Pain and its persistence in herpes zoster

Pain, 67 (1996) 241-251 © 1996 International Association for the Study of Pain. 0304-3959/96/ $15.00

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PAIN 3122

Review article Pain and its persistence in herpes zoster Robert H. Dworkina,* and Russell K. Portenoyb aDepartments of Anesthesiology and Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY 10032 (USA) and bDepartment of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021 (USA)

(Received 23 December 1995, revised version received 21 February 1996, accepted 21 February 1996)

Summary

The nature and duration of pain associated with herpes zoster is highly variable. This review of research on pain in acute herpes zoster and postherpetic neuralgia (PHN) explores those observations relevant to the definition and pathogenesis of PHN and the design of treatment trials. A model for the pathogenesis of PHN is presented, which gains support from studies of risk factors. Several directions for future research are identified.

Key words: Herpes zoster; Postherpetic neuralgia; Acute pain; Chronic pain

'Even the mildest cases of zoster sometimes leave postherpetic neuralgia, and severe cases frequently do so' (Hope-Simpson 1967, p. 155).

Introduction The varicella-zoster virus (VZV) can cause systemic infection, including classic chicken pox, and a localized infection known as herpes zoster (HZ) or 'shingles' (HopeSimpson 1954; Weller et al. 1958). The localized infection, which typically occurs in elderly individuals, represents a recrudescence from a latent phase in which the virus is dormant in sensory ganglia. HZ results from reactivation and spread of the virus from a sensory ganglion to the corresponding dermatome (Hope-Simpson 1965; Straus et al. 1984). Although the presentation of HZ is variable, a prodrome of dermatomal pain typically precedes the appearance of the rash, which becomes pustular after several days and then forms a crust. The nature and duration of the pain that accompanies the acute eruption are variable. Pain that persists beyond a defined period following healing of the rash is termed postherpetic neuralgia (PHN). Like the pain of HZ, the characteristics and duration of PHN are highly

*

Correspondmg author: Robert H. Dworkin, Ph.D., Pain Management Center, Columbia-Presbyterian Medical Center, 622 West 168th Street, New York, NY 10032, USA. Tel.: (212) 305-7114; Fax: (212) 305-8883

PlI S0304-3959(96)03122-3

variable. In some unfortunate cases, the pain is severe, refractory to treatment, and persistent for years. Recent reviews have critically discussed the characteristics and treatment of the pain associated with HZ and PHN (Loeser 1986, 1990; Portenoy et al. 1986; Watson and Evans 1986; Satterthwaite 1989; Watson 1993). This review emphasizes recent research relevant to the definition and pathogenesis of PHN and the design of treatment trials for novel therapies.

Natural history of pain in HZ and PHN In 70-80% of HZ patients, a prodrome of dermatomal pain begins several days before the appearance of the characteristic rash (Rogers and Tindall 1971; Beutner et al. 1995). A small number of patients have longer prodromes, and a series of patients with prodromal pain preceding the rash by 7 to more than 100 days has been reported (Gilden et al. 1991). Prodromal pain is often accompanied by other symptoms, including fatigue and headache. Almost all HZ patients experience pain during the acute infection, and those patients who have not had a painful prodrome typically begin to experience pain at rash onset or shortly afterwards. Dermatomal pain without a rash, referred to as zoster sine herpete, has also been described (Lewis 1958; Gilden et al. 1992). The recent finding of VZV DNA in the cerebrospinal fluid of two patients with prolonged radicular pain and no rash provides strong evidence of the latter syndrome (Gilden et al. 1994).

