Treatment of postherpetic neuralgia: a review of therapeutic options

396 Journal of Pain and Symptom Management

Vol. 28 No. 4 October 2004

Review Article

Treatment of Postherpetic Neuralgia: A Review of Therapeutic Options Charles E. Argoff, MD, Nathaniel Katz, MD, and Miroslav Backonja, MD Cohn Pain Management Center (C.E.A.), North Shore University Hospital, Bethpage, New York; Harvard Medical School (N.K.), Boston, Massachusetts; and Departments of Neurology and Anesthesiology (M.B.), University of Wisconsin Hospitals and Clinics, Madison, Wisconsin, USA

Abstract Postherpetic neuralgia (PHN) is a disabling consequence of the reactivation of the varicella zoster infection. The observation that patients with PHN experience various types of pain suggests that multiple pathophysiologic mechanisms are involved, which may include the peripheral and central nervous systems. A reasonable initial strategy would involve selecting from among multiple agents that have complementary mechanisms of action and that have been proven effective in controlled clinical trials, such as the lidocaine patch 5%, gabapentin, tricyclic antidepressants, and opioids. Based on initial assessment and ongoing reassessment, sequential trials should be undertaken until adequate pain relief is achieved. This may ultimately lead to therapy with more than one medication. Safety and tolerability are important considerations in choosing initial therapy, particularly in older patients. Physicians can either add another agent to the current regimen or switch to a new type of monotherapy if there is inadequate response to initial therapy. Alternative therapies, (i.e., ketamine, intrathecal corticosteroid injections) have not been adequately studied. Welldesigned, multicenter, controlled clinical trials are needed to develop a treatment algorithm that provides an evidence-based, rational approach to treating PHN. J Pain Symptom Manage 2004;28:396–411. 쑖 2004 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Postherpetic neuralgia, herpes zoster, pain, chronic pain, pharmacotherapy

Introduction Herpes zoster (shingles), the clinical manifestation of reactivated varicella zoster virus infection, is one of the most common neurologic diseases in the United States, occurring in 500,000 people each year; lifetime prevalence

Address reprint requests to: Charles E. Argoff, MD, North Shore University Hospital, Cohn Pain Management Center, 4300 Hempstead Turnpike, Bethpage, NY 11714, USA. Accepted for publication: January 19, 2004.

쑖 2004 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.

is estimated to be as high as 20%.1,2 Patients usually experience a painful and dysesthesic prodrome, followed within a few days by a unilaterally distributed vesicular rash most frequently affecting thoracic and cranial dermatomes.3–5 While the rash typically heals within 2 to 4 weeks, for some patients the pain that emerges with the rash persists–a condition known as postherpetic neuralgia (PHN).5 The definition of PHN can seem arbitrary, as it varies with regard to the nature and timing of acute and persistent symptoms.6 In typical clinical settings, PHN is deemed to be present when pain persists more 0885-3924/04/$–see front matter doi:10.1016/j.jpainsymman.2004.01.014

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than a month after the eruption of the acute zoster rash.7,8 For many patients, however, pain will gradually subside over the next 1 to 2 months.4,8 PHN is considered chronic when the pain persists for 4 months or more after rash onset,9 and in clinical trials, PHN is typically designated as pain that continues for at least 3 to 6 months. Most patients meeting these criteria for PHN describe a combination of 1) continuous burning or aching pain, 2) intermittent sharp pains, 3) altered sensory threshold resulting in various sensory complaints, including paresthesia, and 4) pain provoked by otherwise trivial mechanical or thermal stimuli (allodynia).10–12 Some patients with PHN experience profound sensory loss in the most painful areas (anesthesia dolorosa or deafferentation pain).10 Although PHN often resolves with time, in some patients the pain persists for years, usually with a devastating impact on quality of life.13,14

Epidemiology and Risk Factors Based on large-scale epidemiologic studies, the incidence of acute herpes zoster increases with age, ranging from as low as 1.25/1000 person-years in the general population up to 11.8/1000 person-years in the elderly.4,8,15,16 Among immunocompromised patients and those receiving immunosuppressive therapy, the incidence of the zoster rash is also higher than observed in the general population.4,15,17–20 Race, ethnicity, and gender do not appear to be risk factors. Zoster appears to occur with equal frequency among men and women.3,5 Some evidence suggests that it may occur more frequently in whites than in African Americans,21 although others have failed to observe such differences.4,15 Epidemiologic analysis indicates that vulnerability to developing PHN following acute zoster is strongly linked to age, with older patients at much greater risk than younger individuals.4,5,8,22,23 In one meta-analysis of acyclovir trials, 35% of patients ⭌ 50 years of age reported continuing pain 6 months after zoster rash onset.23 The severity and duration of PHN are also age-related, with longer and more severe PHN episodes more frequently seen among older patients.5,8,24 Characteristics of the acute zoster illness such as the presence of a

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painful prodrome, rash severity and painfulness, and fever and inflammation may also influence severity of PHN pain.22,24,25

Pathogenesis of PHN Acute herpes zoster arises when dormant virus particles, persisting within an affected sensory ganglion from an earlier, primary infection with varicella, become reactivated when cellular immunity to varicella decreases. Viral particles replicate and may spread to the dorsal root, into the dorsal horn of the spinal cord, and through peripheral sensory nerve fibers down to the level of the skin. Viral particles also may circulate in the blood. This reactivation is accompanied by inflammation of the skin, immune response, hemorrhage, and destruction of peripheral and central neurons and their fibers. Following such neural degeneration, distinct types of pathophysiological mechanisms involving both the central and peripheral nervous systems may give rise to the pain associated with PHN (Fig. 1).12,26–29 Studies conducted by Rowbotham and colleagues demonstrated that in some PHN patients, peripheral sensory fibers do not die, but rather, sustain axonal damage that gives rise to hyperexcitability, marked by spontaneous firing, exaggerated neural impulses in response to stimuli, and lower excitation thresholds.10,27,29

