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Diagnosis and Assessment of Pain Associated With Herpes Zoster and Postherpetic Neuralgia
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 description of pain associated with herpes zoster and PHN. Perspective: Comprehensive assessments of pain are necessary for clinical research on the epidemiology, 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 most distressing symptom is typically pain and the most feared complication is postherpetic neuralgia (PHN), the persistence of pain long after rash healing. Both the acute pain associated with herpes zoster and RHD has received grants/research support, consulting fees, or honoraria in the past year from Allergan, Balboa, Cara, CombinatoRx, Dara, Eli Lilly, Endo, EpiCept, Fralex, GlaxoSmithKline, Grünenthal, GW Pharmaceuticals, Johnson & Johnson, KAI Pharmaceuticals, Merck & Co., Inc., NeurogesX, Ono, Organon, Pfizer, Supernus, US Food and Drug Administration, US National Institutes of Health, US Veterans Administration, Wyeth, and XTL Development; JWG has received grants/research support, consulting fees, or honoraria in the past year from Astellas, GlaxoSmithKline, Merck & Co., Inc., Novartis, and ViroPharma; ALO has no relevant conflicts to report; SNR has received grants/research support, consulting fees, or honoraria in the past year from Medtronic, Novartis, and Ortho-McNeil; KES has received grants/ research support, consulting fees, or honoraria in the past year from Merck & Co., Inc.; and RJW has received grants/research support, consulting fees, or honoraria in the past year from Chimerix, Gilead, and US National Institutes of Health. Address reprint requests to Dr. Robert H. Dworkin, PhD, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 604, Rochester, NY, 14642. E-mail: [email protected] 1526-5900/$34.00 © 2008 by the American Pain Society doi:10.1016/j.jpain.2007.10.008
the chronic pain of PHN have multiple adverse effects on health-related quality of life. These pain conditions cause substantial interference with physical, emotional, and social functioning9,10,28,29 and result in increased health care costs,2,12,19 (and Dworkin RH, White R, O’Connor A, Hawkins K: Health care expenditure burden of persisting herpes zoster pain. Pain Med, epub July 23, 2007) with excess expenditures ranging as high as $5000 in the first year after a diagnosis of PHN.19 Existing interventions do not completely prevent or adequately treat all cases of herpes zoster pain and PHN.16,22,25,35,54 The development of more effective strategies for the prevention and treatment of pain associated with herpes zoster and PHN is therefore an unmet public health need. In clinical trials evaluating such interventions, primary and secondary end points typically involve determining whether herpes zoster acute pain or PHN is present and then more comprehensively describing the patient’s experience of pain. The evaluation of pain outcomes therefore plays a critical role in identifying new interventions for herpes zoster and PHN S37
S38 and is, more generally, a crucial component of all clinical research on both conditions. 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. Recommendations were made for characterizing pain in patients with herpes zoster and PHN in guidelines published at least 10 years ago.15,51 However, the results of recent studies of herpes zoster and PHN and the development of new methods for assessing neuropathic pain provide an improved foundation for the diagnosis and assessment of pain associated with herpes zoster. The objective of this article is to review the results of recent research and identify the essential components that must be considered in developing an evidence-based description of pain associated with herpes zoster and PHN.
Diagnosis of Herpes Zoster The diagnosis of herpes zoster is generally straightforward once the characteristic unilateral, dermatomal, vesicular rash appears. Although the possibility that reactivation of the varicella-zoster virus can cause dermatomal pain without a rash has received considerable attention, a diagnosis of “zoster sine herpete” cannot be made on the basis of clinical presentation alone and would require evidence of concurrent viral reactivation.16 Important considerations in the diagnosis of herpes zoster include: (1) The presence of a painful prodrome, which occurs in as many as threequarters of all patients3,23,27; (2) a unilateral dermatomal distribution; (3) grouped vesicles or papules; (4) a history of a rash in the same distribution, which is suggestive of recurrent herpes simplex (up to 10% of specimens from patients with presumed herpes zoster have been found to contain herpes simplex virus); and (5) pain and allodynia (ie, pain in response to a normally nonpainful stimulus) in the area of the rash. In addition to herpes simplex, the differential diagnosis of herpes zoster includes contact dermatitis and rash caused by plant exposure (eg, poison ivy). Atypical manifestations that occur in immunocompromised patients include prolonged course, recurrent lesions, and involvement of multiple dermatomes. Diagnostic laboratory tests are recommended when herpes simplex must be ruled out (eg, recurrent rash or sacral lesions) and for patients with atypical lesions.16 These include polymerase chain reaction, immunohistochemistry, and viral culture, which differ in their sensitivity, specificity, time to obtain results, cost, availability, and whether they are useful with crusted lesions.16
Pain Associated With Herpes Zoster and Postherpetic Neuralgia more than 100 days has been reported.21 Because the herpes zoster prodrome can only be accurately diagnosed after the rash appears, the prodrome is not infrequently misdiagnosed as other conditions characterized by pain in the affected dermatome (eg, angina, herpes simplex, lumbar radiculopathy). Once the rash appears, the diagnosis becomes clear and the prodrome can then be assessed retrospectively by asking patients (1) whether or not pain was present in the area of the rash before the rash appeared; (2) the duration of prodromal pain, that is, how many days before the rash appeared did pain begin; and (3) the specific qualities of the prodromal pain. Patients with herpes zoster commonly report other prodromal symptoms, including dermatomal paresthesias (abnormal sensations that are not unpleasant, for example, tingling) and dysesthesias (abnormal sensations that are unpleasant, for example, numbness), itching, malaise, headache, and fever. These can also be retrospectively assessed with respect to presence, duration, and quality. Because there has been very little research on the herpes zoster prodrome, it is unknown whether prodromal symptoms such as malaise and headache are caused by varicella-zoster virus reactivation or whether retrospective reports of these symptoms reflect their high prevalence in the population and/or recall biases associated with a painful illness.
Presence of Pain The presence of pain associated with herpes zoster can be assessed by determining whether patients have pain in the primary dermatome or immediately adjacent cutaneous dermatomes temporally and spatially associated with their herpes zoster rash that cannot be explained by another diagnosis (eg, radiculopathy). For research purposes, any uncertainty regarding whether subjects have pain associated with herpes zoster or pain due to another cause in the same dermatome as their rash should be carefully recorded, making it possible to exclude such patients from analyses. The presence of prodromal pain can be assessed by asking, “Did you have any pain before the rash appeared in the area where you now have your shingles rash?” The presence of herpes zoster pain can be assessed by asking, “Do you have any pain in the area where you now have your shingles rash?” And the presence of pain after rash healing can be assessed by asking, “Do you have any pain in the area where you had your shingles rash?” Although such assessments of the presence of any pain are a necessary first step in evaluating herpes zoster pain and PHN, they must be supplemented by assessments of pain intensity, as discussed below.
Prodromal Pain
Location of Pain
In the majority of patients with herpes zoster, a prodrome of unilateral dermatomal pain precedes the appearance of the rash.3,23,27 This prodrome typically begins several days before rash onset, although a series of patients with prodromal pain preceding the rash by 7 to
It is especially important to assess the location of pain associated with herpes zoster and PHN, and particular attention should be paid to its dermatomal distribution. In clinical trials of topical agents and in the clinical use of these agents, therapy is typically delivered to the area of
ORIGINAL REPORT/Dworkin et al maximal pain, which can be identified and mapped if necessary. Areas with stimulus-independent pain and with stimulus-evoked pain (see below), which may overlap, can be assessed separately. Because either systemic or topical therapies may reduce not only the intensity but also the area of stimulus-evoked pain,48,49 the areas of different types of stimulus-evoked pain can be mapped and serve as secondary end points in clinical trials. It is not unusual for the region of stimulus-evoked pain in patients with herpes zoster and PHN to extend beyond the region of the herpes zoster rash.23,36
Duration of Pain The duration of pain associated with herpes zoster varies greatly, ranging from no pain or pain that lasts for only a few days after rash onset to pain that lasts for years or even decades after rash healing. In patients 50 years or older in antiviral trial placebo groups, approximately 70% had pain 1 month after rash onset, which declined to 40% 6 months after rash onset.17 In the herpes zoster vaccine trial placebo group, 30% of patients who developed herpes zoster (all ⱖ60 years of age) had pain 1 month after rash onset, whereas only 5% had pain 6 months after rash onset (with presence of pain defined as worse pain ⱖ3 on the Zoster Brief Pain Inventory [ZBPI]).35 Possible explanations for the differences in these 2 sets of data include the exclusion of patients with worse pain ⱕ2 from the vaccine trial data as well as a greater severity of herpes zoster in patients enrolled in antiviral trials versus generally healthy individuals in the community enrolled in a vaccine trial who later develop herpes zoster.
Three Phases of Pain Given this marked variability in the duration of pain associated with herpes zoster, various efforts have been made to define and distinguish the acute pain of herpes 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 distinguishing between 3 phases of pain in affected and adjacent dermatomes: (1) Herpes zoster acute pain (also termed acute herpetic neuralgia), defined as pain that occurs within 30 days after rash onset; (2) subacute herpetic neuralgia, defined as pain that persists beyond the acute phase but that resolves before the diagnosis of PHN can be made; and (3) PHN, defined as pain that persists 120 days or more after rash onset.1 Few prospective studies have followed patients with herpes zoster for more than 6 months. Despite the limited data on pain resolution in patients whose pain has persisted for this length of time, it is likely that pain persisting 180 days or more after rash onset is less likely to resolve than pain persisting for shorter durations; such pain could therefore be considered “well-established” PHN. In 2 studies that examined phases of pain associated with herpes zoster, rates of pain resolution were examined in clinical trials of antiviral and corticosteroid therapy.1,13 Transition times (ie, change points) for pain res-
S39 olution in different treatment groups (eg, acyclovir, valacyclovir) and patient samples (eg, immunocompetent, HIV infection) and as a function of covariates (age, acute pain intensity) provided support for these 3 phases of pain and for defining PHN as pain persisting at least 120 days after rash onset. The results of a third study indicated that patients with subacute herpetic neuralgia (defined by the investigators as pain that resolved between 3 and 4 months after rash onset) were younger and less likely to have severe acute pain than patients with PHN but were more likely to have severe rash and affected nonadjacent dermatomes than patients who did not have pain at the 3- and 4-month time points.27 These data suggest that subacute herpetic neuralgia that does not progress to PHN may reflect peripheral tissue damage and inflammation caused by a particularly severe or widespread rash in individuals who are otherwise at reduced risk for the development of PHN because of their younger age or less severe acute pain.