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For many individuals, HZ is a short-lived disorder. Healing of the skin and resolution of pain generally occur within 3 weeks of rash onset. Gradual resolution of the pain over longer periods also occurs commonly. Complications are rare in immunocompetent patients. Because the proportion of HZ patients who experience pain declines with time (De Moragas and Kierland 1957; Raggozzino et al. 1982), treatments for pain described in anecdotal reports may appear effective even if biologically inactive. Placebo-controlled, randomized, double-blind studies are, therefore, necessary to adequately evaluate proposed treatments for zoster pain. The definition and prevalence of PHN The point at which acute HZ pain becomes PHN has important implications for studies of these disorders and has been a focus of disagreement in the medical literature. Some authors have defined PHN as pain persisting after the rash has healed (Burgoon et al. 1957; Bamford and Boundy 1968). Others have defined it as pain persisting beyond a specified interval after rash onset - for example, 4 weeks (Rogers and Tindall 1971), 3 months (Max et al. 1988), or 6 months (Harding et al. 1987) - or as pain persisting beyond a specified interval after rash healing (Rowbotham and Fields 1989; Baron and Saguer 1993; Rowbotham et al. 1995). A recent classification advocates the designation of acute, subacute, and chronic phases as a means to standardize the definition, particularly for research purposes (Dworkin and Portenoy 1994). In this classification, acute herpetic neuralgia is defined as pain that occurs during the initial 30 days after rash onset. PHN is defined as pain that persists more than 3 months after the end of this monthlong acute period (i.e. 4 months after rash onset). Subacute herpetic neuralgia describes pain that resolves within 3 months after the end of the acute phase of HZ. This separation of acute and subacute neuralgia from PHN is consistent with the distinction between acute and chronic pain advanced by the International Association for the Study of Pain classification of chronic pain syndromes (Merskey and Bogduk 1994). It also conforms to the definitions used in recent studies of PHN as a chronic pain syndrome (Max et al. 1988; Watson et al. 1988a, 1991b, 1992; Rowbotham and Fields 1989; Nurmikko and Bowsher 1990; Rowbotham et al. 1991; Bowsher 1992; Dworkin et al. 1992; Baron and Saguer 1993). The variation in the criteria used to define PHN accounts for prevalence estimates that range from 9% to 34% (Burgoon et al. 1957; Hope-Simpson 1975; Brown 1976; Raggozzino et al. 1982). The most useful data for estimating the risk of PHN are provided by a meta-analysis of 14 placebo-controlled trials of acyclovir (Crooks et al. 1991), which showed that 22% of placebo-treated patients had pain that persisted at least 3 months. The pattern of pain may also complicate the diagnosis of PHN and confound prevalence rates and the development of entry criteria for investigations. Although PHN is usu-

ally characterized by constant, fluctuating pain, some patients report discontinuous pain, with pain-free intervals of varying durations (Watson et al. 1991b; Huff et al. 1993; McKendrick et al. 1994). In a study of 156 patients with PHN, 25% with persistent pain could recall a time after the rash when they had little or no pain for weeks or months (Watson et al. 1991b). These findings are consistent with a long-term follow-up survey of patients who participated in a trial of acyclovir: 16 of 132 patients who had reported no pain at the end of the trial 9 years earlier reported pain within the preceding year (McKendrick et al. 1994). The finding in another acyclovir trial that 4 of 187 patients with acute HZ first developed persistent pain at 1 month after enrollment (Huff et al. 1993) suggests that PHN can develop in patients who have not had acute pain. The existence of pain-free intervals followed by pain necessitates long-term follow-up to determine that complete pain cessation has occurred. Antiviral medications are now routinely used for the treatment of acute HZ, and there is evidence that these drugs abbreviate the duration of pain, at least in some cases. Thus, the prevalence of PHN also may be altered by the proportion of treated patients in a population. In double-blind placebo-controlled trials, acyclovir reduces the overall duration of pain and the incidence of PHN, defined as pain at 3 or 6 months after enrollment (Crooks et al. 1991; Wood et al. 1996). Famciclovir reduces the duration of PHN, defined either as pain beyond rash healing (Tyring et al. 1995) or as pain beyond 30 days or 3 months from enrollment (Boon and Griffin 1995; Cunningham 1995). In a recent comparative study of acyclovir and valaciclovir (valacyclovir HCL in the USA), valaciclovir reduced the overall duration of pain considered as a continuum. (Beutner et al. 1995). Although the expense is considerable, antiviral treatment of acute HZ may have diverse economic benefits (Drummond and Backhouse 1993); the results of a recent study suggest ed that such treatment appears to be cost-effective given a reduction in the incidence of PHN (Nathwani et al. 1995). Regardless of the definition used to designate PHN, the risk of this disorder rises with age (Burgoon et al. 1957; De Moragas and Kierland 1957; Rogers and Tindall 1971; Hope-Simpson 1975; Brown 1976; Raggozzino et al. 1982; Guess et al. 1985; Harding et al. 1987). PHN is infrequent in patients under 40, but as many as 65% of patients over 60 and 75% of those over 70 have pain at 1 month following healing; the proportion of patients with pain at 1 year approaches 50% in those over 70 (De Moragas and Kierland 1957). The proportion of elderly patients in a popUlation, therefore, can also be expected to alter reported prevalence rates.

