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. Author manuscript; available in PMC: 2008 Mar 1.
Published in final edited form as: Pain. 2006 Oct 27;128(1-2):148–156. doi: 10.1016/j.pain.2006.09.021

Natural History of Pain Following Herpes Zoster

Hans Gustav Thyregod 1, Michael C Rowbotham 1, Michelle Peters 1, Jessica Possehn 1, Marlene Berro 1, Karin Lottrup Petersen 1
PMCID: PMC1905461  NIHMSID: NIHMS19219  PMID: 17070998

Abstract

In a longitudinal observational study of 94 patients (39M:55F, mean age 69) at elevated risk for developing post herpetic neuralgia (PHN), the natural history of pain during the first 6 months after herpes zoster (HZ) rash onset was determined. Pain severity and impact were rated using pain-VAS, SF-MPQ, and MPI.

Applying a definition of PHN of average daily pain >0/100 on the pain VAS during the last 48 hours, 30 subjects had PHN at 6 months. These 30 subjects reported more pain and a higher SF-MPQ score (p<0.01) at study inclusion than the 64 subjects whose pain completely resolved by 6 months. At 6 months, mean daily pain in the PHN group was 11/100 (95% CI 5,16) and only nine of these subjects were still taking prescription medication for HZ pain. The rate of recovery (pain severity over time) was the same in the PHN and no-pain groups. At study inclusion, the SF-MPQ and MPI scores in our PHN group were similar to historical controls with chronic severe PHN enrolled in clinical trials, but by 6 months the scores in our PHN subjects were significantly lower than historic controls. Only two subjects met the more stringent criteria for ‘clinically meaningful’ PHN at 6 months (≥30/100 on the pain VAS).

Defining PHN as average daily pain >0/100 at 6 months after rash onset appears to substantially overestimate the number of HZ patients negatively impacted by ongoing pain and disability.

Keywords: AHZ, post herpetic neuralgia, questionnaires, SFMPQ, MPI, diagnostic criteria

INTRODUCTION

Herpes zoster (HZ) is caused by reactivation of the varicella-zoster virus (VZV) in dorsal root ganglion neurons. Clinically, the disease manifests as a painful dermatomal, unilateral, vesicular rash (Dworkin and Portenoy 1996). Post-herpetic neuralgia (PHN), the most common complication of HZ in immunocompetent subjects, is characterized by persisting pain in the affected dermatome after rash healing and which lasts for years (Kost and Straus 1996; Rowbotham and Petersen 2001). Identifying those at highest risk for developing PHN as early as possible during HZ could optimize treatment and prevent chronicity in this population (Dworkin 1997; Dworkin and Schmader 2001; Johnson 2001). Longitudinal studies have identified age, initial pain severity, presence of prodrome, and rash severity as risk factors for persistence of pain after HZ (DeMoragas and Kierland 1957; Hope-Simpson 1975; Dworkin and Portenoy 1996; Choo et al. 1997; Dworkin and Schmader 2001; Nagasako et al. 2002; Jung et al. 2004). Other reported risk factors include sensory dysfunction in the affected dermatome (Nurmikko and Bowsher 1990; Bruxelle 1995), mechanical allodynia and prodromal pain(Choo et al. 1997; Whitley et al. 1998; Haanpää et al. 2000; Jung et al. 2004), and psychosocial variables (Dworkin et al. 1992; Rose et al. 1992; Engberg et al. 1995).

Definitions of PHN have varied. Most define PHN as ‘presence of pain’ without specifying a numerical threshold, but use different time points after rash onset or rash healing (Watson et al. 1991; Dworkin and Portenoy 1996; Helgason et al. 2000; Dworkin and Schmader 2001). Across a group of studies that includes those from before the introduction of antiviral drugs, the incidence of PHN defined as ‘presence of pain’ ranges between 7–25% at three months and 5–13% at six months (McKendrick et al. 1989, Crooks et al. 1991; Beutner et al. 1995; Bruxelle 1995; Haanpää et al. 2000; Helgason et al. 2000; Dworkin and Schmader 2001; Coplan et al. 2004, Scott et al. 2006). The term ‘clinically meaningful’ PHN, defined as pain of 30 or higher in the 0-100mm pain VAS to exclude those with mild pain, was employed in the recent shingles vaccine study (Coplan et al. 2004; Oxman et al. 2005).

