Clinical Study of Hydromorphone Combined with Dexmedetomidine via Patient Controlled Analgesia for the Treatment of Acute Herpes Zoster Neuralgia

By Qingwen Yu, Jianxiong Wu, Shuangchun Peng, Changyan Huang

Affiliations

1. Department of Pain, Leshan Hospital of Traditional Chinese Medicine, Leshan, China

doi: 10.29271/jcpsp.2025.08.958

ABSTRACT
Objective: To investigate the efficacy of hydromorphone combined with dexmedetomidine with patient-controlled intravenous analgesia (PCIA) in treating patients with acute herpes zoster (HZ) neuralgia.
Study Design: Randomised controlled trial.
Place and Duration of the Study: Department of Pain, Leshan Hospital of Traditional Chinese Medicine, Leshan, China, from May 2023 to April 2024.
Methodology: The patients diagnosed with acute HZ were randomly divided into two groups: The hydromorphone combined dexmedetomidine PCIA treatment group (Group H) and the oral tramadol control group (Group C). Both groups were given oral pregabalin and vitamin B1. Repeated measures analysis of variance, Chi-square test or Fisher's exact probability test, was used to compare the pain numeric rating scales (NRS) and the Pittsburgh sleep quality index (PSQI) of the two groups before and after 1, 4, and 12 weeks treatment (T0, T3, T4, and T5). The number of people experiencing HZ-related pain was at T4 and T5, with the levels of cluster of differentiation 4 (CD4+), 8 (CD8+), and CD4+ / CD8+ before treatment, 24 hours, and 48 hours after treatment (T0, T1, T2), respectively. And the related adverse effects were also monitored.
Results: NRS and PSQI decreased significantly in both groups after treatment. Compared to Group C, Group H showed a significant decrease in NRS scores at T3 and T4 (p <0.001); the difference between the two groups remained statistically significant (p = 0.003) at T5. PSQI scores in Group H were lower than those in Group C after treatment (p <0.001). The frequency of HZ-related pain in Group H was also significantly lower compared to Group C (p <0.05). CD8+ levels in Group H were significantly lower than in Group C at T1 and T2 (p <0.001), which CD4+ / CD8+ levels were significantly higher than those in Group C (p <0.001). The frequency of drowsiness in Group H was higher than that in Group C (p <0.05). However, there were no significant difference between the two groups (p >0.05) in other adverse reactions, such as dizziness, nausea, and vomiting.
Conclusion: Hydromorphone combined with dexmedetomidine PCIA is effective in relieving HZ-related pain, and reducing the occurrence of postherpetic neuralgia (PHN). It shows a good therapeutic effect, a high safety profile, and an easy clinical application.

Key Words: Patient-controlled analgesia, Hydromorphone, Dexmedetomidine, Acute herpes zoster neuralgia, Oral tramadol.

INTRODUCTION

Postherpetic neuralgia (PHN) refers to persistent pain lasting for more than one month following the resolution of herpes zoster (HZ) lesions. It is the most prevalent and severe consequence of HZ.¹ Research indicates that PHN affects approximately 9-34% of patients with HZ, with incidence rate increasing significantly with age.² PHN is a common, chronic pain disorder that is often difficult to treat. Although the recombinant HZ vaccine effectively prevents HZ, a significant portion of the population remains at risk for PHN due to its additional cost and limited public awareness.^3-5

PHN significantly reduces patients' quality of life and increases healthcare costs.⁶ Therefore, finding safe and effective interventions to prevent the development of PHN early is a priority in the treatment of HZ.

Nerve block is a common treatment to prevent the occurrence of PHN. Some studies have shown that continuous epidural block, paravertebral block, and intercostal nerve block can reduce the incidence of PHN in HZ patients; however, these procedures are complex, may results in tissue damage, elevate the possibility of local infection, and pose complications such as dislocation or blockage of indwelling catheters. Furthermore, they do not provide complete pain relieve or fully prevent PHN.^7,8 Therefore, considering the invasiveness, safety, and price of the operation, it is necessary to explore simpler effective treatments with fewer side effects and greater feasibility.

​Current guidelines recommend treatment with tricyclic anti-depressants, tramadol, or opioids at the early stage of the disease.⁹ However, considering the side effects of these medicines, poor compliance of elderly patients, and poor pain control, it is still necessary to make some innovations in the analgesic programme.