Other salient characteristics of UZ and PUN

The prevalence data suggest that studies of HZ pain or

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PHN must define the latter syndrome and explore antiviral therapy and patient age as potentially influential covariates. Recent studies indicate that other variables may also be important. These include the quality of the pain and a range of quality of life outcomes. Pain quality The quality of pain in HZ and PHN has been examined in two studies using the McGill Pain Questionnaire (Bhala et al. 1988; Bowsher 1993). One-third or more of HZ patients endorsed the sensory sub scale adjectives sharp, tender, stabbing, shooting, throbbing, itching, and/or hot; onethird or more of patients with PHN endorsed the adjectives tender, burning, throbbing, stabbing, shooting, and/or sharp. These words reflect the coexistence of a 'familiar' sharp or throbbing pain and varied dysesthesias (i.e. 'abnormal' pain), particularly burning and lancinating pain. Tender was chosen by both groups of patients to describe allodynia (i.e. pain in response to a stimulus that does not normally provoke pain). Although studies of PHN have distinguished three different types of pain - a steady throbbing or burning pain, an intermittent sharp or shooting pain, and allodynia (Rowbotham and Fields 1989; Watson et al. 1992) - the results of a recent study suggest that throbbing and burning pain should be examined separately. In this study, PHN patients who had received antiviral medication during the acute infection were found to be much less likely to report burning pain than PHN patients who had not received antiviral medication (Bowsher 1992, 1993); reports of throbbing pain in these two groups, however, did not differ. It will therefore be important to distinguish 4 different types of pain in future studies, specifically, steady throbbing pain, steady burning pain, intermittent sharp or shooting pain. and allodynia. Quality of life Quality of life may be adversely affected by HZ, especially in those patients with more severe acute pain (Mauskopf et al. 1994; Lydick et al. 1995), but apparently returns to normal levels in most patients after recovery from the acute infection (Lydick et al. 1995). Patients with prolonged PHN, however, often experience ongoing disturbances in physical and psychosocial functioning (Portenoy et al. 1986; Satterthwaite 1989; Rowbotham and Fields 1989; Schmader 1995). Patients may develop depression, with impaired sleep and appetite, and diminished energy and libido. Many patients develop severe physical, occupational, and social disability as a consequence of their unremitting pain. In a cross-sectional study, patients who had PHN for longer than 6 months had greater disability and psychological dysfunction than patients who had PHN for less than 6 months (Graff-Radford et al. 1986). Not surprisingly, patients with prolonged PHN also use health care resources at a high rate (Davies et al. 1994). These results suggest that increases in psychosocial distress occur

as a result of the unremitting pain of PHN, although it is also possible that prolonged pain is a consequence of greater distress. Future studies must evaluate quality of life variables over time to clarify their complex role as covariates to pain and outcomes affected by analgesic therapy.

More on the definition of PUN: pain as a continuum versus a discrete disorder As noted previously, some studies have considered HZ pain as a continuum and evaluated the efficacy o~ treatments in terms of their impact on overall pain duration. This has been the approach in several antiviral trials in which the primary endpoint has been the time from enrollment to complete cessation of all HZ-associated pain (Crooks et al. 1991; Huff et al. 1993; Degreef et al. 1994; Wood et al. 1994, 1996; Beutner et al. 1995; Whitley et al. 1995). No distinction is made between acute pain and PHN when zoster pain is examined in this manner (Wood et al. 1995). Analyses of zoster pain as a continuum can provide a worthwhile overview of factors associated with pain duration, not only in treatment trials but also in studies of risk factors for persistent pain. The major disadvantage is theoretical: if acute HZ pain and PHN differ clinically and have different pathophysiologies, studies that assume a continuum of pain could be misleading and impede progress in understanding each of these types of pain. The latter concern is substantive. There is evidence that PHN is a discrete disorder that differs from acute HZ pain in important respects. For example, studies of pain quality suggest that sharp, stabbing pain is more common in patients with acute HZ than in patients with PHN, whereas burning pain is more common in PHN patients (Bhala et al. 1988; Bowsher 1993). The occurrence of discontinuous pain, albeit rare, further questions the characterization of zoster pain as an unbroken continuum extending from the acute infection through the development of PHN. Indeed, some HZ patients develop PHN without having had any acute pain (Huff et al. 1993). The results of several studies have also suggested that risk factors for acute HZ pain and PHN differ. In two studies that examined patients whose pain resolved within 30 days of rash onset, the duration of this acute pain did not differ in younger and older patients (Bean et al. 1993; Boon 1994). However, when the duration of pain persisting beyond 30 days was examined, pain duration was greater in older patients than in younger patients (Boon 1994). These data suggest that there is no relationship between age and the duration of acute HZ pain, but that older age is associated with a greater duration of PHN. Psychosocial distress may be an additional risk factor that discriminates acute HZ pain from PHN. In a preliminary study with a small sample of patients, only acute pain severity predicted the presence of what was considered short-term HZ pain (pain at 2 months after rash onset), but both acute pain severity

