The use of narrow band ultraviolet light B in the prevention and treatment of postherpetic neuralgia (a pilot study).

BACKGROUND: Postherpetic neuralgia (PHN) is a common complication of herpes zoster that is frequently unresponsive to most of the available treatment modalities. Broad band ultraviolet B radiation (UVB) has a well-known anti-inflammatory effect. Moreover, it decreases neural damage and cutaneous nerve density. It was found that broad band UVB might have a role in the prevention and treatment of PHN. AIM: This study was carried out to evaluate the effect ofnarrow band UVB (nbUVB) in the treatment PHN. PATIENTS AND METHODS: The study included 17 patients with distressing post herpetic neuralgia. Patients were evaluated using the Verbal Rating Scale (VRS). The patients received nbUVB sessions, three times a week, for a total of 15 sessions or until the pain disappeared. Patients were followed up for a period of 3 months after the end of therapy.
RESULTS: Using intention to treat analysis, more than 50% improvement was achieved in 6 (35.29%) and 8 (47.06%) patients, at the end of therapy and after 3 months follow up, respectively. An improvement less that 50% was achieved in 11 (64.71%) and 9 (52.94%) patients, at the end of therapy and after 3 months follow up, respectively. The pain severity assessed by the VRS significantly improved both at the end of sessions (P = 0.005) and after 3 months follow up (P = 0.005).
CONCLUSION: nbUVB may be of beneficial use in the treatment of PHN. LIMITATION: Small number of patients and limited follow-up period.

Introduction

Postherpetic neuralgia (PHN) is a common complication of herpes zoster (HZ). It is considered to be a chronic neuropathic pain that involves aberrant somatosensory processing in the peripheral and/or central nervous system. Although the exact pathogenesis is unknown, several mechanisms are proposed such as generation of spontaneous action potentials in the afferent peripheral neurons, degeneration of the peripheral neurons with resultant hyperexcitability of spinal cord neurons, deafferentiation pain resulting from sensory deficits due to the destruction of dorsal root ganglion cells, necrosis and possible fibrosis.[1] Central to all of the above-mentioned processes is the neural damage, which is in most part immunologically mediated.[2]

Pain in HZ evolves in three phases: acute, subacute, and chronic.[3] The acute phase occurs with the onset of the herpetic rash and lasts for less than 30 days, the subacute phase lasts for 1–3 months after the onset of the rash, and the chronic phase, or PHN, lasts for 3 months or longer after the onset of the rash.[45] PHN can also be defined as the pain lasting for more than 1 month after healing of the rash.[6]

PHN was found to be frequently unresponsive to most of available treatment modalities. Although several drugs such as antidepressants, anticonvulsants, oral steroids, local anesthetics, topical capsaicin, clonidine, gabapentin, and opioids may demonstrate successful pain relief,[7] the pharmacologic management of neuropathic pain is difficult. Transcutaneous Electrical Nerve Stimulation (TENS) may be effective in some cases. No treatment has been shown to prevent PHN completely, but some treatments (especially in combinations) may shorten the duration or lessen the severity of symptoms.[7] A live attenuated varicella zoster virus (VZV) vaccine has proven to be efficacious in reducing the incidence of and morbidity associated with HZ and PHN in older adults.[8]

Ultraviolet B (UVB) phototherapy (broad band UVB) was used in a previous study done by Jalali et al. in 2008 for the treatment of PHN with promising results.[9]

This study was carried out to evaluate the effect ofnarrow band UVB (nbUVB) in the treatment PHN.

Patients and Methods

Patients

This pilot prospective study included 17 patients, who had intractable pain related to HZ. Patients were recruited from the outpatient clinic of Dermatology Department, Kasr El-Aini Hospital, Cairo University. The patients included nine females and eight males, ranging in age from 23 to 73 years. Patients having disseminated zoster or malignancy were excluded from the trial.

Each patient was graded with regard to his/her pain severity using a 4-point Verbal Rating Scale (VRS): 0 (no pain), 1 (mild pain that does not interfere with daily activities), 2 (moderate pain that interferes with daily activities but does not cause sleeplessness), 3 (severe pain that causes sleeplessness), or 4 (very severe unbearable pain that is extremely incapacitating).[9] VRS was performed for each patient before starting the trial, at the end of the trial, and 3 months after the end of the trial.

Consent was obtained from all the patients and the study was approved by the ethical committee of Dermatology Department, Faculty of Medicine, Cairo University.

Methods

The patients received nbUVB (narrow band UVB-311) sessions (three sessions per week) at the phototherapy unit of Dermatology Department, Kasr El-Aini Hospital, Faculty of Medicine, Cairo University.

