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Research Article| Volume 34, P126-131, May 2015

Predictors of postherpetic neuralgia in patients with herpes zoster: a pooled analysis of prospective cohort studies from North and Latin America and Asia

Open AccessPublished:April 01, 2015DOI:https://doi.org/10.1016/j.ijid.2015.03.022
Predictors of postherpetic neuralgia in patients with herpes zoster: a pooled analysis of prospective cohort studies from North and Latin America and Asia
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      Highlights

      • •
        A pooled analysis of seven prospective cohort studies in North and Latin America and Asia was performed.
      • •
        Predictors of postherpetic neuralgia (PHN) in herpes zoster were assessed in a real-life setting.
      • •
        One-fifth (21.1%) of herpes zoster patients developed PHN.
      • •
        Similar risks of PHN were observed across geographic regions.
      • •
        PHN predictors were age, severe acute pain, and impaired physical/social functioning.

      Summary

      Objectives

      The most common complication of herpes zoster (HZ) is postherpetic neuralgia (PHN), a persistent pain that can substantially affect quality of life (QoL). This analysis aimed to evaluate predictors of PHN in HZ patients.

      Methods

      A pooled analysis of prospective cohort studies of HZ patients aged ≥50 years from North America (Canada), Latin America (Brazil, Mexico, and Argentina), and Asia (Taiwan, South Korea, and Thailand) was performed. Patients within 14 days of rash onset were included. The incidence of PHN was defined as a worst pain score of ≥3, persisting/appearing at >90 days after rash onset. Socio-demographics, HZ disease characteristics, treatment, pain-related interference with activities of daily living, and health-related QoL were assessed.

      Results

      Of 702 patients with HZ, 148 (21.1%) developed PHN. Similar risks of PHN were observed across geographic regions. On multivariate analysis, older age, greater severity of pain at rash onset, employment status, walking problems at enrollment, and pain interference affecting social relationships were significantly associated with the development of PHN.

      Conclusions

      In addition to older age and severe acute pain, this study suggests that impaired physical and social functioning from acute zoster pain may play a role in the development of PHN in this prospective cohort study of HZ patients from North and Latin America and Asia.

      Keywords

      1. Introduction

      Herpes zoster (HZ) is caused by reactivation of the latent varicella zoster virus (VZV) in sensory ganglia and is typically characterized by painful, blistering rashes.
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      The lifetime risk of HZ is approximately 30%.
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      For some patients, pain continues to persist after the rash heals and develops into postherpetic neuralgia (PHN). PHN is the most common complication of HZ and occurs in approximately 5% to 30% of HZ patients.
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      The risk of PHN increases with age. PHN can persist for several months to several years, and even up to 10 years. PHN substantially affects patient quality of life (QoL) and can cause physical disability, emotional distress, and social isolation.
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      However, each treatment has limited efficacy and patients are often refractory to these treatments. As an effective preventive strategy, a live-attenuated VZV vaccine (Zostavax by Merck) has been demonstrated to significantly reduce the risk of HZ and PHN.
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      Understanding the predictors of PHN is important to enable healthcare professionals to identify patients at risk of PHN who might benefit from early treatment. It may also help researchers to better understand the pathophysiology of PHN. It is recognized that older age, greater acute pain severity, and greater rash severity increase the risk of developing PHN.
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      Predictors of postherpetic neuralgia among patients with herpes zoster: a prospective study.
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      However, other factors, such as prodromal pain, female sex, and functional and psychosocial status, have rarely been evaluated or have not been consistently associated with the risk of PHN.
      • Whitley R.J.
      • Shukla S.
      • Crooks R.J.
      The identification of risk factors associated with persistent pain following herpes zoster.
      J Infect Dis. 1998; 178: S71-S75
      , 
      • Decroix J.
      • Partsch H.
      • Gonzalez R.
      • Mobacken H.
      • Goh C.L.
      • Walsh L.
      • et al.
      Factors influencing pain outcome in herpes zoster: an observational study with valaciclovir. Valaciclovir International Zoster Assessment Group (VIZA).
      J Eur Acad Dermatol Venereol. 2000; 14: 23-33
      , 
      • Jung B.F.
      • Johnson R.W.
      • Griffin D.R.
      • Dworkin R.H.
      Risk factors for postherpetic neuralgia in patients with herpes zoster.
      Neurology. 2004; 62: 1545-1551
      Conflicting results could be due to differences in the definition of PHN, study population, and methodology. Furthermore, prior research has been conducted mostly in North America and Europe, but less frequently in other geographic regions.
      The objective of this study was to evaluate the predictors of PHN from a pooled analysis of prospective cohort studies of patients with HZ from North America (Canada), Latin America (Mexico, Brazil, and Argentina), and Asia (Taiwan, South Korea, and Thailand).