Hydromorphone is a semisynthetic morphine derivative with a fast onset of analgesic effect and low incidence of side effects, used for analgesic treatment.¹⁰ Clinically, hydromorphone patient-controlled intravenous analgesia (PCIA) has proven effective in managing PHN, offering patients a personalised and responsive method of pain relief.¹ However, its use in treating acute-phase HZ neuralgia has not been studied. In addition, dexmedetomidine is a highly selective α2 agonist, which is sedative, analgesic, anxiolytic, and antisympathetic and is used clinically as an adjuvant in the treatment of HZ neuralgia.¹¹ Therefore, this study was conducted to observe the therapeutic performance of hydromorphone combined with dexmede- tomidine PCIA in HZ patients and the effectiveness of preventing the occurrence of PHN for clinical treatment.

METHODOLOGY

The Ethics Committee of Leshan Hospital of Traditional Chinese Medicine, Leshan, China, approved this study (No: 2022-14), which was registered with the China Clinical Trial Centre (ChiCTR2400089730). According to the results of the pre-experiment, the alpha level was set at 0.05, the efficacy was set at 80%, and the PASS 15.0 software calculated a minimum sample size of seventy-six cases, and the sample size was at least ninety cases, taking consideration of a 20% dropout rate during the clinical trial. One hundred and ten patients, diagnosed with acute-phase HZ neuralgia (within one month from the onset of disease) and treated at the Leshan Hospital of Traditional Chinese Medicine, Leshan, China, from May 2023 to April 2024, were enrolled. According to the method of the randomised numerical table, participants were assigned to either hydromorphone combined with dexmedetomidine PCIA treatment group (Group H) or oral tramadol control group (Group C).

Patients included in the study were those with HZ history of less than one month, NRS scores ≥4, age over 50 years, had received regular antiviral therapy, with no history of hypotension or bradycardia, who voluntarily signed the informed consent form, and cooperated with the follow-up assessment and the operation of the PCA pump. Patients were excluded if they had allergies to opioids and experimental agent, had serious cardiac, pulmonary, and renal insufficiency, had infections, mental anomalies, and other inabilities preventing cooperation with treatment, had paralytic intestinal obstruction, older patients who had difficulty to communicate with the assessment, had discontinued participation in the study due to subjective or objective factors, as well as other more serious diseases and complications arising during the follow-up process.

Intravenous analgesic pump for patients in Group H used a solution containing 10 mg of hydromorphone plus 0.2 mg of dexmedetomidine hydrochloride, diluted to 200 ml with normal saline, with a background infusion rate of 1.5 ml/h. The patient's self-control volume was 1 ml each time, with a locking time of 15 min, and the background infusion volume was 1 ml each time, adjusted daily according to the self-control dosage of the previous day and the patient's pain condition. According to the principle of equivalent dose conversion, 2 mg of hydromorphone by infusion, is approximately 100 mg of oral tramadol. Patients in Group C were given oral tramadol (50 mg/dose, every 12 hours), and the dose was adjusted according to the pain control until the patient's NRS score was <3, with a maximum amount of 400 mg per day.¹² In addition, both groups received oral pregabalin (75 mg/dose every 12 hours) and vitamin B1 (10 mg/dose, 3 times/day). Both groups were treated for 1 week. Throughout the treatment course, blood pressure, heart rate, and other vital signs were monitored.

General information about patients' age, gender, disease duration, pain location, and comorbidities was collected. The pain was assessed using the NRS score. The degree of pain was expressed as 0 to 10, with 0 describing painlessness and 10 describing the most painful, and patients were scored according to their feelings. The incidence of HZ-associated pain (defined as burning or pins-and-needles pain accompanied by a foreign body sensation, with an NRS score >3 and limited to the dermatomes involved in the initial outbreak of HZ) was recorded in both groups. CD4+, CD8+, and CD4+ / CD8+ levels in the patient's venous blood were measured using flow cytometric techniques. The Pittsburgh sleep quality index (PSQI) was used for the sleep quality score, which was divided into 7 categories, with each category scoring 0-3 points, and the cumulative score for each category was the total score, which ranges from 0-21, with higher score representing the poorer sleep quality.¹³ Numeric rating scale (NRS) scores were recorded and PSQI scores before treatment (T0), 1 week (T3), 4 weeks (T4), 12 weeks after treatment (T5). The incidence of HZ-related pain was recorded after 4 weeks (T4), 12 weeks after treatment (T5). CD4+, CD8+, and CD4+ / CD8+ levels were measured before treatment (T0), and 24 hours, 48 hours post-treatment (T1, T2). The occurrence of adverse reactions was also monitored.

