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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 3  |  Issue : 3  |  Page : 103-108

Evaluation of the efficacy of different regimens in decreasing the incidence of postherpetic neuralgia


Department of Anesthesiology and ICU, Faculty of Medicine, Minia University, Minya, Egypt

Date of Submission29-Jan-2016
Date of Acceptance24-May-2016
Date of Web Publication4-Nov-2016

Correspondence Address:
Josef Z Attia
Department of Anesthesiology and ICU, Faculty of Medicine, Minia University, 61111 Minya
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2356-9115.193413

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  Abstract 

Introduction
Herpes zoster (HZ) is a transient disease caused by reactivation of the varicella-zoster virus that remains dormant within the dorsal root ganglia after varicella. Major complications, such as PHN, often defined as pain that persists for 3 months or more, may occur after the onset of the HZ rash. Our aim is to compare between two regimens in relieving HZ pain and their effects in preventing progression to PHN.
Patients and methods
This study was carried out on 80 outpatients of both sexes who had acute herpetic pain. Group D, which included 40 patients, received acyclovir (800 mg/day), pregabalin (600 mg/day), and fentanyl transdermal patch (75 μg/each 3 days). Group E included 40 patients who received acyclovir (800 mg/day), pregabalin (600 mg/day), and an epidural injection of bupivacaine with 80 mg methylprednisolone twice weekly over 14 days.
Results
In terms of pain assessment, in group D, there was a significant analgesic effect up to the sixth month compared with the first day. However, an insignificant analgesic effect was observed on the fourth and seventh days, with significant changes afterwards up to the sixth month in group E. The incidence of PHN was observed in 40 and 20% of all patients, whereas the incidence of allodynia was observed in 57.5 and 22.5% of patients in groups D and E, respectively. The incidence of herpetic pain in children reaches 2.5%, but usually does not progress to PHN.
Conclusion
Acyclovir together with a pregabalin anticonvulsant results in significant pain relief, although it does not reduce the incidence of PHN. However, use of epidural methylprednisolone leads to a lower analgesic effect in addition to less significant effect in decreasing the incidence of PHN.

Keywords: acyclovir, allodynia, herpes zoster, postherpetic neuralgia


How to cite this article:
Attia JZ. Evaluation of the efficacy of different regimens in decreasing the incidence of postherpetic neuralgia. Res Opin Anesth Intensive Care 2016;3:103-8

How to cite this URL:
Attia JZ. Evaluation of the efficacy of different regimens in decreasing the incidence of postherpetic neuralgia. Res Opin Anesth Intensive Care [serial online] 2016 [cited 2020 Jun 4];3:103-8. Available from: http://www.roaic.eg.net/text.asp?2016/3/3/103/193413


  Introduction Top


Herpes zoster (HZ) is a transient disease caused by reactivation of the varicella-zoster virus (VZV) that has remained dormant within the dorsal root ganglia (DRG), often for decades after the patient’s initial exposure to the virus in the form of varicella results in HZ [1]. It spreads from a single ganglion to the neural tissue of the affected segment and the corresponding cutaneous dermatome. It is characterized by a painful rash in the affected dermatome [2]. The risk of HZ increases with age because a decrease in VZV-specific immunity occurs with aging or immunosuppression secondary to certain diseases or immunosuppressant therapy [3]. The incidence of zoster appears to be inversely correlated with the host’s capacity to mount a cellular immune response. However, many patients with zoster apparently have normal immunity. In these patients, zoster is postulated to occur when VZV antibody titers and cellular immunity decrease to levels that are no longer completely effective in preventing viral invasion. Evidence for this hypothesis includes the observation that pediatricians, who are presumably routinely re-exposed to VZV and thus maintain high levels of immunity, seldom develop zoster [4].

Risk factors for the development of HZ are related to the status of cell-mediated immunity to VZV. Risk factors in children and adults include the following: VZV-specific immunity and cell-mediated immunity, which generally declines with age, immunosuppression disease such as HIV infection or AIDS, patients under immunosuppressive therapy, primary VZV infection in utero or in early infancy when the normal immune response is decreased, antitumor necrosis factor-α agents, immune reconstitution inflammatory syndrome, acute lymphocytic leukemia, and other malignancies [5].

