points were significantly lower in the Dex group, declining to approximately 14 points on postoperative day 14, close to the range observed in healthy individuals. This demonstrates that perioperative intranasal dexmedetomidine effectively breaks the aforementioned vicious cycle.

Unlike traditional benzodiazepine sedative-hypnotic agents, dexmedetomidine induces physiological non-rapid eye movement sleep by stimulating locus coeruleus α₂ receptors, yielding a sleep architecture similar to natural sleep without significant respiratory depression or hangover effects, making it particularly suitable for elderly patients with chronic pain.^16,17 Previous studies on postoperative sleep disturbance have reported that perioperative dexmedetomidine markedly reduces postoperative PSQI scores, alleviates sleep fragmentation and does not increase the risk of respiratory adverse events.¹⁸ A distinctive feature of this research is the extension of drug administration to 3 days postoperatively. This strategy not only ameliorates sleep disruption induced by acute perioperative stress but also improves chronic pain-related sleep disturbances at the etiological level through sustained pain alleviation and anxiety reduction. Notably, the intranasal delivery route eliminates sleep disruption caused by nighttime intravenous puncture; patients can self-administer the spray independently, satisfying clinical demands for ward care and home-based rehabilitation.

No serious adverse events or major complications including respiratory depression and severe arrhythmias occurred in either group throughout the trial. Mild-to-moderate transient bradycardia and hypotension were the primary adverse reactions observed in the Dex group, requiring no targeted pharmaceutical intervention. The incidences of other adverse reactions such as dry mouth, dizziness and somnolence were extremely low, confirming the favorable safety and tolerability profile of this administration regimen. The cardiovascular adverse effects commonly associated with dexmedetomidine are closely correlated with delivery route, dosage and infusion rate; rapid intravenous administration easily triggers profound hypotension and bradycardia.¹⁹ This study adopted an intranasal dose of 40 μg per spray, which undergoes slow mucosal absorption to maintain stable plasma drug concentrations, leading to mild, rare adverse reactions.

Compared with benzodiazepines and opioids routinely used during PRF perioperative management, dexmedetomidine produces minimal respiratory depression. All patients remained alert and cooperative during the procedure without declines in blood oxygen saturation, a critical advantage for local anesthesia-based interventional surgeries: patients can fully cooperate with nerve stimulation localization while respiratory complications are avoided. Additionally, the enrolled population consisted of middle-aged and elderly patients aged 50–76 years, most of whom presented with varying degrees of underlying diseases. The absence of severe cardiovascular events in the Dex group further validates the safety of this regimen for aged patients.

Several limitations of the present study should be acknowledged. 1. Single-center design with small sample size, limited generalizability; underpowered for rare adverse events.2. This study tested a combined preoperative and postoperative dexmedetomidine regimen; the relative contributions of preoperative prophylaxis vs postoperative sustained administration cannot be disentangled. A factorial multi-arm design would be required to isolate phase-specific effects.3. Follow-up limited to 14 days; no long-term PHN prevention data.4. No dose gradient or plasma drug concentration monitoring.5. Modified short-interval PSQI does not fully match standard 1-month version; objective sleep measures are lacking.6. No validated sedation scale (eg, RASS, Ramsay) was used during the procedure, so the degree of sedation and its contribution to outcomes cannot be quantified.7. Heterogeneous patient population across acute/subacute/PHN stages.8. The placebo-controlled design cannot fully distinguish PRF-augmenting effects from the direct pharmacological effects of dexmedetomidine. Improvements in pain and sleep scores may partially reflect the drug’s intrinsic sedative, anxiolytic and analgesic properties, rather than specific enhancement of PRF efficacy. Future studies with active comparators are needed to address this.

In conclusion, perioperative intranasal dexmedetomidine spray (40 μg 30 min preoperatively + 40 μg twice daily for 3 postoperative days) effectively stabilizes perioperative hemodynamics, improves postoperative analgesia and enhances sleep quality in patients with ZAP undergoing PRF. No serious safety signals were observed in this small cohort. This regimen offers a promising clinical option for perioperative management in this patient population, but larger multicenter studies are needed to confirm efficacy and long-term safety.

Funding Statement

The present work was supported by grants from the Anhui Provincial Special Project Fund for Clinical Medical Research and Translational Studies (202527c10020015) and 2024 University-Enterprise Integrated Development – “Hengrui Scientific Research Fund” Horizontal Research Project (XQHR202408).

Data Sharing Statement

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Ethics Approval and Consent to Participate

This prospective randomized controlled trial was conducted in compliance with the World Medical Association Declaration of Helsinki. The study was designed and reported in strict accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines. The study received approval from the Ethics Committee of the First Affiliated Hospital of Wannan Medical University, located at No. 2 Zhe Shan Street, Wuhu, Anhui, China (Approval No: 2024LunShenYan200). Written informed consent was obtained from all participants prior to the commencement of study procedures.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to beaccountable for all aspects of the work.

Disclosure

The authors declare no conflicts of interest.