Overall Duration of Pain In addition to these 3 phases of pain associated with herpes zoster, the overall duration of pain—which has also been termed “zoster-associated pain”— can be examined. Typically, this measure assesses the total number of days of herpes zoster pain, beginning from rash onset and continuing until pain resolution, although it would also be possible to include the duration of prodromal pain in the calculation of overall pain duration. This measure does not distinguish between acute pain and chronic pain, which have different underlying pathophysiologic mechanisms33 and different effects on quality of life9,10 and health care burden.19 However, overall pain duration has been used as an outcome measure in clinical trials of antiviral agents3,46 and other treatments for herpes zoster,50,52 and it can provide useful information and an informative end point in certain circumstances.
Intensity of Pain As recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT)18 for chronic pain clinical trials, the intensity of pain associated with herpes zoster can be described using a 0-to-10 numerical rating scale, with 0 representing “no pain” and 10 representing “pain as bad as you can imagine,” accompanied by the instructions, “Please rate your pain by indicating the number that best describes your pain on average in the last 24 hours.” Depending on the specific aims and design of a study, pain “at its worst” or pain “at its least” can also be assessed using this scale, as can pain extending over shorter (eg, 12 hours) or longer (eg, 1 week) periods of time. The intensity of pain associated with herpes zoster can also be assessed using the ZBPI.10 As noted above, this measure was used in the herpes zoster vaccine trial to assess both herpes zoster acute pain and PHN.35 Although the general instructions for the ZBPI refer to pain and discomfort related to shingles, the anchors used for
S40 its rating scale are the same as those used for the rating scale described above, specifically, “no pain” and “pain as bad as you can imagine.” The extent to which patients administered the ZBPI rate their pain as well as sensory symptoms that cause discomfort but not pain (ie, itching) is therefore unclear.
Clinically Meaningful Pain It has recently been suggested that pain associated with herpes zoster, especially PHN, should be described with respect to whether it is clinically meaningful. Two approaches have been used to define clinically meaningful PHN, which has been considered pain that is severe enough to adversely affect health-related quality of life and interfere with activities of daily living.10,35,43 On the basis of a series of studies conducted in association with the herpes zoster vaccine trial,10,29,35 PHN was defined as the presence of a worst pain score of ⱖ3 on the ZBPI at 3 months or more after rash onset. The validation of this definition was based on the demonstration that patients with pain of this magnitude had poorer health-related quality of life, including interference with physical and emotional functioning and sleep, than those with milder levels of pain, which had limited impact on ZBPI pain interference scale scores.10 In a prospective study of 94 patients with herpes zoster, Thyregod et al43 defined clinically meaningful PHN as average daily pain ratings over the previous 48 hours ⱖ30 on a 100-mm visual analog scale (VAS) at 6 months after rash onset. In addition to using a threshold of pain intensity to identify clinically meaningful pain associated with herpes zoster, a variety of other approaches are possible. For example, classification of pain as clinically meaningful could require that the patient is taking pain medications or is being followed for pain by a physician or other health care provider. Depending on the specific definition of clinically meaningful pain used, the incidence and prevalence will vary substantially. For example, in Thyregod et al’s data,43 if such PHN requires pain ⱖ30/100 on a VAS, as the authors propose, only 2% of patients had clinically meaningful PHN at 6 months after rash onset (which is consistent with what has been found in clinical trials of antiviral agents53). However, if the definition of clinically meaningful PHN requires that prescription analgesic medications are being administered for pain, 10% of their patients had PHN at 6 months.43 And if the definition of PHN includes patients either having pain ⱖ30/100 on a VAS, using prescription analgesic medications, or being followed by a physician for persisting pain, 12% of their patients had PHN at 6 months. These figures have critical implications for the development of improved interventions for preventing pain associated with herpes zoster because of the large sample sizes that would be required to demonstrate that a new treatment would significantly reduce the incidence of PHN compared with or in combination with an existing antiviral agent (a superiority trial or an add-on trial is necessary for ethical reasons, given the well-established
Pain Associated With Herpes Zoster and Postherpetic Neuralgia efficacy of antiviral therapy; a noninferiority trial would be problematic because of regulatory considerations involving the prevention of PHN).14 It is therefore likely that such a definition of PHN would substantially reduce future research on developing interventions for its prevention. The proposed definitions of clinically meaningful PHN have been based on data showing that moderate and severe pain have greater adverse effects than mild pain, which had limited impact on functional status and healthrelated quality of life.10,29 However, current approaches to the assessment of patient-reported outcomes require that the first step in developing new measures is to determine what patients themselves consider important, and this approach has been endorsed by the United States Food and Drug Administration47 and by IMMPACT.45 Unfortunately, no studies have been conducted in which patients with PHN or other types of chronic pain that are mild in intensity have been asked whether their chronic mild pain is inconsequential and not worth treating or preventing. More generally, the factors that are involved in distinguishing reports of discomfort from reports of pain and in determining whether patients desire treatment for their pain have not been adequately investigated in PHN and other chronic pain conditions. Until such research is conducted, it may be premature to establish a definition for clinically meaningful pain in herpes zoster and PHN and to conclude that this is the only type of pain worth preventing or treating.
Overall Burden of Pain The burden of pain associated with herpes zoster has been described using composite measures that reflect both pain intensity and duration. These composite measures can be calculated for the 3 specific phases of pain described above as well as for the overall duration of herpes zoster pain from onset to resolution. Two approaches have been used in calculating such composite measures across the time interval of interest: The sum of time-weighted pain intensity ratings24,28 and the sum of time-weighted pain intensity ratings ⱖ3 on a 0-to-10 scale.10,35 These composite measures of pain intensity and duration combined into a single score are reliable, valid, and responsive approaches to assessing pain associated with herpes zoster and PHN. With such composite measures, however, the same overall score can be obtained by multiple days of relatively mild pain and by relatively fewer days of severe pain. Depending on the specific research objectives of a study, it may therefore be necessary to show similar effects on the components of the composite. This may be particularly important when interpreting the results of clinical trials to ensure that there is an adequate understanding of what is contributing to any treatment benefits that are found.
Quality of Pain The quality of pain and related symptoms associated with herpes zoster and PHN can be described in a comprehensive fashion using several measures that are reliable and valid. The most important distinction in assess-
ORIGINAL REPORT/Dworkin et al ing pain quality in patients with herpes zoster and PHN is between spontaneous pain and stimulus-evoked pain. The following aspects of pain quality and related symptoms associated with herpes zoster can be assessed: (1) Stimulus-independent continuous pain; (2) stimulus-independent intermittent pain; (3) stimulus-evoked pain, especially brush-evoked dynamic allodynia; and (4) paresthesias, dysesthesias, and itching.34 Spontaneous pain is present in the absence of any stimulation, and it can be either continuous or intermittent. Most patients describe more than 1 type of spontaneous pain, that is, their pain has several different qualities (eg, burning, throbbing, aching, shooting). Spontaneous continuous pain is present all or almost all of the time, although patients typically report that it varies in intensity. Spontaneous intermittent pain is episodic and typically has a relatively short duration when it occurs. This type of pain is often paroxysmal and described by patients as shooting, stabbing, or electric shock-like in quality. In assessing spontaneous pain in patients with herpes zoster and PHN, particular attention should be paid to burning pain. This type of pain is very common in patients with neuropathic pain30 and may be more common in patients with PHN than in patients with herpes zoster acute pain, who appear to be more likely to report sharp, stabbing pain.4,7 Burning pain was also reported less frequently by patients with PHN who had been administered antiviral therapy during their herpes zoster than patients with PHN who had not.6,7 Considered together, these findings suggest that burning pain might reflect an important pathophysiologic mechanism in the development of PHN. The most important types of stimulus-evoked pain in patients with herpes zoster and PHN are allodynia and hyperalgesia (ie, increased pain in response to a normally painful stimulus). Various mechanical and thermal stimuli have been used in evaluating stimulus-evoked pain. Dynamic mechanical allodynia, which is the most common type of stimulus-evoked pain in patients with PHN,36 can be elicited by lightly moving a foam paint brush or cotton swab across the skin. Static mechanical allodynia can be elicited by light, blunt pressure with a finger, and punctuate mechanical allodynia can be elicited by light pressure with a von Frey filament or sharp stick. Thermal allodynia can be assessed by applying a heated or cooled tuning fork, ice, or a drop of alcohol or acetone to the skin of the affected region. Various questionnaires have been developed for evaluating the quality of neuropathic pain, some of which include assessments of paresthesias and dysesthesias, and these can be used in patients with herpes zoster and PHN. The Short-Form McGill Pain Questionnaire31 assesses 15 specific sensory and affective pain descriptors and provides a total score as well as sensory and affective subscale scores. Two newer measures, the Neuropathic Pain Scale20 and the Neuropathic Pain Symptom Inventory,5 were specifically developed to assess the symptoms and signs that are characteristic of neuropathic pain conditions, including PHN. The Neuropathic Pain Scale20 includes ratings of 6 specific pain qualities (sharp, hot, dull,
S41 cold, sensitive, and itchy) as well as ratings of spatial characteristics (deep pain, surface pain) and overall pain intensity and pain unpleasantness. The Neuropathic Pain Symptom Inventory5 consists of ratings of 10 pain descriptors, with 2 additional items that assess the duration of spontaneous pain and the frequency of intermittent pain. Each of these 3 measures has been used in multiple studies of patients with neuropathic pain, including clinical trials of treatments for PHN, and they are generally reliable, valid, and responsive to change and treatment effects. In many circumstances, however, it is important to supplement the data from these questionnaire-based assessments of symptoms with more objective sensory testing procedures to evaluate stimulus-evoked pain and other sensory abnormalities.