      2. Methods

      2.1 Study design and population

      Data from the MASTER study (Monitoring and Assessing Shingles Through Education and Research), a prospective cohort study of patients with HZ conducted in seven countries (Canada, Brazil, Mexico, Argentina, Taiwan, South Korea, and Thailand) using the same methodology, were pooled.
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      • Brisson M.
      • Schmader K.
      • Levin M.
      • Johnson R.
      • Oxman M.
      • et al.
      Predictors of postherpetic neuralgia among patients with herpes zoster: a prospective study.
      J Pain. 2010; 11: 1211-1221
      , 
      • Drolet M.
      • Brisson M.
      • Levin M.J.
      • Schmader K.E.
      • Oxman M.N.
      • Johnson R.W.
      • et al.
      A prospective study of the herpes zoster severity of illness.
      Clin J Pain. 2010; 26: 656-666
      , 
      • Aunhachoke K.
      • Bussaratid V.
      • Chirachanakul P.
      • Chua-Intra B.
      • Dhitavat J.
      • Jaisathaporn K.
      • et al.
      Measuring herpes zoster, zoster-associated pain, post-herpetic neuralgia-associated loss of quality of life, and healthcare utilization and costs in Thailand.
      Int J Dermatol. 2011; 50: 428-435
      , 
      • Song H.
      • Lee J.
      • Lee M.
      • Choi W.S.
      • Choi J.H.
      • Lee M.S.
      • et al.
      Burden of illness, quality of life, and healthcare utilization among patients with herpes zoster in South Korea: a prospective clinical–epidemiological study.
      Int J Infect Dis. 2014; 20: 23-30
      , 
      • Vujacich C.
      • De Wouters L.
      • Margari A.
      • Gordovil M.
      • Kawai K.
      • Lemos E.
      • et al.
      Assessment of burden of illness due to herpes zoster in Argentina: a prospective observational study.
      Value in Health. 2013; 16 ([Epub ahead of print]): A668
      , 
      • Tsai T.F.
      • Yao C.A.
      • Yu H.S.
      • Lan C.C.
      • Chao S.C.
      • Yang J.H.
      • et al.
      Herpes zoster-associated severity and duration of pain, health-related quality of life, and healthcare utilization in Taiwan: a prospective observational study.
      Int J Dermatol. 2014;
      Eligible participants were patients with a physician-confirmed diagnosis of HZ rash or zoster-associated pain with documented date of rash onset in the medical chart, ≥50 years of age, and capable of completing the study questionnaires. Patients were recruited at different time points during the course of their disease. However, the current analysis was restricted only to patients enrolled within 14 days of rash onset. Patients were followed prospectively for 6 months to assess their zoster-associated burden of illness, including severity and duration of pain, impact on health-related QoL, and healthcare utilization. All participants signed an informed consent form prior to any study-related procedure. The study was approved by local institutional review boards in each country.

      2.2 Definition of postherpetic neuralgia

      The incidence of PHN was defined as a worst pain score of ≥3, persisting or appearing more than 90 days after the onset of rash. A previous validation study has shown that worst pain scores of ≥3 occurring ≥90 days after rash onset significantly impair QoL and activities of daily living.
      • Coplan P.M.
      • Schmader K.
      • Nikas A.
      • Chan I.S.
      • Choo P.
      • Levin M.J.
      • et al.
      Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: adaptation of the brief pain inventory.
      J Pain. 2004; 5: 344-356
      This definition was used in a clinical trial of zoster vaccination and other studies.
      • Oxman M.N.
      • Levin M.J.
      • Johnson G.R.
      • Schmader K.E.
      • Straus S.E.
      • Gelb L.D.
      • et al.
      A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.
      N Engl J Med. 2005; 352: 2271-2284

      2.3 Assessment

      A physician reviewed the patient's characteristics of HZ and treatment at the time of recruitment. To assess zoster-associated pain and its impact on activities of daily living from the patient's perspective, the Zoster Brief Pain Inventory (ZBPI) and the Initial Zoster Impact Questionnaire (IZIQ) were used. The ZBPI is a validated self-administered questionnaire that assesses the severity of pain associated with HZ using a scale from 0 (no pain) to 10 (pain as bad as you can imagine).
      • Coplan P.M.
      • Schmader K.
      • Nikas A.
      • Chan I.S.
      • Choo P.
      • Levin M.J.
      • et al.
      Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: adaptation of the brief pain inventory.
      J Pain. 2004; 5: 344-356
      The ZBPI also assesses the interference of pain with daily activities, including general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life.
      The following socio-demographics, characteristics of HZ, and health indicators were evaluated as potential predictors of PHN: age, sex, level of education, employment status, living alone, immune status, presence of other pain conditions, and pre-existing problems in the EQ-5D five health domains. The following HZ characteristics were also examined as predictors: severity of rash (number of lesions), worst pain score at rash onset, prodromal pain (duration and severity of pain), problems in EQ-5D health domains at rash onset, pain interference with daily activities at rash onset, and use of antiviral medications.

      2.4 Statistical analysis

      Baseline characteristics of HZ patients by PHN status were compared using the Chi-square test or Fisher's exact test, as appropriate, for categorical variables. To examine factors associated with the risk of developing PHN, binomial regression models were used with a log-link function and computed risk ratio (or relative risk, RR) and associated 95% confidence intervals (CI). The parsimonious multivariate regression model was built using a backward selection procedure. Variables with p < 0.20 in the univariate analysis were considered as candidates for the multivariate model, and variables with p < 0.05 were kept in the final model.

      3. Results

      A total of 702 patients with HZ were included in the analysis (Table 1). Approximately 38% of participants were aged 50–59 years, 31% were aged 60–69 years, and 31% were aged ≥70 years. The majority of patients were women (62%), and 32% reported being employed. The baseline clinical characteristics of HZ disease were generally comparable across the three geographic regions. About 58% of patients reported a severe worst pain score at rash onset (≥7). The majority of patients reported taking antiviral medications (87%).
      Table 1Baseline characteristics
      CharacteristicsAsia (Taiwan, South Korea, Thailand)

      n = 339      		Latin America (Mexico, Brazil, Argentina)

      n = 132      		North America (Canada)