The clinical course of HZ can involve major complications, such as postherpetic neuralgia (PHN), which is often defined as pain that persists for 3 months or more after the onset of the HZ rash [6]. There are no factors that can predict who will develop HZ or how severe the disease will be or whether there will be progression to PHN. In this setting of unpredictability of the disease, its severe outcomes, complications, and prevention are important However, there are no preventative drug treatments for HZ or PHN; although some treatments are available, pain control is often difficult and unsatisfactory, including antiviral (acyclovir), analgesic (NSAIDs and opioids agents), antidepressant drugs, and anticonvulsants agents [7],[8].

In view of the aforementioned information, the present study aimed to (a) compare the use of the two regimens in relieving the pain during HZ and their effects in preventing progression to PHN in the form of (acyclovir+pregablin+dermal fentanyl patch) or (acyclovir+pregabline+epidural methylprednisolone) and (b) detect factors that can predict the severity of pain during the course of the disease.


  Patients and methods Top


After receiving the approval of the local ethics committee of Minia University Hospital, the study was carried out on 40 outpatients of both sexes referred to the Pain Clinic of the El-Minia University Hospital suffering from acute herpetic pain between dermatome (T10–L1).

Patients were included in this study if they had (a) a history of pain along the dermatome distribution within 48 h with or without skin rash and (b) reported pain intensity at more than 4 cm as detected on the visual analog scale (VAS).

Exclusion criteria were as follows: (a) other pain sensations or skin conditions, which could confound the assessment of the neuropathic pain; (b) polyneuropathy or other severe neurologic diseases; (c) immunocompromised patients; and (d) contraindications to epidural anesthesia.

The patients were classified into two groups (group D and group E) according to the regimen of treatment. Group D included 40 patients who received acyclovir (800 mg/day/five times a day for 7–14 days), pregablin (600 mg/day), and fentanyl transdermal patch (75 μg/every 3 days for 14 days). However, pediatric patients in these groups (<18 years old) received acyclovir (400 mg/day/three times a day for 7–14 days), pregablin (150 mg/day), and fentanyl transdermal patch (12.5 μg/every 3 days for 14 days). Group E included 40 patients who received acyclovir (800 mg/day/five times a day for 7–14 days), pregablin (600 mg/day), and an epidural injection of bupivacaine 6–12 ml (0.25%) with 80 mg methylprednisolone injection weekly as two injections over 14 days (total dose of methylprednisolone of 160 mg). However, pediatric patients in this group received acyclovir (400 mg/day/three times a day for 7–14 days), pregablin (150 mg/day), and a caudal injection of bupivacaine 3–6 ml (0.25%) with 20 mg methylprednisolone injection weekly as two injections over 14 days (total dose of methylprednisolone of 40 mg).

The following parameters were recorded.

  1. Demographic: age and sex.
  2. Clinical
    1. Presence of the following stress factors in the form of:
      1. Stress (psychological stress).
      2. Trauma (surgical).
    2. Presence of rash or not.
    3. Follow-up the severity of pain.
      1. The patients were followed up by the VAS (patients were considered to be in pain if scale>3 and drugs were stopped if the scale <3).
    4. Progression to PHN (if the pain continues >3 months) [9],[10].
    5. Presence of allodynea.


Statistical analysis of the data

Data were represented as means±SEM. Statistical analysis was carried out using Graph Pad Prism version 5.00 (San Diego, CA, USA) software and significant differences between groups were assessed using an unpaired t-test one- and within the same group using analysis of variance, followed by the Tukey–Kramar post-hoc test for multiple comparisons, with a value of P less than or equal to 0.05 considered statistically significant. The χ2-test was used to compare proportions.


  Results Top


Demographic data

In terms of demographic data, there were no significant changes for both sex and age between groups D and E [Figure 1] and [Table 1].
Figure 1: Pain assessment in group D.

