Study Of The Prevention Strategy And The Mechanism Of Postherpetic Neuralgia

Herpes zoster(HZ)is a common viral infection disease caused by the reactivation of varicella-zoster virus(VZV)which is latent in the ganglia.The clinical symptoms are unilaterally distributed blisters and pain in the corresponding skin area.Postherpetic neuralgia(PHN)is the most common complication of HZ.It is a complex neuropathic pain that occurs in about 20%of the elderly patients over 50 years of age.PHN often manifests as persistent spontaneous pain,electric shock pain and allodynia.Persistent chronic pain severely interferes with the daily activities of patients,leading to a decline in the quality of life and a severe socioeconomic burden.However,the mechanism of PHN is not clear at present,and there is no effective treatment for PHN.It is difficult to treat PHN once it occurs.Therefore,it is urgent to explore treatment strategies which can effectively prevent the occurrence of PHN and to identify the possible mechanisms of PHN.Firstly,this article verified the effect of the choice and initial time of pain managements on the incidence of PHN to explore effective analgesic strategies that can reduce the incidence of PHN.Secondly,it is clinically found that only a small number of patients develop chronic pain after the onset of HZ.However,the currently known predictors of PHN can only partially explain the reasons for the susceptibility difference to PHN among individuals.Recent human genetic studies have shown that individuals have significant differences in pain sensitivity,response to analgesics and susceptibility to pathological pain states.Single nucleotide polymorphisms in pain-related genes can explain some of these variations.Therefore,we conduct an association study to identify the effect of genetic variation on the susceptibility to PHN.This genetic study will provide a new direction to understand the mechanism of PHN and improve the predictive ability of patients with high risk of PHN.Thirdly,the variability of pain is closely related to the activity of the brain regions involved in pain processing in the central nervous system.Imaging genetics studies by using functional magnetic resonance technology to explore the relationship of genetic variation on the risk of chronic pain may provide new ideas on the biological mechanisms of genetic variation causing the change of pain phenotype.The followings are the four parts of our study.Part ? The Effect of Early Use of Supplemental Therapy on Preventing Postherpetic Neuralgia:A Meta-analysisObjectives:Our aim is to examine the efficacy of supplemental analgesic therapy such as systemic adjunct therapies and interventional procedures in preventing PHN.Methods:A systematic and comprehensive database search was performed in CENTRAL,MEDLINE,and EMBASE.We searched for all randomized controlled trials which evaluated supplemental analgesic methods including systemic adjuncts(gabapenting,pregabalin,amitriptyline)and interventional procedures(nerve block,epidural analgesics,transcutaneous electric nerve stimulation)used during the acute phase of herpes zoster for preventing PHN.The retrieval time is from the construction of the database to December 2016.According to the selection criteria,data of the included studies were extracted by 2 independent reviewers.The primary outcome was the incidence of PHN in three months after the rash presence.Rev Man 5.3 was used to perform this meta-analysis.The incidence of PHN between the treatment group and the control group was compared and subgroup analysis and sensitivity analysis were performed.Results:Nine trials,with a total of 1,757 participants(888 in the treatment group and 867 in the control group),were included in the final analysis.Compared with the control group,the early use of supplemental therapy was associated with a significantly less incidence of PHN in 3 months after acute rash presence(RR:0.53,95%CI:0.34 to 0.81,P=0.004,I~2=71%).After performing sensitivity analysis,the effect of supplemental therapy did not change(RR:0.65,95%CI:0.47-0.90,I~2=30%).The subgroup analysis shows that the systemic adjunct treatments didn't have any benefit(RR:0.76,95%CI:0.46 to 1.26,P=0.290,I~2=0).The early use of interventional procedures was associated with a significantly less incidence of PHN in 3 months after acute rash presence(RR:0.45,95%CI:0.26-0.80,P<0.001,I~2=80%).After performing sensitivity analysis,the effect of interventional procedures did not change(RR:0.53,95%CI:0.31-0.91,I~2=35%).Conclusion:This meta-analysis demonstrates that the early use of supplemental interventional procedures can significantly reduce the incidence of PHN.The early use of interventional procedures for acute pain may be a preferred choice for patients without contraindication,but evidence is moderate.More data from high-quality randomized controlled trials will be needed to confirm these results.Part ? The start time of supplemental pain management is associated with PHNObjectives:This study aimed to evaluate the association between initial time of supplemental pain management and the risk of PHN in older patients with moderate to severe acute pain.Methods:We performed a prospective observational study between May 13,2017 and August 8,2018 in our clinic center.HZ patients were followed up for at least 3 months to determine whether they developed PHN or not.Multivariable logistic regression analysis was conducted to identify the effect of the initial time of supplemental pain