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and psychosocial distress predicted the development of PHN, defined as pain at 4 months after rash onset (Dworkin et al. 1992). Of course, the most compelling evidence that acute HZ pain and PHN are distinct disorders would be the demonstration of different pathophysiologies. In postmortem studies, dorsal horn atrophy and pathological changes in the sensory ganglion were found on the affected side (and not on the unaffected side) in patients with PHN, but not in patients with a history of HZ whose pain did not persist (yY atson et al. 1988b, 1991a). Other findings, such as a marked loss of myelin in the peripheral nerve and sensory root, were found in all HZ patients studied. Although few patients have been studied, these data suggest that different mechanisms account for acute HZ pain and PHN (Bennett 1994). Additional evidence that acute HZ pain and PHN may have distinct pathophysiologies is provided by their different response to oral steroid treatment. The results of several studies suggest that such treatment has a beneficial effect on acute HZ pain but does not appear to reduce the incidence of PHN (Esmann et al. 1987; Wood et al. 1994; Whitely et al. 1995) and is not effective once PHN has developed (Portenoy et al. 1986). Another important reason to maintain the distinction between HZ pain and PHN is the very great difference in the burdens imposed by acute and chronic pain, respectively. The burdens of chronic pain are diverse: health care utilization costs, occupational and social disability, and psychological distress. In a recent study, 59% of PHN patients attending a pain clinic in Liverpool had been unable to perform their usual activities (Davies et al. 1994). The average duration of these impairments was 1.4 years and the range extended to 16 years. Visits to physicians averaged 18 since pain onset (range, 0-69 visits) and visits by home health aides averaged 16 (range, 0-507 visits). Acute HZ pain cannot have such debilitating consequences. Indeed, the principal reason that acute HZ is a significant clinical concern in immunocompetent patients is that some patients develop persistent pain. If acute HZ pain and PHN are fundamentally different, the analysis of pain as a continuum in clinical trials may obscure salient characteristics of PHN. In an examination of 146 placebo-treated patients participating in a doubleblind trial of famciclovir, the median duration of HZ pain examined as a continuum was 26 days, which exceeded by only 4 days the median duration of acute pain in those patients whose pain did not persist beyond rash healing (Dworkin et al. 1996). In contrast, the median pain duration of those patients who met a criterion for PHN was over 6 months (189 days). These data suggest that the results of analyses in which HZ pain is considered as a continuum may be influenced excessively by patients who only have acute pain. Although there is no conclusive evidence that acute HZ pain and PHN are pathophysiologically distinct, the existing data provide considerable support for an analytic ap-

proach that distinguishes them. This approach does not exclude analysis of zoster pain as a continuum, but is necessary to complement it. Information about pain can be examined as a rate of PHN, and as a duration of defined PHN cases and as a continuum of pain duration (Dworkin et al. 1996).

Defining covariates for studies of HZ and PHN There is a consensus that several different pathophysiologies probably contribute to HZ pain and PHN, and that the qualitatively different types of PHN pain probably involve different mechanisms (Rowbotham and Fields 1989; Baron and Saguer 1993, 1995; Bowsher 1993; Fromm 1993; Wall 1993; Watson and Deck 1993; Bennett 1994; Nurmikko 1994, 1995). This variability in the putative mechanisms of HZ and PHN and the physical and psychosocial comorbidity experienced by patients with pain complicate efforts to identify covariates for studies of these conditions. To date, a unifying model of PHN that could help delineate salient covariates has not been proposed. Such a model could be very useful in clarifying the methodology for studies of pain due to HZ and PHN. A diathesis-stress model in which an organic condition (i.e. the diathesis), psychosocial stress (broadly defined), and their interaction account for the development of PHN provides such a unifying framework. Although several findings are not adequately explained by this model, most current data are, and the model offers directions for future research that have the potential to lead to a more complete understanding of the pathogenesis and presentation of PHN. In the case of HZ pain and PHN, the organic elements that are relevant to the model may include the changes in somatosensory processing that result from neural damage produced by the virus and the immune response to the virus. These changes, which presumably evolve over time, are reflected overall by the severity of the acute HZ infection. This diathesis may interact with the stress component of the model, which includes not only stressful life events but also other psychosocial factors, such as low levels of social ~upport and various aspects of personality and psychopathology. A diathesis-stress model can be proposed in which the risk of PHN becomes greater with increases in the severity of neural damage and in the severity of psychosocial stress!. Several risk factors for PHN that are consistent with this model have already been identified and require further examination in future studies. !