Statistical analysis was performed using SPSS version 26.0 software. Enumerated data was analysed by using the Chi-square test or Fisher's exact probability test. The Kolmogorov-Smirnov test was used to check the normality. Data following a normal distribution were presented as mean ± standard deviation. Independent sample t-test was used for comparison between groups. Repeated measures analysis of variance was employed to compare data across different time points; significance was determined at p <0.05.

RESULTS

Of the 110 initially enrolled patients, 20 were excluded from the study as they did not meet the established inclusion criteria. Consequently, 90 patients were enrolled in the study. During follow-up, two patients in Group C received pulsed radiofrequency treatment in the dorsal root ganglion and withdrew from the study. Additionally, one patient was lost to follow-up. In total, 86 patients completed the study (Figure 1).

There was no statistically significant difference in demographic and clinical information between the two groups (Table I).

There was no statistically significant difference in NRS scores between the two groups before treatment (p >0.05). However, NRS scores gradually decreased in both groups at T3, T4, and T5, with the differences between them reaching statistical significance (p <0.05). Notably, Group H showed a significant decrease in NRS scores at both T3 and T4; the difference was statistically significant (p <0.001) at T5, and a statistically significant difference remained between the two groups (p = 0.003, Table II).

Table I: Baseline demographic information of patients.
 

Characteristics	Group H (n = 44)	Group C (n = 42)	p-values
Age, years	68.55 ± 4.80	67.83 ± 4.12	0.466
Disease course (day)	21.57 ± 2.15	20.67 ± 2.01	0.313
Gender	-	-	0.673
Male, n (%)	20 (45.5)	21 (50.0)	-
Female, n (%)	24 (54.5)	21 (50.0)	-
Pain location	-	-	0.240
Head, n (%)	6 (13.6)	3 (7.1)	-
Cervical, n (%)	8 (18.2)	3 (7.1)	-
Thoracic, n (%)	26 (29.1)	29 (69.0)	-
Lumbar, n (%)	4 (9.1)	7 (16.7)	-
Underlying disease	-	-	0.238
Hypertension, n (%)	8 (18.2)	13 (30.1)	-
Diabetes mellitus, n (%)	14 (31.8)	11 (26.2)	-
Cerebral infarction, n (%)	5 (11.4)	2 (4.8)
Note: t-test was used to compare age and disease course, χ2-test was used to compare gender, pain location, and Underlying disease.

Table II: Evaluation of NRS, PSQI scores, CD4+, CD8+, and CD4+ / CD8+ levels before and after therapeutic intervention.

Time points	Group H (n = 44)	Group C (n = 42)	p-values
T0
NRS	6.11 ± 0.92	5.90 ± 0.82	0.285
PSQI	16.16 ± 1.35	15.88 ± 1.34	0.341
CD4+ (%)	43.69 ± 0.55	43.76 ± 0.43	0.546
CD8+ (%)	26.90 ± 0.97	26.97 ± 0.95	0.711
CD4+ / CD8+	1.63 ± 0.58	1.62 ± 0.60	0.866
T1	-	-	-
CD4+ (%)	44.17 ± 1.17	44.10 ± 0.99	0.776
CD8+ (%)	27.28 ± 1.15	31.18 ± 1.20	< 0.001
CD4+ / CD8+	1.62 ± 0.25	1.41 ± 0.22	< 0.001
T2	-		-
CD4+ (%)	44.78 ± 1.24	44.38 ± 1.14	0.117
CD8+ (%)	27.89 ± 1.06	32.60 ± 1.26	< 0.001
CD4+ / CD8+	1.61 ± 0.17	1.36 ± 0.18	< 0.001
T3	-	-	-
NRS	2.98 ± 0.70ᵃ	3.88 ± 0.71ᵇ	< 0.001
PSQI	5.07 ± 1.84ᵃ	9.93 ± 1.90ᵇ	< 0.001
T4	-	-	-
NRS	1.61 ± 1.37ᵃ	3.05 ± 1.09ᵇ	< 0.001
PSQI	2.57 ± 1.74ᵃ	7.79 ± 1.77ᵇ	< 0.001
T5	-	-	-
NRS	1.34 ± 1.26ᵃ	2.26 ± 1.56ᵇ	0.003
PSQI	1.50 ± 1.29ᵃ	5.79 ± 2.49ᵇ	< 0.001
Note: Compared with T0: ap <0.05, bp <0.05; repeated measures analysis of variance was used to compare NRS, PSQI, CD4+, CD8+, and CD4+/CD8+ levels.