management on the development of PHN.Supplemental pain management was defined as any use of opioids,tricyclic antidepressants,or nerve blocks.According to the initial time of supplemental pain management,patients were divided into two groups:the early treatment group(?14 days),and the late treatment group(>14 days).The clinical outcomes in these two groups were compared.Results:A total of 134 HZ patients aged 50 or older with moderate to severe pain(NRS?4)were enrolled in this study.Sixty HZ patients developed PHN and another 74 paitents didn't develop PHN.The delayed initiation of supplemental pain management(>14 days)(OR:4.11,95%CI:1.69-9.92,P=0.002)and severe rash(OR:2.93,95%CI:1.22-7.01,P=0.016)were independent predictors of PHN.According to the initial time of supplemental pain management,patients were divided into the early treatment group(n=62)and the late treatment group(n=72).The pain intensity within the 6 month follow-up time declined in both early and late treatment group,but the pain intensity declined more dramatically in the early treatment group than the late treatment group.Besides,the duration of pain was significantly shorter in the early treatment group.Conclusion:The start time of supplemental pain management significantly affects the prognosis of HZ.Patients with shorter intervals between onset of rash and beginning of treatment with supplemental pain management had significantly greater pain relief and less likely of developing PHN.Therefore,in elderly patients with moderate to severe acute herpetic pain,supplemental pain management should be considered to applied within 14 days following rash onset.Part ? Identification of single nucleotide polymorphisms in pain-related genes associated with postherpetic neuralgia susceptibilityObjectives:The aim of this study was to evaluate whether genetic variation in the pathway of pain related genes was associated with PHN susceptibility in the Chinese population.Methods:70 PHN patients and 111 HZ patients without developing PHN were enrolled.All patients received a standardized antiviral agents and analgesics as needed during the acute phase of HZ.Saliva was collected from patients to extract genomic DNA.Twenty-four candidate genetic polymorphisms in 12 genes(IL1B,SCN9A,KCNK9,TRPV1,P2X7R,HTR1A,HTR2A,ADRB1,ADRB2,BDNF,COMT,and OPRM1)were genotyped by KASP?genotyping assay in all patients.The distribution of the genotype frequencies was calculated in patients with and without PHN.Multivariable logistic regression analyses were used to identify the association between genetic variations and PHN susceptibility.The area under curve(AUC)and the coefficient of determination(R~2)were used to evaluate the improvement of PHN prediction ability by adding genetic variation to the clinical characteristics of the prediction model.Results:Our results suggested that among 12 candidate genes only the variation in P2X7 Rgene was associated with PHN susceptibility.The P2X7R rs7958311 AG heterozygous genotype carriers had a decreased risk for PHN under overdominant model(OR=0.40,95%CI:0.21-0.77,P=0.005).After adding P2X7R rs7958311 polymorphism to the clinical features,the AUC of the prediction model was 0.698(95%CI:0.620-0.776).The model's interpretation of the outcome variation(R~2)increased by 5%to 15%.Conclusion:In the present study,we found that purinergic receptor P2X7 rs7958311 may be related to the susceptibility of PHN.Besides,combining genetic variation with herpes-related clinical features can improve predictive ability in patients with high-risk PHN.Future larger independent cohorts are warranted to replicate these initial findings.Part ? Association between P2X7R gene polymorphism and resting-state brain spontaneous activity in postherpetic neuralgiaObjectives:This study is to investigate the effect of an P2X7R genetic polymorphism(rs7958311)on the brain activity in patients with postherpetic neuralgia.Methods:Thirty-one older participants(13 with PHN and 18 healthy controls)were recruited for this study.All of the participants were genotyped for variant rs7958311 in the P2X7R gene and were scanned using resting-state f MRI.Brain activity was assessed by amplitude of low-frequency fluctuation(ALFF).Two-way analysis of variance was employed to examine the effects of P2X7R gene polymorphyism on ALFF of relevant brain regions.Results:PHN patients had abnormal ALFF in the right temporal lobe,right posterior cerbellar lobe,bilateral parietal lobe and right frontal lobe.P2X7R rs7958311 AG genotype carriers,in comparison to AA/GG carriers,exhibited abnormal ALFF in the right parietal lobe,right occipital lobe,right posterior cerbellar lobe,right frontal lobe and right temporal lobe.There was also a significant diagnosis×genotype interaction effect in the right temporal lobe,right frontal lobe and right posterior cerbellar lobe:within the patient group,increased ALFF of the right posterior cerbellar lobe in AG genotype carriers were confirmed.However,the control subjects with AG genotype had decreased ALFF in this area.The P2X7R polymorphism did not affect activation in the control subjects in the right temporal lobe and right frontal lobe,but the PHN patients who were AG carriers showed significantly higher activation than the AA/GG carriers in this two brain regions.Conclusion:The effect of P2X7R rs7958311 polymorphism on the PHN susceptibility may be related to its effect on brain spontaneous activity in the right temporal lobe,right posterior cerbellar lobe and right frontal lobe.