Exploring viral neuropathic pain: Molecular mechanisms and therapeutic implications.

As the Coronavirus Disease 2019 (COVID-19) pandemic continues, there is a growing concern regarding the relationship between viral infections and neuropathic pain. Chronic neuropathic pain resulting from virus-induced neural dysfunction has emerged as a significant issue currently faced. However, the molecular mechanisms underlying this phenomenon remain unclear, and clinical treatment outcomes are often suboptimal. Therefore, delving into the relationship between viral infections and neuropathic pain, exploring the pathophysiological characteristics and molecular mechanisms of different viral pain models, can contribute to the discovery of potential therapeutic targets and methods, thereby enhancing pain relief and improving the quality of life for patients. This review focuses on HIV-related neuropathic pain (HNP), postherpetic neuralgia (PHN), and neuropathic pain caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections, examining rodent models and relevant cellular molecular pathways. Through elucidating the connection between viral infections and neuropathic pain, it aims to delineate the current limitations and challenges faced by treatments, thereby providing insights and directions for future clinical practice and research.

Herpes zoster: A Review of Clinical Manifestations and Management.

The Varicella-zoster virus (VZV) or human herpes virus 3 is a neurotropic human alpha herpes virus responsible for chickenpox/varicella and shingles/Herpes zoster (HZ). This review will focus on HZ. Since HZ is secondary to varicella, its incidence increases with age. In children and youngsters, HZ is rare and associated to metabolic and neoplastic disorders. In adults, advanced age, distress, other infections (such as AIDS or COVID-19), and immunosuppression are the most common risk factors. HZ reactivation has recently been observed after COVID-19 vaccination. The disease shows different clinical stages of variable clinical manifestations. Some of the manifestations bear a higher risk of complications. Among the possible complications, postherpetic neuralgia, a chronic pain disease, is one of the most frequent. HZ vasculitis is associated with morbidity and mortality. Renal and gastrointestinal complications have been reported. The cornerstone of treatment is early intervention with acyclovir or brivudine. Second-line treatments are available. Pain management is essential. For (secondary) prophylaxis, currently two HZV vaccines are available for healthy older adults, a live attenuated VZV vaccine and a recombinant adjuvanted VZV glycoprotein E subunit vaccine. The latter allows vaccination also in severely immunosuppressed patients. This review focuses on manifestations of HZ and its management. Although several articles have been published on HZ, the literature continues to evolve, especially in regard to patients with comorbidities and immunocompromised patients. VZV reactivation has also emerged as an important point of discussion during the COVID-19 pandemic, especially after vaccination. The objective of this review is to discuss current updates related to clinical presentations, complications, and management of HZ.

Varicella-zoster virus early infection but not complete replication is required for the induction of chronic hypersensitivity in rat models of postherpetic neuralgia.

Herpes zoster, the result of varicella-zoster virus (VZV) reactivation, is frequently complicated by difficult-to-treat chronic pain states termed postherpetic neuralgia (PHN). While there are no animal models of VZV-induced pain following viral reactivation, subcutaneous VZV inoculation of the rat causes long-term nocifensive behaviors indicative of mechanical and thermal hypersensitivity. Previous studies using UV-inactivated VZV in the rat model suggest viral gene expression is required for the development of pain behaviors. However, it remains unclear if complete infection processes are needed for VZV to induce hypersensitivity in this host. To further assess how gene expression and replication contribute, we developed and characterized three replication-conditional VZV using a protein degron system to achieve drug-dependent stability of essential viral proteins. Each virus was then assessed for induction of hypersensitivity in rats under replication permissive and nonpermissive conditions. VZV with a degron fused to ORF9p, a late structural protein that is required for virion assembly, induced nocifensive behaviors under both replication permissive and nonpermissive conditions, indicating that complete VZV replication is dispensable for the induction of hypersensitivity. This conclusion was confirmed by showing that a genetic deletion recombinant VZV lacking DNA packaging protein ORF54p still induced prolonged hypersensitivities in the rat. In contrast, VZV with a degron fused to the essential IE4 or IE63 proteins, which are involved in early gene regulation of expression, induced nocifensive behaviors only under replication permissive conditions, indicating importance of early gene expression events for induction of hypersensitivity. These data establish that while early viral gene expression is required for the development of nocifensive behaviors in the rat, complete replication is dispensable. We postulate this model reflects events leading to clinical PHN, in which a population of ganglionic neurons become abortively infected with VZV during reactivation and survive, but host signaling becomes altered in order to transmit ongoing pain.

