Diagnosis and Assessment of Pain Associated With Herpes Zoster and Postherpetic Neuralgia
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The Journal of Pain, Vol 9, No 1 (January), Supplement 1, 2008: pp S37-S44
Available online at www.sciencedirect.com
Diagnosis and Assessment of Pain Associated With Herpes Zoster
and Postherpetic Neuralgia
Robert H. Dworkin,* John W. Gnann, Jr.,† Anne Louise Oaklander,‡ Srinivasa N. Raja,§
Kenneth E. Schmader,储 and Richard J. Whitley¶
*Departments of Anesthesiology and Neurology, University of Rochester School of Medicine and Dentistry,
Rochester, New York.
†
Department of Medicine, University of Alabama at Birmingham and Birmingham VA Medical Center,
Birmingham, Alabama.
‡
Department of Neurology, Harvard University, Boston, Massachusetts.
§
Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine,
Baltimore, Maryland.
储
Department of Medicine, Duke University, and GRECC, Durham VA Medical Center, Durham, North Carolina.
¶
Department of Pediatrics, University of Alabama, Birmingham, Alabama.
Abstract: Accurate evaluation of pain plays a critical role in identifying new interventions for the
treatment and prevention of herpes zoster and postherpetic neuralgia (PHN). Different types of pain and
other sensory symptoms are found in patients with herpes zoster, and these vary greatly with respect to
their presence, location, duration, intensity, and quality. The results of recent studies of herpes zoster and
PHN and the development of new methods for assessing neuropathic pain provide a foundation for
diagnosing and assessing the pain associated with herpes zoster. We review the results of recent research
to identify the essential components that must be considered in developing an evidence-based descrip-
tion of pain associated with herpes zoster and PHN.
Perspective: Comprehensive assessments of pain are necessary for clinical research on the epidemi-
ology, natural history, pathophysiologic mechanisms, treatment, and prevention of pain in herpes
zoster and PHN.
© 2008 by the American Pain Society
Key words: Herpes zoster, postherpetic neuralgia, diagnosis, assessment, acute pain, chronic pain.
I
n immunocompetent patients with herpes zoster, the the chronic pain of PHN have multiple adverse effects on
most distressing symptom is typically pain and the health-related quality of life. These pain conditions
most feared complication is postherpetic neuralgia cause substantial interference with physical, emotional,
(PHN), the persistence of pain long after rash healing. and social functioning9,10,28,29 and result in increased
Both the acute pain associated with herpes zoster and health care costs,2,12,19 (and Dworkin RH, White R,
O’Connor A, Hawkins K: Health care expenditure burden
RHD has received grants/research support, consulting fees, or honoraria in of persisting herpes zoster pain. Pain Med, epub July 23,
the past year from Allergan, Balboa, Cara, CombinatoRx, Dara, Eli Lilly, 2007) with excess expenditures ranging as high as $5000
Endo, EpiCept, Fralex, GlaxoSmithKline, Grünenthal, GW Pharmaceuticals,
Johnson & Johnson, KAI Pharmaceuticals, Merck & Co., Inc., NeurogesX, in the first year after a diagnosis of PHN.19
Ono, Organon, Pfizer, Supernus, US Food and Drug Administration, US Na- Existing interventions do not completely prevent or
tional Institutes of Health, US Veterans Administration, Wyeth, and XTL
Development; JWG has received grants/research support, consulting fees, or adequately treat all cases of herpes zoster pain and
honoraria in the past year from Astellas, GlaxoSmithKline, Merck & Co., Inc., PHN.16,22,25,35,54 The development of more effective
Novartis, and ViroPharma; ALO has no relevant conflicts to report; SNR has
received grants/research support, consulting fees, or honoraria in the past strategies for the prevention and treatment of pain as-
year from Medtronic, Novartis, and Ortho-McNeil; KES has received grants/ sociated with herpes zoster and PHN is therefore an un-
research support, consulting fees, or honoraria in the past year from Merck
& Co., Inc.; and RJW has received grants/research support, consulting fees, or met public health need. In clinical trials evaluating such
honoraria in the past year from Chimerix, Gilead, and US National Institutes interventions, primary and secondary end points typi-
of Health.