It is important to recognize that the components of the diathesis-stress

model may not be independent (Monroe and Simons 1991). For example, severe acute HZ could cause a high degree of stress, which could further increase the risk of prolonged pain. Alternatively, a high degree of stress could augment organic factors, such as impaired VZV cell-mediated immunity, causing a more severe acute infection and further increasing the risk of prolonged pain.

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Risk/actors/or PHN Other than older age (see above), the best supported risk factor for PHN is the severity of the acute pain accompanying HZ. Data from numerous studies indicate that patients with more severe acute pain are at greater risk for persistent zoster pain (when pain is evaluated as a continuum) and the development of PHN (Bamford and Boundy 1968; Molin 1969; Riopelle et al. 1984; Harding et al. 1987; Dworkin et al. 1992, 1995a,b; Leijon et al. 1993; McKendrick et al. 1994; Beutner et al. 1995; Bruxelle 1995; Fiddian et al. 1995; Whitley et al. 1995; Wood et al. 1996). Most of these studies investigated the persistence of pain over the course of a 6-month follow-up period. One study showed that greater acute pain severity predicted duration of pain that resolves before rash healing (Bamford and Boundy 1968), and another noted an association between acute pain severity and the presence of PHN 9 years later (McKendrick et al. 1994). Notwithstanding methodological shortcomings in some of these studies, the abundance of data suggests that the relationship between acute pain severity and prolonged HZ pain can now be considered an established finding. The focus of future research should, therefore, become the identification of mechanisms that account for this relationship. Clinical studies that examine the different types of HZ pain (see above) and the distinction between the sensory and affective aspects of pain (Melzack and Casey 1968; Gracely 1984; Price 1988; Fernandez and Turk 1992; Chapman 1993) may illuminate basic research in this area. A second risk factor for prolonged pain is greater severity of the cutaneous manifestations (Wildenhoff et al. 1979, 1981; Wilson 1986; Higa et al. 1988, 1992; Dworkin et al. 1995a; Whitley et al. 1995). This factor more clearly reflects the overall severity of the acute infection. Cutaneous signs have been assessed in different ways, including duration of time until various parameters of rash healing are reached (e.g. cessation of new vesicle formation, loss of all scabs) and assessments of rash severity (e.g. counts of the number of vesicles, ratings of the proportion of the dermatome affected). Although it is possible that pain may be associated with a specific cutaneous manifestation, additional studies will be needed to clarify this. Scarring is common in patients following healing of the rash, but few studies have systematically examined the relationship between scarring and PHN. It has been reported that scarring in the affected dermatome distinguishes patients with PHN from patients whose pain did not persist (Nurmikko and Bowsher 1990). Because it is likely that scarring is a consequence of a more severe rash, this finding is consistent with the association between greater cutaneous signs during infection and prolonged pain. It has also been reported that scarring is less severe in PHN patients with predominantly allodynic pain (Rowbotham and Fields 1989), which suggests that scarring, and perhaps the more severe rash this implies, may be differen-