Fig. 1. Spontaneous impulses and hyperexcitability in peripheral afferent fibers. After injury of peripheral nociceptive fibers, the tips of the damaged axons begin to regenerate and form numerous “sprouts.” Damaged nerve endings as well as axonal “sprouts” exhibit spontaneous impulses and increased sensitivity to thermal, mechanical, and chemical stimuli. The region of the fiber near the dorsal root ganglion also begins to exhibit spontaneous activity (Figure used with permission from Fields HL, Rowbotham N, Baron R. Postherpetic Neuralgia: Irritable Nociceptors and Deafferentiation. Neurobiology of Disease, 1998; 5: 209–227).

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Other research conducted in both human and animal models of neuropathic pain indicate that this increased excitability is likely mediated by a wide range of variables, including the presence of inflammation or inflammatory signals,30 increased axonal expression of voltage-gated sodium channels31,32 and excitatory adrenergic receptors,33 and axonal “sprouts” at the damaged nerve tip.27 In response to this increased level of peripheral sensory input, dorsal horn neurons in the spinal cord react more robustly and the size of the receptive fields increases (a component of central sensitization; see Fig. 2a)27,34 In some patients, however, sensory fiber loss is quite extensive.10 Studies in animals indicate that with such extensive death of peripheral sensory fibers, central processes of the surviving axons may develop aberrant connections with deafferentiated cells in the spinal cord (Fig. 2b).35,36 This type of functional and anatomical reorganization may account for spontaneous pain as well as allodynia.27 In other cases, near complete sensory fiber destruction alternatively may lead to degeneration of inhibitory interneurons in the dorsal horn, which contributes to spontaneous firing of deafferentiated, excitatory dorsal horn neurons.37 In such cases, spontaneous pain may occur in the absence of significant allodynia.10,27 The clinical challenge of successfully treating PHN is made all the more difficult by the possibility that more than one of these and other as-yet-undefined mechanisms may be operative in a single given patient, as well as over the course of PHN development and maintenance.

Diagnosis and Evaluation of Patients with PHN In most cases, the clinical diagnosis of PHN is not difficult, since the majority of patients remember a symptomatic painful rash in the affected dermatomal region. In many patients, skin color changes and scarring assist in the diagnosis. The most common diagnostic challenge is characteristic PHN pain without a history of the zoster rash, an entity known as zoster sine herpete, or zoster without rash.38 In this case, serologic studies can be used to confirm the diagnosis.

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Fig. 2. a) Following degeneration of primary afferent nociceptive C-fibers (C), neurons located in the substantia gelatinosa (SG) of the spinal cord (shown in the shaded area) suffer a loss of afferent connectivity b) Possibly in response to neurochemical signals released during fiber damage and degeneration, central terminals of surviving afferents (AB) that convey information about non-noxious stimuli and project ventrally form axonal sprouts that travel dorsally and establish aberrant connections with the deafferentiated SG neurons (Figures 2a and 2b used with permission from Fields HL, Rowbotham N, Baron R. Postherpetic Neuralgia: Irritable Nociceptors and Deafferentiation. Neurobiology of Disease, 1998; 5: 209–227).

As in all patients with chronic neuropathic pain, it is important to perform a complete medical and neurologic evaluation, as well as to assess comorbidities and the negative impact that pain has on the quality of life and functionality of the patient with suspected PHN. These assessments should serve as the basis of all treatment planning for PHN.39 Although it would be ideal if a specific simple diagnostic test or pain questionnaire were available to help assess PHN, no such tools currently exist; consequently, the diagnosis of PHN relies heavily on

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the recognition of the clinical presentation of the disorder and the exclusion of other processes that can mimic the presentation.39 It should be noted, however, that validated neuropathic pain assessment tools, such as the Neuropathic Pain Scale40 and the Neuropathic Pain Questionnaire,41 have been developed. Each of these tools could be used for the assessment of neuropathic pain, not only in the research setting, but also during long-term treatment. The following sections provide an overview of treatment options for the management of PHN, with emphasis on pharmacological therapies. Materials for this review include primary research and review articles identified in MEDLINE using postherpetic neuralgia and neuropathic pain as search terms, and published reports of randomized clinical trials and non-randomized, open-label clinical trials.

Treatment Options for PHN Pharmacological treatment options for PHN include several classes of drugs. Some agents have been effective in randomized, placebo-controlled trials (Table 1), whereas others have not been rigorously studied or appear to have limited value. As with many neuropathic pain syndromes, PHN is often refractory to treatment with traditional therapeutic approaches and standard analgesic regimens. Given what is known about the pathophysiologic mechanisms that underlie PHN, it follows that pain mechanisms may differ from patient to patient and in any single patient, several pain mechanisms may be operative.27 Because of such refractoriness and heterogeneity, clinicians who treat patients with PHN should be familiar with the entire spectrum of therapeutic options and their appropriate application for specific types of symptoms.