Address reprint requests to Dr. Robert H. Dworkin, PhD, University of cally involve determining whether herpes zoster acute
Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box pain or PHN is present and then more comprehensively
604, Rochester, NY, 14642. E-mail: robert_dworkin@urmc.rochester.edu
1526-5900/$34.00
describing the patient’s experience of pain. The evalua-
© 2008 by the American Pain Society tion of pain outcomes therefore plays a critical role in
doi:10.1016/j.jpain.2007.10.008 identifying new interventions for herpes zoster and PHN
S37S38 Pain Associated With Herpes Zoster and Postherpetic Neuralgia
and is, more generally, a crucial component of all clinical more than 100 days has been reported.21 Because the
research on both conditions. herpes zoster prodrome can only be accurately diag-
Different types of pain and other sensory symptoms nosed after the rash appears, the prodrome is not infre-
are found in patients with herpes zoster, and these vary quently misdiagnosed as other conditions characterized
greatly with respect to their presence, location, duration, by pain in the affected dermatome (eg, angina, herpes
intensity, and quality. Recommendations were made for simplex, lumbar radiculopathy). Once the rash ap-
characterizing pain in patients with herpes zoster and pears, the diagnosis becomes clear and the prodrome
PHN in guidelines published at least 10 years ago.15,51 can then be assessed retrospectively by asking patients
However, the results of recent studies of herpes zoster (1) whether or not pain was present in the area of the
and PHN and the development of new methods for as- rash before the rash appeared; (2) the duration of pro-
sessing neuropathic pain provide an improved founda- dromal pain, that is, how many days before the rash
tion for the diagnosis and assessment of pain associated appeared did pain begin; and (3) the specific qualities of
with herpes zoster. The objective of this article is to re- the prodromal pain.
view the results of recent research and identify the es- Patients with herpes zoster commonly report other
sential components that must be considered in develop- prodromal symptoms, including dermatomal paresthe-
ing an evidence-based description of pain associated sias (abnormal sensations that are not unpleasant, for
with herpes zoster and PHN. example, tingling) and dysesthesias (abnormal sensa-
tions that are unpleasant, for example, numbness), itch-
ing, malaise, headache, and fever. These can also be ret-
Diagnosis of Herpes Zoster rospectively assessed with respect to presence, duration,
The diagnosis of herpes zoster is generally straight- and quality. Because there has been very little research
forward once the characteristic unilateral, dermato- on the herpes zoster prodrome, it is unknown whether
mal, vesicular rash appears. Although the possibility prodromal symptoms such as malaise and headache are
that reactivation of the varicella-zoster virus can cause caused by varicella-zoster virus reactivation or whether
dermatomal pain without a rash has received consid- retrospective reports of these symptoms reflect their
erable attention, a diagnosis of “zoster sine herpete” high prevalence in the population and/or recall biases
cannot be made on the basis of clinical presentation associated with a painful illness.
alone and would require evidence of concurrent viral
reactivation.16 Important considerations in the diag-
nosis of herpes zoster include: (1) The presence of a
Presence of Pain
painful prodrome, which occurs in as many as three- The presence of pain associated with herpes zoster can
quarters of all patients3,23,27; (2) a unilateral dermato- be assessed by determining whether patients have pain
mal distribution; (3) grouped vesicles or papules; (4) a in the primary dermatome or immediately adjacent cu-
history of a rash in the same distribution, which is taneous dermatomes temporally and spatially associated
suggestive of recurrent herpes simplex (up to 10% of with their herpes zoster rash that cannot be explained by
specimens from patients with presumed herpes zoster another diagnosis (eg, radiculopathy). For research pur-
have been found to contain herpes simplex virus); and poses, any uncertainty regarding whether subjects have
(5) pain and allodynia (ie, pain in response to a nor- pain associated with herpes zoster or pain due to an-
mally nonpainful stimulus) in the area of the rash. other cause in the same dermatome as their rash should
In addition to herpes simplex, the differential diagno- be carefully recorded, making it possible to exclude such
sis of herpes zoster includes contact dermatitis and rash patients from analyses. The presence of prodromal pain
caused by plant exposure (eg, poison ivy). Atypical man- can be assessed by asking, “Did you have any pain before
ifestations that occur in immunocompromised patients the rash appeared in the area where you now have your
include prolonged course, recurrent lesions, and involve- shingles rash?” The presence of herpes zoster pain can be
ment of multiple dermatomes. Diagnostic laboratory assessed by asking, “Do you have any pain in the area
tests are recommended when herpes simplex must be where you now have your shingles rash?” And the pres-
ruled out (eg, recurrent rash or sacral lesions) and for ence of pain after rash healing can be assessed by asking,
patients with atypical lesions.16 These include polymer- “Do you have any pain in the area where you had your
ase chain reaction, immunohistochemistry, and viral cul- shingles rash?” Although such assessments of the pres-
ture, which differ in their sensitivity, specificity, time to ence of any pain are a necessary first step in evaluating
obtain results, cost, availability, and whether they are herpes zoster pain and PHN, they must be supplemented
useful with crusted lesions.16 by assessments of pain intensity, as discussed below.