The objective of this longitudinal observational study was to describe the natural history of pain severity and impact during the first 6 months after HZ onset in a cohort of patients whose age and pain severity conferred an elevated risk of developing PHN.

METHODS

Subjects

Immunocompetent subjects in stable health over the age of 50 with cervical, thoracic, lumbar, or sacral outbreaks of HZ were eligible if subject-reported average daily pain over the last 48 hours prior to the study inclusion visit was at least 20 on the 0–100 mm pain VAS. Subjects were excluded if they had other neurological dysfunction, significant cognitive impairment, psychiatric disorder severe enough to interfere with study procedures, another pain problem of equal or greater severity than HZ, or signs of stroke, myelopathy or progressive malignant disease. Subjects were not permitted to use medicated topical agents or receive nerve blocks or neurosurgical procedures for pain while enrolled, but were allowed to use oral medications prescribed by their treating physician. The diagnosis of HZ was based on physical exam by the study physician and review of available medical records. Subjects were recruited through newspaper ads, physician referrals, and community outreach efforts. All subjects provided written informed consent. The study was conducted in accordance with the Helsinki Declaration and approved by the Committee on Human Research at the University of California, San Francisco.

Study procedures and outcome measures

The study included a total of four visits over a 6 month period. The study inclusion visit was performed within 2–6 weeks after rash onset, visit 2 at 6–8 weeks, visit 3 at 3 months, and visit 4 at 6 months. The study inclusion visit included a detailed general medical history and a complete physical and neurological exam that was updated at subsequent visits. At every visit, subjects rated their ‘average daily pain over the last 48 hours’ using a handheld 0–100 mm pain VAS (0 mm=’no pain’ and 100 mm=’worst pain imaginable’). Rash severity was graded by the investigator at the study inclusion visit as mild (<25% of the linear dermatome affected with lesions), moderate (25–75%), or severe (>75%). Detailed sensory examination, quantitative assessments of thermal and touch sensation, capsaicin response test, and skin biopsies for assessment of cutaneous nerve density were also performed and will be reported separately. Subjects with facial or ophthalmic HZ were not eligible to avoid application of capsaicin and collection of skin biopsies in the face. Specific case examples from the study cohort have been previously reported (Berry et al. 2004).

Definition of PHN

PHN was defined as average daily pain ratings over the last 48 hours > 0/100 on the pain VAS at 6 months after rash onset. ‘Clinically meaningful’ PHN was defined as average daily pain ratings over the previous 48 hours ≥30/100 on the pain VAS at 6 months after rash onset (Coplan et al. 2004).

Questionnaires

Short-Form McGill Pain Questionnaire (SF-MPQ)

The SF-MPQ (Melzack 1987) was used to assess pain at all four visits. Fifteen pain descriptors (11 sensory, 4 affective) are rated by the subjects on a four-point intensity scale (0=none to 3=severe) regarding the preceeding week. For data analysis, three scores are derived: 1) sensory score (descriptors: ‘throbbing’, ‘shooting’, ‘stabbing’, ‘sharp’, ‘cramping’, ‘gnawing’, ‘hot-burning’, ‘aching’, ‘heavy’, ‘tender’, and ‘splitting’); 2) affective score (descriptors: ‘tiring-exhausting’, ‘sickening’, ‘fearful’, and ‘punishing-cruel’); and 3) total score (sensory plus affective score).

Multidimensional Pain Inventory (MPI)

The MPI (Kerns et al. 1985) was administered at all four visits. The MPI consists of 12 scales grouped into three domains: 1) the impact of pain on the subject’s life, 2) the responses of others to the subject’s communications of pain, and 3) the extent to which the subject participates in common daily activities. Five scales are used to assess pain impact (‘pain severity’, ‘interference’, ‘life control’, ‘affective distress’, and ‘support’). Three scales are used to assess the response by others to the subject’s pain complaint (‘negative’, ‘solicitous’, and ‘distracting responses’). Four scales are used to assess effect on daily activities (‘household chores’, ‘outdoor work’, ‘activities away from home’, and ‘social activities’). After completion, a ‘general activity level’ is calculated as a mean of the four activity scales. Each scale is comprised of between 3–11 statements (e.g., “How much has your pain interfered with your ability to get enough sleep?”), and each statement is rated on a seven-point scale (0=’no interference’ and 6=’extreme interference’). The mean score for each of the 12 scales is the sum of all the scale’s statement ratings divided by the number of statements in the scale.