Rescue and Concomitant Analgesic Treatments The effect of rescue and concomitant analgesics on assessments of the presence, location, intensity, and quality of pain associated with herpes zoster has not received adequate attention. Nevertheless, in studies of pain in patients with herpes zoster and PHN, the use of all pain-related treatments should be assessed, including rescue analgesics and any other concomitant pain treatments. Some clinical trials have allowed previously used analgesic medications to be continued throughout the trial, and dosage stabilization is often required before patients are allowed to enroll in such trials. However, when changes in the use of concomitant pain treatments are permitted, they can be evaluated as an outcome measure. Providing patients with access to rescue analgesics may make it easier to include a placebo group in clinical trials because patients not obtaining adequate pain relief are provided with an analgesic. However, administration of rescue treatment complicates the interpretation of differences in pain ratings between patients taking placebo and active treatments because of reductions in pain associated with use of rescue analgesics. Patients in a placebo group can be expected to use more of a rescue treatment than patients administered an efficacious treatment. Rescue treatment can therefore be used as an outcome measure in clinical trials, with assessments including total amount used and time to first use. Assessments of the use of rescue and concomitant analgesic must not only consider the dosages used by patients but also differences in efficacy between different medications. Although there are few head-to-head comparisons of the medications that have demonstrated efficacy in PHN,25,54 these medications are generally comparable in their ability to relieve pain. However, there are other medications that are widely used in the treatment of PHN—for example, acetaminophen and nonsteroidal anti-inflammatory drugs—which have not been evaluated in randomized clinical trials and which are thought to have limited effectiveness based on clinical experience. In evaluating use of rescue and concomitant analgesics, it would therefore be important to con-
S42 sider potential differences in the analgesic benefits of, for example, tricyclic antidepressants or opioid analgesics versus acetaminophen. Composite measures have been developed that combine rescue medication use and pain intensity ratings into a single score.42 Unfortunately, none of these composite measures are well-accepted, and their psychometric properties are not well-established. Moreover, because no composite measures of pain intensity and rescue or concomitant analgesic use have been developed for pain associated with herpes zoster, the measures that are available can only be recommended for exploratory use. One strategy that can be used until such measures are developed is to provide a comprehensive cross-tabulation of pain intensity with use of analgesic medications. Using such an approach, Whitley et al51 showed that greater pain severity and greater use of analgesics were associated, and that as pain severity increased, the percentage of patients using opioid analgesics and parenteral administration increased. These relationships were found during the first month after rash onset and throughout a 6-month follow-up.
Conclusions The number of patients with herpes zoster and PHN may increase substantially in the future. Because older age and immune compromise are both potent risk factors for herpes zoster, increases in the incidence of herpes zoster and its complications, including PHN, can be expected as the general population ages and as the prevalence of diseases and medical treatments that are associated with immunosuppression increases.40 It can also be predicted that the number of adults developing herpes zoster in the United States may increase as a consequence of reduced opportunities for subclinical immune boosting resulting from near-universal varicella vaccination of children.8,41 Recent data showing an increase in herpes zoster in the United States are consistent with this prediction.32,55 An increase in the incidence of herpes zoster could be offset by zoster vaccination,35 but the extent to which widespread herpes zoster vaccination will occur is presently unknown. For these reasons, efforts to develop new interventions to prevent and treat herpes zoster and PHN will need to be expanded. A crucial aspect of such efforts will be the careful characterization of the acute pain of herpes zoster and the
References 1. Arani RB, Soong S-J, Weiss HL, Wood MJ, Fiddian PA, Gnann JW, Whitley R: Phase specific analysis of herpes zoster associated pain data: A new statistical approach. Stat Med 20:2429-2439, 2001 2. Berger A, Dukes EM, Oster G: Clinical characteristics and economic costs of patients with painful neuropathic disorders. J Pain 5:143-149, 2004
Pain Associated With Herpes Zoster and Postherpetic Neuralgia chronic pain of PHN. To provide a foundation for the diagnosis and assessment of pain associated with herpes zoster, we have reviewed the results of recent research on herpes zoster and PHN and methods for assessing neuropathic pain. However, detailed consideration of several important components of a comprehensive evaluation of pain associated with herpes zoster and PHN is beyond the scope of this article. These components include the neurologic evaluation of motor, sensory, and autonomic signs and symptoms, and the use of quantitative sensory testing and various laboratory tests (eg, microneurography, laser-evoked potentials, neuroimaging, punch skin biopsy) in patients with herpes zoster and PHN. Further information about these procedures and their role in the assessment of neuropathic pain is provided by the guidelines of the European Federation of Neurological Societies11 and the comprehensive protocol and reference values for quantitative sensory testing of the German Research Network on Neuropathic Pain.37,38 Much of this information is relevant for herpes zoster and PHN, and standardized approaches for the quantitative assessment of signs and symptoms of neurologic dysfunction in patients with herpes zoster and PHN are likely to play an increasing role in clinical research on these conditions. Herpes zoster, PHN, and other conditions that cause neuropathic pain all adversely affect health-related quality of life, including physical and emotional functioning.26,39 Evaluating the impact of pain on patients’ daily lives, including their physical and mental activities, well-being, and social relationships, is an additional important component of the assessment of pain in herpes zoster and PHN that is beyond the scope of this article. Recommendations have been published for chronic pain clinical trials for core outcome domains,44 and for existing measures18 and the development of new measures45 of these outcome domains. Although these recommendations are specifically intended for clinical trials of treatments for chronic pain, they are also more generally applicable to clinical research on pain and its consequences. Such assessments of the impact of pain on health-related quality of life, combined with evaluations of the presence, location, duration, intensity, and quality of pain, can provide the basis for future studies of pain and its response to treatment or prevention in patients with herpes zoster and PHN.
3. Beutner KR, Friedman DJ, Forszpaniak C, Andersen PL, Wood MJ: Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 39:1546-1553, 1995 4. Bhala B, Ramamoorthy C, Bowsher D, Yelnoorkler K: Shingles and postherpetic neuralgia. Clin J Pain 4:169-174, 1988 5. Bouhassira D, Attal N, Fermanian J, Alchaar H, Gautron M, Masquelier E, Postaing S, Lanteri-Minet M, Collin E, Grisart J, Boureau F: Development and validation of the
ORIGINAL REPORT/Dworkin et al Neuropathic Pain Symptom Inventory. Pain 108:248-257, 2004 6. Bowsher D: Acute herpes zoster and postherpetic neuralgia: Effects of acyclovir and outcome of treatment with amitriptyline. Br J Gen Pract 42:244-246, 1992 7. Bowsher D: Sensory change in postherpetic neuralgia, in Watson CP (ed): Pain Research and Clinical Management: Herpes Zoster and Postherpetic Neuralgia. Amsterdam, the Netherlands, Elsevier, 1993, pp 97-107 8. Brisson M, Edmunds WJ, Gay NJ: Varicella vaccination: Impact of vaccine efficacy on the epidemiology of VZV. J Med Virol 70(Suppl 1):S31-S37, 2003 9. Chidiac C, Bruxelle J, Daures JP, Hoang-Xuan T, Morel P, Leplège A, El Hasnaoui A, de Labareyre C: Characteristics of patients with herpes zoster on presentation to practitioners in France. Clin Infect Dis 33:62-69, 2001 10. Coplan PM, Schmader K, Nikas A, Chan IS, Choo P, Levin MJ, Johnson G, Bauer M, Williams HM, Kaplan KM, Guess HA, Oxman MN: Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: Adaptation of the brief pain inventory. J Pain 5:344-356, 2004
S43 20. Galer BS, Jensen MP: Development and preliminary validation of a pain measure specific to neuropathic pain: the Neuropathic Pain Scale. Neurology 48:332-338, 1997 21. Gilden DH, Dueland AN, Cohrs R, Martin JR, Kleinschmidt-DeMasters BK, Mahalingam R: Preherpetic neuralgia. Neurology 41:1215-1218, 1991 22. Gnann JW Jr: Preventing herpes zoster. J Pain 9:S31-S36, 2008 23. Haanpää M, Laippala P, Nurmikko T: Pain and somatosensory dysfunction in acute herpes zoster. Clin J Pain 15:7884, 1999 24. Harrison RA, Soong S, Weiss HL, Gnann JW Jr, Whitley RJ: A mixed model for factors predictive of pain in AIDS patients with herpes zoster. J Pain Symptom Manage 17: 410-417, 1999 25. Hempenstall K, Nurmikko TJ, Johnson RW, A’Hern RP, Rice AS: Analgesic therapy in postherpetic neuralgia: A quantitative systematic review. PLoS Med 2:e164, 2005 26. Jensen MP, Chodroff M, Dworkin RH: The impact of neuropathic pain on health-related quality of life: Review and implications. Neurology 68:1178-1182, 2007
11. Cruccu G, Anand P, Attal N, Garcia-Larrea L, Haanpää M, Jørum E, Serra J, Jensen TS: EFNS guidelines on neuropathic pain assessment. Eur J Neurol 11:153-162, 2004
27. Jung BF, Johnson RW, Griffin DR, Dworkin RH: Risk factors for postherpetic neuralgia in patients with herpes zoster. Neurology 62:1545-1551, 2004