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Table 1: Demographic data

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Clinical assessment

In terms of clinical assessments, there were no significant changes in the dermatome affection, average pain value, and presence of skin rash between groups D and E [Table 2].
Table 2: Clinical assessment

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Pain assessment

In terms of pain assessment in group D, there were significant changes in the analgesic effect on the fourth, seventh, 10th, 13th, and 16th days, the first, the third, and the sixth month compared with the first day [Figure 1].

In terms of pain assessment in group E, there were insignificant changes in the analgesic effect on the fourth and seventh days compare with the first day. However, there was a significant change in the analgesic effect on the 10th, 13th, 16th days, the first, the third, and the sixth month compared with the first day [Figure 2].
Figure 2: Pain assessment in group E.

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Postherpatic neuralgia

A significant change was detected between groups D and E [Table 3].
Table 3: Incidence of postherpetic neuralgia

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Allodynea

In terms of allodynea, significant changes were detected [Table 4].
Table 4: Incidence of allodynea

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  Discussion Top


Patients with HZ describe several different types of pain, including continuous burning or throbbing pain, intermittent sharp or electric shock-like pain, and allodynia [3]. Early diagnosis and treatment with antiviral agents plus intervention treatments are believed to shorten the duration and severity of acute HZ and reduce the risk of PHN [1]. PHN is often resistant to current analgesic treatments such as antidepressants, anticonvulsants, opioids, and topical agents including lidocaine patches and capsaicin cream and can persist for several years [2].

Watson [11], and Yawn and Gilden [12], reported that the incidence of PHN in patients older than 70 years of age ranges between 30 and 50%, requiring optimal treatment during the acute phase of the disease. PHN still persists in more than 2% of patients with HZ after 5 years; this can be attributed to the decline in cell-mediated immunity that results in viral replication and distal spread in the corresponding dermatome. Our study agree with this incidence as common age was (62.4 years), but we founded that between 2.5–5% of HZ case occurred in younger age (12.5 years) and all these children’s were in stress in relation to their age [11],[12].

Kay R [13], Desmond et al. [14], and Jung et al. [9] suggested a specific definition of PHN as pain persisting for at least 120 days after rash onset and this may be considered a validated definition of PHN for research purposes.

In addition, Jung et al. [9] reported that old age and greater presence of rash are risk factors for prediction of the severity of pain and progression to PHN; our study is in agreement with their result in terms of age as our study included 2.5–5% young patients who experienced low-intensity pain (4±1.5 on VAS) and there was no progression to PHN. However, in contrast to the result reported by Jung et al. [9], patients who had HZ without the appearance of skin rash (2.5–5%) experienced higher levels of pain (8±1.5 on VAS) and all patients showed progression to PHN [9].

Our study found that allodynea and PHN occurred in group D (57.5–40%) compared with group E (22.5–20%); this result may indicate that the use of epidural methylprednisolone decreases the incidence of both allodynea and PHN, and these results are in agreement with those of Van Wijck et al. [10], who carried out a randomized study on the effectiveness of a single epidural injection of steroids and local anesthetics for prevention of PHN in old patients with HZ and randomly assigned 598 patients older than 50 years, with acute HZ (rash<7 days) below dermatome C6, to receive either standard therapy (oral antivirals and analgesics) or standard therapy with one additional epidural injection of 80 mg methylprednisolone acetate and 10 mg bupivacaine. The primary endpoint was the proportion of patients with zoster-associated pain 1 month after inclusion. Analyses were carried out on an intention-to-treat basis At 1 month, 137 (48%) patients in the epidural group reported pain compared with 164 (58%) in the control group. After 3 months, these values were 58 (21%) and 63 (24%), respectively (P=0.47), and, at 6 months, these values were 39 (15%) and 44. No patient developed major adverse events related to an epidural injection. A single epidural injection of steroids and local anesthetics in the acute phase of HZ has a modest effect in reducing zoster-associated pain for 1 month. This treatment is not effective for the prevention of long-term PHN [15].

Furthermore, Kotani et al. [15] and Dworkin et al. [16] reported excellent pain relief with administration of methylprednisolone intrathecally in four patients.

In contrast, McGrath et al. [17] reported an increase in pain a few days after the administration of methylprednisolone intrathecally. The observations here indicate that intrathecal methylprednisolone has a proinflammatory action, but there are reports on an increase in pain in the days after epidural administration of methylprednisolone. In a review of the complications after epidural steroid administration, an increase in pain was the most common complication [17].