      n = 231      		Total

      n = 702
      Age, years, n (%)
       50–59147 (43.4%)33 (25.2%)84 (36.4%)264 (37.7%)
       60–69110 (32.4%)44 (33.6%)64 (27.7%)218 (31.1%)
       ≥7082 (24.2%)54 (41.2%)83 (35.9%)219 (31.2%)
      Sex, n (%)
       Female205 (60.5%)87 (66.4%)140 (60.6%)432 (61.6%)
       Male134 (39.5%)44 (33.6%)91 (39.4%)269 (38.4%)
      Level of education, n (%)
       Primary/grade school128 (38.6%)63 (48.1%)32 (14.0%)223 (32.3%)
       High school120 (36.1%)27 (20.6%)94 (41.2%)241 (34.9%)
       College or university84 (25.3%)41 (31.3%)102 (44.7%)227 (32.8%)
      Employed, n (%)111 (32.7%)43 (32.8%)71 (31.0%)225 (32.2%)
      Living alone, n (%)30 (8.8%)36 (27.5%)71 (33.0%)137 (20.0%)
      Presence of other pain condition, n (%)96 (28.3%)48 (36.6%)114 (49.4%)258 (36.8%)
      Impaired immune status, n (%)36 (10.6%)21 (15.9%)9 (3.9%)66 (9.4%)
      Herpes zoster characteristics
      Primary dermatome region, n (%)
       Thoracic152 (45.0%)53 (41.7%)109 (49.3%)314 (45.8%)
       Trigeminal nerve65 (19.2%)10 (7.9%)12 (5.4%)87 (12.7%)
       Cervical67 (19.8%)36 (28.3%)42 (19.0%)145 (21.1%)
       Lumbar39 (11.5%)19 (15.0%)43 (19.5%)101 (14.7%)
       Sacral15 (4.4%)9 (7.1%)15 (6.8%)39 (5.7%)
      Severity of rash (number of lesions), n (%)
       None or <20 (mild)129 (38.1%)84 (63.6%)141 (61.3%)354 (50.5%)
       21–50 (moderate)117 (34.5%)28 (21.2%)49 (21.3%)194 (27.7%)
       ≥50 (severe)93 (27.4%)20 (15.2%)40 (17.4%)153 (21.8%)
      Worst pain score at rash onset, n (%)
       No/mild (0–2)36 (10.7%)9 (6.9%)26 (11.5%)71 (10.2%)
       Moderate (3–6)124 (36.8%)21 (16.2%)74 (32.6%)219 (31.6%)
       Severe (≥7)177 (52.5%)100 (76.9%)127 (55.9%)404 (58.2%)
      Presence of prodromal pain, n (%)227 (67.0%)88 (67.2%)175 (76.8%)490 (70.2%)
      Antiviral medications, n (%)
       Aciclovir, valaciclovir, famciclovir282 (83.2%)118 (89.4%)212 (91.8%)612 (87.2%)
       Did not receive57 (16.8%)14 (10.6%)19 (8.2%)90 (12.8%)
      Of 702 patients with HZ, 148 (21.1%) developed PHN. The age-specific risk of PHN ranged from 14.0% in adults 50–59 years of age and 20.6% in adults 60–69 years of age, to 29.7% in adults ≥70 years of age. In the univariate analysis, older age, employment status, greater severity of pain at rash onset, severe prodromal pain, problems in health domains in the EQ-5D at enrollment (except being anxious or depressed), and reported pain interference from acute HZ on activities of daily living (all seven items of ZBPI) were significantly associated with an increased risk of PHN (Table 2). No significant differences in the risk of PHN were found by geographic region, sex, level of education, living alone, immune status, presence of other pain conditions, pre-existing problems in the EQ-5D health domains, severity of rash, or use of antiviral medications during the acute phase.
      Table 2Univariate analysis: predictors of postherpetic neuralgia among patients with herpes zoster
      PredictorsDeveloped PHN, n (%)Crude RR95% CIp-Value
      Region
       Taiwan, South Korea, and Thailand66 (19.5%)0.80(0.59, 1.10)0.17
       Mexico, Brazil, and Argentina26 (19.7%)0.81(0.54, 1.23)0.32
       Canada56 (24.2%)Reference
      Age, years
       50–5937 (14.0%)Reference
       60–6945 (20.6%)1.47(0.99, 2.19)0.055
       ≥7065 (29.7%)2.12(1.48, 3.04)<0.001
      Sex
       Male55 (20.4%)Reference
       Female93 (21.5%)1.05(0.78, 1.42)0.73
      Level of education
       Primary/grade school52 (23.3%)Reference
       High school51 (21.2%)0.79(0.55, 1.14)0.21
       College or university42 (18.5%)0.91(0.65, 1.28)0.58
      Employment status
       Yes27 (12.0%)0.47(0.32, 0.69)<0.001
       No121 (25.5%)Reference
      Living alone
       Yes35 (25.5%)1.32(0.95, 1.84)0.10
       No106 (19.3%)Reference
      Health conditions
      Immune status