Phototherapy technique: nbUVB sessions were delivered in whole body cabins. Patients were instructed to expose the involved body part while the rest of the body was covered using clothing. The apparatus used was Waldmann (UV 100L). The starting dose was 0.21 J/cm 2 and the dose was increased by one increment every session (as long as there is no adverse effect reported such as persistent erythema, burn, itching).

Duration of the study: Patients received sessions until the pain was cured or for a maximum of 15 sessions.

Patients who had active HZ were given acyclovir in a dose of 800 mg for five times a day for 7 days. Analgesics were given for all the patients to control the pain.

Classification of the patients: Pain was classified into acute neuralgia, subacute neuralgia, and established PHN. Acute herpetic neuralgia was defined as neuralgia that accompanied the rash and lasted for less than 30 days. Subacute herpetic neuralgia was defined as neuralgia that lasted for 30-120 days and established PHN was defined as neuralgia that persisted for at least 120 days after the onset of the rash.

Assessment: Patients were subjectively evaluated regarding their pain and degree of improvement, once weekly. VRS was scored before starting the treatment and at the end of the therapeutic period. VRS was also used to evaluate the patients at the end of the 3 months follow-up period.

Grading of clinical response: Improvement on the VRS with 1 degree was scored as 25% improvement (mild improvement), 2 grades of improvement were scored as 50% improvement (moderate improvement), 3 grades of improvement were scored as 75% improvement (marked improvement) and 4 grades of improvement were considered as 100% improvement (cure). No change in the VRS was considered as 0% improvement (no improvement).

Data management and statistical analysis

Data were coded and entered using the statistical package SPSS version 17. Data were analyzed using mean ± SD for quantitative variables and % for qualitative variables. Comparisons between groups were done using non-parametric test (Wilcoxon Signed Ranks). Correlation was done to test linear relation between quantitative variables. P value ≤0.05 was considered statistically significant.

Results

Patients’ data

The patients included nine females and eight males ranging in age from 23 to 73 years with a mean of 52.06 ± 11.86. The patients included nine patients with acute herpetic neuralgia, six patients with subacute herpetic neuralgia, and two patients with established PHN. The duration of pain ranged from 2 to 150 days with a mean of 4.729 ± 5.038 days.

Regarding the site of pain, two patients had cervical dermatome involvement, four patients had thoracic dermatome involvement, eight patients had lumber dermatome involvement, and three patients had upper limb involvement (the right upper limb was involved in two of them and the left upper limb was involved in one of them; one had thoracic involvement in addition).

Different types of pain were detected in our patients. Continuous burning pain was found in seven patients, continuous stabbing pain in three patients, intermittent stabbing pain in five patients, and intermittent burning pain in two patients.

Out of the 17 patients enrolled in the study, 12 completed the designed sessions. Five patients dropped out at sessions 2, 4, 7, 10, and 12 due to lack of satisfactory improvement. Out of the 12 patients who completed the designed sessions, 10 completed 15 sessions and 2 were discharged after 9 sessions due to complete disappearance of pain.

Results of verbal rating scale

Table 1 illustrates the VRS of the patients before starting treatment, at the end of the treatment period and at the end of the 3 months follow-up period. The mean VRS before treatment, at the end of sessions and after 3 months follow up are presented in Table 2. The comparison between the mean VRS at the baseline and at the end of the sessions revealed statistically significant decrease in the VRS (P = 0.005). Also, comparison of the VRS at the baseline and after the follow-up period showed statistically significant decrease in the VRS (P = 0.005). Comparison between the VRS at the end of sessions and after the follow-up period revealed statistically significant decrease in the VRS (P = 0.039).

Table 1

Baseline VRS, VRS at the end of the treatment period and at the end of the 3 months follow-up period

Table 2

Comparison between VRS of the patients before starting sessions, after the end of sessions and after 3 months follow up

Table 3 presents the percentage of patients having achieved different degrees of clinical improvement using intention to treat analysis. Ten patients (58.82%) showed variable grades of improvement both at the end of the treatment sessions and at the end of the 3 months follow up. An improvement less than 50% was achieved in 11 patients (64.71%) and 9 patients (52.94%) at the end of sessions and 3 months later, respectively. An improvement of more than 50 % was achieved in 6 patients (35.29%) and 8 patients (47.06%) at the end of sessions and 3 months later, respectively. Total cure was achieved in two patients (11.67%) at the end of sessions and in 4 patients (23.53%) after 3 months follow up.