Tricyclic Antidepressants A number of the tricyclic antidepressants (TCAs), including amitriptyline, desipramine, and nortriptyline, are commonly used as primary treatment for PHN, based on positive findings from several randomized, controlled trials

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(Table 1).42–45 TCAs are believed to exert an analgesic effect unrelated to any antidepressant effects via inhibition of the neuronal reuptake of norepinephrine and serotonin, which potentiates inhibition of spinal neurons involved in pain perception.46 Amitriptyline and other TCAs also have been shown to inhibit sodium (Na⫹) channels, which appear to contribute to their analgesic activities.47,48 Analgesic effects of amitriptyline and other antidepressants may also be mediated by the blockade of excitatory N-methyl-d-aspartate (NMDA) and adrenergic receptors on nociceptive fibers.49 Amitriptyline has been the most extensively studied TCA.50 Just over 20 years ago, Watson42 evaluated amitriptyline therapy (median dose: 75 mg/d) in a placebo-controlled, double-blind, crossover study in patients with PHN. With at least 3 weeks of amitriptyline treatment, pain relief was rated good to excellent in 16 patients (67%) (median dose: 75 mg/d).42 In subsequent studies, the response rate associated with amitriptyline ranged from 47% to 66%.44,45,51 In other investigations, similar rates of patient response have been observed with nortriptyline (55%) and desipramine (63%).43,52 Despite the analgesic efficacy of TCAs in PHN, the use of these compounds has been limited by adverse effects and safety concerns (e.g., sedation, anticholinergic effects, and postural hypotension).45,53 Among elderly patients receiving TCAs, there are increased risks of glaucoma, falls related to dizziness, postural hypotension and sedation, and cardiac dysfunction. Tolerability can be improved with more gradual dose titration and use of more selective TCAs such as nortriptyline, which have a somewhat better side-effect profile compared to amitriptyline. Because double-blind trials have not exceeded 6 weeks, the optimal duration of therapy is unknown; generally accepted treatment involves maintaining analgesic TCA doses for several months before attempting dosage reduction.53

Other Antidepressants Newer antidepressants that have shown success in treating other types of neuropathies may also be useful in the treatment of PHN; however, these antidepressants require further investigation for this disease state. For example, placebo-controlled studies have demonstrated the selective serotonin reuptake inhibitors paroxetine and citalopram to be significant pain

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Table 1 Positive Trials of Established Pharmacologic Therapies for PHN Author, Year

Trial Design

Tricyclic Antidepressants Watson Randomized, double-blind, et al., 1982 placebo-controlled, crossover Kishore-Kumar Randomized, double-blind, et al., 1990 placebo-controlled, crossover Watson Randomized, double-blind, et al., 1998 crossover Watson and Evans, Open-label, crossover 1985 Watson Randomized, double-blind, et al., 1992 crossover Watson and Evans, Open-label, crossover 1985 Max Double-blind, randomized, et al., 1988 placebo-controlled, crossover Graff-Rradford Double-blind, et al., 2000 placebo-controlled, single center

Author, Year Gabapentin Rowbotham et al., 1998 Rice et al., 2001

Raja et al., 2002

a

Duration

24

Amitriptyline: 75 mg

7–8 weeks

16, 66%

19

Desipramine: mean dose, 167 mg

6 weeks

12, 63%

31

Nortriptyline: 10–20 mg Amitriptyline:10–20 mg Amitriptyline: 10–25 mg Zimeldine: 100 mg–300 mg Amitriptyline: 12.5–25 mg Maprotiline:12.5–25 mg Amitriptyline: 10–25 mg Zimeldine:100 mg–300 mg Amitriptyline: 12.5–150 mg Lorazepam: 0.5–6 mg

12 weeks

21, 67%

15 35 15 58 49

n

Multicenter, randomized, double-blind, placebocontrolled, parallel design

229

Multicenter, double-blind, randomized, placebocontrolled

334

12 weeks 7 weeks 6 weeks

Amitriptyline: up to 200 mg 8 weeks Fluphenazine: up to 3 mg Amitriptyline ⫹ fluphenazine: Up to 200 mg and 3 mg

Daily Dose(s)

Amitriptyline: 8, 53% Zimeldine: 1, 7% Amitriptyline: 15, 37% Maprotiline: 12, 38% Amitriptyline: 8, 53% Zimeldine: 1, 7% Amitriptyline: 47%b Lorazepam: 15%b Significant decrease in VAS pain scores with amitriptyline (55.9 to 26.6) and amitriptyline ⫹ fluphenazine (47.6 to 35.41)a Pain Relief

3600 mg

8 weeks

1800 mg and 2400 mg

7 weeks

43.2% Change in mean pain score 6.3 to 4.2 with gabapentin, 6.5 to 6.0 placeboa Change in pain score from baseline, ⫺34.5% 1,800 mg dose ⫺34.4, 2400 mg dose ⫺15.7% placebo

35

Up to 3 patches

32

Up to 3 patches

4 12-hour Lidocaine reduced pain sessions intensity on VAS scale at all time points compared to vehicle patches 2–14 days, 29/32 (90.6%)

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Up to 3 patches

28 days

66%

20

Long-acting opioids: Dose to come

6 months

placebodouble-blind,

38

Oxycodone up to 30 mg q 12 h

4 weeks

Mean pain score decreased from 9.0 to 4.0a 58%

placebodouble-blind,

50

(Mean) Slow-release Morphine: 91 mg Methadone: 15 mg Nortriptyline: 89 mg Desipramine: 63 mg

24 weeks

Randomized, two-treatment period, vehicle-controlled, crossover Open-label, nonrandomized, multicenter

Randomized, controlled, crossover Randomized, controlled, crossover

7 weeks

Duration

Katz et al., 2002 Opioids Pappagallo and Open-label, uncontrolled Campbell, 1994 Watson et al., 1998

Drug(s): Daily Dose(s)

Trial Design

Lidocaine Patch 5% Rowbotham Randomized, double-blind, et al., 1996 vehicle-controlled

Galer et al., 1999

Respondersa (n, %)

n

Mean pain score point decreases: Morphine: 2.2 Methadone: 1.2 Nortriptyline: 1.2 Desipramine: 1.6

10-point pain scale. In cases where only a percentage is given, the number of patients responding was not specified in the study report.

b

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relievers in patients with diabetic neuropathy.54,55 In smaller trials, bupropion and venlafaxine have also been found to alleviate neuropathic pain.56,57 In contrast, clinical trials of the tetracyclic antidepressant maprotiline have not supported the widespread use of this agent in PHN, due mainly to its poor side-effect profile and lower analgesic efficacy in comparison to amitriptyline.45 Overall, these newer antidepressants are better tolerated and safer than TCAs.50 While evidence of analgesic efficacy and improved tolerability suggests that certain newer antidepressants may be useful for PHN, adequate controlled clinical trials of these agents have not been conducted in patients with PHN.