       Impaired13 (19.7%)0.93(0.56, 1.55)0.77
       Normal135 (21.2%)Reference
      Presence of other pain condition
       Yes56 (21.7%)1.05(0.78, 1.40)0.77
       No92 (20.8%)Reference
      Pre-existing problems in EQ-5D health domains before HZ (no problem as reference)
       Walking23 (26.4%)1.29(0.88, 1.90)0.19
       Self-care9 (25.0%)1.19(0.66, 2.14)0.56
       Usual activities17 (23.0%)1.10(0.71 1.72)0.68
       Having pain or discomfort49 (23.8%)1.18(0.88, 1.60)0.27
       Being anxious or depressed28 (17.7%)0.80(0.55, 1.16)0.23
      Herpes zoster characteristics
      Severity of rash (number of lesions)
       <20 (no/mild)65 (18.4%)Reference
       21–50 (moderate)47 (24.2%)1.32(0.95, 1.84)0.10
       ≥50 (severe)36 (23.5%)1.28(0.89, 1.84)0.18
      Worst pain score at rash onset
       No/mild (0–2)4 (5.6%)Reference
       Moderate (3–6)33 (15.1%)2.68(0.98, 7.29)0.054
       Severe (≥7)109 (27.0%)4.79(1.82, 12.58)0.001
      Duration of prodromal pain
       None38 (18.3%)Reference
       1–2 days25 (17.5%)0.96(0.61, 1.51)0.85
       3–4 days41 (24.3%)1.33(0.90, 1.97)0.16
       ≥5 days40 (23.3%)1.27(0.86, 1.89)0.23
      Worst pain score for prodromal pain
       No/mild (0–2)39 (15.5%)Reference
       Moderate (3–6)39 (20.4%)1.32(0.88, 1.97)0.18
       Severe (≥7)67 (27.1%)1.75(1.23, 2.50)0.002
      Problems in EQ-5D health domains at enrollment (no problem as reference)
       Walking62 (31.8%)1.87(1.41, 2.48)<0.001
       Self-care42 (32.8%)1.77(1.31, 2.39)<0.001
       Usual activities80 (27.8%)1.69(1.27, 2.25)<0.001
       Having pain or discomfort130 (23.4%)1.91(1.20, 3.06)0.007
       Being anxious or depressed82 (23.6%)1.27(0.95, 1.69)0.11
      Pain interference at enrollment, reported ≥5 (<5 as reference)
       General activity91 (27.7%)1.83(1.36, 2.47)<0.001
       Mood86 (26.1%)1.59(1.18, 2.12)0.002
       Walking ability50 (31.3%)1.73(1.29, 2.32)<0.001
       Normal work77 (27.4%)1.64(1.23, 2.19)0.001
       Relations with other people65 (31.9%)1.94(1.46, 2.57)<0.001
       Sleep94 (26.0%)1.65(1.22, 2.23)0.001
       Enjoyment of life85 (26.0%)1.56(1.17, 2.09)0.003
      Antiviral medications
       Aciclovir, valaciclovir, famciclovir133 (21.7%)1.30(0.80, 2.12)0.28
       Did not receive15 (16.7%)Reference
      Timely antiviral medications
       Received within 72 h of rash onset70 (18.6%)1.61(0.97, 2.67)0.067
       Received after 72 h of rash onset63 (26.8%)1.11(0.67, 1.85)0.68
       Did not receive15 (16.7%)Reference
      PHN, postherpetic neuralgia; RR, relative risk; CI, confidence interval; HZ, herpes zoster.
      In the multivariable regression model (Table 3), older age (60–69 vs. 50–59 years, RR 1.20, 95% CI 0.81–1.79; ≥70 vs. 50–59 years, RR 1.72, 95% CI 1.18–2.51), greater severity of pain at rash onset (moderate vs. no/mild, RR 2.46, 95% CI 0.91–6.66; severe vs. no/mild RR 3.58, 95% CI 1.36–9.45), employment status (RR 0.58, 95% CI 0.38–0.89), walking problems at enrollment (RR 1.47, 95% CI 1.11–1.93), and pain interference affecting relationships with other people (RR 1.69, 95% CI 1.27–2.25) were significantly associated with the development of PHN.
      Table 3Multivariate analysis: predictors of postherpetic neuralgia among patients with herpes zoster
      PredictorsAdjusted RR95% CIp-Value
      Age, years
       50–59Reference
       60–691.20(0.81, 1.79)0.36
       ≥701.72(1.18, 2.51)0.005
      Employment status
       Yes0.58(0.38, 0.89)0.012
       NoReference
      Worst pain score at rash onset
       No/mild (0–2)Reference
       Moderate (3–6)2.46(0.91, 6.66)0.077
       Severe (≥7)3.58(1.36, 9.45)0.01
      Walking problems at enrollment
       Yes1.47(1.11, 1.93)0.006
       NoReference
      Pain interference at enrollment, relations with other people
       Yes1.69(1.27, 2.25)<0.001
       NoReference
      RR, relative risk; CI, confidence interval.