Ways of Coping Questionnaire (WAYS)

As a measure of subject coping strategies, WAYS (Folkman and Lazarus 1988) was administered at study inclusion and 6 months after rash onset. The questionnaire is used to assess the thoughts and actions subjects employ in order to cope with stressful events in everyday living. In this study, coping was assessed as a trait and not specifically related to coping with the pain of HZ. Subjects were asked to think of a time or an event that was particularly stressful, but were not asked to specify the time or event. The questionnaire consists of 66 statements on ways of coping with stress (e.g., “I tried to keep my feelings to myself” or “I asked a relative or friend I respect for advice”). Statements are grouped into 8 overall coping strategies (between 4–8 statements per strategy): ‘Confrontive coping’, ‘distancing’, ‘seeking social support’, ‘accepting responsibility’, ‘planful problem solving’, ‘positive appraisal’, ‘self-controlling’, and ‘escape-avoidance’. The subjects rate to what extent they use each of the ways of coping described in the 66 statements on a four-point scale (0=“does not apply or not used” to 3=“used a great deal”). Two scores were calculated: A mean score for each strategy (the sum of the ratings on the statements within the strategy divided by the number of statements within the strategy), and a relative score for each strategy (the mean score for each strategy divided by the sum of mean scores for all 8 strategies). Relative scores reflect the proportion of the total coping effort represented by each type of coping strategy.

Life Events Checklist (LEC)

To assess the impact of stressful life events within the last 12 months on the natural history of pain, the LEC (Cohen et al. 1991) was administered at study entry and again at 6 months after rash onset. The checklist consists of 24 common potentially stressful events that are grouped into those that might have occurred in the life of the subject (‘self’ events) or in those close to the subject (‘other’ events). Events are grouped as ‘negative’ or ‘positive’ based on additional questions regarding the perception of each life event. Examples of events were moving, death, divorce, and broken relationship. A sum of all events (negative and positive ‘self’ and ‘other’ events) was calculated.

Data Analysis

Demographic and non-repeated measures were analyzed using a non-parametric two-tailed Fisher’s exact test for categorical variables and two-tailed Mann-Whitney rank-sum test for continuous variables. Because the interval from rash onset to the 4 study visits was variable between subjects, the repeated measures data were analyzed using a mixed effects regression model with predictors: PHN at 6 months (y/n), Visit Day (days since rash onset), and the interaction of PHN at 6 months and Visit Day. Data are presented as the slope across the four visit days for the PHN and no-pain groups with estimates for the following time points: 0, 30, 50, 90, and 180 days after rash onset. Analyses included comparisons of predicted slopes of PHN and no-pain groups along with comparisons at relevant time points. No adjustment was done for multiple comparisons (Katz 2003). A p-value less than 0.05 was considered statistically significant.

A post-hoc analysis compared the SF-MPQ data to historic data from 110 patients with chronic PHN from the placebo group (Rowbotham et al. 1998). In this study PHN was defined as average daily pain ratings ≥4 on a 0-10 numerical pain rating scale and median duration since zoster eruption was 27 months. Another post-hoc analysis compared the MPI data to historic data from 26 patients with chronic PHN (unpublished data from Rowbotham et al. 2003). In this study PHN was defined as average daily pain ≥25 on the 0-100 VAS and duration of pain was > 11 months). The p-values for post-hoc analyses were based on a one-way ANOVA. The data-analysis was performed in collaboration with Dr. Alan Bostrom, Department of Biostatistics and Epidemiology, UCSF.

RESULTS

Subjects

A total of 1003 subjects were screened on the telephone between December 1999 and December 2003. Of these, 870 did not come for a screening/inclusion visit for the following reasons: 156 already had PHN of long duration; 91 were already beyond the inclusion time window; 75 had pain that was too mild to qualify; 52 felt participation would be too time consuming; 69 had exclusionary medical conditions or medications; 65 had cranial zoster; 31 were too young; and in 11 there was uncertainty about the diagnosis. Another 320 either failed to attend a screening examination, were just seeking information, or were not interested in participating (often due to distance from the research center or lack of transportation). No potential subject cited their pain as being too severe to allow study participation.

