The effectiveness of repetitive paravertebral block with ropivacaine and dexmedetomidine for the prevention of postherpetic neuralgia in patients with acute herpes zoster

Introduction

Herpes zoster (HZ) is a disease caused by the reactivation of the varicella zoster virus. The global incidence of HZ is 3–5 per 1000 person-years. Herpes zoster is an acute infectious skin-neurological disease caused by reactivation of the varicella zoster virus. After initial infection (chickenpox) or vaccination, the virus remains latent inside the posterior-sensory root ganglion cells. As cellular immunity decreases, the latent virus reactivates, then multiplies inside the posterior-sensory root ganglion cells and migrates back to the sensory nerves of the skin, leading to shingles [1]. Postherpetic neuralgia (PHN) is the most common and the most serious complication of HZ [2]. A study shows that the incidence of PHN in patients with HZ above 50 years old is 49%, and the incidence in patients above 70 years is 74% [3]. PHN decreases the life quality of patients and increases the economic burden of health care [4, 5]. Hence, prevention of PHN is the focus in our treatment for HZ.
Nerve block is a common means to avoid PHN. Some researches have indicated that continuous epidural block, repetitive paravertebral block (PVB), and sympathetic block can effectively reduce the incidence of PHN in patients with acute HZ [6, 7]. Dexmedetomidine (Dex) is a highly selective a2 receptor agonist, currently widely used in regional anaesthesia as an adjuvant. In two basic studies, Dex shows its analgesic potency in vincristine-evoked painful neuropathic rats and spinal nerve ligation model rats [8, 9]. But the efficacy of Dex in the prevention and therapy for human neuropathic pain still lacks relevant research.

Aim

Therefore, this study aims to evaluate the effectiveness of repetitive paravertebral block with ropivacaine (Rop) and Dex for the prevention of PHN in patients with acute HZ.

Material and methods

This study was a prospective, randomised, clinical trial with a 6-month follow-up period. The protocol of the study was approved by the Human Ethics Committee of the Second. Affiliated Hospital of Nanchang University. All the patients signed an informed consent form before they received PVB.

Patients

From January 2018 to December 2019, 122 patients with HZ-associated pain in the Pain Department of the Second Affiliated Hospital of Nanchang University were enrolled in this trial. Inclusion criteria were HZ within 30 days after onset of the rash, rash on the trunk and extremities, age older than 50 years, history of antiviral medication (acyclovir 800 mg five times daily for 7 days or valacyclovir 1000 mg three times daily for 7 days), and no history of bradycardia or hypotension. Exclusion criteria were HZ over 30 days after onset of the rash, rash on perineum, head, and face, age less than 50 years, history of bradycardia or hypotension, and inability to correctly express the severity of pain. Eighteen patients were excluded because they did not meet the inclusion criteria; finally, 104 patients were enrolled in this trial, including 51 males and 53 females.

Protocol

All the patients were randomly divided into two groups. Before the therapy, all of them were taught how to use the VAS to assess their severity of pain by the same doctor, and the initial VAS scores were recorded. Group Rop (n = 53) were allowed to take tramadol when VAS ≥ 4; the dose depended on the requirements of the patient (the permitted maximum daily dose was 400 mg). In addition, all the patients accepted PVB once per 72 h 3 times; every time before PVB we chose two adjacent paravertebral spaces according to nerve segments of the pain, and the injection was 0.25% ropivacaine 10 ml per space. Group Dex (n = 54) received the same drug and PVB treatment. The injection in this group was a mixture of 0.25% ropivacaine 10 ml and 10 ug dexmedetomidine per space. A 10 cm, 22G needle was punctured to each paravertebral space under the guidance of CT (as Figure 1 shows). After aspiration of the syringe, the drug was injected. All injections were administered by the same physician.

Outcome measures

Pain severity was evaluated by using VAS (0 = no pain, 10 = worst pain imaginable) score. VAS scores were assessed at the initial visit (basal) and 7 days, 14 days, 30 days, 60 days, and 180 days after the end of PVB treatment. The incidence of zoster-related pain (defined as burning and lancinating pain that was accompanied by allodynia and that was restricted to the dermatomes involved in the original eruption of HZ) was evaluated at 1, 3, and 6 months after treatment. The dose of tramadol (mg/day) for each patient was also recorded, but the use of tramadol was not permitted during the 24 h before each evaluation. All of the assessments were completed by the same physician.

Statistical analysis

Statistical analysis was performed using SPSS version 23.0 (SPSS Inc., Chicago, IL). Measurement data were expressed as mean and standard deviation. Frequency and proportion were used for enumeration data. For measurement data, an independent sample test was used to compare the two groups. For enumeration data, Fisher’s exact test and the c2 test were used. P < 0.05 was considered statistically significant.