12. Davies L, Cossins L, Bowsher D, Drummond M: The cost of treatment for post-herpetic neuralgia in the UK. Pharmacoeconomics 6:142-148, 1994
28. Katz J, Cooper EM, Walther RR, Sweeney EW, Dworkin RH: Acute pain in herpes zoster and its impact on healthrelated quality of life. Clin Infect Dis 39:342-348, 2004
13. Desmond RA, Weiss HL, Arani RB, Soong S-J, Wood MJ, Fiddian PA, Gnann JW, Whitley RJ: Clinical applications for change-point analysis of herpes zoster pain. J Pain Symptom Manage 23:510-516, 2002
29. Lydick E, Epstein RS, Himmelberger D, White CJ: Herpes zoster and quality of life: A self-limited disease with severe impact. Neurology 45:S52-S53, 1995
14. Dworkin RH: Inadequate evidence for a revised definition of postherpetic neuralgia (PHN). Pain 128:189-190, 2007 15. Dworkin RH, Carrington D, Cunningham A, Kost RG, Levin MJ, McKendrick MW, Oxman MN, Rentier B, Schmader KE, Tappeiner G, Wassilew SW, Whitley RJ: Assessment of pain in herpes zoster: lessons learned from antiviral trials. Antiviral Res 33:73-85, 1997 16. Dworkin RH, Johnson RW, Breuer J, Gnann JW, Levin MJ, Backonja M, Betts RF, Gershon AA, Haanpää ML, McKendrick MW, Nurmikko TJ, Oaklander AL, Oxman MN, Pavan-Langston D, Petersen KL, Rowbotham MC, Schmader KE, Stacey BR, Tyring SK, van Wijck AJ, Wallace MS, Wassilew SW, Whitley RJ: Recommendations for the management of herpes zoster. Clin Infect Dis 44(Suppl 1):S1-26, 2007 17. Dworkin RH, Schmader KE: The epidemiology and natural history of herpes zoster and postherpetic neuralgia, in Watson CP, Gershon AA (eds): Herpes Zoster and Postherpetic Neuralgia. 2nd ed. New York, NY, Elsevier Press, 2001, pp 39-64 18. Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, Kerns RD, Stucki G, Allen RR, Bellamy N, Carr DB, Chandler J, Cowan P, Dionne R, Galer BS, Hertz S, Jadad AR, Kramer LD, Manning DC, Martin S, McCormick CG, McDermott MP, McGrath P, Quessy S, Rappaport BA, Robbins W, Robinson JP, Rothman M, Royal MA, Simon L, Stauffer JW, Stein W, Tollett J, Wernicke J, Witter J: Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 113:9-19, 2005 19. Dworkin RH, White R, O’Connor A, Baser O, Hawkins K: Health care costs of acute and chronic pain associated with a diagnosis of herpes zoster. J Am Geriatr Soc 55:1168-1175, 2007
30. Marchettini P: The burning case of neuropathic pain wording. Pain 114:313-314, 2005 31. Melzack R: The short-form McGill Pain Questionnaire. Pain 30:191-197, 1987 32. Mullooly JP, Riedlinger K, Chun C, Weinmann S, Houston H: Incidence of herpes zoster, 1997-2002. Epidemiol Infect 133:245-253, 2005 33. Oaklander AL: Pain mechanisms in herpes zoster and postherpetic neuralgia. J Pain 9:S10-S18, 2008 34. Oaklander AL, Bowsher D, Galer B, Haanpää M, Jensen MP: Herpes zoster itch: Preliminary epidemiologic data. J Pain 4:338-343, 2003 35. Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, Arbeit RD, Simberkoff MS, Gershon AA, Davis LE, Weinberg A, Boardman KD, Williams HM, Zhang JH, Peduzzi PN, Beisel CE, Morrison VA, Guatelli JC, Brooks PA, Kauffman CA, Pachucki CT, Neuzil KM, Betts RF, Wright PF, Griffin MR, Brunell P, Soto NE, Marques AR, Keay SK, Goodman RP, Cotton DJ, Gnann JW Jr, Loutit J, Holodniy M, Keitel WA, Crawford GE, Yeh S-S, Lobo Z, Toney JF, Greenberg RN, Keller PM, Harbecke R, Hayward AR, Irwin MR, Kyriakides TC, Chan CY, Chan IS, Wang WW, Annunziato PW, Silber JL, for the Shingles Prevention Study Group: A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 352:2271-2284, 2005 36. Pappagallo M, Oaklander AL, Quatrano-Piacentini AL, Clark MR, Raja SN: Heterogenous patterns of sensory dysfunction in postherpetic neuralgia suggest multiple pathophysiologic mechanisms. Anesthesiology 92:691-698, 2000 37. Rolke R, Baron R, Maier C, Tölle TR, Treede R-D, Beyer A,
S44 Binder A, Birbaumer N, Birklein F, Bötefür IC, Braune S, Flor H, Huge V, Klug R, Landwehrmeyer GB, Magerl W, Maihöfner C, Rolko C, Schaub C, Scherens A, Sprenger T, Valet M, Wasserka B: Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values. Pain 123:231-243, 2006 38. Rolke R, Magerl W, Campbell KA, Schalber C, Caspari S, Birklein F, Treede R-D: Quantitative sensory testing: A comprehensive protocol for clinical trials. Eur J Pain 10:77-88, 2006 39. Schmader KE: Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clin J Pain 18:350-354, 2002 40. Schmader KE, Dworkin RH: Natural history and treatment of herpes zoster. J Pain 9:S3-S9, 2008 41. Schuette MC, Hethcote HW: Modeling the effects of varicella vaccination programs on the incidence of chickenpox and shingles. Bull Math Biol 61:1031-1064, 1999 42. Silverman DG, O’Connor TZ, Brull SJ: Integrated assessment of pain scores and rescue morphine use during studies of analgesic efficacy. Anesth Analg 77:168-170, 1993 43. Thyregod HG, Rowbotham MC, Peters M, Possehn J, Berro M, Petersen KL: Natural history of pain following herpes zoster. Pain 128:148-156, 2007 44. Turk DC, Dworkin RH, Allen RR, Bellamy N, Brandenburg N, Carr DB, Cleeland C, Dionne R, Farrar JT, Galer BS, Hewitt DJ, Jadad AR, Katz NP, Kramer LD, Manning DC, McCormick CG, McDermott MP, McGrath P, Quessy S, Rappaport BA, Robinson JP, Royal MA, Simon L, Stauffer JW, Stein W, Tollett J, Witter J: Core outcome domains for chronic pain clinical trials: IMMPACT recommendations. Pain 106:337345, 2003 45. Turk DC, Dworkin RH, Burke LB, Gershon R, Rothman M, Scott J, Allen RR, Atkinson JH, Chandler J, Cleeland C, Cowan P, Dimitrova R, Dionne R, Farrar JT, Haythornthwaite JA, Hertz S, Jadad AR, Jensen MP, Kellstein D, Kerns RD, Manning DC, Martin S, Max MB, McDermott MP, McGrath P, Moulin DE, Nurmikko T, Quessy S, Raja S, Rappaport BA, Rauschkolb C, Robinson JP, Royal MA, Simon L, Stauffer JW, Stucki G, Tollett J, von Stein T, Wallace MS, Wernicke J, White RE, Williams AC, Witter J, Wyrwich KW: Developing patient-reported outcome measures for pain clinical trials: IMMPACT recommendations. Pain 125:208-215, 2006
Pain Associated With Herpes Zoster and Postherpetic Neuralgia 46. Tyring SK, Beutner KR, Tucker BA, Anderson WC, Crooks RJ: Antiviral therapy for herpes zoster: Randomized, controlled clinical trial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older. Arch Fam Med 9:863-869, 2000 47. US Department of Health and Human Services; Guidance for industry: patient-reported outcome measures: Use in medical product development to support labeling claims. US Department of Health and Human Services, 2006 48. Wallace MS, Rowbotham M, Bennett GJ, Jensen TS, Pladna R, Quessy S: A multicenter, double-blind, randomized, placebo-controlled crossover evaluation of a short course of 4030W92 in patients with chronic neuropathic pain. J Pain 3:227-233, 2002 49. Wallace MS, Rowbotham MC, Katz NP, Dworkin RH, Dotson RM, Galer BS, Rauck RL, Backonja MM, Quessy SN, Meisner PD: A randomized, double-blind, placebo-controlled trial of a glycine antagonist in neuropathic pain. Neurology 59:1694-1700, 2002 50. Whitley RJ, Weiss H, Gnann JW Jr, Tyring S, Mertz GJ, Pappas PG, Schleupner CJ, Hayden F, Wolf J, Soong S-J: Acyclovir with and without prednisone for the treatment of herpes zoster: A randomized, placebo-controlled trial. Ann Intern Med 125:376-383, 1996 51. Wood MJ: How should zoster trials be conducted? J Antimicrob Chemother 36:1089-1101, 1995 52. Wood MJ, Johnson RW, McKendrick MW, Taylor J, Mandal BK, Crooks J: A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med 330:896-900, 1994 53. Wood MJ, Kay R, Dworkin RH, Soong SJ, Whitley RJ: Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: A meta-analysis of placebo-controlled trials. Clin Infect Dis 22:341-347, 1996 54. Wu CL, Raja SN: An update on the treatment of postherpetic neuralgia. J Pain 9:S19-S30, 2008 55. Yih WK, Brooks DR, Lett SM, Jumaan AO, Zhang Z, Clements KM, Seward JF: The incidence of varicella and herpes zoster in Massachusetts as measured by the Behavioral Risk Factor Surveillance System (BRFSS) during a period of increasing varicella vaccine coverage, 1998-2003. BMC Public Health 5:68, 2005
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 description of pain associated with herpes zoster and PHN. Perspective: Comprehensive assessments of pain are necessary for clinical research on the epidemiology, 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 most distressing symptom is typically pain and the most feared complication is postherpetic neuralgia (PHN), the persistence of pain long after rash healing. Both the acute pain associated with herpes zoster and RHD has received grants/research support, consulting fees, or honoraria in the past year from Allergan, Balboa, Cara, CombinatoRx, Dara, Eli Lilly, Endo, EpiCept, Fralex, GlaxoSmithKline, Grünenthal, GW Pharmaceuticals, Johnson & Johnson, KAI Pharmaceuticals, Merck & Co., Inc., NeurogesX, Ono, Organon, Pfizer, Supernus, US Food and Drug Administration, US National Institutes of Health, US Veterans Administration, Wyeth, and XTL Development; JWG has received grants/research support, consulting fees, or honoraria in the past year from Astellas, GlaxoSmithKline, Merck & Co., Inc., Novartis, and ViroPharma; ALO has no relevant conflicts to report; SNR has received grants/research support, consulting fees, or honoraria in the past year from Medtronic, Novartis, and Ortho-McNeil; KES has received grants/ research support, consulting fees, or honoraria in the past year from Merck & Co., Inc.; and RJW has received grants/research support, consulting fees, or honoraria in the past year from Chimerix, Gilead, and US National Institutes of Health. Address reprint requests to Dr. Robert H. Dworkin, PhD, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 604, Rochester, NY, 14642. E-mail: [email protected] 1526-5900/$34.00 © 2008 by the American Pain Society doi:10.1016/j.jpain.2007.10.008