P2X7 receptor antagonist BBG inhibits endoplasmic reticulum stress and pyroptosis to alleviate postherpetic neuralgia.

Postherpetic neuralgia (PHN) is the most common complication of acute herpes zoster. The treatment of PHN remains a challenge for clinical pain management. The present study investigated the P2X7 receptor antagonist brilliant blue G (BBG) whether inhibits endoplasmic reticulum stress and pyroptosis (a necrotic form of cell death) and alleviates PHN. Varicella zoster virus (VZV)-infected CV-1 cells were used to induce PHN model. Mechanical paw withdrawal thresholds were measured using an ascending series of von Frey filaments. Immunohistochemistry was used to detect the expression of P2X7R in nerve tissues. Western blot was used to determine the expression of endoplasmic reticulum (ER) stress and pyroptosis-related molecules. The expression of IL-1ß and IL-18 in tissue homogenate was detected by ELISA. The PHN rat has the lower paw withdrawal threshold, but higher expression of P2X7 in nerve tissues. And, endoplasmic reticulum stress was activated and pyroptosis was increased in PHN rats. BBG can decrease pain thresholds and reduce ER stress and pyroptosis in PHN rats. In addition, ER stress activator tunicamycin (TM) can reverse the effect of BBG on the paw withdrawal thresholds, endoplasmic reticulum stress, and pyroptosis. Therefore, P2X7 receptor antagonist BBG alleviates PHN by activating ER stress and reducing pyroptosis.

Outpatient healthcare utilization and prescribing patterns for herpes zoster in United States adults.

Little is known about health resource utilization and treatment patterns for herpes zoster (HZV) after the introduction of HZV virus vaccination. The objective of this study is to characterize trends in HZV utilization, racial disparities, and treatment patterns in the United States. Data from the 1993-2015 National Ambulatory Medical Care Survey were analyzed, including 15,400,000 weighted primary acute HZV visits in adults. Overall, the weighted frequency (95% confidence interval) of HZV visits increased from 1993-1998 to 2007-2015 (1,269,815 [565,455-1,974,175]-8,017,911 [6,424,491-9,611,331], P = 0.0001). HZV visits were associated with African-American (38.8% [35.8-41.7%] vs. 8.2% [7.4-9.0%]) and Hispanic race/ethnicity (12.6% [6.6-18.5%] vs. 8.0% [7.3-8.5%]), public insurance (42.7% [36.6-49.2%] vs. 33.7% [32.2-35.2%]) in comparison with all other visits. Oral antiviral agents were prescribed in 64.3% (58.1-70.1%) of HZV visits. HZV visits were associated with higher rates of opioid prescriptions compared to all other visits (18.4% [14.0-23.9%] vs. 6.1% [5.6-6.6%], P < 0.0001). The limitation is no data on HZV severity. HZV visits increased over time, even after introduction of HZV vaccines. There were significant racial/ethnic and healthcare disparities of, and high rates of opiate and corticosteroid prescriptions at HZV visits. Future efforts are needed to address these practice gaps, and encourage vaccination and evidence-based prescribing in HZV.

Inhibitory effect of amenamevir on acute herpetic pain and postherpetic neuralgia in mice infected with herpes simplex virus-1.