Anticonvulsants Although anticonvulsants have been used to treat several types of neuropathic pain, only one anticonvulsant, gabapentin, has been shown in appropriate studies to be effective in the management of PHN.58 Most of these agents have either not been formally studied or studies have yielded unfavorable outcomes. For example, although carbamazepine, valproic acid and phenytoin have been shown to be effective treatments in a variety of neuropathic syndromes, including trigeminal neuralgia and diabetic neuropathy, they have not been well studied in PHN.59–61 Similarly, clinical trials with newer anticonvulsant agents, such as lamotrigine,62–65 topiramate,66 oxcarbazepine,67 and benzodiazepine anticonvulsants such as clonazepam68,69 and nitrazepam, indicate possible efficacy in the treatment of neuropathic pain, but none of these agents have been studied in patients with PHN. However, as demonstrated in the case of lorazepam, efficacy in other painful neuropathic conditions (i.e., diabetic neuropathy) does not necessarily predict utility for successful treatment of PHN.44,70 An exception among anticonvulsants is gabapentin, an agent that exerts a potent analgesic effect in several animal models of neuropathic pain.71–73 Evidence points to the effect of gabapentin on the α-2-δ subunit of a voltagegated calcium (Ca⫹⫹) channel as an important mechanism of neuronal inhibition that underlies the analgesia seen with this agent.74 Gabapentin was recently approved by the United

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States Food and Drug Administration (USFDA) for the treatment of PHN on the basis of efficacy and safety results from 2 large, randomized, placebo-controlled trials (Table 1).75,76 In the first trial, patients (n ⫽ 229) received either gabapentin treatment at the maximum tolerated dose (up to 3600 mg/d) or placebo for 4 weeks.75 With gabapentin, average daily pain scores decreased significantly versus placebo (P ⬍ 0.001) and improvements in sleep interference were also observed (P ⬍ 0.001).75 Similar results were obtained in a second placebocontrolled trial in which gabapentin 1800 or 2400 mg/d was administered for 7 weeks to 334 patients with PHN, marked by 34% reductions in pain scores with both doses of gabapentin (versus placebo, P ⬍ 0.01) and improvements in sleep quality.76 Data from these studies suggest that gabapentin is generally well tolerated; adverse events reported with gabapentin included somnolence, dizziness, ataxia, peripheral edema, asthenia, and dry mouth.75,76 Withdrawal rates were slightly higher with gabapentin (9.5% and 13.3%) than with placebo (4.3%).75,76 Encouragingly, gabapentin was not associated with evidence of organ toxicity or adverse reactions when combined with other medications, which may be of particular concern among the elderly patients who are most likely to suffer from PHN.75,76 A recent consensus issued by the faculty of the Fourth International Conference on the Mechanisms and Treatment of Neuropathic Pain recommends that gabapentin be initiated as a single dose of 100-300 mg nightly or 100-300 mg three times daily, then titrated as needed by 100-300 mg three times daily every 1 to 7 days.77 The dose can subsequently be titrated up to 1200 mg three times daily (3600 mg/d) as needed for pain relief.77

Lidocaine Patch 5% Lidocaine is an amide-type local anesthetic agent that appears to act by blocking the voltage-gated sodium channels on excitable membranes, thereby preventing the generation and conduction of nerve impulses.78,79 The first treatment for PHN approved by the USFDA, the lidocaine patch 5% is a soft, stretchy adhesive patch (10 ⫻ 14 cm) containing 5% lidocaine (700 mg).80 An initial study of topical

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lidocaine was conducted in patients with PHN (n ⫽ 39) using 5% lidocaine gel; treatment was found to yield significant analgesia that had a rapid onset (about 30 minutes following gel application) and a long duration (up to 24 hours).81 The local anesthetic action of the gel and the nonsignificant level of systemic absorption and action of the drug were confirmed based on the absence of pain relief when the gel was applied to contralateral nonpainful skin, as well as negligible blood levels of lidocaine (⬍0.6 µg/mL).81 The analgesic efficacy of the subsequently developed lidocaine patch 5% for PHN has been established in a number of clinical trials (Table 1).82–85 In these trials, patients without allodynia (most of whom had partially or even markedly anesthetic skin) were also eligible to participate. In a double-blind, multiple cross-over, vehicle-controlled study82 involving 35 patients with allodynia and PHN of the torso or extremities, 12-hour application of the lidocaine patch (up to 3 patches, covering a maximum of 420 cm2) significantly reduced pain intensity at all time points between 30 minutes and 12 hours compared to no treatment at all, and between 4 and 12 hours compared to vehicle patch application.82 The highest blood lidocaine level was 0.1 µg/mL, and no systemic side effects were reported.82 Pain relief with the lidocaine patch 5% appears to be well maintained with longterm use and the patch is well tolerated.83 In a randomized, vehicle-controlled, time-to-exit study,83 patients with PHN (n ⫽ 32) who had an established, successful analgesic response to lidocaine patch 5% therapy for at least 1 month prior to study entry were either switched to a placebo patch or were assigned to continue receiving active lidocaine patch 5% treatment. The mean length of lidocaine patch treatment prior to study entry was 3.3 years; all of these patients reported continued moderate or greater pain relief.83 Those patients who were switched to a vehicle patch reported significant worsening of pain (pain scores that decreased by ⱖ2 categories) and were discontinued after an average of only 3.8 days, while all patients assigned to continue receiving active lidocaine patch 5% treatment remained in the study until completion (14 days) (P ⬍ 0.001).83 No significant difference was noted between active and placebo treatments with regard to side effects, including application site reaction.83 Evidence suggests