the chronic pain of PHN have multiple adverse effects on health-related quality of life. These pain conditions cause substantial interference with physical, emotional, and social functioning9,10,28,29 and result in increased health care costs,2,12,19 (and Dworkin RH, White R, O’Connor A, Hawkins K: Health care expenditure burden of persisting herpes zoster pain. Pain Med, epub July 23, 2007) with excess expenditures ranging as high as $5000 in the first year after a diagnosis of PHN.19 Existing interventions do not completely prevent or adequately treat all cases of herpes zoster pain and PHN.16,22,25,35,54 The development of more effective strategies for the prevention and treatment of pain associated with herpes zoster and PHN is therefore an unmet public health need. In clinical trials evaluating such interventions, primary and secondary end points typically involve determining whether herpes zoster acute pain or PHN is present and then more comprehensively describing the patient’s experience of pain. The evaluation of pain outcomes therefore plays a critical role in identifying new interventions for herpes zoster and PHN S37
S38 and is, more generally, a crucial component of all clinical research on both conditions. 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. Recommendations were made for characterizing pain in patients with herpes zoster and PHN in guidelines published at least 10 years ago.15,51 However, the results of recent studies of herpes zoster and PHN and the development of new methods for assessing neuropathic pain provide an improved foundation for the diagnosis and assessment of pain associated with herpes zoster. The objective of this article is to review the results of recent research and identify the essential components that must be considered in developing an evidence-based description of pain associated with herpes zoster and PHN.
Diagnosis of Herpes Zoster The diagnosis of herpes zoster is generally straightforward once the characteristic unilateral, dermatomal, vesicular rash appears. Although the possibility that reactivation of the varicella-zoster virus can cause dermatomal pain without a rash has received considerable attention, a diagnosis of “zoster sine herpete” cannot be made on the basis of clinical presentation alone and would require evidence of concurrent viral reactivation.16 Important considerations in the diagnosis of herpes zoster include: (1) The presence of a painful prodrome, which occurs in as many as threequarters of all patients3,23,27; (2) a unilateral dermatomal distribution; (3) grouped vesicles or papules; (4) a history of a rash in the same distribution, which is suggestive of recurrent herpes simplex (up to 10% of specimens from patients with presumed herpes zoster have been found to contain herpes simplex virus); and (5) pain and allodynia (ie, pain in response to a normally nonpainful stimulus) in the area of the rash. In addition to herpes simplex, the differential diagnosis of herpes zoster includes contact dermatitis and rash caused by plant exposure (eg, poison ivy). Atypical manifestations that occur in immunocompromised patients include prolonged course, recurrent lesions, and involvement of multiple dermatomes. Diagnostic laboratory tests are recommended when herpes simplex must be ruled out (eg, recurrent rash or sacral lesions) and for patients with atypical lesions.16 These include polymerase chain reaction, immunohistochemistry, and viral culture, which differ in their sensitivity, specificity, time to obtain results, cost, availability, and whether they are useful with crusted lesions.16
Pain Associated With Herpes Zoster and Postherpetic Neuralgia more than 100 days has been reported.21 Because the herpes zoster prodrome can only be accurately diagnosed after the rash appears, the prodrome is not infrequently misdiagnosed as other conditions characterized by pain in the affected dermatome (eg, angina, herpes simplex, lumbar radiculopathy). Once the rash appears, the diagnosis becomes clear and the prodrome can then be assessed retrospectively by asking patients (1) whether or not pain was present in the area of the rash before the rash appeared; (2) the duration of prodromal pain, that is, how many days before the rash appeared did pain begin; and (3) the specific qualities of the prodromal pain. Patients with herpes zoster commonly report other prodromal symptoms, including dermatomal paresthesias (abnormal sensations that are not unpleasant, for example, tingling) and dysesthesias (abnormal sensations that are unpleasant, for example, numbness), itching, malaise, headache, and fever. These can also be retrospectively assessed with respect to presence, duration, and quality. Because there has been very little research on the herpes zoster prodrome, it is unknown whether prodromal symptoms such as malaise and headache are caused by varicella-zoster virus reactivation or whether retrospective reports of these symptoms reflect their high prevalence in the population and/or recall biases associated with a painful illness.
Presence of Pain The presence of pain associated with herpes zoster can be assessed by determining whether patients have pain in the primary dermatome or immediately adjacent cutaneous dermatomes temporally and spatially associated with their herpes zoster rash that cannot be explained by another diagnosis (eg, radiculopathy). For research purposes, any uncertainty regarding whether subjects have pain associated with herpes zoster or pain due to another cause in the same dermatome as their rash should be carefully recorded, making it possible to exclude such patients from analyses. The presence of prodromal pain can be assessed by asking, “Did you have any pain before the rash appeared in the area where you now have your shingles rash?” The presence of herpes zoster pain can be assessed by asking, “Do you have any pain in the area where you now have your shingles rash?” And the presence of pain after rash healing can be assessed by asking, “Do you have any pain in the area where you had your shingles rash?” Although such assessments of the presence of any pain are a necessary first step in evaluating herpes zoster pain and PHN, they must be supplemented by assessments of pain intensity, as discussed below.
Prodromal Pain
Location of Pain
In the majority of patients with herpes zoster, a prodrome of unilateral dermatomal pain precedes the appearance of the rash.3,23,27 This prodrome typically begins several days before rash onset, although a series of patients with prodromal pain preceding the rash by 7 to
It is especially important to assess the location of pain associated with herpes zoster and PHN, and particular attention should be paid to its dermatomal distribution. In clinical trials of topical agents and in the clinical use of these agents, therapy is typically delivered to the area of
ORIGINAL REPORT/Dworkin et al maximal pain, which can be identified and mapped if necessary. Areas with stimulus-independent pain and with stimulus-evoked pain (see below), which may overlap, can be assessed separately. Because either systemic or topical therapies may reduce not only the intensity but also the area of stimulus-evoked pain,48,49 the areas of different types of stimulus-evoked pain can be mapped and serve as secondary end points in clinical trials. It is not unusual for the region of stimulus-evoked pain in patients with herpes zoster and PHN to extend beyond the region of the herpes zoster rash.23,36
Duration of Pain The duration of pain associated with herpes zoster varies greatly, ranging from no pain or pain that lasts for only a few days after rash onset to pain that lasts for years or even decades after rash healing. In patients 50 years or older in antiviral trial placebo groups, approximately 70% had pain 1 month after rash onset, which declined to 40% 6 months after rash onset.17 In the herpes zoster vaccine trial placebo group, 30% of patients who developed herpes zoster (all ⱖ60 years of age) had pain 1 month after rash onset, whereas only 5% had pain 6 months after rash onset (with presence of pain defined as worse pain ⱖ3 on the Zoster Brief Pain Inventory [ZBPI]).35 Possible explanations for the differences in these 2 sets of data include the exclusion of patients with worse pain ⱕ2 from the vaccine trial data as well as a greater severity of herpes zoster in patients enrolled in antiviral trials versus generally healthy individuals in the community enrolled in a vaccine trial who later develop herpes zoster.
Three Phases of Pain Given this marked variability in the duration of pain associated with herpes zoster, various efforts have been made to define and distinguish the acute pain of herpes 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 distinguishing between 3 phases of pain in affected and adjacent dermatomes: (1) Herpes zoster acute pain (also termed acute herpetic neuralgia), defined as pain that occurs within 30 days after rash onset; (2) subacute herpetic neuralgia, defined as pain that persists beyond the acute phase but that resolves before the diagnosis of PHN can be made; and (3) PHN, defined as pain that persists 120 days or more after rash onset.1 Few prospective studies have followed patients with herpes zoster for more than 6 months. Despite the limited data on pain resolution in patients whose pain has persisted for this length of time, it is likely that pain persisting 180 days or more after rash onset is less likely to resolve than pain persisting for shorter durations; such pain could therefore be considered “well-established” PHN. In 2 studies that examined phases of pain associated with herpes zoster, rates of pain resolution were examined in clinical trials of antiviral and corticosteroid therapy.1,13 Transition times (ie, change points) for pain res-
S39 olution in different treatment groups (eg, acyclovir, valacyclovir) and patient samples (eg, immunocompetent, HIV infection) and as a function of covariates (age, acute pain intensity) provided support for these 3 phases of pain and for defining PHN as pain persisting at least 120 days after rash onset. The results of a third study indicated that patients with subacute herpetic neuralgia (defined by the investigators as pain that resolved between 3 and 4 months after rash onset) were younger and less likely to have severe acute pain than patients with PHN but were more likely to have severe rash and affected nonadjacent dermatomes than patients who did not have pain at the 3- and 4-month time points.27 These data suggest that subacute herpetic neuralgia that does not progress to PHN may reflect peripheral tissue damage and inflammation caused by a particularly severe or widespread rash in individuals who are otherwise at reduced risk for the development of PHN because of their younger age or less severe acute pain.