BACKGROUND: Amenamevir (AMNV) is a helicase-primase inhibitor with antiviral activity against herpesviruses [herpes simplex viruses (HSV)-1 and -2, and varicella-zoster virus], which are associated with the development of acute herpetic pain (AHP) and postherpetic neuralgia. However, the inhibitory effects of helicase-primase inhibitors on AHP and postherpetic neuralgia remain incompletely understood. OBJECTIVE: In this study, we investigated the effects of AMNV on AHP and postherpetic pain (PHP) in HSV-1-infected mice accompanied by zosteriform-like skin lesions. METHODS: HSV-1 was percutaneously infected on the femoral region of mice. AMNV was orally administered twice a day for 5 days. Pain-related response in the hind paw was evaluated using a paintbrush. The infiltration of inflammatory cells in dorsal root ganglion (DRG) and spinal cord (SC) was evaluated by hematoxylin and eosin staining. The viral load in DRG and the expression of pain-related genes in SC were measured by real-time PCR. RESULTS: Pain response was begun to be observed from day 3 post-infection (pi) in HSV-1-infected mice. AMNV administered repeatedly from day 3 pi or day 4 pi, but not day 5 pi, showed an inhibitory effect on the development of AHP and the transition to PHP. Repeated AMNV administration inhibited inflammatory cell infiltration and increases in the viral load and the expression of pain-related genes (ATF-3, TNF-α, COX-2). CONCLUSION: These results demonstrate that AMNV potently suppresses the development of AHP and the transition to PHP as a consequence of decreased viral load in DRG and reduced expression of pain-related genes in SC.

Efficacy of extracorporeal shockwave therapy in the treatment of postherpetic neuralgia: A pilot study.

Established conventional treatments for postherpetic neuralgia (PHN) and postherpetic itch (PHI) are difficult and often disappointing. In this study, the authors investigated the effect and mechanisms of extracorporeal shockwave therapy (ESWT) on pain and itch associated with PHN and PHI.Thirteen patients, 50 to 80 years of age, with symptoms associated with PHN or PHI (duration of persistent pain >3 months) and complaints of pain or itch rated >4 on a numerical rating scale (NRS), were included. ESWT was administered using a shockwave device (Piezo Shockwave, Richard Wolf GmbH, Knittlingen, Germany) to skin areas affected by pain or itch. An energy flux density of 0.09 to 0.16 mJ/mm at a frequency of 5 Hz and 2000 impulses was administered at 3-day intervals for 6 sessions. The NRS, 5D-Itch Scale, and Patients Global Impression of Change (PGIC) scale were used to evaluate the efficacy of ESWT.NRS scores of pain and itch and 5D-Itch Scale scores decreased significantly compared with before treatment and at the end of the treatment sessions (P < .0001, P = .001, P = .0002, respectively). There was a statistically significant difference between PGIC scores, which were checked every 2 sessions (P < .0001).ESWT is a noninvasive modality that significantly reduced PHN-associated pain and itch.

Hypovitaminosis Din Postherpetic Neuralgia-High Prevalence and Inverse Association with Pain: A Retrospective Study.

Hypovitaminosis D (25-hydroxyvitamin D (25(OH)D) <75 nmol/L) is associated with neuropathic pain and varicella-zoster virus (VZV) immunity. A two-part retrospective hospital-based study was conducted. Part I (a case-control study): To investigate the prevalence and risk of hypovitaminosis D in postherpetic neuralgia (PHN) patients compared to those in gender/index-month/age-auto matched controls who underwent health examinations. Patients aged ≥50 years were automatically selected by ICD-9 codes for shingle/PHN. Charts were reviewed. Part II (a cross-sectional study): To determine associations between 25(OH)D, VZV IgG/M, pain and items in the DN4 questionnaire at the first pain clinic visit of patients. Independent predictors of PHN were presented as adjusted odds ratios(AOR) and 95% confidence intervals (CI). Prevalence (73.9%) of hypovitaminosis D in 88 patients was high. In conditional logistic regressions, independent predictors for PHN were hypovitaminosis D (AOR3.12, 95% CI1.73-5.61), malignancy (AOR3.21, 95% CI 1.38-7.48) and Helicobacter pylori-related peptic ulcer disease (AOR3.47, 95% CI 1.71-7.03). 25(OH)D was inversely correlated to spontaneous/brush-evoked pain. Spontaneous pain was positively correlated to VZV IgM. Based on the receiver operator characteristic curve, cutoffs for 25(OH)D to predict spontaneous and brush-evoked pain were 67.0 and 169.0 nmol/L, respectively. A prospective, longitudinal study is needed to elucidate the findings.