Table III: Incidence of side effects during and after treatment [n, (%)].

	Dizziness	Drowsiness	Nausea and vomiting
During treatment
Group H	6 (13.6)	10 (22.7)*	5 (11.4)
Group C	9 (21.4)	2 (4.8)	4 (9.5)
p-value	0.341	0.016	0.530
T1	-	-	-
Group H	5 (11.4)	1 (2.3)	0 (0)
Group C	7 (16.7)	1 (2.4)	0 (0)
p-value	0.478	0.741	-
T2	-	-	-
Group H	2 (4.5)	0 (0)	0 (0)
Group C	4 (9.5)	0 (0)	0 (0)
p-value	-	-	-
T3	0.316	-	-
Group H	0 (0)	0 (0)	0 (0)
Group C	2 (4.8)	0 (0)	0 (0)
p-value	0.236	-	-
Note: Compared with Group C: *p <0.05, χ2-test was used to compare the incidence of side effects.

Figure 1: Assignment of patients to treatment groups.

Figure 2: The incidence of zoster-related pain in the studied groups. Compared with Group C: **p <0.01 (T4, p = 0.004, T5, p = 0.004).

As shown in Figure 2 five case (11.36%) of HZ-related pain were reported in Group H, compared to sixteen cases (38.10%) in Group C. The number of HZ-related pain occurred in 3 (6.80%) cases in Group H and 13 (30.95%) cases in Group C at T5. The incidence of HZ-related pain was significantly lower in Group H than in Group C (p <0.05). There was no statistical significant difference in CD4+ levels between the groups at T1 and T2 (p >0.05). However, the CD8+ levels in Group H were lower than in Group C, and the CD4+ / CD8+ level in Group H was higher with significant statistic difference (p <0.001, Table II). There was no statistically significant difference in PSQI scores between the two groups of patients at T0 (p >0.05). A PSQI scores of both groups gradually decreased after treatment compared to those before treatment (p <0.05). However, compared with Group C, Group H showed a statistically significant decrease at T3, T4, and T5 (p <0.001, Table II).

This clinical trial has recorded and evaluated all treatment-related adverse reactions (Table III). The incidence of somno-lence in patients in Group H was higher with statistically significant difference (p <0.05). At T1, T2, and T3, none of the differences between the two groups were statistically significant. There were no symptoms of brady-cardia and respiratory depression in both groups, and the adverse reactions were transient and improved after symptomatic treatment.

DISCUSSION

Acute-phase herpes zoster neuralgia is a specific pain asso-ciated with a herpes zoster outbreak within a month. Acute pain develops in more than 95% of patients over the age of 50 years, and approximately 60-70% of patients experience persistent pain after 1 month. Older patients with, chronic diseases such as comorbid tumours or those who are immunocompromised HZ are prone to progression to PHN.⁸ The intractable and severe pain of PHN can lead to depression, fatigue, and sleep disorders. The aetiology of PHN is complex and clinically difficult to cure.¹⁴ Early medical intervention for acute HZ pain is therefore critical for better clinical outcomes and prognosis.