      4. Discussion

      The risk of developing PHN, defined as a pain score of ≥3 lasting or appearing more than 90 days after rash onset, was approximately 21% in this prospective cohort study of patients with HZ from North and Latin America and Asia. Older age, greater severity of pain at rash onset, employment status, walking problems at enrollment, and pain interference affecting relationships with other people, were identified as independent predictors of PHN.
      Approximately 21% of patients aged ≥50 years developed PHN, with the risk increasing with older age. The risk of PHN was almost 30% among patients aged ≥70 years. A number of prospective cohort studies across countries have also noted a high risk of PHN, ranging from approximately 10% to ≥30%, in elderly patients with HZ.
      • Yawn B.P.
      • Saddier P.
      • Wollan P.C.
      • St Sauver J.L.
      • Kurland M.J.
      • Sy L.S.
      A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction.
      Mayo Clin Proc. 2007; 82: 1341-1349
      , 
      • Kawai K.
      • Gebremeskel B.G.
      • Acosta C.J.
      Systematic review of incidence and complications of herpes zoster: towards a global perspective.
      BMJ Open. 2014; 4: e004833
      , 
      • Parruti G.
      • Tontodonati M.
      • Rebuzzi C.
      • Polilli E.
      • Sozio F.
      • Consorte A.
      • et al.
      Predictors of pain intensity and persistence in a prospective Italian cohort of patients with herpes zoster: relevance of smoking, trauma and antiviral therapy.
      BMC Med. 2010; 8: 58
      , 
      • Gauthier A.
      • Breuer J.
      • Carrington D.
      • Martin M.
      • Rémy V.
      Epidemiology and cost of herpes zoster and post-herpetic neuralgia in the United Kingdom.
      Epidemiol Infect. 2009; 137: 38-47
      A population-based, retrospective cohort study in the USA found that the risk of PHN (defined as at least 90 days of documented pain) was 10% in adults 60–69 years of age, 17% in adults 70–79 years of age, and 20% in adults ≥80 years of age.
      • Yawn B.P.
      • Saddier P.
      • Wollan P.C.
      • St Sauver J.L.
      • Kurland M.J.
      • Sy L.S.
      A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction.
      Mayo Clin Proc. 2007; 82: 1341-1349
      The generally higher estimate in the current analysis could be explained by the fact that patients were followed prospectively thus allowing a more accurate assessment of pain, or by differences in the populations included. It is also possible that patients with severe cases of HZ were more likely to have participated in the present study.
      It is well-recognized that a greater severity of acute pain at rash onset is a risk factor for PHN (Table 4).
      • Whitley R.J.
      • Shukla S.
      • Crooks R.J.
      The identification of risk factors associated with persistent pain following herpes zoster.
      J Infect Dis. 1998; 178: S71-S75
      , 
      • Dworkin R.H.
      • Boon R.J.
      • Griffin D.R.
      • Phung D.
      Postherpetic neuralgia: impact of famciclovir, age, rash severity, and acute pain in herpes zoster patients.
      J Infect Dis. 1998; 178: S76-S80
      , 
      • Nagasako E.M.
      • Johnson R.W.
      • Griffin D.R.
      • Dworkin R.H.
      Rash severity in herpes zoster: correlates and relationship to postherpetic neuralgia.
      J Am Acad Dermatol. 2002; 46: 834-839
      , 
      • Decroix J.
      • Partsch H.
      • Gonzalez R.
      • Mobacken H.
      • Goh C.L.
      • Walsh L.
      • et al.
      Factors influencing pain outcome in herpes zoster: an observational study with valaciclovir. Valaciclovir International Zoster Assessment Group (VIZA).
      J Eur Acad Dermatol Venereol. 2000; 14: 23-33
      , 
      • Haanpaa M.
      • Laippala P.
      • Nurmikko T.
      Allodynia and pinprick hypesthesia in acute herpes zoster, and the development of postherpetic neuralgia.
      J Pain Symptom Manage. 2000; 20: 50-58
      , 
      • Kurokawa I.
      • Kumano K.
      • Murakawa K.
      Clinical correlates of prolonged pain in Japanese patients with acute herpes zoster.
      J Int Med Res. 2002; 30: 56-65
      , 
      • Scott F.T.
      • Leedham-Green M.E.
      • Barrett-Muir W.Y.
      • Hawrami K.
      • Gallagher W.J.
      • Johnson R.
      • et al.
      A study of shingles and the development of postherpetic neuralgia in East London.
      J Med Virol. 2003; 70: S24-S30
      , 
      • Jung B.F.
      • Johnson R.W.
      • Griffin D.R.
      • Dworkin R.H.
      Risk factors for postherpetic neuralgia in patients with herpes zoster.
      Neurology. 2004; 62: 1545-1551
      , 
      • Katz J.
      • McDermott M.P.
      • Cooper E.M.
      • Walther R.R.
      • Sweeney E.W.
      • Dworkin R.H.
      Psychosocial risk factors for postherpetic neuralgia: a prospective study of patients with herpes zoster.
      J Pain. 2005; 6: 782-790
      , 
      • Coen P.G.
      • Scott F.
      • Leedham-Green M.
      • Nia T.
      • Jamil A.
      • Johnson R.W.
      • et al.
      Predicting and preventing post-herpetic neuralgia: are current risk factors useful in clinical practice?.
      Eur J Pain. 2006; 10: 695-700
      , 
      • Opstelten W.
      • Zuithoff N.P.
      • van Essen G.A.
      • van Loon A.M.
      • van Wijck A.J.
      • Kalkman C.J.
      • et al.
      Predicting postherpetic neuralgia in elderly primary care patients with herpes zoster: prospective prognostic study.
      Pain. 2007; 132: S52-S59
      , 
      • Volpi A.
      • Gatti A.
      • Pica F.
      • Bellino S.
      • Marsella L.T.
      • Sabato A.F.
      Clinical and psychosocial correlates of post-herpetic neuralgia.
      J Med Virol. 2008; 80: 1646-1652
      , 
      • Drolet M.
      • Brisson M.
      • Schmader K.
      • Levin M.
      • Johnson R.
      • Oxman M.
      • et al.
      Predictors of postherpetic neuralgia among patients with herpes zoster: a prospective study.
      J Pain. 2010; 11: 1211-1221
      , 
      • Parruti G.
      • Tontodonati M.
      • Rebuzzi C.
      • Polilli E.
      • Sozio F.