Patient characteristics and analgesic efficacy of antiviral therapy in postherpetic neuralgia.

Postherpetic neuralgia (PHN) is the most common complication of shingles caused by reactivation of varicella zoster virus (VZV). Management of PHN is often suboptimal while using current conventional treatments. Antiviral therapy was used to reduce PHN-associated pain in two small trials which showed conflicting results. We hypothesize the analgesic efficacy of antiviral therapy on PHN is affected by patient characteristics including pathophysiology of the participants and serum vitamin D levels. Pathophysiology of PHN includes neuronal excitability and chronic VZV ganglionitis (persistent active VZV infection in ganglions). VZV-DNA positivity or a positive IgG coupled with a positive IgM indicates recent or current VZV infection. Positive VZV-DNA or IgG/IgM tests are used to confirm whether the patients experience chronic VZV ganglionitis. Antiviral therapy decreases pain in PHN patients with chronic VZV ganglionitis; whereas, antiviral therapy shows no effects in PHN patients with negative VZV-DNA or IgM. Vitamin D is a natural antiviral mediator. Studies show a high prevalence of vitamin D deficiency in hepatitis B/C virus-infected patients. Serum vitamin D levels and vitamin D supplementation are factors which affect the antiviral efficacy on hepatitis B/C virus infection. Serum 25-OHD levels of hospitalized patients with shingles were significantly lower compared to healthy controls. Accordingly, PHN patient may have a high prevalence of vitamin D deficiency which negatively affects the antiviral efficacy. Vitamin D supplementation may improve the antiviral efficacy on PHN. Future trials regarding antiviral therapy on PHN should consider patient characteristics and should be conducted among different subgroups of PHN patients.

Relationships of varicella zoster virus (VZV)-specific cell-mediated immunity and persistence of VZV DNA in saliva and the development of postherpetic neuralgia in patients with herpes zoster.

There are no surrogate markers for the development of postherpetic neuralgia (PHN) in patients with herpes zoster (HZ). All patients with HZ were prospectively enrolled to evaluate the associations of saliva varicella zoster virus (VZV) DNA persistence and VZV-specific cell-mediated immunity (CMI) with the development of PHN. Slow clearers were defined if salivary VZV DNA persisted after day 15. Salivary VZV was detected in 60 (85.7%) of a total of 70 patients with HZ on initial presentation. Of 38 patients for whom follow-up saliva samples were available, 26 (68.4%) were classified as rapid clearers and 12 (31.6%) as slow cleares. Initial VZV-specific CMI was lower in slow clearers than rapid clearers (median 45 vs 158 spot forming cells/10 6 cells, P = .02). Of the 70 patients with HZ, 22 (31.4%) eventually developed PHN. Multivariate analysis showed that slow clearers (OR, 15.7, P = .01) and lower initial VZV-specific CMI (OR, 13.8, P = .04) were independent predictors of the development of PHN, after adjustment for age and immunocompromised status. Initial low VZV CMI response and persistence of VZV DNA in saliva may be associated with the development of PHN.

Herpes zoster incidence in Germany - an indirect validation study for self-reported disease data from pretest studies of the population-based German National Cohort.