Prodromal Pain Location of Pain
In the majority of patients with herpes zoster, a pro- It is especially important to assess the location of pain
drome of unilateral dermatomal pain precedes the ap- associated with herpes zoster and PHN, and particular
pearance of the rash.3,23,27 This prodrome typically be- attention should be paid to its dermatomal distribution.
gins several days before rash onset, although a series of In clinical trials of topical agents and in the clinical use of
patients with prodromal pain preceding the rash by 7 to these agents, therapy is typically delivered to the area ofORIGINAL REPORT/Dworkin et al S39
maximal pain, which can be identified and mapped if olution in different treatment groups (eg, acyclovir,
necessary. Areas with stimulus-independent pain and valacyclovir) and patient samples (eg, immunocompe-
with stimulus-evoked pain (see below), which may over- tent, HIV infection) and as a function of covariates (age,
lap, can be assessed separately. Because either systemic acute pain intensity) provided support for these 3 phases
or topical therapies may reduce not only the intensity of pain and for defining PHN as pain persisting at least
but also the area of stimulus-evoked pain,48,49 the areas 120 days after rash onset. The results of a third study
of different types of stimulus-evoked pain can be indicated that patients with subacute herpetic neuralgia
mapped and serve as secondary end points in clinical (defined by the investigators as pain that resolved be-
trials. It is not unusual for the region of stimulus-evoked tween 3 and 4 months after rash onset) were younger
pain in patients with herpes zoster and PHN to extend and less likely to have severe acute pain than patients
beyond the region of the herpes zoster rash.23,36 with PHN but were more likely to have severe rash and
affected nonadjacent dermatomes than patients who
Duration of Pain did not have pain at the 3- and 4-month time points.27
These data suggest that subacute herpetic neuralgia that
The duration of pain associated with herpes zoster var- does not progress to PHN may reflect peripheral tissue
ies greatly, ranging from no pain or pain that lasts for damage and inflammation caused by a particularly se-
only a few days after rash onset to pain that lasts for vere or widespread rash in individuals who are otherwise
years or even decades after rash healing. In patients 50 at reduced risk for the development of PHN because of
years or older in antiviral trial placebo groups, approxi- their younger age or less severe acute pain.
mately 70% had pain 1 month after rash onset, which
declined to 40% 6 months after rash onset.17 In the her- Overall Duration of Pain
pes zoster vaccine trial placebo group, 30% of patients In addition to these 3 phases of pain associated with
who developed herpes zoster (all ⱖ60 years of age) had herpes zoster, the overall duration of pain—which has
pain 1 month after rash onset, whereas only 5% had pain also been termed “zoster-associated pain”— can be ex-
6 months after rash onset (with presence of pain defined amined. Typically, this measure assesses the total num-
as worse pain ⱖ3 on the Zoster Brief Pain Inventory ber of days of herpes zoster pain, beginning from rash
[ZBPI]).35 Possible explanations for the differences in onset and continuing until pain resolution, although it
these 2 sets of data include the exclusion of patients with would also be possible to include the duration of prodro-
worse pain ⱕ2 from the vaccine trial data as well as a mal pain in the calculation of overall pain duration. This
greater severity of herpes zoster in patients enrolled in measure does not distinguish between acute pain and
antiviral trials versus generally healthy individuals in the chronic pain, which have different underlying patho-
community enrolled in a vaccine trial who later develop physiologic mechanisms33 and different effects on qual-
herpes zoster. ity of life9,10 and health care burden.19 However, overall
pain duration has been used as an outcome measure in
Three Phases of Pain clinical trials of antiviral agents3,46 and other treatments
Given this marked variability in the duration of pain for herpes zoster,50,52 and it can provide useful informa-
associated with herpes zoster, various efforts have been tion and an informative end point in certain circum-
made to define and distinguish the acute pain of herpes stances.