Table 3

Percentage of patients showing variable degrees of improvement at the end of the treatment period and at the end of the 3 months follow-up period

No significant correlation existed between the age of the patients and the duration of pain (P = 0.66). There was no significant correlation between the degree of improvement (either at the end of sessions or after the follow-up period) and the age of the patients (P = 0.338 and 0.959, respectively).

Incidence of adverse effects

No adverse side effects of nbUVB were detected in any patient throughout the sessions.

Discussion

The most common, distressing, and intractable complication of HZ is PHN. It can cause insomnia, fatigue, depression, and interference with daily activities in affected individuals. More than 5% of elderly patients have PHN at 1 year after acute HZ. Predictors of PHN are greater age, acute pain and rash severity, prodromal pain, the presence of virus in peripheral blood, as well as adverse psychosocial factors.[7]

The inflammatory response plays a major role in the pathogenesis of acute zoster pain and PHN. Reactivation of the latent VZV within sensory ganglia results in HZ.[9] The presence of the virus in the skin and nerves causes recruitment and activation of immunocytes. Their paracrine secretions, including complement, prostaglandins (PG), interferons (INF), histamine, bradykinin, cytokines, endogenous opiates, and tumor necrosis factor (TNF)-α, influence the nociceptive properties of neurons and might mediate the sensation of pain.[10]

UVB may affect the course of PHN through its suppressing effect on the inflammatory response in the acute zoster attack, thus decreasing the neuronal damage contributing to PHN. Also, it might directly influence the cutaneous nerve endings. Narrow band UVB-311 is better than broad band UVB as it is more selective, has much lower doses, and greater effects.[11] So, based on this hypothesis, we used nbUVB therapy aiming to enhance the improvement of PHN.

One of the probable targets of UVB in reducing zoster associated pain is the Langerhans's cell (LC) network. Previous studies have shown important interactions between LCs and cutaneous neuritis. Several molecules that can sensitize cutaneous nociceptors are released by LCs.[12] In addition to this direct neuron-sensitizing effect, LCs play a pivotal role in immune response. So, they might well be involved in the inflammatory response to VZV. Although a recent study failed to show evidence for activation of LCs in subjects with PHN,[13] the study was performed on patients with long-standing established PHN and cannot rule out the likely role of LCs in acute herpetic neuralgia and recent-onset PHN. UVB radiation suppresses antigen presentation of LCs in different ways. It stimulates keratinocytes and mast cells to secrete immunosuppressive cytokines such as IL-10, TNF-α, IL-4, PG-E2, α-MSH or CGRP, which inhibit the antigen-presenting function of LCs.[14] Furthermore, it causes depletion of the LCs in the epidermis,[15] which may also explain the improvement induced by UVB in PHN.

In addition to suppression of LCs, UVB modifies the T-cell response to persistent VZV particles in nerve fibers, which might be involved in the pathogenesis of PHN.[16] The inflammatory response of the body to VZV is predominantly of Th-1 type with the release of IFN-γ and IL-2,[17] whereas UVB induces a shift from a Th-1 immune response to a Th-2 response in different ways.

In addition, there is a direct effect of UV radiation on the nerve endings in the superficial dermis and epidermis. Electron microscopic findings revealed reduced epidermal nerve fibers in chronically photodamaged skin areas as compared with sun-protected skin.[18] Both UVB and psoralen plus UVA (PUVA) can reduce the cutaneous nerve density in a dose-dependent manner.[19] So, using UV might be relevant in cases of postherpetic neuralgia by decreasing the nerve fibers.

As far as our knowledge goes, this is the first study to use nbUVB in the management of PHN. Ten patients (58.82%) (out of the 12 who completed the study) reported various degrees of improvement. The pain severity (assessed by the mean VRS) of the patients with acute pain showed marked improvement (3.75, 2.5, and 1.63 at the start of therapy, at the end of sessions, and at the follow up, respectively). The severity of pain in the patients with subacute pain showed less improvement (3.67, 3, and 2.67 at the start of therapy, at the end of sessions, and at the follow up, respectively). The patient who had established PHN showed no improvement. It appears that nbUVB has a weak effect on the established PHN and a probable better effect on the early PHN. The pain severity assessed by VRS was significantly improved both at the end of sessions and after the follow up period.

Our findings are supported by the results of the only study that used broad band UVB in the management of PHN. The authors reported 58.33 and 83.33% complete pain relief at 1 month and 3 months follow up, respectively.

In conclusion, nbUVB may provide a potential tool in the management of PHN. The limitations of our study were smaller number of patients and limited period of follow-up. Further studies on larger number of patients and longer follow-up are needed to further validate our findings.