BACKGROUND: Until now, herpes zoster (HZ)-related disease burden in Germany has been estimated based on health insurance data and clinical findings. However, the validity of self-reported HZ is unclear. This study investigated the validity of self-reported herpes zoster (HZ) and its complication postherpetic neuralgia (PHN) using data from the pretest studies of the German National Cohort (GNC) in comparison with estimates based on health insurance data. METHODS: Data of 4751 participants aged between 20 and 69 years from two pretest studies of the GNC carried out in 2011 and 2012 were used. Based on self-reports of physician-diagnosed HZ and PHN, age- and sex-specific HZ incidence rates and PHN proportions were estimated. For comparison, estimates based on statutory health insurance data from the German population were considered. RESULTS: Eleven percent (95%-CI, 10.4 to 12.3, n = 539) of the participants reported at least one HZ episode in their lifetime. Our estimated age-specific HZ incidence rates were lower than previous estimates based on statutory health insurance data. The PHN proportion in participants older than 50 years was 5.9% (1.9 to 13.9%), which was in line with estimates based on health insurance data. CONCLUSION: As age- and sex-specific patterns were comparable with that in health insurance data, self-reported diagnosis of HZ seems to be a valid instrument for overall disease trends. Possible reasons for observed differences in incidence rates are recall bias in self-reported data or overestimation in health insurance data.

Premedication With Gabapentin Significantly Reduces the Risk of Postherpetic Neuralgia in Patients With Neuropathy.

Postherpetic neuralgia (PHN) is the most common complication of varicella zoster virus (VZV) reactivation and a cause of considerable physical and psychosocial morbidity. No known treatment effectively prevents the development of PHN in patients with VZV reactivation. In this study, our objective was to evaluate the efficacy of premedication with gabapentin for reducing the risk of PHN in patients with diabetic and nondiabetic neuropathy. We retrospectively searched the electronic health records of patients with diabetic and nondiabetic neuropathy treated with gabapentin at Mayo Clinic before diagnosis of VZV reactivation. In total, PHN developed in 7 patients with diabetic neuropathy receiving gabapentin (n=62 [11.3%]) compared with 26 not receiving premedication with gabapentin (n=50 [52.0%]) (odds ratio, 0.12; 95% CI, 0.05-0.31; P<.001); PHN developed in 11 patients with nondiabetic neuropathy receiving gabapentin (n=109 [10.1%]) compared with 108 not receiving premedication with gabapentin (n=217 [49.8%]) (odds ratio, 0.11; 95% CI, 0.06-0.22; P<.001). In this cohort of patients with neuropathy, gabapentin administration before the onset of VZV reactivation significantly reduced the risk of PHN.

What are the new vaccination recommendations for herpes zoster?

A new vaccine to prevent herpes zoster (shingles) has been included in the 2018 Advisory Committee on Immunization Practices' adult immunization schedule as the preferred herpes zoster vaccination for all immunocompetent adults age 50 years and older. This article discusses new vaccination recommendations for herpes zoster.

Effectiveness of continuous epidural analgesia on acute herpes zoster and postherpetic neuralgia: A retrospective study.