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that lidocaine patch therapy for PHN also may help to improve quality of life in most patients.83,84 In the study conducted by Galer et al., most patients indicated a preference for lidocaine patch therapy over placebo and informally noted improved quality of life.83 More recently, in a large, open-label, multicenter 28day study in patients with PHN (n ⫽ 332),84 74% of patients reported improvements in quality of life within the first week of treatment. The most common adverse event was localized rash, which occurred in 14% of patients and was usually considered mild.84 Topical analgesic agents such as the lidocaine patch target their activity at the site of pain, thereby providing directed analgesia with minimal risks for adverse events.78 Since the lidocaine patch rapidly alleviates pain and may help to improve quality of life without producing serious side effects or drugdrug interactions, it has been argued that this agent is a reasonable first-line treatment for PHN.83,86 In addition to its efficacy and safety, the lidocaine patch 5% presents considerable ease of administration and little obstacle to good patient compliance; it can be applied directly to the most painful areas without the need for dose titration or repeated dosing. Currently, the recommended dosage is up to 3 patches for 12 hours every 24 hours,77 although recent pharmacokinetic studies suggest that 4 patches applied for up to 24 hours on 3 consecutive days can produce analgesia without systemic adverse effects or edema.87 Systemic absorption from the lidocaine patch is estimated to be 3% of the dose.88 While the duration of use is dependent on the individual patient’s needs, some patients have been reported to have used the lidocaine patch for ⬎8 years without evidence of tolerance or increased adverse effects.83

Alternative Topical Agents A number of other topical analgesic agents with differing mechanisms of action have been considered for use in patients with PHN, including capsaicin, aspirin, lidocaine cream, and clonidine hydrochloride ointment. Among these, only capsaicin, an over-the-counter agent derived from chili peppers, has been extensively examined in patients with PHN.89–91 It is believed that analgesia with topical application of capsaicin occurs, in part, as a result of epidermal nerve fiber degeneration.92 Outcomes with

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this agent in patients with PHN have been mixed; while significant reductions in pain severity and improvements in ability to perform daily activities were seen during both the acute double-blind and the 2-year open-label phases of a large controlled study (n ⫽ 143),90 other investigations have failed to yield such positive results.91,93 Indeed, studies have revealed worsening of pain and allodynia, as well as unbearable post-application burning in PHN patients treated with capsaicin.91,93 It has also been noted that conducting a true blinded study with capsaicin would be difficult because of the characteristic stinging sensation associated with topical application. This stinging sensation, along with the need for multiple applications per day, may also negatively affect compliance.93 Similar mixed results have been observed with other topical agents. For instance, a number of investigators report that topical aspirin or benzydamine provided relief for some patients,94–98 but other studies failed to show a treatment benefit.99 Moreover, in some of these studies the mixture of aspirin with potentially unstable and flammable compounds like ether or chloroform raises some question as to the safety and stability of certain aspirin preparations.94,9,51 Lidocaine cream and clonidine hydrochloride ointment have been shown to be effective in preliminary trials,100,101 but confirmation of their utility requires further investigation.

Opioids Based on results from numerous clinical studies, caregivers are beginning to move beyond the long-held belief that neuropathic pain, including that associated with PHN, responds poorly to opioid therapy.102–107 In addition to augmenting inhibitory spinal norepinephrine and serotonin systems, opioids directly inhibit primary nociceptive afferent and spinal dorsal horn neurons, which may be particularly useful in light of suspected multiple mechanisms underlying pain with PHN. A number of studies have demonstrated significant pain relief with opioid agents in patients with PHN (Table 1).103,106,108 Positive results have been observed in patients with intractable PHN pain who were administered controlled-release (CR) oxycodone;108,109 long-term follow-up from one of these studies indicates that the pain relief obtained with CR oxycodone is maintained up to 6 months, suggesting minimal development of

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tolerance with long-term opioid use in these patients.108 Similarly positive findings have been reported more recently by Rowbotham and colleagues, who observed significant relief of chronic neuropathic pain, including that related to PHN, with the potent µ opioid agonist levorphanol.107 Reductions in pain (36% reduction versus baseline) with the higher dose of levorphanol (mean dose: 8.9 mg/d) were similar in magnitude to those typically observed with TCAs or gabapentin.107 Patients in this study further noted improvements in sleep and daily functioning and decreased affective distress with levorphanol treatment as compared to these measures at baseline.107 In a recent randomized, double-blind, crossover design (n ⫽ 91), a head-to-head comparison of the efficacy and tolerability of 2 opioids (slow-release morphine and methadone) and 2 TCAs (nortriptyline and amitriptyline) was investigated in patients with PHN.106 Findings indicated that pain reduction with slow-release morphine was significantly greater in magnitude than that observed with the nortriptyline (P ⫽ 0.004), and analgesic efficacy of methadone was comparable to that seen with either amitriptyline or nortriptyline.106 Moreover, the TCAs appeared to be associated with significant decrements in cognitive functions, such as concentration and psychomotor speed and dexterity, while no such decrements were reported with the use of either opioid.106 Although more patients discontinued due to adverse events during the initial phases of opioid titration in comparison to the TCA phase, the majority of patients (54%) preferred opioid therapy to TCA treatment, owing probably to the greater pain relief experienced with these agents.106 These findings suggest that opioids may be a more effective alternative to TCA treatment for PHN in some patients. While opioid-related side effects such as nausea, constipation, dizziness, and loss of appetite were frequently observed in these studies, some of these effects (e.g., dizziness, nausea) may abate with continued opioid use. To help minimize the side effects experienced during initiation of opioid therapy, clinicians should begin with low doses and titrate upward slowly, particularly in elderly patients. Although the possibility of addiction (psychological dependence on a substance) should always be considered with opioid therapy, clinical experience indicates that the risk of

