CDDO regulates central and peripheral sensitization to attenuate post-herpetic neuralgia by targeting TRPV1/PKC-δ/p-Akt signals.

Postherpetic neuralgia (PHN) is a notorious neuropathic pain featuring persistent profound mechanical hyperalgesia with significant negative impact on patients' life quality. CDDO can regulate inflammatory response and programmed cell death. Its derivative also protects neurons from damages by modulating microglia activities. As a consequence of central and peripheral sensitization, applying neural blocks may benefit to minimize the risk of PHN. This study aimed to explore whether CDDO could generate analgesic action in a PHN-rats' model. The behavioural test was determined by calibrated forceps testing. The number of apoptotic neurons and degree of glial cell reaction were assessed by immunofluorescence assay. Activation of PKC-δ and the phosphorylation of Akt were measured by western blots. CDDO improved PHN by decreasing TRPV1-positive nociceptive neurons, the apoptotic neurons, and reversed glial cell reaction in adult rats. It also suppressed the enhanced PKC-δ and p-Akt signalling in the sciatic nerve, dorsal root ganglia (DRG) and spinal dorsal horn. Our research is the promising report demonstrating the analgesic and neuroprotective action of CDDO in a PHN-rat's model by regulating central and peripheral sensitization targeting TRPV1, PKC-δ and p-Akt. It also is the first study to elucidate the role of oligodendrocyte in PHN.

PROCESS Trial: Effect of Duloxetine Premedication for Postherpetic Neuralgia Within 72 Hours of Herpes Zoster Reactivation-A Randomized Controlled Trial.

BACKGROUND: Postherpetic neuralgia (PHN) is the most common chronic complication of herpes zoster (HZ) and results in severe refractory neuropathic pain. This study aimed at evaluating the efficacy of premedication with duloxetine in the prevention of PHN. METHODS: The PROCESS trial is a multicenter, randomized, open-label, blinded-endpoint trial used a 1:1 duloxetine:control ratio. Adults 50 years or older with HZ who presented with vesicles within 72 hours were recruited. The primary outcome was the incidence of PHN at 12 weeks. PHN was defined as any pain intensity score other than 0 mm on the visual analog scale (VAS) at week 12 after the onset of the rash. The secondary outcomes were the number of participants with VAS >0 and VAS ≥3. The modified intention-to-treat (mITT) principle and per-protocol (PP) principle were used for the primary outcome analysis. RESULTS: A total of 375 participants were randomly assigned to the duloxetine group and 375 were assigned to the control group. There was no significant difference in the incidence of PHN in the duloxetine group compared with the control group in the mITT analysis (86 [22.9%] of 375 vs 108 [28.8%] of 375; P = .067). PP analysis produced similar results. However, there were significant differences between the 2 groups in the number of participants with VAS >0 and VAS ≥3 (P < .05 for all comparisons). CONCLUSIONS: Although absolute prevention of PHN does not occur, this trial found that premedication with duloxetine can reduce pain associated with HZ, and therefore can have clinically relevant benefits. Clinical Trials Registration. Clinicaltrials.gov, NCT04313335. Registered on 18 March 2020.

A Guide to Preclinical Models of Zoster-Associated Pain and Postherpetic Neuralgia.