Despite early treatment of herpes zoster (HZ), postherpetic neuralgia (PHN) can persist. This study was designed to compare the therapeutic and pain relief effects of continuous epidural analgesia (CEA) on the chronic phase as well as the acute phase of HZ with standard medical treatment.Medical records of 227 patients with moderate to severe zoster-associated pain that had not responded to standard medications were retrospectively reviewed. Patients received standard treatment alone (medical group) or standard treatment plus concurrent CEA (epidural group). The acute and chronic groups were classified according to a 4-week cut-off with regard to time between the onset of the rash and the first treatment. Four groups were studied: Group A (acute/medical group); Group B (acute/epidural group); Group C (chronic/medical group); and Group D (chronic/epidural group). Pain was assessed using the visual analog scale (VAS) and measured every 2 weeks for 6 months. We compared the pain rating at 6 months after the first treatment with the initial pain rating. Response to treatment was defined as a ≥50% reduction in pain severity since the initial visit. Remission was considered complete for patients whose VAS pain score was ≤2 for >3 successive visits and who no longer needed medical support.Patients who received a combination of standard treatment plus CEA (Groups B and D) had significantly higher response to treatment (P = .001) than patients receiving standard treatment alone (Groups A and C). The adjusted odds ratio (OR) for response to treatment in the epidural group versus the medical group was 5.17 (95% confidence interval [CI]: 1.75-15.23) in the acute group and 5.37 (95% CI: 1.62-17.79) in the chronic groups. The adjusted OR for complete remission in the epidural group versus the medical group was 3.05 (95% CI: 1.20-7.73) in the acute group and 4.46 (95% CI: 1.20-16.54) in the chronic group.CEA can effectively relieve pain caused by PHN and acute HZ and increase remission rates. Combining CEA with standard medical treatment may offer a clinical advantage in the management of pain caused by PHN as well as acute HZ.

A Rare Presentation of Cranial Polyneuropathy Without Rash Caused by Varicella Zoster Virus.

INTRODUCTION: Varicella Zoster Virus (VZV) is associated with many disorders of the central and peripheral nervous systems including neuralgia, meningitis, meningoencephalitis, cerebellitis, vasculopathy, myelopathy, Ramsay-Hunt syndrome, and polyneuritis cranialis. Cranial nerves V, VI, VII, VIII, IX, X, XI, and/or XII may be affected. The neurological disorders caused by VZV usually present with rash, but may rarely present without rash. CASE REPORT: We herein present a case of polyneuritis cranialis without rash caused by VZV affecting cranial nerves VII, VIII, IX, and X. After excluding other causes of the condition, we diagnosed VZV infection based on VZV DNA in the CSF and an elevated anti-VZV IgG level in serum. The patient responded well to antiviral therapy. CONCLUSION: VZV infection should be kept in mind during the differential diagnosis of polyneuritis cranialis; it is important to note that VZV re-activation may occur without rash.

Assessment of the potential public health impact of Herpes Zoster vaccination in Germany.

The aim of this study was to compare the public health impact of introducing 2 Herpes Zoster (HZ) vaccines, Zoster Vaccine Live (ZVL) versus a non-live adjuvanted subunit candidate vaccine (HZ/su), in the German population aged 50+ years split into 3 age cohorts, i.e. 50-59, 60-69 and 70+ years, respectively. A multi-cohort static Markov model was developed following age cohorts over their lifetime. Demographic data were obtained from the German federal statistical office. HZ incidence and the proportion of HZ individuals developing post-herpetic neuralgia (PHN) were derived from German specific sources. Age-specific vaccine efficacy and waning rates were based on published clinical trial data. Vaccine coverage for both vaccines was assumed to be 40%, with compliance of the second dose of the HZ/su vaccine of 70%. Sensitivity analyses were performed to assess the robustness of the results. It was estimated that, over the remaining lifetime since vaccination, the HZ/su vaccine would reduce the number of HZ cases by 725,233, 533,162 and 486,794 in the 3 age cohorts, respectively, compared with 198,477, 196,000 and 104,640, using ZVL. The number needed to vaccinate (NNV) to prevent one HZ case ranged from 8 to 11 using the HZ/su vaccine compared with 20 to 50 using ZVL. Corresponding NNV to prevent one PHN case ranged from 39 to 53 using the HZ/su vaccine compared with 94 to 198 using ZVL. Due to the higher, sustained vaccine efficacy, the candidate HZ/su vaccine demonstrated superior public health impact compared with ZVL.

Lateral thalamic control of nociceptive response after whisker pad injection of varicella zoster virus.