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acquiring addiction behaviors in a non-addict is low in patients who use opioids for PHN.108

Miscellaneous Therapies A variety of other treatment strategies for reducing the pain and allodynia of PHN have been studied in both small and large clinical trials or have been described in anecdotal case reports. These include use of N-methyl-d-aspartate (NMDA)-receptor antagonists such as ketamine and dextromethorphan,110–112 antiviral agents,113,114 nerve blocks115,116 and intrathecal corticosteroid administration,117,118 the γ-aminobutyric acid antagonist baclofen,119 spinal stimulation,120–122 intraspinal analgesia,123 and even surgical removal of painful skin.124 In most cases, efficacy has not been adequately examined with controlled trials or consistently observed across separate investigations; some reports detail successful outcomes in only a single patient.123,124 A number of outcomes have been disappointing, with minimal pain relief reported, as in patients administered dextromethorphan110,111 or acyclovir.114 In a placebo-controlled trial of dextromethorphan in PHN, patients failed to respond to active treatment, while those with comparative neuropathic disorders, such as diabetic neuropathy, responded to dextromethorphan treatment.111 Other studies have offered more encouraging findings.117,118,120,121,125 The largest involved 277 patients with intractable PHN who were randomized to receive up to 4 weeks of treatment with weekly intrathecal injection of methylprednisolone (60 mg) and lidocaine (3 mg), lidocaine alone, or no treatment;118 only those receiving the intrathecal combination of methylprednisolone and lidocaine experienced significant, nearly complete relief of their pain.118 While no treatmentrelated adverse events were reported with the intrathecal injections, others have raised concern about the safety of this approach, pointing out the association between such treatment and serious adverse events, such as aseptic meningitis, adhesive or calcific arachnoiditis, and spinal pachymeningitis, which primarily has been observed in patients with pre-existing neurologic disease.126 Other approaches, such as surgical removal of painful skin,124 placement of indwelling epidural catheters for ongoing epidural analgesic administration,123 and implantation of spinal

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cord stimulation devices,120 are associated with inherent risks related to their highly invasive nature. With such variable findings and associated risk potential, alternative treatments might be considered only for those patients whose pain is refractory to other, better-characterized pharmacologic treatments. As some of the alternative approaches to treatment show promise, further investigation is required to better characterize their efficacy and safety for treating PHN in a greater number of patients.

Prevention of PHN Strategies aimed at preventing the development of PHN involve more aggressive treatment of the acute herpes zoster infection or earlier intervention with pain medication.127 Since more severe infections are accompanied by greater neural damage, it follows that attenuating the severity of herpes zoster infection or reducing the accompanying acute pain may play an important role in limiting the likelihood of subsequent PHN.

Antiviral Agents At present, the most effective means of reducing the severity of herpes zoster is administration of an antiviral drug. A number of clinical trials suggest that if promptly treated after rash onset for 7 to 14 days with adequate doses of antiviral agents, such as acyclovir, famciclovir, and valacyclovir, which inhibit replication of the varicella zoster virus, patients may experience hastened rash healing and reduced severity and duration of acute zoster-related pain.25,128–131 Among 7 large, placebo-controlled, doubleblind clinical trials of acyclovir treatment initiated within 72 hours of zoster rash onset (800 mg given 5 times daily for 7 to 10 days), results from 3 trials indicated significant reduction of pain with the rash.131 Evidence derived from these and other trials also indicates that antiviral therapy in herpes zoster may significantly reduce the risk of developing PHN or reduce its duration.25,129,130,132–134 Recently published treatment guidelines recommend, however, that antiviral treatment be reserved for patients who are older, have moderate or severe rash or pain, or have ophthalmic involvement; antivirals are

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not deemed necessary for younger patients with only mild rash and little or no pain.131,135,136

Prophylactic PHN Therapy With proven efficacy in PHN, some investigators have proposed earlier administration of drugs such as TCAs and opioids during acute herpes zoster infection.116,127,135,137 There is some support for such an approach.137,138 In one study of acute herpes zoster infection, the concomitant administration of amitriptyline to an existing treatment regimen of acyclovir further reduced the risk of PHN.137 Irrespective of the method chosen, some researchers have suggested that therapy be initiated immediately after rash onset, regardless of whether the treatment goal is to limit nerve damage, reduce central sensitization, or attenuate acute pain.127