Reactivation of latent varicella-zoster virus (VZV) causes herpes zoster (HZ), which is commonly accompanied by acute pain and pruritus over the time course of a zosteriform rash. Although the rash and associated pain are self-limiting, a considerable fraction of HZ cases will subsequently develop debilitating chronic pain states termed postherpetic neuralgia (PHN). How VZV causes acute pain and the mechanisms underlying the transition to PHN are far from clear. The human-specific nature of VZV has made in vivo modeling of pain following reactivation difficult to study because no single animal can reproduce reactivated VZV disease as observed in the clinic. Investigations of VZV pathogenesis following primary infection have benefited greatly from human tissues harbored in immune-deficient mice, but modeling of acute and chronic pain requires an intact nervous system with the capability of transmitting ascending and descending sensory signals. Several groups have found that subcutaneous VZV inoculation of the rat induces prolonged and measurable changes in nociceptive behavior, indicating sensitivity that partially mimics the development of mechanical allodynia and thermal hyperalgesia seen in HZ and PHN patients. Although it is not a model of reactivation, the rat is beginning to inform how VZV infection can evoke a pain response and induce long-lasting alterations to nociception. In this review, we will summarize the rat pain models from a practical perspective and discuss avenues that have opened for testing of novel treatments for both zoster-associated pain and chronic PHN conditions, which remain in critical need of effective therapies.

Bone morphogenetic protein 4 derived from the cerebrospinal fluid in patients with postherpetic neuralgia induces allodynia via the crosstalk between microglia and astrocyte.

INTRODUCTION: During postherpetic neuralgia (PHN), the cerebral spinal fluid (CSF) possesses the capability to trigger glial activation and inflammation, yet the specific changes in its composition remain unclear. Recent findings from our research indicate elevations of central bone morphogenetic protein 4 (BMP4) during neuropathic pain (NP), serving as an independent modulator of glial cells. Herein, the aim of the present study is to test the CSF-BMP4 expressions and its role in the glial modulation in the process of PHN. METHODS: CSF samples were collected from both PHN patients and non-painful individuals (Control) to assess BMP4 and its antagonist Noggin levels. Besides, intrathecal administration of both CSF types was conducted in normal rats to evaluate the impact on pain behavior, glial activity, and inflammation.; Additionally, both Noggin and STAT3 antagonist-Stattic were employed to treat the PHN-CSF or exogenous BMP4 challenged cultured astrocytes to explore downstream signals. Finally, microglial depletion was performed prior to the PHN-CSF intervention so as to elucidate the microglia-astrocyte crosstalk. RESULTS: BMP4 levels were significantly higher in PHN-CSF compared to Control-CSF (P < 0.001), with a positive correlation with pain duration (P < 0.05, r = 0.502). Comparing with the Control-CSF producing moderate paw withdrawal threshold (PWT) decline and microglial activation, PHN-CSF further exacerbated allodynia and triggered both microglial and astrocytic activation (P < 0.05). Moreover, PHN-CSF rather than Control-CSF evoked microglial proliferation and pro-inflammatory transformation, reinforced iron storage, and activated astrocytes possibly through both SMAD159 and STAT3 signaling, which were all mitigated by the Noggin application (P < 0.05). Next, both Noggin and Stattic effectively attenuated BMP4-induced GFAP and IL-6 upregulation, as well as SMAD159 and STAT3 phosphorylation in the cultured astrocytes (P < 0.05). Finally, microglial depletion diminished PHN-CSF induced astrogliosis, inflammation and endogenous BMP4 expression (P < 0.05). CONCLUSION: Our study highlights the role of CSF-BMP4 elevation in glial activation and allodynia during PHN, suggesting a potential therapeutic avenue for future exploration.

Associations between organic erectile dysfunction and the risk of herpes zoster and postherpetic neuralgia in men.

BACKGROUND: Whether erectile dysfunction (ED) leads to considerable stress for affected men remains unclear? In this study, we investigated whether organic ED (OED) is associated with increased risks of herpes zoster (HZ) and postherpetic neuralgia (PHN). METHODS: A representative subset of Taiwan's National Health Insurance Research Database was employed for this study. Enrollees with OED from the years 2000 to 2018 were selected. To ensure comparability between the case and control groups, we implemented 1:1 propensity score matching based on age, index year, comorbidities, and medications. RESULTS: The case group included 20,808 patients with OED, while the control group consisted of 20,808 individuals without OED. The OED group exhibited a significantly elevated risk of HZ (adjusted hazard ratio [aHR] = 1.74) and PHN (aHR = 1.56) compared to the non-OED group. CONCLUSIONS: Men experiencing OED seem to face elevated risks of HZ and PHN compared to those without OED. ED may serve as a warning sign for individuals at HZ risk.