Of the 133 subjects who came in for the screening/study inclusion visit, 103 were eligible and completed the study inclusion visit. Ninety-four subjects completed all four study visits and their data are included in the data analysis. Six subjects withdrew consent due to the time commitment involved in study participation, two subjects were dropped due to uncertainty about the diagnosis of HZ, and one was excluded due to progressive cognitive impairment. Demographic data and characteristics at the study inclusion visit are shown in Table 1. Twenty-nine of the 94 subjects had average daily pain over the preceeding 48 hours of 50 or higher prior to study inclusion.

Table 1.

Demographics at the study inclusion visit (n=94). PHN defined at average daily pain >0 on the 0–100 pain VAS.

PHN at 6 months (n=30) No-Pain at 6 months (n=64)

Age (median [range]) 70.5 [46*–89] 67 [51–89]
Gender (% female) 57 59
Race (% Caucasian) 87 92
Work status (% employed) 37 44
Marital status (% married, S/O) 57 66
Alcohol use (% high): 3 4
Substance abuse (%) 7 8
Tobacco use (%) 7 9
History of psychiatric disease (%) 20 13
History of depression (%) 23 16
*

: One subject was 46 years of age, but met all other inclusion criteria.

Resolution of pain over the study observation period is shown in Figure 1. At 3 months, 47 subjects (50%) met criteria for PHN (average daily pain >0/100), and of these, three subjects (3%) met the more stringent criteria for clinically meaningful PHN (average daily pain ≥30/100). At 6 months, 30 subjects (32%) met criteria for PHN, with two subjects (2%) also meeting criteria for clinically meaningful PHN.

Figure 1.

Figure 1

Estimates of Average Daily Pain in 30 subjects with PHN at 6 months (dashed line with 95% CI) and 64 subjects with no-pain at 6 months (solid line with 95% CI). PHN was defined as average daily pain over the last 48 hours > 0/100 on 100 mm pain VAS.

Comparison of subjects with and without PHN at 6 months

There was no difference in demographics at study inclusion between subjects with and without PHN at 6 months (Table 1). PHN subjects completed the study inclusion visit a median of 5 days later than subjects whose pain fully resolved (PHN group: 27 days (±13) (mean (SD)) vs. no-pain group: 22 (±10); p=0.05). The timing of the remainder of the visits was the same in the two groups.

Pain and medication use

At study inclusion, subjects with PHN at 6 months (referred to below as PHN subjects) reported higher average daily pain compared to subjects with complete resolution of pain (Figure 1, Table 2). However, the rate of pain resolution over time was not different between PHN subjects and those whose pain resolved fully (slopes analysis: PHN: −0.18 [95% CI: −0.20 to –0.15] vs no pain: −0.19 [−0.24 to –0.15], p=0.52). PHN subjects more often had outbreaks in the cervical or lumbar region, and were somewhat more likely to have had a ‘severe’ rash (p=0.07). The majority of subjects in both groups had received a course of antiviral medication and was taking an analgesic medication at the time of study inclusion. PHN subjects were taking a greater number of analgesics and were more likely to be taking an antidepressant for pain. The majority of subjects in both groups reported that HZ affected their ability to sleep, work and participate in recreational activities.

Table 2.

Subject characteristics at study inclusion visit (n=94). PHN defined as average daily pain >0 on the 0–100 pain VAS over the last 48 hours.

PHN at 6 months (n=30) No-Pain at 6 months (n=64)

Average daily pain VAS (median [range]) 49 [20–82] 34 [20–98]**
Prodromal pain (% present) 83 77
 Duration, days (median [range]) 3 [0–11] 3 [0–20]
Dermatome affected (%)
 Cervical 33 15 *
 Thoracic 47 72
 Lumbar 20 8 *
 Sacral 0 5
Rash severity (%)
 Mild 27 33
 Moderate 17 36
 Severe 53 31
Antiviral treatment (%) 93 91
Taking any analgesic 100% 97%
Number of analgesics taken (median [range]) 4 (1–8) 3 (0–6)**
 Acetaminophen (% of subjects) 97 84
 Opioid 83 78
 NSAID 47 47
 Gabapentin 37 23
 Antidepressant 30 11*
*

: p<0.05,

**

: P< 0.001.