zoster from the chronic pain of PHN. Until recently, these
definitions have been arbitrary, but the results of recent
research now provide support for the validity of distin-
Intensity of Pain
guishing between 3 phases of pain in affected and adja- As recommended by the Initiative on Methods, Mea-
cent dermatomes: (1) Herpes zoster acute pain (also surement, and Pain Assessment in Clinical Trials
termed acute herpetic neuralgia), defined as pain that (IMMPACT)18 for chronic pain clinical trials, the intensity
occurs within 30 days after rash onset; (2) subacute her- of pain associated with herpes zoster can be described
petic neuralgia, defined as pain that persists beyond the using a 0-to-10 numerical rating scale, with 0 represent-
acute phase but that resolves before the diagnosis of ing “no pain” and 10 representing “pain as bad as you
PHN can be made; and (3) PHN, defined as pain that can imagine,” accompanied by the instructions, “Please
persists 120 days or more after rash onset.1 Few prospec- rate your pain by indicating the number that best de-
tive studies have followed patients with herpes zoster scribes your pain on average in the last 24 hours.” De-
for more than 6 months. Despite the limited data on pain pending on the specific aims and design of a study, pain
resolution in patients whose pain has persisted for this “at its worst” or pain “at its least” can also be assessed
length of time, it is likely that pain persisting 180 days or using this scale, as can pain extending over shorter (eg,
more after rash onset is less likely to resolve than pain 12 hours) or longer (eg, 1 week) periods of time.
persisting for shorter durations; such pain could there- The intensity of pain associated with herpes zoster can
fore be considered “well-established” PHN. also be assessed using the ZBPI.10 As noted above, this
In 2 studies that examined phases of pain associated measure was used in the herpes zoster vaccine trial to
with herpes zoster, rates of pain resolution were exam- assess both herpes zoster acute pain and PHN.35 Al-
ined in clinical trials of antiviral and corticosteroid ther- though the general instructions for the ZBPI refer to pain
apy.1,13 Transition times (ie, change points) for pain res- and discomfort related to shingles, the anchors used forS40 Pain Associated With Herpes Zoster and Postherpetic Neuralgia
its rating scale are the same as those used for the rating efficacy of antiviral therapy; a noninferiority trial would
scale described above, specifically, “no pain” and “pain be problematic because of regulatory considerations in-
as bad as you can imagine.” The extent to which patients volving the prevention of PHN).14 It is therefore likely
administered the ZBPI rate their pain as well as sensory that such a definition of PHN would substantially reduce
symptoms that cause discomfort but not pain (ie, itching) future research on developing interventions for its pre-
is therefore unclear. vention.
The proposed definitions of clinically meaningful PHN
Clinically Meaningful Pain have been based on data showing that moderate and se-
It has recently been suggested that pain associated vere pain have greater adverse effects than mild pain,
with herpes zoster, especially PHN, should be de- which had limited impact on functional status and health-
scribed with respect to whether it is clinically meaning- related quality of life.10,29 However, current approaches to
ful. Two approaches have been used to define clini- the assessment of patient-reported outcomes require that
cally meaningful PHN, which has been considered pain the first step in developing new measures is to determine
that is severe enough to adversely affect health-re- what patients themselves consider important, and this ap-
lated quality of life and interfere with activities of proach has been endorsed by the United States Food and
daily living.10,35,43 On the basis of a series of studies Drug Administration47 and by IMMPACT.45 Unfortunately,
conducted in association with the herpes zoster vac- no studies have been conducted in which patients with
cine trial,10,29,35 PHN was defined as the presence of a PHN or other types of chronic pain that are mild in intensity
worst pain score of ⱖ3 on the ZBPI at 3 months or more have been asked whether their chronic mild pain is incon-
after rash onset. The validation of this definition was sequential and not worth treating or preventing. More
based on the demonstration that patients with pain of generally, the factors that are involved in distinguishing
this magnitude had poorer health-related quality of reports of discomfort from reports of pain and in determin-
life, including interference with physical and emo- ing whether patients desire treatment for their pain have
tional functioning and sleep, than those with milder not been adequately investigated in PHN and other chronic
levels of pain, which had limited impact on ZBPI pain pain conditions. Until such research is conducted, it may be
interference scale scores.10 In a prospective study of 94 premature to establish a definition for clinically meaning-
patients with herpes zoster, Thyregod et al43 defined ful pain in herpes zoster and PHN and to conclude that this
clinically meaningful PHN as average daily pain ratings is the only type of pain worth preventing or treating.