A bibliometric analysis and visualization of acupuncture and moxibustion therapy for herpes zoster and postherpetic neuralgia.

OBJECTIVE: To identify major contributors, current research status, and to forecast research trends and future development prospects on acupuncture and moxibustion therapy for herpes zoster (HZ) and postherpetic neuralgia (PHN). METHODS: A systematic search was conducted on the China National Knowledge Infrastructure (CNKI), Weipu, WanFang databases, and the Web of Science Core Collection (WoSCC), PubMed, and Scopus databases. The search strategy included relevant terms for HZ, PHN, acupuncture, and moxibustion. The reference type was limited to articles or reviews, with a publication date from January 1, 2014 to December 31, 2023. Data analysis was performed using CiteSpace software, focusing on author, institution, source, and keyword distributions, and temporal trends. RESULTS: A total of 1612 publications were identified from both Chinese and English databases. The analysis revealed a rising trend in publication numbers in the English database, with a significant increase observed in 2020. In the Chinese database, publication activity exhibited two peaks in 2019 and 2023. Guohua Lin and Jingchun Zeng were the most prolific authors in the Chinese and English databases, respectively. The Chengdu University of TCM and Zhejiang Chinese Medicine University were the most active institutions. The keyword analysis revealed "herpes zoster" as the most frequent keyword in the Chinese database, while "postherpetic neuralgia," "acupuncture," and "management" were prominent in the English database. The study also identified several therapeutic approaches, including fire needle therapy and electroacupuncture, which have shown efficacy in treating HZ and PHN. Animal studies provided insights into the mechanisms of these therapies, suggesting potential modulation of neuroinflammatory markers and intracellular signaling pathways. CONCLUSION: The bibliometric analysis underscores the growing interest in acupuncture and moxibustion therapy for HZ and PHN. It highlights the contributions of key authors and institutions while pinpointing potential areas for future research. The study advocates for the necessity of large-scale, multi-center clinical trials and further basic mechanical research to optimize these therapies. Moreover, it also emphasizes the importance of international collaboration to strengthen the evidence base and expand the global impact of this traditional treatment modality.

Herpes zoster: treatment, management, and prevention with the recombinant DNA vaccine.

Herpes zoster (HZ) is a reactivation of dormant varicella-zoster virus that most often erupts as painful vesicles in a unilateral dermatomal distribution. A sequela of HZ is postherpetic neuralgia (PHN), which is debilitating and may be persistent. Therefore, vaccination for the prevention of HZ and its sequelae is recommended for adults aged 50 years and older as well as immunocompromised adults. In 2017, the US Food and Drug Administration approved a recombinant DNA vaccine (Shingrix) that is safe to use in immunocompromised individuals and an improvement on the live-attenuated vaccine approved in 2006. This report discusses HZ, PHN, treatment of HZ and PHN, and prevention with vaccines.

Transforaminal Epidural Block and Erector Spinae Plane Block to Manage Acute Zoster-Associated Pain: A Retrospective Case-Control Study.