tially associated with the various types of pain reported by these patients. Another risk factor is greater sensory dysfunction in the affected dermatome during acute HZ (Noda et al. 1987; Nurmikko et al. 1990; Leijon et aI. 1993; Bruxelle 1995). Sensory dysfunction has been evaluated by clinical assessments of hypesthesia and by quantitative sensory testing of thermal and vibration thresholds. Patients with greater sensory abnormalities (e.g. hypesthesia, elevated thermal and vibration thresholds) in the affected dermatome, compared to the contralateral dermatome, are at greater risk for prolonged pain. It has also been reported that there is greater sensory dysfunction in the affected dermatome in patients with PHN than in HZ patients whose pain did not persist (Wildenhoff et al. 1979, 1981; Nurmikko and Bowsher 1990; Leijon et al. 1993). Greater magnitude and duration of the humoral and cellmediated immune response during acute HZ have also been reported to predict prolonged pain (Dan et al. 1983; Higa et al. 1988, 1992). These associations may reflect a relationship between severity of the infection and extent of the immune response. Several findings are consistent with this hypothesis. VZV-specific cell-mediated immune responses reach their maximum 1-2 weeks after the onset of HZ (usually the time of maximal infection) (Arvin et al. 1978), and a relationship between antibody titers and the extent of viral reactivation has been inferred for two other herpesviruses, herpes simplex and Epstein-Barr virus (Glaser and Kiecolt-Glaser 1994). In addition, antiviral treatment, which inhibits viral replication, is associated with a less pronounced immune response to VZV (Mitchell et al. 1986; Balfour et al. 1990). Two additional risk factors, the presence of a painful prodrome (Beutner et al. 1995) and fever greater than 38°C during acute HZ (Wilden hoff et al. 1981), have also been reported to predict prolonged pain. Studies have attempted to identify a role for the specific dermatome (Burgoon et al. 1957; De Moragas and Kierland 1957; Hope-Simpson 1975; Wilden hoff et al. 1979, 1981; Bruxelle 1995; Fiddian et al. 1995) and gender (Hope-Simpson 1975; Brown 1976; Wilden hoff et al. 1981; Harding et al. 1987; Beutner et al. 1995; Dworkin et al. 1995a; Fiddian et al. 1995; Wood et al. 1996), but neither have been consistently associated with prolonged pain or the development of PHN. It has recently been reported that blacks are appreciably less likely to develop herpes zoster than whites (Schmader et al. 1995), perhaps because of a later age of varicella infection (Dworkin 1996); to our knowledge, however, the relationship between racial group and risk of PHN has not been examined. Thus, six ri5k factors for prolonged zoster pain have been identified in these studies: acute pain severity, the severity of cutaneous signs, sensory dysfunction, the magnitude and duration of the immune response, prodromal pain, and fever. All can be considered aspects of more severe infection. Together, these risk factors provide considerable support for the hypothesis that the degree of neural

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damage during acute HZ contributes prominently to the duration of pain and the development of PHN (Bennett 1994). Other observations, however, indicate that the severity of infection does not completely account for the persistence of pain. For example, a higher incidence of cutaneous dissemination in immunocompromised patients (Balfour 1988; Gershon 1993) does not appear to translate into an increased risk of PHN (Balfour 1988; Rusthoven et al. 1988; Wood 1991; Gershon 1993). Similarly, the robust association between age and increased risk of PHN, which has been ascribed to an increased severity of infection in the elderly (Higa et al. 1988), cannot be fully explained by this factor. Older age does not appear to be associated with greater acute pain severity (Bamford and Boundy 1968; Harding et al. 1987), and the results of four recent studies suggest that age and acute pain severity are independent predictors of prolonged pain (Beutner et al. 1995; Dworkin et al. 1995a,b; Wood et al. 1996). The diathesis-stress model proposes that psychosocial factors contribute to the development of PHN. Based on interviews of patients with PHN, Pilowsky (1977) suggested that patients who develop prolonged pain are characterized by a specific constellation of premorbid personality traits and stressful life events. In a cross-sectional study, PHN patients had more symptoms of anxiety and rated their past experiences of pain as more intense than HZ patients whose pain did not persist (Rose et al. 1992); PHN patients had also experienced fewer stressful life events in the preceding year, a finding that the authors attributed to the withdrawal from activities that characterizes some chronic pain patients. In a recent retrospective study of patients with a history of HZ, those who reported having other diseases and/or psychosocial stress at the onset of HZ were significantly more likely to have PHN, changed daily activities, and lower levels of well-being than patients who reported no other diseases or psychosocial stress at the onset of HZ (Bergbom Engberg et al. 1995). In a prospective study of a small sample of HZ patients, patients who developed PHN had greater depression, anxiety, and disease conviction, and lower life satisfaction during their acute infection than patients who did not develop PHN (Dworkin et al. 1992). Analyses of the data from the first 70 acute HZ patients enrolled in an ongoing study generally replicated these findings and also indicated that a psychosocial factor (i.e. disease conviction) had a more pronounced effect on the risk of developing PHN at more severe levels of acute sensory pain (Dworkin et al. 1995b). It was suggested that acute sensory pain may reflect the severity of the neural damage caused by the acute HZ infection and that this finding therefore provides preliminary support for an interaction between diathesis and stress in the etiology of PHN. It has also been reported that stressful negative life events precede the appearance of acute HZ (Schmader et al. 1990). Together, the results of these studies suggest that

psychosocial factors playa role in both the onset of HZ and the development of PHN, and are consistent with evidence indicating that psychosocial factors contribute to the onset and course of other herpesvirus infections (Glaser and Kiecolt-Glaser 1994).