      • Consorte A.
      • et al.
      Predictors of pain intensity and persistence in a prospective Italian cohort of patients with herpes zoster: relevance of smoking, trauma and antiviral therapy.
      BMC Med. 2010; 8: 58
      , 
      • Kanbayashi Y.
      • Onishi K.
      • Fukazawa K.
      • Okamoto K.
      • Ueno H.
      • Takagi T.
      • et al.
      Predictive factors for postherpetic neuralgia using ordered logistic regression analysis.
      Clin J Pain. 2012; 28: 712-714
      , 
      • Bouhassira D.
      • Chassany O.
      • Gaillat J.
      • Hanslik T.
      • Launay O.
      • Mann C.
      • et al.
      Patient perspective on herpes zoster and its complications: an observational prospective study in patients aged over 50 years in general practice.
      Pain. 2012; 153: 342-349
      Those who suffered from severe pain most likely had a severe infection, resulting in substantial neural damage. Consistent with prior studies, the present study confirmed that the severity of acute pain is a risk factor for PHN. Biological and psychosocial factors are important in understanding the pathophysiology of chronic pain.
      • Katz J.
      • McDermott M.P.
      • Cooper E.M.
      • Walther R.R.
      • Sweeney E.W.
      • Dworkin R.H.
      Psychosocial risk factors for postherpetic neuralgia: a prospective study of patients with herpes zoster.
      J Pain. 2005; 6: 782-790
      , 
      • Dworkin R.H.
      • Banks S.M.
      A vulnerability–diathesis–stress model of chronic pain: herpes zoster and the development of postherpetic neuralgia.
      in: Gatchel R.J. Turk D.C. Psychosocial factors in pain: critical perspectives. The Guilford Press, 1999
      Thus, an evaluation was done to determine whether pain-related interference with diverse activities of daily living and living alone are associated with an increased risk of the development of PHN. It was found that walking problems at enrollment and HZ pain interference affecting relationships with other people remained significant predictors of PHN in the multivariate analysis. It was also found that working adults, who are most likely healthy and active, were less likely to develop PHN. Although few studies have evaluated such factors, they have also suggested that impaired physical and social functioning may play a role in the development of PHN.
      • Katz J.
      • McDermott M.P.
      • Cooper E.M.
      • Walther R.R.
      • Sweeney E.W.
      • Dworkin R.H.
      Psychosocial risk factors for postherpetic neuralgia: a prospective study of patients with herpes zoster.
      J Pain. 2005; 6: 782-790
      , 
      • Drolet M.
      • Brisson M.
      • Schmader K.
      • Levin M.
      • Johnson R.
      • Oxman M.
      • et al.
      Predictors of postherpetic neuralgia among patients with herpes zoster: a prospective study.
      J Pain. 2010; 11: 1211-1221
      , 
      • Bouhassira D.
      • Chassany O.
      • Gaillat J.
      • Hanslik T.
      • Launay O.
      • Mann C.
      • et al.
      Patient perspective on herpes zoster and its complications: an observational prospective study in patients aged over 50 years in general practice.
      Pain. 2012; 153: 342-349
      , 
      • Haythornthwaite J.A.
      • Clark M.R.
      • Pappagallo M.
      • Raja S.N.
      Pain coping strategies play a role in the persistence of pain in post-herpetic neuralgia.
      Pain. 2003; 106: 453-460
      Patients with predisposing vulnerabilities, possibly with a reduced threshold of nociception as a result of genetic factors or prior stressful life events, are more likely to be vulnerable and suffer greatly from severe infection and develop PHN.
      • Dworkin R.H.
      • Banks S.M.
      A vulnerability–diathesis–stress model of chronic pain: herpes zoster and the development of postherpetic neuralgia.
      in: Gatchel R.J. Turk D.C. Psychosocial factors in pain: critical perspectives. The Guilford Press, 1999
      Table 4Prior studies examining predictors of postherpetic neuralgia (PHN)
      ReferencesPHN definitionRisk of PHNPredictors of PHN
      Whitley et al.
      • Whitley R.J.
      • Shukla S.
      • Crooks R.J.
      The identification of risk factors associated with persistent pain following herpes zoster.
      J Infect Dis. 1998; 178: S71-S75
      		Prolonged HZ-associated painNA (n = 2367)Age, severity of acute pain, and presence of prodromal pain
      Dworkin et al.
      • Dworkin R.H.
      • Boon R.J.
      • Griffin D.R.
      • Phung D.
      Postherpetic neuralgia: impact of famciclovir, age, rash severity, and acute pain in herpes zoster patients.
      J Infect Dis. 1998; 178: S76-S80
      ; Nagasako et al.
      • Nagasako E.M.
      • Johnson R.W.
      • Griffin D.R.
      • Dworkin R.H.
      Rash severity in herpes zoster: correlates and relationship to postherpetic neuralgia.
      J Am Acad Dermatol. 2002; 46: 834-839
      		Pain persisting for ≥30 or ≥90 days30% (n = 419)Age, severity of acute pain, severity of rash, and antiviral treatment
      Decroix et al.
      • Decroix J.
      • Partsch H.
      • Gonzalez R.
      • Mobacken H.
      • Goh C.L.
      • Walsh L.
      • et al.
      Factors influencing pain outcome in herpes zoster: an observational study with valaciclovir. Valaciclovir International Zoster Assessment Group (VIZA).
      J Eur Acad Dermatol Venereol. 2000; 14: 23-33
      		Prolonged HZ-associated painNA (n = 1897)Age, severity of acute pain, intensity of prodromal pain, HZ ophthalmicus
      Haanpaa et al.
      • Haanpaa M.
      • Laippala P.
      • Nurmikko T.
      Allodynia and pinprick hypesthesia in acute herpes zoster, and the development of postherpetic neuralgia.
      J Pain Symptom Manage. 2000; 20: 50-58
      		Pain persisting for ≥90 days25% (28/113)Age, severity of acute pain, and allodynia
      Kurokawa et al.
      • Kurokawa I.
      • Kumano K.
      • Murakawa K.
      Clinical correlates of prolonged pain in Japanese patients with acute herpes zoster.
      J Int Med Res. 2002; 30: 56-65
      		Pain persisting for ≥90 daysNA (n = 263)Age, severity of rash, disturbed sleep, and hypaesthesia