over the previous 48 hours ⱖ30 on a 100-mm visual
analog scale (VAS) at 6 months after rash onset. Overall Burden of Pain
In addition to using a threshold of pain intensity to The burden of pain associated with herpes zoster has
identify clinically meaningful pain associated with her- been described using composite measures that reflect
pes zoster, a variety of other approaches are possible. both pain intensity and duration. These composite mea-
For example, classification of pain as clinically mean- sures can be calculated for the 3 specific phases of pain
ingful could require that the patient is taking pain described above as well as for the overall duration of
medications or is being followed for pain by a physi- herpes zoster pain from onset to resolution. Two ap-
cian or other health care provider. Depending on the proaches have been used in calculating such composite
specific definition of clinically meaningful pain used, measures across the time interval of interest: The sum of
the incidence and prevalence will vary substantially. time-weighted pain intensity ratings24,28 and the sum of
For example, in Thyregod et al’s data,43 if such PHN time-weighted pain intensity ratings ⱖ3 on a 0-to-10
requires pain ⱖ30/100 on a VAS, as the authors pro- scale.10,35 These composite measures of pain intensity
pose, only 2% of patients had clinically meaningful and duration combined into a single score are reliable,
PHN at 6 months after rash onset (which is consistent valid, and responsive approaches to assessing pain asso-
with what has been found in clinical trials of antiviral ciated with herpes zoster and PHN. With such composite
agents53). However, if the definition of clinically measures, however, the same overall score can be ob-
meaningful PHN requires that prescription analgesic tained by multiple days of relatively mild pain and by
medications are being administered for pain, 10% of relatively fewer days of severe pain. Depending on the
their patients had PHN at 6 months.43 And if the defi- specific research objectives of a study, it may therefore
nition of PHN includes patients either having pain be necessary to show similar effects on the components
ⱖ30/100 on a VAS, using prescription analgesic medi- of the composite. This may be particularly important
cations, or being followed by a physician for persisting when interpreting the results of clinical trials to ensure
pain, 12% of their patients had PHN at 6 months. that there is an adequate understanding of what is con-
These figures have critical implications for the devel- tributing to any treatment benefits that are found.
opment of improved interventions for preventing pain
associated with herpes zoster because of the large sam-
ple sizes that would be required to demonstrate that a
Quality of Pain
new treatment would significantly reduce the incidence The quality of pain and related symptoms associated
of PHN compared with or in combination with an exist- with herpes zoster and PHN can be described in a com-
ing antiviral agent (a superiority trial or an add-on trial is prehensive fashion using several measures that are reli-
necessary for ethical reasons, given the well-established able and valid. The most important distinction in assess-ORIGINAL REPORT/Dworkin et al S41
ing pain quality in patients with herpes zoster and PHN is cold, sensitive, and itchy) as well as ratings of spatial
between spontaneous pain and stimulus-evoked pain. characteristics (deep pain, surface pain) and overall pain
The following aspects of pain quality and related symp- intensity and pain unpleasantness. The Neuropathic Pain
toms associated with herpes zoster can be assessed: (1) Symptom Inventory5 consists of ratings of 10 pain de-
Stimulus-independent continuous pain; (2) stimulus-in- scriptors, with 2 additional items that assess the duration
dependent intermittent pain; (3) stimulus-evoked pain, of spontaneous pain and the frequency of intermittent
especially brush-evoked dynamic allodynia; and (4) par- pain. Each of these 3 measures has been used in multiple
esthesias, dysesthesias, and itching.34 studies of patients with neuropathic pain, including clin-
Spontaneous pain is present in the absence of any stim- ical trials of treatments for PHN, and they are generally
ulation, and it can be either continuous or intermittent. reliable, valid, and responsive to change and treatment
Most patients describe more than 1 type of spontaneous effects. In many circumstances, however, it is important
pain, that is, their pain has several different qualities (eg, to supplement the data from these questionnaire-based
burning, throbbing, aching, shooting). Spontaneous assessments of symptoms with more objective sensory
continuous pain is present all or almost all of the time, testing procedures to evaluate stimulus-evoked pain and
although patients typically report that it varies in inten- other sensory abnormalities.