Future directions

Other, as yet unidentified, processes may also contribute to the development of PHN. The diathesis-stress model provides a foundation for the exploration of new hypotheses to explain the pain of HZ and PHN. Such hypotheses are needed, for example, to explain the previously discussed observation that severity of infection does not completely account for persistence of pain, the finding that recurrences of PHN can follow pain-free intervals, and the evidence of ongoing inflammation found in postmortem studies of some patients with PHN (Head and Campbell 1900; Smith 1978; Watson et al. 1991a). Gilden (1994) has proposed that PHN may involve the persistence of VZV at levels above those found during latency (Mahalingam et al. 1993), compounded by continued inflammation. This hypothesis could potentially explain the effect of age on the risk for PHN; VZV -specific cellmediated immunity is decreased in the elderly (Miller 1980; Berger et al. 1981; Burke et al. 1982; Hayward and Herberger 1987), and this immune deficiency could contribute to a low-level ganglionitis that sustains the pain. The possibility that antiviral drugs might be used to treat some patients with PHN related to low-level ganglionitis has been suggested by the effective use of acyclovir in two patients with prolonged radicular pain, no rash, and VZV DNA in blood mononuclear cells and cerebrospinal fluid (Gilden et al. 1994). Interestingly, each of these two patients suffered from recurrent pain, which suggests that if ganglionitis contributes to PHN it may be intermittent in some patients (Gilden et al. 1994). Although a doubleblind, placebo-controlled study of oral acyclovir administered for 12 weeks failed to find an effect of treatment in a sample of PHN patients (Surman et al. 1990), the small number of patients in this study and the possibility that the intracellular drug levels achieved with oral acyclovir may be inadequate for a beneficial effect (Gilden 1994) limits the importance of this finding. The hypothesized role for low-level ganglionitis is consistent with the reports of recurrent pain and the evidence of ongoing inflammation in some patients with PHN, but it does not explain the absence of an increased risk of PHN in immunocompromised patients. Patients with impaired cellmediated immunity have subclinical reactivations of VZV (Gershon 1993) and would therefore be expected to have an increased risk of PHN if low-level ganglionitis were a major factor contributing to prolonged pain. Hence, other disturbances are also likely to be involved in the pathogenesis of PHN.

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Another interesting hypothesis postulates a role for immunopathological processes in the persistence of pain after HZ. With aging, there is an increased production of autoantibodies, including antineuronal antibodies. Inflammatory autoimmune processes have been implicated in the pathophysiology of Alzheimer's disease and other neuropsychiatric disorders (Nandy et al. 1986; Aisen and Davis 1994), and it is possible that age-associated autoimmune phenomena, such as disturbed cytokine production, may result in nerve damage and contribute to the development of prolonged pain in patients with HZ (Weksler 1994). The hypothesis that immunopathological processes contribute to the development of PHN is consistent with the evidence of inflammation in patients with PHN and the greater risk of prolonged pain in the elderly. It is also consistent with the absence of an increased risk of PHN in immunocompromised patients, who suffer from immune deficiency but not necessarily from the immunopathological changes that occur with aging. Because many autoimmune disorders have a chronic course with intermittent exacerbations, this hypothesis is also consistent with the evidence of pain-free intervals followed by recurrences of pain. As is true of other hypotheses regarding the pathophysiology of PHN, the hypotheses that persisting ganglionitis and immunopathogenesis contribute to PHN are not mutually exclusive, or exclusive of the other risk factors, organic and psychosocial, that may be subsumed under the diathesisstress model. The role of these factors and their interaction in the development of PHN is an important area for future investigation.