Overall Duration of Pain In addition to these 3 phases of pain associated with herpes zoster, the overall duration of pain—which has also been termed “zoster-associated pain”— can be examined. Typically, this measure assesses the total number of days of herpes zoster pain, beginning from rash onset and continuing until pain resolution, although it would also be possible to include the duration of prodromal pain in the calculation of overall pain duration. This measure does not distinguish between acute pain and chronic pain, which have different underlying pathophysiologic mechanisms33 and different effects on quality of life9,10 and health care burden.19 However, overall pain duration has been used as an outcome measure in clinical trials of antiviral agents3,46 and other treatments for herpes zoster,50,52 and it can provide useful information and an informative end point in certain circumstances.
Intensity of Pain As recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT)18 for chronic pain clinical trials, the intensity of pain associated with herpes zoster can be described using a 0-to-10 numerical rating scale, with 0 representing “no pain” and 10 representing “pain as bad as you can imagine,” accompanied by the instructions, “Please rate your pain by indicating the number that best describes your pain on average in the last 24 hours.” Depending on the specific aims and design of a study, pain “at its worst” or pain “at its least” can also be assessed using this scale, as can pain extending over shorter (eg, 12 hours) or longer (eg, 1 week) periods of time. The intensity of pain associated with herpes zoster can also be assessed using the ZBPI.10 As noted above, this measure was used in the herpes zoster vaccine trial to assess both herpes zoster acute pain and PHN.35 Although the general instructions for the ZBPI refer to pain and discomfort related to shingles, the anchors used for
S40 its rating scale are the same as those used for the rating scale described above, specifically, “no pain” and “pain as bad as you can imagine.” The extent to which patients administered the ZBPI rate their pain as well as sensory symptoms that cause discomfort but not pain (ie, itching) is therefore unclear.
Clinically Meaningful Pain It has recently been suggested that pain associated with herpes zoster, especially PHN, should be described with respect to whether it is clinically meaningful. Two approaches have been used to define clinically meaningful PHN, which has been considered pain that is severe enough to adversely affect health-related quality of life and interfere with activities of daily living.10,35,43 On the basis of a series of studies conducted in association with the herpes zoster vaccine trial,10,29,35 PHN was defined as the presence of a worst pain score of ⱖ3 on the ZBPI at 3 months or more after rash onset. The validation of this definition was based on the demonstration that patients with pain of this magnitude had poorer health-related quality of life, including interference with physical and emotional functioning and sleep, than those with milder levels of pain, which had limited impact on ZBPI pain interference scale scores.10 In a prospective study of 94 patients with herpes zoster, Thyregod et al43 defined clinically meaningful PHN as average daily pain ratings over the previous 48 hours ⱖ30 on a 100-mm visual analog scale (VAS) at 6 months after rash onset. In addition to using a threshold of pain intensity to identify clinically meaningful pain associated with herpes zoster, a variety of other approaches are possible. For example, classification of pain as clinically meaningful could require that the patient is taking pain medications or is being followed for pain by a physician or other health care provider. Depending on the specific definition of clinically meaningful pain used, the incidence and prevalence will vary substantially. For example, in Thyregod et al’s data,43 if such PHN requires pain ⱖ30/100 on a VAS, as the authors propose, only 2% of patients had clinically meaningful PHN at 6 months after rash onset (which is consistent with what has been found in clinical trials of antiviral agents53). However, if the definition of clinically meaningful PHN requires that prescription analgesic medications are being administered for pain, 10% of their patients had PHN at 6 months.43 And if the definition of PHN includes patients either having pain ⱖ30/100 on a VAS, using prescription analgesic medications, or being followed by a physician for persisting pain, 12% of their patients had PHN at 6 months. These figures have critical implications for the development of improved interventions for preventing pain associated with herpes zoster because of the large sample sizes that would be required to demonstrate that a new treatment would significantly reduce the incidence of PHN compared with or in combination with an existing antiviral agent (a superiority trial or an add-on trial is necessary for ethical reasons, given the well-established
Pain Associated With Herpes Zoster and Postherpetic Neuralgia efficacy of antiviral therapy; a noninferiority trial would be problematic because of regulatory considerations involving the prevention of PHN).14 It is therefore likely that such a definition of PHN would substantially reduce future research on developing interventions for its prevention. The proposed definitions of clinically meaningful PHN have been based on data showing that moderate and severe pain have greater adverse effects than mild pain, which had limited impact on functional status and healthrelated quality of life.10,29 However, current approaches to the assessment of patient-reported outcomes require that the first step in developing new measures is to determine what patients themselves consider important, and this approach has been endorsed by the United States Food and Drug Administration47 and by IMMPACT.45 Unfortunately, no studies have been conducted in which patients with PHN or other types of chronic pain that are mild in intensity have been asked whether their chronic mild pain is inconsequential and not worth treating or preventing. More generally, the factors that are involved in distinguishing reports of discomfort from reports of pain and in determining whether patients desire treatment for their pain have not been adequately investigated in PHN and other chronic pain conditions. Until such research is conducted, it may be premature to establish a definition for clinically meaningful pain in herpes zoster and PHN and to conclude that this is the only type of pain worth preventing or treating.
Overall Burden of Pain The burden of pain associated with herpes zoster has been described using composite measures that reflect both pain intensity and duration. These composite measures can be calculated for the 3 specific phases of pain described above as well as for the overall duration of herpes zoster pain from onset to resolution. Two approaches have been used in calculating such composite measures across the time interval of interest: The sum of time-weighted pain intensity ratings24,28 and the sum of time-weighted pain intensity ratings ⱖ3 on a 0-to-10 scale.10,35 These composite measures of pain intensity and duration combined into a single score are reliable, valid, and responsive approaches to assessing pain associated with herpes zoster and PHN. With such composite measures, however, the same overall score can be obtained by multiple days of relatively mild pain and by relatively fewer days of severe pain. Depending on the specific research objectives of a study, it may therefore be necessary to show similar effects on the components of the composite. This may be particularly important when interpreting the results of clinical trials to ensure that there is an adequate understanding of what is contributing to any treatment benefits that are found.
Quality of Pain The quality of pain and related symptoms associated with herpes zoster and PHN can be described in a comprehensive fashion using several measures that are reliable and valid. The most important distinction in assess-
ORIGINAL REPORT/Dworkin et al ing pain quality in patients with herpes zoster and PHN is between spontaneous pain and stimulus-evoked pain. The following aspects of pain quality and related symptoms associated with herpes zoster can be assessed: (1) Stimulus-independent continuous pain; (2) stimulus-independent intermittent pain; (3) stimulus-evoked pain, especially brush-evoked dynamic allodynia; and (4) paresthesias, dysesthesias, and itching.34 Spontaneous pain is present in the absence of any stimulation, and it can be either continuous or intermittent. Most patients describe more than 1 type of spontaneous pain, that is, their pain has several different qualities (eg, burning, throbbing, aching, shooting). Spontaneous continuous pain is present all or almost all of the time, although patients typically report that it varies in intensity. Spontaneous intermittent pain is episodic and typically has a relatively short duration when it occurs. This type of pain is often paroxysmal and described by patients as shooting, stabbing, or electric shock-like in quality. In assessing spontaneous pain in patients with herpes zoster and PHN, particular attention should be paid to burning pain. This type of pain is very common in patients with neuropathic pain30 and may be more common in patients with PHN than in patients with herpes zoster acute pain, who appear to be more likely to report sharp, stabbing pain.4,7 Burning pain was also reported less frequently by patients with PHN who had been administered antiviral therapy during their herpes zoster than patients with PHN who had not.6,7 Considered together, these findings suggest that burning pain might reflect an important pathophysiologic mechanism in the development of PHN. The most important types of stimulus-evoked pain in patients with herpes zoster and PHN are allodynia and hyperalgesia (ie, increased pain in response to a normally painful stimulus). Various mechanical and thermal stimuli have been used in evaluating stimulus-evoked pain. Dynamic mechanical allodynia, which is the most common type of stimulus-evoked pain in patients with PHN,36 can be elicited by lightly moving a foam paint brush or cotton swab across the skin. Static mechanical allodynia can be elicited by light, blunt pressure with a finger, and punctuate mechanical allodynia can be elicited by light pressure with a von Frey filament or sharp stick. Thermal allodynia can be assessed by applying a heated or cooled tuning fork, ice, or a drop of alcohol or acetone to the skin of the affected region. Various questionnaires have been developed for evaluating the quality of neuropathic pain, some of which include assessments of paresthesias and dysesthesias, and these can be used in patients with herpes zoster and PHN. The Short-Form McGill Pain Questionnaire31 assesses 15 specific sensory and affective pain descriptors and provides a total score as well as sensory and affective subscale scores. Two newer measures, the Neuropathic Pain Scale20 and the Neuropathic Pain Symptom Inventory,5 were specifically developed to assess the symptoms and signs that are characteristic of neuropathic pain conditions, including PHN. The Neuropathic Pain Scale20 includes ratings of 6 specific pain qualities (sharp, hot, dull,
S41 cold, sensitive, and itchy) as well as ratings of spatial characteristics (deep pain, surface pain) and overall pain intensity and pain unpleasantness. The Neuropathic Pain Symptom Inventory5 consists of ratings of 10 pain descriptors, with 2 additional items that assess the duration of spontaneous pain and the frequency of intermittent pain. Each of these 3 measures has been used in multiple studies of patients with neuropathic pain, including clinical trials of treatments for PHN, and they are generally reliable, valid, and responsive to change and treatment effects. In many circumstances, however, it is important to supplement the data from these questionnaire-based assessments of symptoms with more objective sensory testing procedures to evaluate stimulus-evoked pain and other sensory abnormalities.