sity. Spontaneous intermittent pain is episodic and typi-
cally has a relatively short duration when it occurs. This Rescue and Concomitant Analgesic
type of pain is often paroxysmal and described by pa-
tients as shooting, stabbing, or electric shock-like in qual-
Treatments
ity. In assessing spontaneous pain in patients with herpes The effect of rescue and concomitant analgesics on
zoster and PHN, particular attention should be paid to assessments of the presence, location, intensity, and
burning pain. This type of pain is very common in pa- quality of pain associated with herpes zoster has not
tients with neuropathic pain30 and may be more com- received adequate attention. Nevertheless, in studies of
mon in patients with PHN than in patients with herpes pain in patients with herpes zoster and PHN, the use of
zoster acute pain, who appear to be more likely to report all pain-related treatments should be assessed, including
sharp, stabbing pain.4,7 Burning pain was also reported rescue analgesics and any other concomitant pain treat-
less frequently by patients with PHN who had been ad- ments. Some clinical trials have allowed previously used
ministered antiviral therapy during their herpes zoster analgesic medications to be continued throughout the
than patients with PHN who had not.6,7 Considered to- trial, and dosage stabilization is often required before
gether, these findings suggest that burning pain might patients are allowed to enroll in such trials. However,
reflect an important pathophysiologic mechanism in the when changes in the use of concomitant pain treatments
development of PHN. are permitted, they can be evaluated as an outcome
The most important types of stimulus-evoked pain in measure.
patients with herpes zoster and PHN are allodynia and Providing patients with access to rescue analgesics may
hyperalgesia (ie, increased pain in response to a normally make it easier to include a placebo group in clinical trials
painful stimulus). Various mechanical and thermal stim- because patients not obtaining adequate pain relief are
uli have been used in evaluating stimulus-evoked pain. provided with an analgesic. However, administration of
Dynamic mechanical allodynia, which is the most com- rescue treatment complicates the interpretation of dif-
mon type of stimulus-evoked pain in patients with ferences in pain ratings between patients taking placebo
PHN,36 can be elicited by lightly moving a foam paint and active treatments because of reductions in pain as-
brush or cotton swab across the skin. Static mechanical sociated with use of rescue analgesics. Patients in a pla-
allodynia can be elicited by light, blunt pressure with a cebo group can be expected to use more of a rescue
finger, and punctuate mechanical allodynia can be elic- treatment than patients administered an efficacious
ited by light pressure with a von Frey filament or sharp treatment. Rescue treatment can therefore be used as an
stick. Thermal allodynia can be assessed by applying a outcome measure in clinical trials, with assessments in-
heated or cooled tuning fork, ice, or a drop of alcohol or cluding total amount used and time to first use.