Background and Objectives: Achieving adequate pain reduction in the acute phase of herpes zoster is essential for preventing postherpetic neuralgia (PHN). For this purpose, appropriate antiviral medications, oral analgesic medications, and various nerve block methods could be applied. Erector spinae plane block (ESPB) is a simple, novel ultrasound-guided block technique, and its use has increased because the procedure is convenient and relatively safe. Although several cases have reported the zoster-associated pain (ZAP) control effect of ESPB, the efficacy of ESPB has not been compared with that of other types of nerve blocks for managing ZAP. This study aimed to compare the efficacy of ESPB with that of other types of nerve blocks for managing ZAP. Study Design: Retrospective case-control study. Materials and Methods: Medical records of 53 patients with acute thoracic herpes zoster were reviewed. We divided the participants into two groups: patients who received transforaminal epidural injection (TFEI) (n = 32) and those who received ESPB (n = 21). The efficacy of the procedure was assessed by a numerical rating scale (NRS) and by recording patient medication doses before the procedure and at 1 week, 1 month, 2 months, and 3 months after the procedure. Results: The time required for pain intensity to decrease to NRS ≤ 2 was not significantly different between the groups. The rate of medication discontinuation also was not different between the groups. There was no significant difference between the two groups in the proportion of clinically significant PHN (NRS ≥ 3) at any time point. Limitations: The relatively small sample size from a single center and the retrospective nature of the study served as limitations. Conclusions: The clinical effects of ESPB and TFEI were similar in patients with acute thoracic herpes zoster. ESPB could be considered an interventional option for ZAP management.

[Electrical dorsal root ganglion stimulation (DRGS) for the treatment of refractory postherpetic neuralgia]. / Elektricheskaya stimulyatsiya gangliya zadnikh koreshkov spinnogo mozga (DRGS) dlya lecheniya refrakternoi postgerpeticheskoi nevralgii.

Postherpetic neuralgia (PHN) is a rare complication of herpes zoster characterized by prolonged and excruciating pain. Traditional treatments for PHN, such as analgesics, anticonvulsants and antidepressants, do not always bring the desired result. One promising alternative that is attracting the attention of the scientific community is dorsal root ganglion stimulation (DRGS). This method focuses on targeted and precise targeting of the source of pain, providing a new level of effectiveness in the treatment of PHN. OBJECTIVE: A retrospective analysis of the technique and results of implantation of a permanent device for stimulating the spinal ganglia in patients with refractory PHN at the Burdenko Neurosurgical Center. MATERIAL AND METHODS: The study was conducted in 7 patients (5 men, 2 women) with refractory PHN in the period from 2018 to 2020. The age of the patients ranged from 57 to 84 years (average age 74±8.4). All patients were implanted with Boston systems (Precision or Spectra versions). Stimulation parameters: pulse width - 120-210 µs, frequency - 30-130 Hz, amplitude at the lower limit of the appearance of paresthesia with the possibility of increasing with increased pain up to 5 mA. The position of the electrode depended on the location of the pain. All systems were implanted under X-ray guidance. RESULTS: The duration of follow-up observation was more than 2.5 years. The average pain intensity one year after treatment was 3.42±2.45 points on the visual analogue scale (VAS) (a 62.3% decrease in intensity compared to baseline). In 3 (42.8%) patients, the result was characterized by us as «excellent¼ (intensity according to VAS decreased by 75% or more), in 1 (14.2%) - as «good¼ (intensity according to VAS decreased by 50-74%), in 1 (14.2%) - as «moderate¼ (VAS intensity decreased by 25-49% and in 2 (28.5%) as «unsatisfactory¼ (VAS intensity decreased by less than 25%, or postoperative complications occurred). CONCLUSION: Given the complicated nature of PHN, the use of dorsal ganglion stimulation appears to be a promising and innovative treatment approach. Further research is needed to introduce this technique into clinical practice for the treatment of patients suffering from PHN.

Cerebrospinal Fluid Proteomic Profiles in Patients with Postherpetic Neuralgia.