Rescue and Concomitant Analgesic Treatments The effect of rescue and concomitant analgesics on assessments of the presence, location, intensity, and quality of pain associated with herpes zoster has not received adequate attention. Nevertheless, in studies of pain in patients with herpes zoster and PHN, the use of all pain-related treatments should be assessed, including rescue analgesics and any other concomitant pain treatments. Some clinical trials have allowed previously used analgesic medications to be continued throughout the trial, and dosage stabilization is often required before patients are allowed to enroll in such trials. However, when changes in the use of concomitant pain treatments are permitted, they can be evaluated as an outcome measure. Providing patients with access to rescue analgesics may make it easier to include a placebo group in clinical trials because patients not obtaining adequate pain relief are provided with an analgesic. However, administration of rescue treatment complicates the interpretation of differences in pain ratings between patients taking placebo and active treatments because of reductions in pain associated with use of rescue analgesics. Patients in a placebo group can be expected to use more of a rescue treatment than patients administered an efficacious treatment. Rescue treatment can therefore be used as an outcome measure in clinical trials, with assessments including total amount used and time to first use. Assessments of the use of rescue and concomitant analgesic must not only consider the dosages used by patients but also differences in efficacy between different medications. Although there are few head-to-head comparisons of the medications that have demonstrated efficacy in PHN,25,54 these medications are generally comparable in their ability to relieve pain. However, there are other medications that are widely used in the treatment of PHN—for example, acetaminophen and nonsteroidal anti-inflammatory drugs—which have not been evaluated in randomized clinical trials and which are thought to have limited effectiveness based on clinical experience. In evaluating use of rescue and concomitant analgesics, it would therefore be important to con-
S42 sider potential differences in the analgesic benefits of, for example, tricyclic antidepressants or opioid analgesics versus acetaminophen. Composite measures have been developed that combine rescue medication use and pain intensity ratings into a single score.42 Unfortunately, none of these composite measures are well-accepted, and their psychometric properties are not well-established. Moreover, because no composite measures of pain intensity and rescue or concomitant analgesic use have been developed for pain associated with herpes zoster, the measures that are available can only be recommended for exploratory use. One strategy that can be used until such measures are developed is to provide a comprehensive cross-tabulation of pain intensity with use of analgesic medications. Using such an approach, Whitley et al51 showed that greater pain severity and greater use of analgesics were associated, and that as pain severity increased, the percentage of patients using opioid analgesics and parenteral administration increased. These relationships were found during the first month after rash onset and throughout a 6-month follow-up.
Conclusions The number of patients with herpes zoster and PHN may increase substantially in the future. Because older age and immune compromise are both potent risk factors for herpes zoster, increases in the incidence of herpes zoster and its complications, including PHN, can be expected as the general population ages and as the prevalence of diseases and medical treatments that are associated with immunosuppression increases.40 It can also be predicted that the number of adults developing herpes zoster in the United States may increase as a consequence of reduced opportunities for subclinical immune boosting resulting from near-universal varicella vaccination of children.8,41 Recent data showing an increase in herpes zoster in the United States are consistent with this prediction.32,55 An increase in the incidence of herpes zoster could be offset by zoster vaccination,35 but the extent to which widespread herpes zoster vaccination will occur is presently unknown. For these reasons, efforts to develop new interventions to prevent and treat herpes zoster and PHN will need to be expanded. A crucial aspect of such efforts will be the careful characterization of the acute pain of herpes zoster and the
References 1. Arani RB, Soong S-J, Weiss HL, Wood MJ, Fiddian PA, Gnann JW, Whitley R: Phase specific analysis of herpes zoster associated pain data: A new statistical approach. Stat Med 20:2429-2439, 2001 2. Berger A, Dukes EM, Oster G: Clinical characteristics and economic costs of patients with painful neuropathic disorders. J Pain 5:143-149, 2004
Pain Associated With Herpes Zoster and Postherpetic Neuralgia chronic pain of PHN. To provide a foundation for the diagnosis and assessment of pain associated with herpes zoster, we have reviewed the results of recent research on herpes zoster and PHN and methods for assessing neuropathic pain. However, detailed consideration of several important components of a comprehensive evaluation of pain associated with herpes zoster and PHN is beyond the scope of this article. These components include the neurologic evaluation of motor, sensory, and autonomic signs and symptoms, and the use of quantitative sensory testing and various laboratory tests (eg, microneurography, laser-evoked potentials, neuroimaging, punch skin biopsy) in patients with herpes zoster and PHN. Further information about these procedures and their role in the assessment of neuropathic pain is provided by the guidelines of the European Federation of Neurological Societies11 and the comprehensive protocol and reference values for quantitative sensory testing of the German Research Network on Neuropathic Pain.37,38 Much of this information is relevant for herpes zoster and PHN, and standardized approaches for the quantitative assessment of signs and symptoms of neurologic dysfunction in patients with herpes zoster and PHN are likely to play an increasing role in clinical research on these conditions. Herpes zoster, PHN, and other conditions that cause neuropathic pain all adversely affect health-related quality of life, including physical and emotional functioning.26,39 Evaluating the impact of pain on patients’ daily lives, including their physical and mental activities, well-being, and social relationships, is an additional important component of the assessment of pain in herpes zoster and PHN that is beyond the scope of this article. Recommendations have been published for chronic pain clinical trials for core outcome domains,44 and for existing measures18 and the development of new measures45 of these outcome domains. Although these recommendations are specifically intended for clinical trials of treatments for chronic pain, they are also more generally applicable to clinical research on pain and its consequences. Such assessments of the impact of pain on health-related quality of life, combined with evaluations of the presence, location, duration, intensity, and quality of pain, can provide the basis for future studies of pain and its response to treatment or prevention in patients with herpes zoster and PHN.
3. Beutner KR, Friedman DJ, Forszpaniak C, Andersen PL, Wood MJ: Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 39:1546-1553, 1995 4. Bhala B, Ramamoorthy C, Bowsher D, Yelnoorkler K: Shingles and postherpetic neuralgia. Clin J Pain 4:169-174, 1988 5. Bouhassira D, Attal N, Fermanian J, Alchaar H, Gautron M, Masquelier E, Postaing S, Lanteri-Minet M, Collin E, Grisart J, Boureau F: Development and validation of the
ORIGINAL REPORT/Dworkin et al Neuropathic Pain Symptom Inventory. Pain 108:248-257, 2004 6. Bowsher D: Acute herpes zoster and postherpetic neuralgia: Effects of acyclovir and outcome of treatment with amitriptyline. Br J Gen Pract 42:244-246, 1992 7. Bowsher D: Sensory change in postherpetic neuralgia, in Watson CP (ed): Pain Research and Clinical Management: Herpes Zoster and Postherpetic Neuralgia. Amsterdam, the Netherlands, Elsevier, 1993, pp 97-107 8. Brisson M, Edmunds WJ, Gay NJ: Varicella vaccination: Impact of vaccine efficacy on the epidemiology of VZV. J Med Virol 70(Suppl 1):S31-S37, 2003 9. Chidiac C, Bruxelle J, Daures JP, Hoang-Xuan T, Morel P, Leplège A, El Hasnaoui A, de Labareyre C: Characteristics of patients with herpes zoster on presentation to practitioners in France. Clin Infect Dis 33:62-69, 2001 10. Coplan PM, Schmader K, Nikas A, Chan IS, Choo P, Levin MJ, Johnson G, Bauer M, Williams HM, Kaplan KM, Guess HA, Oxman MN: Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: Adaptation of the brief pain inventory. J Pain 5:344-356, 2004