      Scott et al.
      • Scott F.T.
      • Leedham-Green M.E.
      • Barrett-Muir W.Y.
      • Hawrami K.
      • Gallagher W.J.
      • Johnson R.
      • et al.
      A study of shingles and the development of postherpetic neuralgia in East London.
      J Med Virol. 2003; 70: S24-S30
      		Pain persisting for ≥90 days27% (42/153)Age and severity of acute pain
      Jung et al.
      • Jung B.F.
      • Johnson R.W.
      • Griffin D.R.
      • Dworkin R.H.
      Risk factors for postherpetic neuralgia in patients with herpes zoster.
      Neurology. 2004; 62: 1545-1551
      		Pain persisting for ≥120 days12% (114/965)Age, female sex, severity of acute pain, severity of rash, and presence of prodromal pain
      Katz et al.
      • Katz J.
      • McDermott M.P.
      • Cooper E.M.
      • Walther R.R.
      • Sweeney E.W.
      • Dworkin R.H.
      Psychosocial risk factors for postherpetic neuralgia: a prospective study of patients with herpes zoster.
      J Pain. 2005; 6: 782-790
      		Pain persisting for ≥120 days20% (20/102)Age, severity of acute pain, and psychosocial factors
      Coen et al.
      • Coen P.G.
      • Scott F.
      • Leedham-Green M.
      • Nia T.
      • Jamil A.
      • Johnson R.W.
      • et al.
      Predicting and preventing post-herpetic neuralgia: are current risk factors useful in clinical practice?.
      Eur J Pain. 2006; 10: 695-700
      		Pain score ≥3 persisting for ≥90 or ≥180 days9.6% (24/250)Age and severity of acute pain
      Opstelten et al.
      • Opstelten W.
      • Zuithoff N.P.
      • van Essen G.A.
      • van Loon A.M.
      • van Wijck A.J.
      • Kalkman C.J.
      • et al.
      Predicting postherpetic neuralgia in elderly primary care patients with herpes zoster: prospective prognostic study.
      Pain. 2007; 132: S52-S59
      		Pain score ≥3 persisting for ≥90 days8% (46/598)Age, severity of acute pain, severity of rash, and duration of rash before consultation
      Volpi et al.
      • Volpi A.
      • Gatti A.
      • Pica F.
      • Bellino S.
      • Marsella L.T.
      • Sabato A.F.
      Clinical and psychosocial correlates of post-herpetic neuralgia.
      J Med Virol. 2008; 80: 1646-1652
      		Pain score ≥3 persisting for ≥180 days32% (70/219)Age, severity of acute pain, severity of rash, and longer duration of prodromal pain
      Drolet et al.
      • Drolet M.
      • Brisson M.
      • Schmader K.
      • Levin M.
      • Johnson R.
      • Oxman M.
      • et al.
      Predictors of postherpetic neuralgia among patients with herpes zoster: a prospective study.
      J Pain. 2010; 11: 1211-1221
      		Pain score ≥3 persisting for ≥90 days22.5% (56/249)Age, severity of acute pain, and limitation in performing usual activities
      Parruti et al.
      • Parruti G.
      • Tontodonati M.
      • Rebuzzi C.
      • Polilli E.
      • Sozio F.
      • Consorte A.
      • et al.
      Predictors of pain intensity and persistence in a prospective Italian cohort of patients with herpes zoster: relevance of smoking, trauma and antiviral therapy.
      BMC Med. 2010; 8: 58
      		Pain persisting for ≥30 or ≥90 days30% (130/441)Age, severity of acute pain, smoking, trauma, and missed antiviral prescription
      Kanbayashi et al.
      • Kanbayashi Y.
      • Onishi K.
      • Fukazawa K.
      • Okamoto K.
      • Ueno H.
      • Takagi T.
      • et al.
      Predictive factors for postherpetic neuralgia using ordered logistic regression analysis.
      Clin J Pain. 2012; 28: 712-714
      		Pain persisting for ≥90 days52% (38/73)Age and deep pain
      Bouhassira et al.
      • Bouhassira D.
      • Chassany O.
      • Gaillat J.
      • Hanslik T.
      • Launay O.
      • Mann C.
      • et al.
      Patient perspective on herpes zoster and its complications: an observational prospective study in patients aged over 50 years in general practice.
      Pain. 2012; 153: 342-349
      		Pain persisting for ≥90 days11.6% (127/1091)Age, male sex, neuropathic quality of pain, interference of pain on daily activities, and physical component summary score
      NA, not available.
      Dworkin et al. and several other investigators have found that a greater severity of rash is a risk factor for PHN.
      • Dworkin R.H.
      • Boon R.J.
      • Griffin D.R.
      • Phung D.
      Postherpetic neuralgia: impact of famciclovir, age, rash severity, and acute pain in herpes zoster patients.
      J Infect Dis. 1998; 178: S76-S80
      , 
      • Kurokawa I.
      • Kumano K.
      • Murakawa K.
      Clinical correlates of prolonged pain in Japanese patients with acute herpes zoster.
      J Int Med Res. 2002; 30: 56-65
      , 
      • Jung B.F.
      • Johnson R.W.
      • Griffin D.R.
      • Dworkin R.H.
      Risk factors for postherpetic neuralgia in patients with herpes zoster.
      Neurology. 2004; 62: 1545-1551
      , 
      • Opstelten W.
      • Zuithoff N.P.
      • van Essen G.A.
      • van Loon A.M.
      • van Wijck A.J.
      • Kalkman C.J.
      • et al.
      Predicting postherpetic neuralgia in elderly primary care patients with herpes zoster: prospective prognostic study.
      Pain. 2007; 132: S52-S59
      , 
      • Volpi A.
      • Gatti A.
      • Pica F.
      • Bellino S.
      • Marsella L.T.
      • Sabato A.F.
      Clinical and psychosocial correlates of post-herpetic neuralgia.
      J Med Virol. 2008; 80: 1646-1652
      However, the present study did not confirm this association. Prospective cohort studies with participants recruited from real-world community settings (as opposed to participants in clinical trials) have also shown the severity of rash not to be a risk factor for PHN.
      • Scott F.T.
      • Leedham-Green M.E.
      • Barrett-Muir W.Y.
      • Hawrami K.
      • Gallagher W.J.
      • Johnson R.
      • et al.
      A study of shingles and the development of postherpetic neuralgia in East London.
      J Med Virol. 2003; 70: S24-S30
      , 
      • Coen P.G.
      • Scott F.
      • Leedham-Green M.
      • Nia T.
      • Jamil A.
      • Johnson R.W.