The characteristics of the 30 PHN subjects at 6 months are presented in Table 3. From the slopes analysis, the mean pain rating in this group was estimated to be 10.6 on the 0–100 pain VAS (95% CI: 5,16). At the 6-month study visit, 18 of the 30 PHN subjects rated their average daily pain during the last 48 hours as 10 on the pain VAS and 13 subjects chose the category ‘no pain’ on the Present Pain Intensity Scale of the SF-MPQ. Only 2 PHN subjects rated their average daily pain over the last 48 hours as ≥30 on the pain VAS. Only 9 PHN subjects were still using prescription medications for their pain, and of these, 5 subjects rated their average daily pain ≤10 on the pain VAS.

Table 3.

Characteristics of the 30 PHN subjects at 6 months. PHN was defined as average daily pain >0 on the 0–100 pain VAS over the last 48 hours.

Subject Average daily pain (48 hr pre visit) Present Pain Intensity (SFMPQ) Prescription Medication Followed by MD for HZ pain

0–100 VAS (0–5) (total daily dose) yes/no
001 8 no pain (0) gabapentin 300 mg yes
002 2 no pain (0) none no
005 71 n/a oxycodone 40 mg
amitriptyline 50 mg
yes
014 1 no pain (0) none no
016 2 mild (1) none no
019 18 mild (1) none no
020 25 distressing (3) gabapentin 1200 mg
nortriptyline 25 mg
yes
025 5 no pain (0) none no
026 20 no pain (0) gabapentin 1800 mg
hydrocodone 22.5 mg
no
039 12 discomforting (2) none no
043 28 no pain (0) none no
046 2 no pain (0) none no
047 12 discomforting (2) none no
048 1 no pain (0) gabapentin 600 mg yes
059 37 distressing/ horrible (3/4) none no
060 7 no pain (0) gabapentin 600 mg yes
062 5 no pain (0) none no
066 2 no pain (0) none no
067 7 mild (1) none no
069 6 mild (1) none no
070 9 mild (1) gabapentin 1500 mg yes
072 18 discomforting (2) hydrocodone 5 mg at most 1/d no
075 23 mild (1) none no
080 8 no pain (0) none no
081 5 mild (1) none no
087 8 mild (1) none no
095 8 no pain (0) none no
096 6 n/a none no
098 10 mild (1) gabapentin 900 mg no
102 13 discomforting (2) none yes

Questionnaires

SF-MPQ

Descriptors used by more than 70% of subjects at study inclusion were: ‘tender’, ‘hot-burning’, aching’, stabbing’, ‘throbbing’, ‘shooting’, ‘sharp’, and ‘tiring-exhausting’. At the 6 month visit, the only descriptor used significantly less often was ‘hot-burning’. PHN subjects had significantly higher SF-MPQ scores at study inclusion and at 6 months after rash onset (Table 4), but the only descriptor used more frequently at study inclusion by PHN subjects was ‘sharp’ (90% vs. 64%, p=0.042, Fisher’s exact test). At the time of study inclusion, the SF-MPQ scores in PHN subjects were similar to the scores in historic control patients with chronic PHN (Table 4). At 6 months after rash onset, the scores in PHN subjects were significantly lower than the historic controls. For subjects whose pain fully resolved by 6 months, their SF-MPQ scores were lower than historic control PHN patients at study inclusion and at 6 months.

Table 4.

Short Form McGill Pain Questionnaire.

Study inclusion 6 months after rash onset Historic PHN controls [Rowbotham et al., 1998]

SF-MPQ PHN (n=30) No-Pain (n=64) PHN (n=30) No-Pain (n=64) PHN (placebo group) (n=110)

Sensory score (range 0–33) 14.8 (7.6)* 10.3 (6.3) 4.2 (4.2)** 0.2 (0.7) 14.5 (6.4)
Affective score (range 0–1) 4.0 (3.5)* 2.3 (2.5) 0.6 (1.2)** 0 (0) 4.1 (3.2)
Total score (range 0–45) 18.5(10.4)** 12.3(8.3) 4.8 (5.0)** 0.2 (0.7) 18.7 (8.5)

Comparison with historic PHN controls No difference P<0.02 P<0.0001 P<0.0001

Total, sensory, and affective scores (mean (SD)) on the SF-MPQ at study inclusion and 6 months after rash onset for subjects with and without PHN at 6 months. For reference historic PHN controls were included from Rowbotham et al., 1998.