Conclusions The prevalence of PHN can be expected to increase substantially in the next several decades because both the incidence of HZ and the risk of PHN will increase as the population ages (Donohue et al. 1995; Schmader 1995; Weller 1995). Treatments for established PHN are inadequate and the increased prevalence, which will be associated with increased disability and health care utilization, is a major public health concern. In addition to the development of more effective treatments (Watson and Chipman 1993), future research should target methods for reducing or even eliminating the risk that patients with acute HZ will develop PHN. Preventive measures can be proposed on the basis of studies of risk factors (Johnson 1995). For example, because older age and greater acute pain are both associated with an increased risk of PHN, it can be suggested that aggressive antiviral and analgesic treatment may lessen the risk of PHN in older HZ patients with acute pain of moderate or greater intensity. Prospective systematic studies that compare patients who do not progress to PHN with those who do may clarify the pathogenesis of PHN (Rowbotham and Fields 1989)

and lead to interventions that effectively prevent the disorder. In such studies, multivariate analyses of the covariate data specified in Table I have the potential to identify combinations of risk factors that identify the acute HZ patients who have the greatest risk of developing PHN. New research designs also have the potential to significantly increase understanding of HZ and PHN. Few studies have provided data addressing the interrelationships among the characteristics of acute HZ, including those that are risk factors for PHN. For example, it would be valuable to know whether greater acute pain severity and cutaneous signs are associated. This relationship has been addressed in only two studies: Molin (1969) reported th~t greater acute pain severity and greater rash duration were associated, whereas Bruxelle (1995) found no relationship between acute pain severity and the number of vesicles (acute pain severity and sensory dysfunction, however, were significantly associated in this study). In addition, although several recent studies of the efficacy of antiviral treatment of HZ on prolonged pain have examined the role of several of the covariates discussed above (Beutner et al. 1995; Dworkin et al. 1995a; Fiddian et al. 1995; Whitley et al. 1995; Wood et al. 1996), analyses of treatment--covariate interactions have not been reported. Such analyses have the potential to reveal whether certain HZ patients are more responsive to treatment than others; for example, it has been suggested that intravenous acyclovir has a greater effect on acute HZ pain in older patients than in younger patients (Peterslund et al. 1981). We have suggested that HZ and PHN can be expected to increase as the population ages. It is possible, however, that HZ and PHN may ultimately decrease with the advent of the live attenuated varicella vaccine that has now been approved in a number of countries, including the USA (White et al. 1991). If the prevalence and severity of HZ declines as the use of this vaccine becomes widespread (Hardy et al. TABLE I POTENTIALL Y IMPORTANT COY ARIA TES IN FUTURE STUDIES OF PAIN IN HZ AND PHN Demographic

Age RaCIal group

Treatment

Antiviral drugs Steroids Analgesics and antidepressants

Acute pain

Prodromal pain Severity after eruptton Qualitative aspects (e.g. burning, aching, lancinating, presence or absence of hyperalgesia, allodynia, etc.)

Severity of eruption

Cutaneous signs Sensory dysfunctIOn Immune response Fever

Psychosocial factors

Stressful hfe events Depression and anxiety SomatizatIOn

248

1991; White 1992), the prevalence and severity of PHN may also diminish. This decline could be dramatic, but it would take several generations to occur. Although this putative impact of the varicella vaccine on HZ and PHN seems likely, it has also been suggested that widespread use of the vaccine might be accompanied by an increase in the incidence of HZ (Garnett and Grenfell 1992); this could occur because exposure to exogenous VZV, which will decrease with widespread use of the vaccine, boosts immunity (Arvin 1992) and may thereby prevent viral reactivation and the development of HZ. Substantial reductions in the prevalence and severity of PHN, however, could occur within the next generation. Administration of the varicella vaccine to elderly subjects who have not had HZ results in increases in VZV -specific cell-mediated immunity to levels comparable to those found in elderly subjects with a history of HZ (Hayward et al. 1991). It has been suggested that the varicella vaccine could be used in older adults who have had varicella to enhance these immune responses, and thereby possibly decrease the incidence and severity of HZ (Hayward et al. 1991; Levin et al. 1992, 1994). To evaluate the effects of the varicella vaccine on HZ in older adults, a large doubleblind placebo-controlled trial has been designed (Oxman 1995). If the varicella vaccine is determined to have a beneficial impact on HZ in older adults and subsequently receives approval for routine use in this age group, it is possible that PHN will become so rare that it ceases to be a feared complication of herpes zoster.

Acknowledgements Preparation of this article was supported by grant NS30714 from the National Institute of Neurological Disorders and Stroke to the first author.

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