      • et al.
      Predicting and preventing post-herpetic neuralgia: are current risk factors useful in clinical practice?.
      Eur J Pain. 2006; 10: 695-700
      , 
      • Bouhassira D.
      • Chassany O.
      • Gaillat J.
      • Hanslik T.
      • Launay O.
      • Mann C.
      • et al.
      Patient perspective on herpes zoster and its complications: an observational prospective study in patients aged over 50 years in general practice.
      Pain. 2012; 153: 342-349
      It is possible that due to the wide recruitment window in the present study (up to 14 days since rash onset), the rash in some patients may have alleviated, which may have limited our ability to observe such an association.
      Other possible predictors of PHN were also evaluated. Several studies have suggested that a severe or longer duration of prodromal pain may increase the risk of developing PHN.
      • Whitley R.J.
      • Shukla S.
      • Crooks R.J.
      The identification of risk factors associated with persistent pain following herpes zoster.
      J Infect Dis. 1998; 178: S71-S75
      , 
      • Decroix J.
      • Partsch H.
      • Gonzalez R.
      • Mobacken H.
      • Goh C.L.
      • Walsh L.
      • et al.
      Factors influencing pain outcome in herpes zoster: an observational study with valaciclovir. Valaciclovir International Zoster Assessment Group (VIZA).
      J Eur Acad Dermatol Venereol. 2000; 14: 23-33
      , 
      • Jung B.F.
      • Johnson R.W.
      • Griffin D.R.
      • Dworkin R.H.
      Risk factors for postherpetic neuralgia in patients with herpes zoster.
      Neurology. 2004; 62: 1545-1551
      In the present study, the presence of severe prodromal pain was associated with an increased risk of PHN in the univariate analysis, but it did not remain significant after adjusting for severity of acute pain and other factors in the multivariate analysis. Although a few studies have suggested that female sex may be a risk factor, the majority of prior studies and the present study found no difference in the risk of PHN between women and men. Antiviral therapy is important to reduce the replication of the virus and the severity and duration of pain during the acute phase. However, consistent with a recent review, timely antiviral medication was not associated with the incidence of PHN in the present study.
      • Chen N.
      • Li Q.
      • Yang J.
      • Zhou M.
      • Zhou D.
      • He L.
      Antiviral treatment for preventing postherpetic neuralgia.
      Cochrane Database Syst Rev. 2014; 2: CD006866
      Several limitations of this study are worth noting. Patients who participated may not comprise a random sample of patients from the general population, possibly limiting the generalizability of the results. The type of pain was not characterized, which may have allowed a better understanding of the pathophysiology of PHN. Patients suffering from PHN experience different types of pain, presumably because of different pathophysiological mechanisms involving sensitization in the peripheral and central nervous system, deafferentation, and possibly chronic inflammation.
      • Johnson R.W.
      • Wasner G.
      • Saddier P.
      • Baron R.
      Postherpetic neuralgia: epidemiology, pathophysiology and management.
      Expert Rev Neurother. 2007; 7: 1581-1595
      , 
      • Schmader K.E.
      • Dworkin R.H.
      Herpes zoster and postherpetic neuralgia.
      in: Benzon H.T. Raja S.N. Liu S.S. Fishman S.M. Cohen S.P. Hurley R.W. Essentials of pain medicine.Third ed. W.B. Saunders, Saint Louis2011: 358-364
      This study has several strengths. The findings are based on a methodologically robust, prospective cohort study using the same questionnaires across countries. Prior research has rarely been conducted in Latin America and Asia; thus, a multi-country study including those regions was conducted. Multiple different definitions of PHN have been used previously. However, the validated definition of PHN, which is a pain score of ≥3 (clinically meaningful pain) lasting or appearing more than 90 days after rash onset, was used in the present research.
      In conclusion, the risk of developing PHN was over 20% in this prospective cohort study of patients with HZ from North and Latin America and Asia. It is confirmed that older age and a greater severity of pain at rash onset are risk factors for PHN. Additionally, this study suggests that impaired physical and social functioning from acute pain of HZ may also be risk factors for PHN. HZ patients who are at greater risk of developing PHN should be monitored closely for early treatment. Early prevention through vaccination should be considered to reduce the risk of developing HZ and PHN.
      Funding: The funding for this analysis was provided by Merck & Co., Inc.
      Ethical approval: Approval for this post-hoc analysis of available data was not required.
      Conflict of interest: KK was a consultant for Merck & Co., Inc. ER, LY, and JSS are employees of JSS Medical Research, the contract Research Organization responsible for the management of the MASTER studies and data analysis. TFT has performed clinical trials and has received speaking fees from MSD. HJC and JD have no conflicts of interest. AOC has received payments to speak from Merck Sharp & Dohme, Abbott Laboratories, Bayer Health Care, and Sanofi Laboratories. HM is an employee of Merck (Latin America Health Outcomes Research Ugad). KJ is a post-doctoral research fellow at Temple University funded by Merck & Co., Inc. MCC is an employee of Merck and Co., Inc. CJA is an employee of Merck Global Health Outcomes – Vaccines.

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      Article info

      Publication history

      Published online: April 01, 2015
      Accepted: March 26, 2015
      Received in revised form: March 19, 2015
      Received: December 23, 2014
      Corresponding Editor: Eskild Petersen, Aarhus, Denmark

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      DOI: https://doi.org/10.1016/j.ijid.2015.03.022

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