The intrinsic mechanism of postherpetic neuralgia (PHN) remains unclear. Herein, we aimed to seek the hub proteins in the cerebrospinal fluid (CSF), which display significant changes between the PHN and nonpainful patients (Control). First, the proteomic results showed that compared with the Control-CSF, there were 100 upregulated and 50 downregulated differentially expressed proteins (DEPs) in the PHN-CSF. Besides, functional analyses including gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) revealed that biological processes and pathways including complement activation, infection, coagulation, and lipid metabolism were activated, while synaptic organization was suppressed. Next, the protein-protein interaction (PPI) analysis indicated that increased PLG, F2, APOA1, APOA2, SERPINC1, and KNG1 and reduced APOE, which were all enriched in the top pathways according to the KEGG analysis, were defined as hub proteins. Finally, three of the hub proteins, such as PLG, APOA1, and APOE, were reconfirmed in a larger cohort using both enzyme-linked immunosorbent assay (ELISA) and Western blotting methods. Above all, the results indicated that PLG, APOA1, and APOE and their involved processes such as infection, inflammation, cholesterol metabolism, and coagulation shall be potential therapeutic approaches. (The raw mass spectrometry proteome data and search results have been deposited to the iProx-integrated Proteome Resources (http://www.iprox.cn) with the data set identifier IPX0007372000.).

Metformin use and the risks of herpes zoster and postherpetic neuralgia in patients with type 2 diabetes.

Herpes zoster and postherpetic neuralgia cause substantial pain in patients. Persons with type 2 diabetes (T2D) are prone to zoster infection and postherpetic neuralgia due to compromised immunity. We conducted this study to evaluate the risks of herpes zoster and postherpetic neuralgia between metformin users and nonusers. Propensity score matching was utilized to select 47 472 pairs of metformin users and nonusers from Taiwan's National Health Insurance Research Database between January 1, 2000, and December 31, 2017. The Cox proportional hazards models were used for comparing the risks of herpes zoster and postherpetic neuralgia between metformin users and nonusers in patients with T2D. Compared with no-use of metformin, the adjusted hazard ratios (95% confidence interval) for metformin use in herpes zoster and postherpetic neuralgia were 0.70 (0.66, 0.75) and 0.510 (0.39, 0.68), respectively. A higher cumulative dose of metformin had further lower risks of herpes zoster and postherpetic neuralgia than metformin no-use. This nationwide cohort study demonstrated that metformin use was associated with a significantly lower risk of herpes zoster and postherpetic neuralgia than metformin no-use. Moreover, a higher cumulative dose of metformin was associated with further lower risks of these outcomes.

Capsaicin 8% Patch for Spinal Cord Injury Focal Neuropathic Pain, a Randomized Controlled Trial.

BACKGROUND: Neuropathic pain (NP) after spinal cord injury (SCI) exacerbates disability, decreases quality of life (QOL), and is often refractory to available therapies. Patients report willingness to trade potential recovery of strength, bowel, bladder, or sexual function for pain relief. One proposed mechanism causing NP is up-regulation of transient receptor potential vanilloid 1 (TRPV 1) proteins in uninjured C fibers and dorsal root ganglia causing neuronal excitability. Recent studies have found up-regulation of TRPV 1 proteins after SCI. OBJECTIVE: We hypothesize the application of capsaicin 8% patch (C8P), FDA approved for NP in diabetic peripheral neuropathy and post-herpetic neuralgia, will improve pain, function and QOL in persons with SCI. METHODS: Randomized single-blind crossover design in which 11 persons with SCI and NP refractory to two oral pain medications received C8P or a control low dose Capsaicin 0.025% patch (CON) over two 12-week periods. Pain (VAS, MPI-SCI), quality of life (WHO-QOL), and functional status (SCIM) were measured at 2-4-week intervals. RESULTS: There was a main treatment effect of C8P over CON on VAS and MPI-SCI outcomes with pain reduction of 35% and 29% at weeks 2 and 4, respectively. C8P also demonstrated a main treatment effect over CON on the SCIM mobility subscale. WHO-QOL scores did not improve with C8P. CONCLUSIONS: C8P improves pain and mobility for patients with SCI and refractory NP. Larger studies should be performed to evaluate impact of repeat applications and QOL outcomes.

Therapeutic Strategies for Postherpetic Neuralgia: Mechanisms, Treatments, and Perspectives.