: In this study PHN was defined as average daily pain ≥4 on the 0–10 numerical pain rating scale and median duration since last zoster eruption was 27 month. Comparison PHN vs no-pain groups at study inclusion and at 6 months:

*

: p<0.05,

**

: p<0.001

MPI

At study inclusion, MPI ratings of ‘pain severity’ and ‘affective distress’ were higher in PHN subjects than subjects whose pain resolved by 6 months (Table 5). Six months after rash onset, PHN subjects rated higher on ‘pain severity’, ‘interference’, and ‘affective distress’ and lower on ‘life control’ and ‘general activity level’ than subjects without pain. At study inclusion, ratings on ‘affective distress’ were higher in PHN subjects than in historic PHN controls, while the remaining scores were similar. However, at 6 months, PHN subjects’ scores on ‘pain intensity’, ‘interference’ and ‘negative response’ were significantly lower than scores from historic control patients with severe PHN.

Table 5.

Multidimensional Pain Inventory at study inclusion and 6 months for subjects with and without PHN 6 months after rash onset (mean (SD)). For reference historic PHN controls were included from Rowbotham et al., 2003 (previously unpublished data).

MPI Scales Study Inclusion 6 Months After Rash Onset Historic PHN controls [Rowbotham et al., 2003]

PHN (n=30) No-pain (n=64) PHN (n=30) No-pain (n=64) PHN¥ (n=26)
Pain severity 3.6 (1.2)** 2.6 (1.3) 1.3 (1.2)**,‡‡ 0.09 (0.3) 3.77 (1.1)
Interference 3.2 (1.4) 2.6 (1.5) 1.2 (1.2)**,‡‡ 0.3 (0.6) 2.66 (1.6)
Life control 3.2 (0.8) 3.3 (1.0) 3.7 (1.3)** 4.5 (1.3) 3.65 (1.2)
Affective distress 3.1 (1.0)*, 2.6 (1.0) 2.1 (1.2)* 1.5 (1.1) 2.28 (1.2)
Support 4.3 (1.1) 4.2 (1.1) 3.4 (1.6) 2.6 (1.9) 4.29 (1.6)
Negative responses 1.6 (1.3) 0.9 (0.8) 1.1 (1.1) 0.9 (0.8) 1.74 (1.1)
Solicitous responses 3.3 (1.4) 3.1 (1.7) 3.1 (1.5) 2.9 (1.6) 2.95 (1.6)
Distracting responses 2.0 (1.1) 1.5 (1.3) 2.1 (1.4) 1.7 (1.1) 1.93 (1.5)
Household chores 3.5 (1.4) 3.4 (1.4) 3.4 (1.4) 3.6 (1.6) 3.18 (1.6)
Outdoor work 1.4 (1.1) 1.4 (1.3) 1.1 (0.9) 1.7 (1.2) 1.68 (1.5)
Activities away from home 2.8 (1.1) 2.7 (1.2) 2.7 (1.0) 3.2 (1.1) 3.13 (1.0)
Social activities 2.3 (1.1) 2.1 (1.3) 2.3 (0.9) 2.6 (1.2) 2.15 (1.5)
General activity level 2.5 (0.8) 2.4 (1.0) 2.4 (0.7)* 2.8 (0.9)
¥

In this study PHN was defined as average daily pain ≥25 on the 0–100 pain VAS and duration of pain was greater than 11 months. Comparison PHN vs no-pain groups at study inclusion and at 6 months:

*

: P<0.05,

**

: P<0.001. Comparison PHN/no-pain vs historic PHN controls:

P<0.05,

‡‡

P<0.01.

WAYS and LEC

Coping strategies did not change between the two assessments. Coping strategies did not differ between subjects with and without PHN at study inclusion or at 6 months. The two most used coping strategies for both groups at study entry and 6 months were ‘seeking social support’ and ‘planful problem solving’, which are both active coping strategies. Subjects with PHN at 6 months reported the same number of negative and positive life events as those subjects whose pain resolved.