Results

At 1-month follow-up, all the patients completed the assessment. At 3-month follow-up, one patient in Group Rop received spinal cord stimulation and withdrew. There was one patient lost to follow-up in both two groups at 6-month follow-up (Figure 2). There were no statistically significant differences between the two groups with respect to demographic and clinical characteristics (Table 1). As shown in Figure 3, compared to Group Rop, Group Dex reported a lower incidence of zoster-related pain at each time point. At 1 month post therapy, the incidence in Group Dex was significantly lower than Group Rop (6/52 vs. 18/52, p = 0.005). At 3 months post therapy, the people with zoster-related pain in Group Dex were still significantly fewer than Group Rop (4/52 vs. 14/51, p = 0.008), but there were no statistically significant differences between the two groups at 6 months after treatment (3/51 vs. 9/50, p = 0.06). Regarding the VAS scores in the two groups, Group Dex showed significantly lower scores than Group Rop at 1, 3, and 6 months after treatment (Figure 4). In the comparison of rescue drug in the two groups, significantly lower doses were noted in Group Dex at 2 weeks, 1 month, 3 months, and 6 months post therapy (Figure 5). It is worth noting that common complications of Dex are bradycardia and hypotension; therefore, we recorded the heart rate and blood pressure of each patient a 1, 3, and 6 h after PVB. However, no bradycardia and hypotension occurred in Group Dex – of course, the same as Group Rop.

Discussion

This clinical randomised trial shows that compared to using Rop only, repetitive paravertebral block with a combination of Rop and Dex in patients with acute herpes zoster can significantly reduce the incidence of zoster-related pain. Acute HZ is usually defined as occurring up to 30 days after rash onset, the subacute phase and PHN are often defined as 30–90 days, and the pain persists for ≥ 90 days after rash onset [10, 11]. In this study, we chose the patients who were within 30 days of onset of rash. Because current research indicates that decreasing repetitive painful stimuli during the early phase of HZ substantially reduces the incidence of development of chronic pain, and some of the patients with a long-term zoster-related pain had already developed into central sensitisation, the efficacy of nerve block in these patients is always pessimistic [12, 13]. Nerve block has been used to treat and prevent PHN for a long time, including epidural block, PVB, and sympathetic block, but only continuous epidural block, repetitive PVB, and repetitive sympathetic block show effectiveness in the prevention of PHN [6, 7, 14, 15]. In the patients with single epidural block, PVB, and sympathetic block, the incidence of PHN has no significant difference compared to the patients with simple drug therapy [14–16]. Therefore, the project of repetitive PVB 3 times was adopted. a2-Adrenoceptor has been confirmed as an important target in neuropathic pain treatment [17, 18]. Feng et al. found that intrathecal clonidine in a rat model of partial sciatic nerve ligation-induced hypersensitivity could attenuate mechanical and thermal hyperalgesia [19], and in a clinical study, Kaygusuz et al. demonstrated that a mixture of local anaesthetics and Dex in regional anaesthesia was able to effectively prolong the anaesthesia time and significantly decrease post-operative pain [20].
Based on animal and clinical research, we suggest that the nerve block with an injection of mixed Rop and Dex in early HZ can efficiently reduce the incidence of PHN, and our findings confirm this suggestion. There are some probable mechanisms: first, Dex may directly act on the dorsal root ganglion and cause the inhibition of substance P release in the nociceptive pathway; second, Dex could also act on the presynaptic a2-adrenoceptor to reduce neurotransmitter release by inhibiting calcium influx. However, in traditional studies the usual nerve block drug is a mixture of local anaesthetics and steroids. Steroids are eutherapeutic in preventing PHN because they can decrease neuronal damage and inhibit the inflammatory process [21]. But systemic absorption of corticosteroid may still increase the risk of infection; in order to avoid these risks, we explored more choices and possibilities. If the additional Dex can furtherly reduce the incidence of PHN, compared to Rop combined with corticosteroid, we need more studies. Our study showed that repetitive paravertebral block with local anaesthetics and dexmedetomidine in patients with acute herpes zoster can significantly reduce the incidence of zoster-related pain.
The common side effects of Dex are dose-dependent bradycardia and hypotension. In order to avert severe bradycardia and hypotension, we abandoned intravenous injection. We used 10 µg dexmedetomidine for each paravertebral space only and did not find haemodynamic side-effects, which supports the safety profile of our study medication regime. Our study still has some limitations. Firstly, we selected the patients within 30 days after the onset of rash, and the effect of this method in patients with a long-term zoster related pain is still unclear. Secondly, further studies are required to observe the efficacy of Dex in epidural block and sympathetic block.

Conclusions

Our study demonstrated that repetitive PVB with ropivacaine and dexmedetomidine in patients with acute HZ could effectively reduce the incidence of PHN, and decrease the VAS scores and the dosage of rescue drugs.

Conflict of interest

The authors declare no conflict of interest.

References