Guidelines for the management of HZ state that opioids in combination with calcium channel modulators are recommended for patients with risk factors that may lead to PHN.¹⁵ In clinical practice, the weak opioid agent tramadol is frequently chosen for co-administration to reduce the adverse effects of opioids. However, as a new strong opioid, studies have reported that oral administration of hydromorphone in combination with pregabalin significantly reduces chronic non-cancer neuropathic pain and is well tolerated.¹⁶ However, oral administration does not allow for on-demand, timely, and effective administration. Additionally, medication adherence may be lacking, especially in some middle-aged and elderly patients, leading to poor pain control, and increased risk of developing PHN. Therefore, in this study, PCIA technology was used in the treatment of acute-phase HZ patients. Unlike the traditional oral administration of medication, patients can readily adjust the dose of medication according to their pain sensation through PCIA, which avoids the accumulation and sudden eruption of pain, enhances the autonomy of the patient, facilitates personalised of pain management, and reduces the operation of the medical staff. Dexmedetomidine acts as an α2 agonist, and the α2 receptor has been proven as an important target for treating neuropathic pain.¹⁷ In related basic studies, dexmedeto-midine showed analgesic effects in both vincristine-induced neuropathic pain in rats and spinal nerve ligation model rats. The above studies show the therapeutic potential of dexmedetomidine in acute HZ neuralgia.^18,19 In general, neurological alterations such as central sensitisation may not have been identified in the acute phase of pain that occurs within one month of the appearance of HZ. Neuropathic changes occurring in damaged sensory ganglia may become more severe if pain is not adequately relieved after the onset of HZ.²⁰ Therefore, finding appropriate and effective interventions during this acute phase is important to prevent the development of chronic neuropathy.

In this study, Group H was treated in the acute phase with hydromorphone combined with dexmedetomidine PCIA, while Group C was treated with conventional oral tramadol. The results showed that although both groups experienced pain relief compared to pre-treatment, patients in Group H showed significantly greater improvement in pain control, and a lower incidence of HZ-related pain than those in Group C. The research team analysed and hypothesised the following reasons: hydromorphone is a strong opioid, with an analgesic strength of about five times that of morphine. The PCIA approach also maintains a stable agent concentration, reduces pain fluctuations, improves patient comfort, on-demand dosing reduces agent dosage, and the incidence of adverse reactions. Dexmedetomidine can act synergistically to prolong hydromorphone analgesia, enhance analgesia, and reduce drug dosage and adverse effects, whereas adequate analgesia during the acute phase of HZ is key to preventing the development of PHN.²⁰ In addition, dexmedetomidine has sedative and anxiolytic effects, helping to improve sleep quality and reduce patients’ anxiety. These findings align closely with the observations reported in the present study. Group H patients’ sleep quality is improved, which is conducive to the maintenance of the immune function and physical recovery, and reduces the occurrence of PHN. Finally, the inflammatory response of the body can inhibit the activity of immune cells, and dexmedetomidine has been shown to suppress the release of inflammatory mediators to reduce the inflammatory response, thus indirectly protecting the immune function.²¹ The findings revealed that the CD8+ levels in Group H were significantly lower than those in Group C, and the CD4+ / CD8+ were significantly higher than those in Group C. This result aligns with previous reports that dexmedetomidine may help to restore the impaired immune function in patients and improve the recovery and prognosis of HZ patients.^22,23

Both groups experienced different degrees of adverse effects. The occurrence of nausea and vomiting during treatment in Group H was no different from that in Group C, but the occurrence of drowsiness was higher than Group H. The use of Dexmedetomidine in Group H resulted in an increased incidence of drowsiness, however, patients could be awakened and communicated normally after waking. In addition, the team monitored the heart rate and blood pressure of the patients during the treatment, but bradycardia and hypotension did not occur in Group H as they did in Group C. This study still has some limitations. First, it was a single-centre study, and the reliability of the conclusions may need to be further confirmed in a multi-centre randomised controlled trial. Second, the follow-up period was short.

CONCLUSION

Hydromorphone combined with dexmedetomidine PCIA is effective in relieving HZ-related pain, which can enhance the quality of patients’ sleep, improve immune function, and reduce the incidence of PHN without having any serious adverse effects.

FUNDING:
Major research initiatives were supported by the Leshan Science and Technology Programme. It also provided funding for this study (Project No: 22SZD09).

ETHICAL APPROVAL:
The study was approved by the Ethics Committee of the Hospital (No: 2022-14) and has been registered with the China Clinical Trial Centre (ChiCTR2400089730). The research was conducted in accordance with the Declaration of Helsinki, and all patients provided informed consent.

PATIENTS’ CONSENT:
Informed consent was obtained from all the patients included in the study.

COMPETING INTEREST:
The authors declared no conflict of interest.

AUTHORS’ CONTRIBUTION:
QY: Designing, drafting, revising the manuscript, and providing study conception.
JW, SP, CH: Data acquisition, analysis, and interpretation.
All authors approved the final version of the manuscript to be published.

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