Developing a Treatment Approach PHN is a complex disease state that is best understood and treated as a biopsychosocial condition. After confirming the medical diagnosis of PHN, caregivers must assess the nature and severity of the PHN-related pain, as well as the impact of this pain on the patient’s psychological and social well-being and on physical functioning (i.e., the key domains of healthrelated quality of life). Determining these characteristics prior to beginning any treatment will later allow for clearer judgments to be made regarding the efficacy of therapeutic interventions across the full spectrum of disease components. Patient education should also begin immediately following diagnosis and prior to treatment intervention. Educational efforts should be made to help the patient develop a better understanding of what is causing the pain and to develop appropriate expectations about the extent of pain relief that may occur with a chosen treatment regimen. At present, no clear-cut treatment algorithm has been devised for patients with PHN. For many years, standard therapy consisted of a low dose TCA, such as amitriptyline or nortriptyline. With USFDA approval of the lidocaine patch 5% and the anticonvulsant gabapentin, evidence-based treatments are now available for PHN. Based upon the recent findings of Raja and colleagues, the opioids also appear to be emerging as a preferred therapeutic alternative to TCAs.106 Additional comparative studies

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are needed, however, to more firmly establish an evidence-based treatment algorithm for PHN. In the absence of such an evidence-based, defined treatment algorithm, it seems reasonable to begin PHN treatment with a safe, welltolerated agent with proven efficacy based on randomized controlled clinical trials. Consideration of possible interactions with other medications, and ease of administration and titration must also play an important role in choosing initial therapy, especially when treating older patients affected by PHN. Gabapentin, the lidocaine patch 5%, and minimally anticholinergic TCAs, such as desipramine and nortriptyline, form the group of possible first-line therapies for a patient with PHN, replacing older TCAs such as amitriptyline. Currently, there are no direct comparative studies that would enable clinicians to determine whether—and under what conditions— any of these individual agents is preferable over any of the others. While no comparative studies have been published with the lidocaine patch 5%, clinical experience clearly supports its degree of efficacy; the patch’s ease of administration, safety, and tolerability exceed those of gabapentin, opioids, and TCAs. Moreover, onset of relief is generally rapid, although some patients may require a trial of up to 2 weeks.84 Preliminary evidence suggests that both gabapentin and opioids are safer than TCAs and are at least as effective.75,76,106 Unlike gabapentin and the lidocaine patch 5%, both TCAs and opioids present considerable tolerability, drug interaction, and safety issues that warrant cautious and careful administration in elderly patients. TCA use is associated with an elevated risk of glaucoma, falls related to dizziness, postural hypotension and sedation, and cardiac dysfunction.139 Caution should be used when considering opioid therapy for a chronic pain syndrome. Tolerance and adverse events have not been well studied in long-term, controlled clinical trials. Although opioid addiction appears to be rare in patients treated for chronic pain conditions, physicians who prescribe opioids for long-term use should be familiar with the basic principles of recognizing and treating addiction. Regardless of the first-line treatment approach, the complex and often heterogeneous nature of the mechanisms that underlie PHN pain make it likely that a single agent, acting

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via a single, predominant mechanism, may not yield adequate symptom relief. This notion is borne out by evidence of extensive polypharmacy among patients with PHN. Clearly, if the initial approach to therapy yields an unsatisfactory outcome (defined as less than a 33% reduction from baseline pain and little improvement in key dimensions of patient functioning based upon past clinical trials), practitioners should begin systematic trials of other approved agents before moving on to unproven and possibly less well-tolerated options. Additional agents may be cautiously added to an existing treatment regimen or initial therapy may be tapered off and eventually replaced by another agent. Therefore, strategies for treating patients with PHN should be developed on an individual basis. Theoretically, combination therapy with the lidocaine patch 5% and gabapentin, the two agents approved for PHN, appears to be an attractive option for patients who might only partially respond to one of these agents as monotherapy. Potentially, relief may be more rapid or of greater magnitude given the possible additive effects of these agents. In addition, this may be a particularly well-tolerated and safe treatment combination, given the apparent safety of both agents and the extremely low reported incidence of drug-drug interaction. Clinical trials studying the efficacy and safety of the combination are currently ongoing. Patients whose PHN remains refractory can also be offered a number of investigational pain management options, including spinal stimulation, intraspinal analgesics, and epidural or intrathecal steroids with a modified protocol under investigational conditions. Earlier rather than later use of interventional pain management approaches should be considered with special attention paid not only to the efficacy of the procedure but also to the risk of adverse effects. If the provider of the pharmacotherapeutic care and the provider of the interventional care are not the same, then coordination of care is absolutely necessary to minimize side effects. Psychological and behavioral interventions may also be introduced at any time in the course of treatment of PHN and are recommended as an integral part of treatment for patients with refractory PHN or those who have suffered

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from PHN for an extended period of time. Similarly, rehabilitative issues (e.g., deconditioning, decreased physical functioning, and work disability) that may result from chronic pain may be best managed by physical and occupational rehabilitative approaches.

Summary PHN is a painful neuropathy that can lead to impaired physical, social, and emotional functioning. The pain of PHN is believed to arise from varying degrees of central and peripheral nociceptive hyperexcitability resulting from the neural degeneration caused by acute herpes zoster. Until recently, TCAs were the treatment of choice for PHN; however, randomized clinical trials have demonstrated that effective pain relief with TCA treatment is reported in only about half of all patients. Moreover, TCAs present risks of numerous side effects that are of particular concern among the elderly, who comprise the majority of PHN patients. A wide variety of other treatment strategies have emerged as a result of the inadequacies and risks of TCA treatment. Based on randomized controlled clinical trials in PHN patients, the USFDA has approved the anticonvulsant gabapentin and the local anesthetic lidocaine, administered in the form of an adhesive patch, for pain in PHN. Unlike TCAs, both of these agents appear to be well tolerated and present little risk of drug-drug interaction. Other therapies, including long-acting opioid treatment, also have shown promise in controlled clinical trials for the management of PHN. Despite recent strides in the number of approved and well-studied options for treating PHN, questions remain: Which agent is more effective and for which patients? Which combinations of therapeutic agents provide the best pain relief and under what conditions? When should interventional pain management techniques be integrated? Until these questions are resolved by further investigations, physicians must base treatment choices on a common sense approach.