PURPOSE OF REVIEW: Postherpetic neuralgia is an annoying pain that mainly affects older people. In order to give patients more options, this review summarizes the pharmacological and interventional treatments for postherpetic neuralgia and updates the research on the efficacy, thereby providing doctors with more treatment options. The adverse effects and effective doses of its various treatments are also presented so that the therapy can be prescribed according to their concrete physical conditions. In a word, this review is dedicated to providing a comprehensive overview of the treatment options for postherpetic neuralgia and offering patients more choices. RECENT FINDINGS: Combinational therapy is more excellent than monotherapy. The local anesthesia and gabapentin comprised outstanding compatibility. In addition, two therapeutic tools for PHN patients, especially for the intractable ones, electroacupuncture (EA), and osteopathic manipulative treatment (OMT), show their efficacy and become potential options to alleviate pain. In terms of treatment, guidelines recommend patients use tricyclic antidepressants (TCAs), gabapentin, pregabalin, and 5% lidocaine patches as the first-line medications, and gabapentin is investigated most, especially the gabapentin enacarbil (GEn). And drug efficacy can be limited by adverse effects and tolerated doses. Interventional treatments, with their invasiveness and operational difficulty, are usually considered for intractable patients. Combinational therapies may be used when a single therapy cannot achieve the desired effect. Therapies such as OMT and EA have also been proposed to palliate pain in some cases, and future directions of treatment may be investigated in Chinese medicine and acupuncture.

Utilization of Truncal Fascial Plane Nerve Blocks for Chronic Pain Management: A Narrative Review.

PURPOSE OF REVIEW: Nerve blocks constitute an integral portion in the management of chronic pain. The widespread use of ultrasound imaging opened the door to a flood of newer blocks especially truncal plane nerve blocks. We reviewed the current medical literature for studies and case reports utilizing the two most common truncal plane nerve blocks, transversus abdominis plane and erector spinae plane blocks, to manage chronic pain. RECENT FINDINGS: We found some evidence, mostly in case reports and retrospective observational studies, that supports the use of transversus abdominis plane and erector spinae plane nerve blocks, usually with steroids, as a safe and valuable part of interdisciplinary management of chronic abdominal and chest walls pain. Ultrasound-guided truncal fascial plane nerve blocks are safe, easy to learn, and proven to help with post-operative acute pain management. Although limited, our current review provides evidence from the current medical literature regarding the utility of these blocks to manage some of the challenging chronic and cancer-related pain conditions of the trunk region.

Evaluating public interest in herpes zoster in Germany by leveraging the internet: a retrospective search data analysis.

BACKGROUND: Herpes zoster (HZ) and its complication postherpetic neuralgia (PHN), whose incidence are both expected to increase with an ageing population, have demonstrated high costs on healthcare systems and burden on individual quality of life. Previous studies have shown the possibility of assessing public interest in a disease and factors that influence search behaviour using internet search data. The aim of this study was to analyze internet search data for HZ in Germany to evaluate public interest in the disease and relevant influential temporal and geographic factors that modify search behavior. METHODS: Google Ads Keyword Planner was used to generate a list of HZ-related keywords including their search volume for Germany as a whole and its sixteen federal states from October 2016 to September 2020. All keywords were qualitatively categorized, and changes over time and correlations with population density, physician density, and vaccination rates were assessed using Welch's ANOVA, Bonferroni correction for post-hoc analyses, and Pearson's correlation. RESULTS: A total of 1,651 relevant keywords with a search volume of 20,816,210 searches were identified. Overall, national search volume increased each year of the study period with a peak in August 2020. More than half of the total search volume related to general queries (55.1%). The highest average monthly search volumes were observed in the states of Hamburg, Saarland, and Bremen. Average monthly search volume showed strong positive correlations with population density (r = .512, p = .043) and a strong negative correlation with the number of inhabitants per working physician (r = -.689, p = .003). CONCLUSIONS: The study demonstrated that evaluating internet search data is a viable method for assessing public interest in HZ, thereby identifying areas of unmet need to support targeted public health campaigns.