acetone to the skin of the affected region. Assessments of the use of rescue and concomitant an-
Various questionnaires have been developed for eval- algesic must not only consider the dosages used by pa-
uating the quality of neuropathic pain, some of which tients but also differences in efficacy between different
include assessments of paresthesias and dysesthesias, medications. Although there are few head-to-head com-
and these can be used in patients with herpes zoster and parisons of the medications that have demonstrated ef-
PHN. The Short-Form McGill Pain Questionnaire31 as- ficacy in PHN,25,54 these medications are generally com-
sesses 15 specific sensory and affective pain descriptors parable in their ability to relieve pain. However, there
and provides a total score as well as sensory and affective are other medications that are widely used in the treat-
subscale scores. Two newer measures, the Neuropathic ment of PHN—for example, acetaminophen and non-
Pain Scale20 and the Neuropathic Pain Symptom Inven- steroidal anti-inflammatory drugs—which have not
tory,5 were specifically developed to assess the symptoms been evaluated in randomized clinical trials and which
and signs that are characteristic of neuropathic pain con- are thought to have limited effectiveness based on clin-
ditions, including PHN. The Neuropathic Pain Scale20 in- ical experience. In evaluating use of rescue and concom-
cludes ratings of 6 specific pain qualities (sharp, hot, dull, itant analgesics, it would therefore be important to con-S42 Pain Associated With Herpes Zoster and Postherpetic Neuralgia
sider potential differences in the analgesic benefits of, chronic pain of PHN. To provide a foundation for the
for example, tricyclic antidepressants or opioid analge- diagnosis and assessment of pain associated with herpes
sics versus acetaminophen. zoster, we have reviewed the results of recent research
Composite measures have been developed that com- on herpes zoster and PHN and methods for assessing
bine rescue medication use and pain intensity ratings neuropathic pain. However, detailed consideration of
into a single score.42 Unfortunately, none of these com- several important components of a comprehensive eval-
posite measures are well-accepted, and their psychomet- uation of pain associated with herpes zoster and PHN is
ric properties are not well-established. Moreover, be- beyond the scope of this article. These components in-
cause no composite measures of pain intensity and clude the neurologic evaluation of motor, sensory, and
rescue or concomitant analgesic use have been devel- autonomic signs and symptoms, and the use of quantita-
oped for pain associated with herpes zoster, the mea- tive sensory testing and various laboratory tests (eg, mi-
sures that are available can only be recommended for croneurography, laser-evoked potentials, neuroimag-
exploratory use. One strategy that can be used until such ing, punch skin biopsy) in patients with herpes zoster and
measures are developed is to provide a comprehensive PHN. Further information about these procedures and
cross-tabulation of pain intensity with use of analgesic their role in the assessment of neuropathic pain is pro-
medications. Using such an approach, Whitley et al51 vided by the guidelines of the European Federation of
showed that greater pain severity and greater use of Neurological Societies11 and the comprehensive protocol
analgesics were associated, and that as pain severity in- and reference values for quantitative sensory testing of
creased, the percentage of patients using opioid analge- the German Research Network on Neuropathic Pain.37,38
sics and parenteral administration increased. These rela- Much of this information is relevant for herpes zoster
tionships were found during the first month after rash and PHN, and standardized approaches for the quantita-
onset and throughout a 6-month follow-up. tive assessment of signs and symptoms of neurologic dys-
function in patients with herpes zoster and PHN are
Conclusions likely to play an increasing role in clinical research on
The number of patients with herpes zoster and PHN these conditions.
may increase substantially in the future. Because older Herpes zoster, PHN, and other conditions that cause
age and immune compromise are both potent risk fac- neuropathic pain all adversely affect health-related
tors for herpes zoster, increases in the incidence of her- quality of life, including physical and emotional func-
pes zoster and its complications, including PHN, can be tioning.26,39 Evaluating the impact of pain on patients’
expected as the general population ages and as the prev- daily lives, including their physical and mental activities,
alence of diseases and medical treatments that are asso- well-being, and social relationships, is an additional im-
ciated with immunosuppression increases.40 It can also portant component of the assessment of pain in herpes
be predicted that the number of adults developing her- zoster and PHN that is beyond the scope of this article.
pes zoster in the United States may increase as a conse- Recommendations have been published for chronic pain
quence of reduced opportunities for subclinical immune clinical trials for core outcome domains,44 and for exist-
boosting resulting from near-universal varicella vaccina- ing measures18 and the development of new measures45
tion of children.8,41 Recent data showing an increase in of these outcome domains. Although these recommen-
herpes zoster in the United States are consistent with this dations are specifically intended for clinical trials of
prediction.32,55 An increase in the incidence of herpes treatments for chronic pain, they are also more generally
zoster could be offset by zoster vaccination,35 but the applicable to clinical research on pain and its conse-
extent to which widespread herpes zoster vaccination quences. Such assessments of the impact of pain on
will occur is presently unknown. For these reasons, ef- health-related quality of life, combined with evaluations
forts to develop new interventions to prevent and treat of the presence, location, duration, intensity, and quality
herpes zoster and PHN will need to be expanded. of pain, can provide the basis for future studies of pain
A crucial aspect of such efforts will be the careful char- and its response to treatment or prevention in patients
acterization of the acute pain of herpes zoster and the with herpes zoster and PHN.
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