DISCUSSION

In this population of HZ subjects aged ≥50 with pain persisting at >2 weeks after rash onset, 30 subjects (32%) met criteria for PHN at 6 months (average daily pain >0/100 on the pain VAS over the last 48 hours), a percentage similar to that reported in antiviral trials (Whitley et al. 1998). Only two of our subjects met the additional criteria for clinically meaningful PHN at 6 months (average daily pain ≥30/100 on the pain VAS). Slopes analysis showed that the rate of pain resolution was the same in subjects with or without PHN at 6 months. Because the PHN subjects started at a higher average pain level, the projected time to full pain resolution would be greater. It still remains unknown what trajectory the slope of subjects with clinically meaningful PHN would follow in the course of 6 months following HZ.

Even though our group of PHN subjects met the criteria for PHN used most often in longitudinal studies, their pain at 6 months was very mild compared to the pain reported by patients with longstanding PHN entering clinical trials of pain therapies for PHN or studies of pain mechanisms. The total SF-MPQ score and MPI ratings at study inclusion among the PHN subjects in the present study were similar to the total score observed in patients with severe longstanding PHN seen previously in our research center (Table 4; Rowbotham et al. 1998) and elsewhere (Graff-Radford et al. 1986; Bhala et al. 1988; King 1993). However, at 6 months the SF-MPQ total score in the PHN subjects in the present study were dramatically lower than in the historic controls. Ratings of ‘pain intensity’, ‘interference’ and ‘negative response’ on the MPI were not only significantly lower than ratings from the historic PHN controls, but also lower than in other chronic pain conditions (Kerns et al. 1985; Reitsma and Meijler 1997).

Most longitudinal HZ studies, including studies of predictors of PHN, have defined PHN as ‘presence of pain’ at variable time points after rash onset or healing without specifying a numerical threshold (Wood 1995; Wood et al. 1995; Dworkin and Portenoy 1996; Dworkin and Schmader 2001). Lydick and colleagues demonstrated that pain ratings less than 3 on the 0–10 NRS were associated with minimal impact on quality of life and functional levels (Lydick et al. 1995). Coplan and colleagues (Coplan et al. 2004) recently demonstrated that numerical pain ratings ≥3/10 corresponded to ratings higher than ‘mild’ on the SFMPQ and suggested that average daily pain ratings of ≥3 on the 0–10 NRS is a clinically meaningful definition of PHN.

Long before the introduction of effective and safe antivirals, Hope-Simpson found that only 2% had protracted neuralgia after 5 years (Hope-Simpson 1975). Haanpää and colleagues studied 112 patients of all ages referred by primary care doctors in Finland (Haanpää et al. 2000). While 25% of her subjects ‘complained of pain’ at 3 months, only 4 had severe pain. In a prospective study of an unselected primary care cohort in Iceland interviewed about their pain (Helgason et al. 2000), 6 of 168 subjects older than 50 years of age contacted 3 months after rash outbreak reported moderate discomfort (25–75 on a 100 point numerical pain rating scale), and 2 reported severe discomfort (75–100 on the pain NPRS). By 12 months post-HZ, 2 reported moderate pain, and none severe, leading the authors to suggest that previous studies have overestimated the problem of PHN (Helgason et al. 2000). In the recent zoster vaccine trial, the definition of PHN proposed by Coplan and colleagues (numerical pain ratings ≥3/10) was used. The incidence of PHN was 5.1% at 6 months in placebo vaccinated subjects aged 60 or older (Oxman et al. 2005). In contrast, all clinical trials of new therapies for PHN and studies of mechanisms of PHN use a stringent definition of PHN. Most have been restricted to those with ‘moderate to severe pain’ or ratings ≥40 on the 0–100 pain VAS despite analgesics (Rowbotham et al. 1998; Raja et al. 2002; Hempenstall et al. 2005).