Efficacy of Long-Term Spinal Nerve Posterior Ramus Pulsed Radiofrequency in Treating Subacute Herpetic Neuralgia: A Prospective Randomized Controlled Trial.

OBJECTIVE: This study aimed to observe the clinical efficacy of long-term spinal nerve posterior ramus pulsed radiofrequency (PRF) in treating subacute herpes zoster neuralgia (HZN). METHODS: A total of 120 patients with subacute HZN in the thoracolumbar region and back were equally randomized to the conventional PRF group (P group, n = 60), with a pulse of 180 s, or to the long-term PRF group (LP group, n = 60), with a pulse of 600 s. The patients' baseline characteristics, the incidence rate of postherpetic neuralgia (PHN), and the dose of analgesics were compared between the two groups. RESULTS: Based on the pain-rating index (PRI), the PRI-sensory, PRI-affective, visual analogue scale, and present pain intensity scores in the two groups were lower at T2, T3, and T4 time points than at the T1 time point after treatment (p < 0.05). After 2 months, the dose of analgesics was significantly lower in the LP group than in the P group (p < 0.05), and the incidence of PHN was considerably lower. CONCLUSIONS: Long-term spinal nerve posterior ramus PRF is a more effective treatment strategy for subacute HZN than conventional PRF. It can effectively prevent the occurrence of PHN.

Correlation between pain catastrophizing in acute herpes zoster and postherpetic neuralgia: a retrospective analysis.

PURPOSE: The objective of this study was to examine the association between pain catastrophizing in acute phase herpes zoster and the development of postherpetic neuralgia. METHODS: The medical records of all patients diagnosed with herpes zoster between February 2016 and December 2021 were retrieved. Inclusion criteria were patients aged > 50 years who visited our pain center within 60 days after rash onset and reported a pain intensity of ≥ 3 in a numerical rating scale. Patients with a score of 30 or more in the pain catastrophizing scale at baseline were assigned to the catastrophizer group, and those with a score < 30 were assigned to the non-catastrophizer group. We defined patients with "postherpetic neuralgia" and "severe postherpetic neuralgia" as those with a numerical rating scale score of 3 or more and 7 or more at 3 months after baseline, respectively. RESULTS: Data of 189 patients were available for complete analysis. Age, baseline numerical rating scale, and prevalence of anxiety and depression were significantly higher in the catastrophizer than those in the non-catastrophizer group. Incidence of postherpetic neuralgia did not differ significantly between the groups (p = 0.26). Multiple logistic regression analysis showed that age, severe pain at baseline, and immunosuppressive state were the factors which were independently associated with developing postherpetic neuralgia. Severe pain at baseline was the only factor related to developing severe postherpetic neuralgia. CONCLUSION: Pain catastrophizing in the acute phase of herpes zoster may not be related to the development of postherpetic neuralgia.

Longitudinal Change in Brain Functional Connectivity with Herpes Zoster Patients: Neuroimaging Case Series.

The exact mechanism involved in the development of postherpetic neuralgia (PHN) is not yet known. The objective of this study was to evaluate longitudinal functional connectivity (FC) changes in the neuroimaging case series of patients with acute herpes zoster (HZ). Cases: This study included five patients who had symptoms of HZ. Functional magnetic resonance imaging was conducted at enrollment and 3 months to determine FC changes. Of the five patients, three developed PHN. In the PHN subjects, the FC of the left superior frontal gyrus (SFG) and the right inferior frontal gyrus (IFG) were activated. The left SFG is known to contribute to higher cognitive functions and working memory. The right IFG is associated with pain processing and empathy for pain. Conclusions: Although only a few patients were enrolled in this study, the PHN could be affected by pain itself, as well as pain memory and psychological aspects such as empathy for pain.