Pain is a common complication of herpes zoster (HZ) infection which results from reactivation of a latent varicella zoster virus (VZV). A third of HZ patients' progress to a chronic pain state known as post herpetic neuralgia (PHN), and about a quarter of these patients' have orofacial pain. The mechanisms controlling the pain responses are not understood. Studies suggest central pathways involving the thalamus could control pain related to HZ, and studies in our lab suggest (VGAT) in the lateral thalamus influences orofacial pain. We hypothesized that thalamic VGAT functions, in part, to reduce pain, particularly orofacial pain, associated with VZV. To address this hypothesis VZV was injected into the whisker pad. Affective and motivational aspects of pain were measured using the Place Escape/Avoidance Paradigm. Thalamic neuronal activity was modulated after injecting an adeno-associated virus (AAV) expressing an engineered acetylcholine Gi-protein-coupled receptor. This receptor inhibits neuronal firing when bound by clozapine-n-oxide (CNO). VGAT expression was attenuated in the thalamus by injecting an AAV construct that expressed a VGAT silencing shRNA. VZV-induced nociception was significantly decreased after administering CNO in male rats. Nociception significantly increased concomitant with increased thalamic c-fos expression after attenuating thalamic VGAT expression. These data establish that the lateral thalamus (posterior, ventral posteromedial, ventral posterolateral and/or reticular thalamic nucleus) controls VZV-induced nociception in the orofacial region, and that GABA in this region appears to reduce the response to VZV-induced nociception possibly by gating facial pain input.

Varicella-Zoster Virus Gastritis: Case Report and Review of the Literature.

We report varicella-zoster virus (VZV) gastritis in a 70-year-old woman postchemotherapy for lymphoma, presenting with abdominal pain, vomiting, and delirium without rash. A gastric biopsy demonstrated viral inclusions but posed a diagnostic challenge as immunohistochemistry for cytomegalovirus and herpes simplex virus were negative, and VZV immunohistochemistry was not available. The patient developed a vesicular rash 7 days after her symptoms began. Molecular testing of the gastric biopsy and a skin swab both confirmed VZV infection. She also had probable involvement of her liver and pancreas based on imaging and serum chemistry, and possible central nervous system involvement. She recovered with appropriate antiviral therapy but later developed a postherpetic neuralgia, and chronic intrahepatic biliary strictures; liver biopsy demonstrated a cholangiopathy of uncertain etiology. A literature review of the pathogenesis, epidemiology and sequelae of VZV infection is included.

Efficacy of gabapentin for prevention of postherpetic neuralgia: study protocol for a randomized controlled clinical trial.

BACKGROUND: Postherpetic neuralgia (PHN) is a chronic neuropathic pain that results from alterations of the peripheral nervous system in areas affected by the herpes zoster virus. The symptoms include pain, paresthesia, dysesthesia, hyperalgesia, and allodynia. Despite the availability of pharmacological treatments to control these symptoms, no treatments are available to control the underlying pathophysiology responsible for this disabling condition. METHODS/DESIGN: Patients with herpes zoster who are at least 50 years old and have a pain score of 4 or higher on a visual analogue scale (VAS) will be recruited. The aim is to recruit 134 patients from the practices of general physicians. Participants will be randomized to receive gabapentin to a maximum of 1800 mg/day for 5 weeks or placebo. Both arms will receive 1000-mg caplets of valacyclovir three times daily for 7 days (initiated within 72 h of the onset of symptoms) and analgesics as needed. The primary outcome measure is the percentage of patients with a VAS pain score of 0 at 12 weeks from rash onset. The secondary outcomes measures are changes in quality of life (measured by the SF-12 questionnaire), sleep disturbance (measured by the Medical Outcomes Study Sleep Scale), and percentage of patients with neuropathic pain (measured by the Douleur Neuropathique in 4 Questions). DISCUSSION: Gabapentin is an anticonvulsant type of analgesic that could prevent the onset of PHN by its antihypersensitivity action in dorsal horn neurons. TRIAL REGISTRATION: ISRCTN Registry identifier: ISRCTN79871784 . Registered on 2 May 2013.