To link the results from risk factor and antiviral studies that recruit subjects shortly after HZ onset to clinical trials and mechanistic studies of established PHN, the definition of PHN needs to be standardized. HZ patients who go on to develop ‘clinically meaningful’ PHN constitute a very small (2% in our group) but distinct sub-population of zoster patients (Hope-Simpson 1975; McKendrick et al. 1989; Coplan et al. 2004). These are patients with moderate to severe pain who may find their lives devastated by pain and require daily medication and frequent physician visits. Scott and colleagues recently evaluated the burden of HZ (defined as presence of pain) on patients, health care system and society and estimated an average cost of £ 520 per patient aged 65 and older (Scott et al. 2006). This study did not include a cost estimate for patients with clinically meaningful PHN. Cost estimates in this group would be expected to be considerably higher due to involvement of secondary and tertiary health services. Moreover, it remains unknown if the mechanisms underlying pain in patients with severe PHN are different from the mechanisms underlying pain in subjects with PHN defined as any pain at 6 months after rash onset.

A standardized definition of PHN should also take into account the use of prescription medication for pain, since successful analgesic medication reduces pain severity. If the definition of clinically meaningful PHN described by Coplan and colleagues (Coplan et al 2004) was modified to include prescription medication use for pain at 6 months, the incidence of clinically meaningful PHN in our cohort would be 9%.

Given the low incidence of clinically meaningful PHN, a longitudinal study designed to understand predictors of development of clinically meaningful PHN would require a sample of 1000–5000 HZ patients to generate 50 subjects with clinically meaningful PHN. Hence, future studies should use a case-control design, or other more efficient designs.

The present study evaluated several other risk factors for pain persistence. Depression, as measured with the Beck Depression Inventory, has been suggested to be a risk factor for PHN (Dworkin et al. 1992). Affective distress, which has a high positive correlation with the Beck Depression Inventory (Kerns et al. 1985), was assessed in the present study. PHN subjects were in more affective distress at study inclusion and at 6 months, suggesting that affective distress at zoster onset may be a predictor and that the persisting pain was associated with affective distress. Likewise, life events in the preceding year did not appear to affect the likelihood of pain persistence, nor did the response of others in the subject’s environment to their communications of pain. In the literature, coping strategies have only been examined after PHN has been established (Haythornthwaite et al. 2003). Assessing ways of coping both at HZ onset and 6 months later, we did not find a change in coping style or significant differences between PHN subjects and those who recovered fully. Passive coping efforts have been associated with more perceived pain and maladaptive physical and psychological adjustment (Folkman and Lazarus 1988; Jensen et al. 1991; Rose et al. 1992; Snow-Turek et al. 1996). The active coping style used by our HZ cohort suggests a psychologically well-functioning elderly population.

The picture of HZ is continuously changing. As reviewed by Dworkin and Schmader (2001) the introduction of antivirals treatments have reduced the overall duration of pain and the incidence of PHN. Studies are ongoing to determine if more aggressive analgesic treatment of the acute HZ pain will further reduce the risk of PHN. Recent data cast doubt about the ability of a single epidural steroid injection to prevent PHN (van Wijck et al. 2006). It is clear from the shingles vaccine trial that the vaccine will reduce the burden associated with HZ, but the very low incidence of clinically meaningful PHN cases must be considered (Coplan et al. 2004; Oxman et al. 2005).

In conclusion, the present study shows that persistence of mild pain was common 6 months after rash onset, but clinically meaningful PHN was a rare outcome. The findings have important implications. First, they suggest that the definition of PHN should be revised and only include cases with clinically meaningful PHN, where pain is severe enough to produce disability or require medical treatment. Second, the rarity of severe longstanding PHN should be kept in mind when generalizing the results of treatment trials. As the slope of pain reduction was the same in both the PHN and no-pain groups, the higher starting level of pain in our PHN group implies that the majority of patients with persistent pain at 6 months simply need more time for pain resolution. Third, since only a very small sub-group of all zoster patients develop severe PHN, there may be important mechanistic differences that have yet to be elucidated.

Acknowledgments

Supported by NINDS grants K24 NS02164 (MCR) and RO-1 NS39521 and a grant from the VZV Research Foundation Inc (KLP). HGT received support from Familien Hede Nielsen’s Fond and Direktør Jakob Madsens og Hustru Olga Madsen’s Fond. We are grateful to Dr. Alan Bostrom for his invaluable assistance with the statistical analysis. HGT completed the Doris Duke Fellowship Program and is grateful to Dr. Joel Palefsky and Terry O’Donnell for their invaluable help.

Footnotes

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