Efficacy and safety of twice-daily tramadol hydrochloride bilayer sustained-release tablets with an immediate release component for postherpetic neuralgia: Results of a Phase III, randomized, double-blind, placebo-controlled, treatment-withdrawal study.

BACKGROUND: We investigated the efficacy and safety of twice-daily bilayer sustained-release tramadol hydrochloride tablets (35% immediate-release; 65% sustained-release) in patients with postherpetic neuralgia. METHODS: This was a Phase III treatment-withdrawal study with 1-4-week dose-escalation, 1-week fixed-dose, and 4-week randomized, double-blind, placebo-controlled withdrawal periods performed at 43 medical institutions in Japan. Patients aged ≥20 years, ≥3 months after the onset of herpes zoster with localized, persistent pain despite fixed-dose analgesics for ≥2 weeks before enrollment were eligible. Patients started tramadol at 100 mg/day and its dose escalated to a maximum of 400 mg/day to achieve a reduction in their Numeric Rating Scale (NRS) for pain of ≥2 points. Eligible patients were randomized to continue tramadol or switched to placebo for 4 weeks (double-blind period). Patients were withdrawn due to inadequate analgesia (NRS deteriorated on ≥2 consecutive days) or their request. RESULTS: Overall, 252 patients started tramadol and 173 were randomized (tramadol: 85; placebo: 88). Tramadol was superior to placebo for the primary endpoint (time from randomization to an inadequate analgesic effect) with log-rank test p = 0.0005. The hazard ratio was 0.353 (95% confidence interval 0.190-0.657) in favor of tramadol and fewer patients in the tramadol group experienced inadequate analgesic effects (16.9% vs. 39.8%). Adverse events in ≥10% of patients in the open-label period were constipation (43.8%), nausea (34.9%), somnolence (18.5%), and dizziness (11.6%). The frequencies of adverse events in the double-blind period were similar in both groups. CONCLUSION: Sustained-release tramadol tablets with an immediate-release component are effective and well tolerated for managing postherpetic neuralgia.

Extracellular signal-regulated kinase phosphorylation enhancement and NaV1.7 sodium channel upregulation in rat dorsal root ganglia neurons contribute to resiniferatoxin-induced neuropathic pain: The efficacy and mechanism of pulsed radiofrequency therapy.

Pulsed radiofrequency (PRF) therapy is one of the most common treatment options for neuropathic pain, albeit the underlying mechanism has not been hitherto elucidated. In this study, we investigated the efficacy and mechanism of PRF therapy on resiniferatoxin (RTX)-induced mechanical allodynia, which has been used as a model of postherpetic neuralgia (PHN). Adult male rats were intraperitoneally injected with a vehicle or RTX. Furthermore, PRF current was applied on a unilateral sciatic nerve in all RTX-treated rats. On both ipsilateral and contralateral sides, the paw mechanical withdrawal thresholds were examined and L4-6 dorsal root ganglia (DRG) were harvested. In the DRG of rats with RTX-induced mechanical allodynia, NaV1.7, a voltage-gated Na+ channel, was upregulated following the enhancement of extracellular signal-regulated kinase phosphorylation. Early PRF therapy, which was applied 1 week after RTX exposure, suppressed this NaV1.7 upregulation and showed an anti-allodynic effect; however, late PRF therapy, which was applied after 5 weeks of RTX exposure, failed to inhibit allodynia. Interestingly, late PRF therapy became effective after daily tramadol administration for 7 days, starting from 2 weeks after RTX exposure. Both early PRF therapy and late PRF therapy combined with early tramadol treatment suppressed NaV1.7 upregulation in the DRG of rats with RTX-induced mechanical allodynia. Therefore, NaV1.7 upregulation in DRG is related to the development of RTX-induced neuropathic pain; moreover, PRF therapy may be effective in the clinical management of patients with PHN via NaV1.7 upregulation inhibition.