S43 20. Galer BS, Jensen MP: Development and preliminary validation of a pain measure specific to neuropathic pain: the Neuropathic Pain Scale. Neurology 48:332-338, 1997 21. Gilden DH, Dueland AN, Cohrs R, Martin JR, Kleinschmidt-DeMasters BK, Mahalingam R: Preherpetic neuralgia. Neurology 41:1215-1218, 1991 22. Gnann JW Jr: Preventing herpes zoster. J Pain 9:S31-S36, 2008 23. Haanpää M, Laippala P, Nurmikko T: Pain and somatosensory dysfunction in acute herpes zoster. Clin J Pain 15:7884, 1999 24. Harrison RA, Soong S, Weiss HL, Gnann JW Jr, Whitley RJ: A mixed model for factors predictive of pain in AIDS patients with herpes zoster. J Pain Symptom Manage 17: 410-417, 1999 25. Hempenstall K, Nurmikko TJ, Johnson RW, A’Hern RP, Rice AS: Analgesic therapy in postherpetic neuralgia: A quantitative systematic review. PLoS Med 2:e164, 2005 26. Jensen MP, Chodroff M, Dworkin RH: The impact of neuropathic pain on health-related quality of life: Review and implications. Neurology 68:1178-1182, 2007
11. Cruccu G, Anand P, Attal N, Garcia-Larrea L, Haanpää M, Jørum E, Serra J, Jensen TS: EFNS guidelines on neuropathic pain assessment. Eur J Neurol 11:153-162, 2004
27. Jung BF, Johnson RW, Griffin DR, Dworkin RH: Risk factors for postherpetic neuralgia in patients with herpes zoster. Neurology 62:1545-1551, 2004
12. Davies L, Cossins L, Bowsher D, Drummond M: The cost of treatment for post-herpetic neuralgia in the UK. Pharmacoeconomics 6:142-148, 1994
28. Katz J, Cooper EM, Walther RR, Sweeney EW, Dworkin RH: Acute pain in herpes zoster and its impact on healthrelated quality of life. Clin Infect Dis 39:342-348, 2004
13. Desmond RA, Weiss HL, Arani RB, Soong S-J, Wood MJ, Fiddian PA, Gnann JW, Whitley RJ: Clinical applications for change-point analysis of herpes zoster pain. J Pain Symptom Manage 23:510-516, 2002
29. Lydick E, Epstein RS, Himmelberger D, White CJ: Herpes zoster and quality of life: A self-limited disease with severe impact. Neurology 45:S52-S53, 1995
14. Dworkin RH: Inadequate evidence for a revised definition of postherpetic neuralgia (PHN). Pain 128:189-190, 2007 15. Dworkin RH, Carrington D, Cunningham A, Kost RG, Levin MJ, McKendrick MW, Oxman MN, Rentier B, Schmader KE, Tappeiner G, Wassilew SW, Whitley RJ: Assessment of pain in herpes zoster: lessons learned from antiviral trials. Antiviral Res 33:73-85, 1997 16. Dworkin RH, Johnson RW, Breuer J, Gnann JW, Levin MJ, Backonja M, Betts RF, Gershon AA, Haanpää ML, McKendrick MW, Nurmikko TJ, Oaklander AL, Oxman MN, Pavan-Langston D, Petersen KL, Rowbotham MC, Schmader KE, Stacey BR, Tyring SK, van Wijck AJ, Wallace MS, Wassilew SW, Whitley RJ: Recommendations for the management of herpes zoster. Clin Infect Dis 44(Suppl 1):S1-26, 2007 17. Dworkin RH, Schmader KE: The epidemiology and natural history of herpes zoster and postherpetic neuralgia, in Watson CP, Gershon AA (eds): Herpes Zoster and Postherpetic Neuralgia. 2nd ed. New York, NY, Elsevier Press, 2001, pp 39-64 18. Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, Kerns RD, Stucki G, Allen RR, Bellamy N, Carr DB, Chandler J, Cowan P, Dionne R, Galer BS, Hertz S, Jadad AR, Kramer LD, Manning DC, Martin S, McCormick CG, McDermott MP, McGrath P, Quessy S, Rappaport BA, Robbins W, Robinson JP, Rothman M, Royal MA, Simon L, Stauffer JW, Stein W, Tollett J, Wernicke J, Witter J: Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 113:9-19, 2005 19. Dworkin RH, White R, O’Connor A, Baser O, Hawkins K: Health care costs of acute and chronic pain associated with a diagnosis of herpes zoster. J Am Geriatr Soc 55:1168-1175, 2007
30. Marchettini P: The burning case of neuropathic pain wording. Pain 114:313-314, 2005 31. Melzack R: The short-form McGill Pain Questionnaire. Pain 30:191-197, 1987 32. Mullooly JP, Riedlinger K, Chun C, Weinmann S, Houston H: Incidence of herpes zoster, 1997-2002. Epidemiol Infect 133:245-253, 2005 33. Oaklander AL: Pain mechanisms in herpes zoster and postherpetic neuralgia. J Pain 9:S10-S18, 2008 34. Oaklander AL, Bowsher D, Galer B, Haanpää M, Jensen MP: Herpes zoster itch: Preliminary epidemiologic data. J Pain 4:338-343, 2003 35. Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, Arbeit RD, Simberkoff MS, Gershon AA, Davis LE, Weinberg A, Boardman KD, Williams HM, Zhang JH, Peduzzi PN, Beisel CE, Morrison VA, Guatelli JC, Brooks PA, Kauffman CA, Pachucki CT, Neuzil KM, Betts RF, Wright PF, Griffin MR, Brunell P, Soto NE, Marques AR, Keay SK, Goodman RP, Cotton DJ, Gnann JW Jr, Loutit J, Holodniy M, Keitel WA, Crawford GE, Yeh S-S, Lobo Z, Toney JF, Greenberg RN, Keller PM, Harbecke R, Hayward AR, Irwin MR, Kyriakides TC, Chan CY, Chan IS, Wang WW, Annunziato PW, Silber JL, for the Shingles Prevention Study Group: A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 352:2271-2284, 2005 36. Pappagallo M, Oaklander AL, Quatrano-Piacentini AL, Clark MR, Raja SN: Heterogenous patterns of sensory dysfunction in postherpetic neuralgia suggest multiple pathophysiologic mechanisms. Anesthesiology 92:691-698, 2000 37. Rolke R, Baron R, Maier C, Tölle TR, Treede R-D, Beyer A,
S44 Binder A, Birbaumer N, Birklein F, Bötefür IC, Braune S, Flor H, Huge V, Klug R, Landwehrmeyer GB, Magerl W, Maihöfner C, Rolko C, Schaub C, Scherens A, Sprenger T, Valet M, Wasserka B: Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values. Pain 123:231-243, 2006 38. Rolke R, Magerl W, Campbell KA, Schalber C, Caspari S, Birklein F, Treede R-D: Quantitative sensory testing: A comprehensive protocol for clinical trials. Eur J Pain 10:77-88, 2006 39. Schmader KE: Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clin J Pain 18:350-354, 2002 40. Schmader KE, Dworkin RH: Natural history and treatment of herpes zoster. J Pain 9:S3-S9, 2008 41. Schuette MC, Hethcote HW: Modeling the effects of varicella vaccination programs on the incidence of chickenpox and shingles. Bull Math Biol 61:1031-1064, 1999 42. Silverman DG, O’Connor TZ, Brull SJ: Integrated assessment of pain scores and rescue morphine use during studies of analgesic efficacy. Anesth Analg 77:168-170, 1993 43. Thyregod HG, Rowbotham MC, Peters M, Possehn J, Berro M, Petersen KL: Natural history of pain following herpes zoster. Pain 128:148-156, 2007 44. Turk DC, Dworkin RH, Allen RR, Bellamy N, Brandenburg N, Carr DB, Cleeland C, Dionne R, Farrar JT, Galer BS, Hewitt DJ, Jadad AR, Katz NP, Kramer LD, Manning DC, McCormick CG, McDermott MP, McGrath P, Quessy S, Rappaport BA, Robinson JP, Royal MA, Simon L, Stauffer JW, Stein W, Tollett J, Witter J: Core outcome domains for chronic pain clinical trials: IMMPACT recommendations. Pain 106:337345, 2003 45. Turk DC, Dworkin RH, Burke LB, Gershon R, Rothman M, Scott J, Allen RR, Atkinson JH, Chandler J, Cleeland C, Cowan P, Dimitrova R, Dionne R, Farrar JT, Haythornthwaite JA, Hertz S, Jadad AR, Jensen MP, Kellstein D, Kerns RD, Manning DC, Martin S, Max MB, McDermott MP, McGrath P, Moulin DE, Nurmikko T, Quessy S, Raja S, Rappaport BA, Rauschkolb C, Robinson JP, Royal MA, Simon L, Stauffer JW, Stucki G, Tollett J, von Stein T, Wallace MS, Wernicke J, White RE, Williams AC, Witter J, Wyrwich KW: Developing patient-reported outcome measures for pain clinical trials: IMMPACT recommendations. Pain 125:208-215, 2006
Pain Associated With Herpes Zoster and Postherpetic Neuralgia 46. Tyring SK, Beutner KR, Tucker BA, Anderson WC, Crooks RJ: Antiviral therapy for herpes zoster: Randomized, controlled clinical trial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older. Arch Fam Med 9:863-869, 2000 47. US Department of Health and Human Services; Guidance for industry: patient-reported outcome measures: Use in medical product development to support labeling claims. US Department of Health and Human Services, 2006 48. Wallace MS, Rowbotham M, Bennett GJ, Jensen TS, Pladna R, Quessy S: A multicenter, double-blind, randomized, placebo-controlled crossover evaluation of a short course of 4030W92 in patients with chronic neuropathic pain. J Pain 3:227-233, 2002 49. Wallace MS, Rowbotham MC, Katz NP, Dworkin RH, Dotson RM, Galer BS, Rauck RL, Backonja MM, Quessy SN, Meisner PD: A randomized, double-blind, placebo-controlled trial of a glycine antagonist in neuropathic pain. Neurology 59:1694-1700, 2002 50. Whitley RJ, Weiss H, Gnann JW Jr, Tyring S, Mertz GJ, Pappas PG, Schleupner CJ, Hayden F, Wolf J, Soong S-J: Acyclovir with and without prednisone for the treatment of herpes zoster: A randomized, placebo-controlled trial. Ann Intern Med 125:376-383, 1996 51. Wood MJ: How should zoster trials be conducted? J Antimicrob Chemother 36:1089-1101, 1995 52. Wood MJ, Johnson RW, McKendrick MW, Taylor J, Mandal BK, Crooks J: A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med 330:896-900, 1994 53. Wood MJ, Kay R, Dworkin RH, Soong SJ, Whitley RJ: Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: A meta-analysis of placebo-controlled trials. Clin Infect Dis 22:341-347, 1996 54. Wu CL, Raja SN: An update on the treatment of postherpetic neuralgia. J Pain 9:S19-S30, 2008 55. Yih WK, Brooks DR, Lett SM, Jumaan AO, Zhang Z, Clements KM, Seward JF: The incidence of varicella and herpes zoster in Massachusetts as measured by the Behavioral Risk Factor Surveillance System (BRFSS) during a period of increasing varicella vaccine coverage, 1998-2003. BMC Public Health 5:68, 2005