Opstelten et al. [18] reported that a single epidural injection of steroids and local anesthetics in the acute phase of HZ resulted in a modest decrease in zoster-associated pain in the first month, but did not prevent long-term PHN.

Rivera and Arcila [19] reported that the use of epidural infusions in patients with HZ is a treatment option for acute pain; it promotes passive motion of the affected limb preventing atrophy and prevents PHN, with a low incidence of complications.

Ding et al. [20] found that IL-8 is a proinflammatory cytokine that can attract neutrophils as mediators of acute inflammation. Steroids may, under certain proinflammatory conditions, enhance the release of chemoattractants such as IL-8. The cerebrospinal fluid levels of monocyte chemoattractant protein-1, a lymphocyte, and inflammatory chemokine associated with persistent inflammatory states decreased in patients treated with methylprednisolone. This finding is in line with the immunosuppressive effects attributed to steroids. The finding that monocyte chemoattractant protein-1 levels decreased in patients treated and IL-8 levels increased with MPA may be attributed to differences in the cellular source of these two proinflammatory mediators [20].

Lima et al. [21] have been hypothesized that intrathecal administration of steroids in PHN patients could lead to the reactivation of the VZV or that PHN is associated with persistent viral activity. However, in the present study, no viral reactivation was observed after treatment with methylprednisolone, thus not providing an explanation for the observed increase in pain.

Rijsdijk et al. [22] reported no beneficial effect of intrathecal methylprednisolone acetate in PHN patients. The pathophysiology of PHN is poorly understood. However, it is clear that HZ affects the central and peripheral nervous systems, which can subsequently lead to the occurrence of PHN. Two main processes play roles in the development of PHN: sensitization and differentiation. After resolution of the primary infection of VZV, replication of latent VZV in the sensory ganglia leads to inflammatory neural damage, resulting in acute zoster pain and PHN. Sometimes, motor paresis may occur because of the spread of infection and inflammation from the dorsal horn to the anterior horn [23].

Previous research found increases in the subtype of voltage-gated sodium channels, alteration of voltage-gated potassium channels, and increases in transient receptor potential vanilloid 1 in animal studies of a neuropathic pain mode [24].

In addition, the loss of γ-aminobutyric acid inhibitory neurons in the DRG after nerve injury causes loss of descending inhibition, leading to excessive reaction of nociceptive neurons of the spinal DRG [24].

The inflammatory mediators released from injured tissue, including substance P, bradykinin, histamine, cytokines, and ions (K+, H+), activate peripheral nociceptors directly by lowering the threshold of nociceptors, leading to peripheral sensitization. These changes also increase the ectopic discharge rate of C-fiber nociceptors. Thus, repetitive discharge of C-fibers can lead to a prolonged response of neurons in the DRG, which contributes toward central sensitization. Therefore, sensitization of the peripheral and/or the central nervous systems produces spontaneous pain, allodynia, and hyperalgesia [25].

The allodynia and sensory loss in the affected dermatomes are associated with deafferentation, which results in dorsal horn reorganization [24]. The decreased number of C-fibers of the peripheral nerves, in combination with deafferentation, induces sprouting of Aβ-fibers, which normally transmit innocuous touch and pressure. Aβ-fiber rewiring in the DRG, which is linked to with the pain-transmitting spinothalamic tracts, produces dynamic and tactile allodynia [25].


  Conclusion Top


Use of epidural steroids decreases the incidence of PHN in patients with acute herpes despite an inadequate analgesic effect during an acute attack.

Recommendation

This study recommends further research study on the use of different epidural regimens (different doses and addition of an adjuvant) in the management of acute herpetic lesions to determine the best regimen that can decrease the incidence of PHN.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflict of interest.

 
  References Top

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Dworkin RH, Johnson RW, Breuer J, Gnann JW, Levin MJ, Backonja M et al. Recommendations for the management of herpes zoster. Clin Infect Dis 2007; 44(Suppl 1):S1–26.  Back to cited text no. 1
    
2.
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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