References 1. Kurtzke JF. Neuroepidemiology. Ann Neurol 1984;16:265–277.

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407

2. Donahue JE, Choo PW, Manson JE, et al. The incidence of herpes zoster. Arch Intern Med 1995; 155:1605–1609.

20. Veenstra J, Krol A, Van Praag RM, et al. Herpes zoster, immunological deterioration and disease progression in HIV-1 infection. AIDS 1995;9:1153–1158.

3. Hope-Simpson RE. Herpes zoster in general practice: postherpetic neuralgia. J R Col Gen Pract 1965;25:571–575.

21. Schmader K. Management of herpes zoster in elderly patients. Infect Dis Clin Pract 1995;4:293– 299.

4. Ragozzino MW, Melton LJ III, Kurland LT, et al. Population-based study of herpes zoster and its sequelae. Medicine 1982;61:310–316.

22. Choo PW, Galil K, Donahue JG, et al. Risk factors for postherpetic neuralgia. Arch Intern Med 1997;157:1217–1224.

5. Burgoon CF, Burgoon JS, Baldridge GD. The natural history of herpes zoster. JAMA 1957;164: 265–269.

23. Wood MJ, Kay R, Dworkin RH, et al. Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebocontrolled trials. Clin Infect Dis 1996;22:341–347.

6. Dworkin RH, Portenoy RK. Proposed classification of herpes zoster pain. Lancet 1994;343:1648. 7. Dworkin RH, Carrington D, Cunningham A, et al. Assessment of pain in herpes zoster: Lessons learned from antiviral trials. Antiviral Res 1997; 33:73–85. 8. Hope-Simpson RE. Postherpetic neuralgia. J R Coll Gen Pract 1975;25:571–575. 9. Dworkin RH, Portenoy RK. Pain and its persistence in herpes zoster. Pain 1996;67:241–251. 10. Rowbotham MC, Fields HL. Postherpetic neuralgia: the relation of pain complaint, sensory disturbance and skin temperature. Pain 1989;39:129–144. 11. Nurmikko T, Bowsher D. Somatosensory findings in postherpetic neuralgia. J Neurol Neurosurg Psychiatry 1990;53:135–141.

24. Dworkin RH, Boon RJ, Griffin DR, et al. Postherpetic neuralgia: impact of famciclovir, age, rash, severity and acute pain in herpes zoster patients. J Infect Dis 1998;178(Suppl 1):76S–80S. 25. Riopelle JM, Naraghi M, Grush KP. Chronic neuralgia incidence following local anesthetic therapy for herpes zoster. Arch Dermatol 1984;120: 747–750. 26. Baron S, Saguer M. Postherpetic neuralgia: are C-nociceptors involved in signaling and maintenance of tactile allodynia? Brain 1993;116:1477– 1496. 27. Fields HL, Rowbotham M, Baron R. Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol Dis 1998;5:209–227.

12. Watson CPN, Deck JH, Morshead C, et al. Postherpetic neuralgia: further post-mortem studies of cases with and without pain. Pain 1991;44:105–117.

28. Oaklander AL, Romans K, Horasek S, et al. Unilateral postherpetic neuralgia is associated with bilateral sensory neuron damage. Ann Neurol 1989; 44:789–795.

13. Davies L, Cossins L, Bowsher D, et al. The cost of treatment for post-herpetic neuralgia in the UK. Pharmacoeconomics 1994;6:142–148.

29. Rowbotham MC, Fields HL. The relationship of pain, allodynia and thermal sensation in post-herpetic neuralgia. Brain 1996;119:347–354.

14. Chidiac C, Bruxelle J, Daures JP, et al. Characteristics of patients with herpes zoster on presentation to practitioners in France. Clin Infect Dis 2001; 33:62–69.

30. Sorkin LS, Xiao WH, Wagner R, et al. Tumor necrosis factor-alpha induces ectopic activity in nociceptive primary afferent fibers. Neuroscience 1997; 81:255–262.

15. Donahue JG, Choo PW, Manson JE, et al. The incidence of herpes zoster. Arch Intern Med 1995; 155:1605–1609.

31. Devor M, Govrin-Lippmann R, Angelides K. Na⫹ channel immunolocalization in peripheral mammalian axons and changes following nerve injury and neuroma formation. J Neurosci 1993;13(5): 1976–1992.

16. Helgason S, Petursson G, Gudmundsson S, et al. Prevalence of postherpetic neuralgia after a first episode of herpes zoster: prospective study with long-term follow up. BMJ 2000;321:794–796. 17. Buchbinder SP, Katz MH, Hessol NA, et al. Herpes zoster and human immunodeficiency virus infection. J Infect Dis 1992;166:1153–1156. 18. Guinee VF, Guido JJ, Pfalzgraf KA, et al. The incidence of herpes zoster in patients with Hodgkin’s disease. An analysis of prognostic factors. Cancer 1985;56:642–648. 19. Rusthoven JJ, Ahlggen P, Elhakim T, et al. Varicella-zoster infection in adult cancer patients. A population study. Arch Intern Med 1988;148:1561–1566.

32. Omana-Zapata I, Khabbaz MA, Hunter JC, et al. Tetrodotoxin inhibits neuropathic ectopic activity in neuromas, dorsal root ganglia and dorsal horn neurons. Pain 1997;72:41–49. 33. Janig W, Levine JD, Michaelis M. Interactions of sympathetic and primary afferent neurons following nerve injury and tissue trauma. Prog Brain Res 1996; 113:161–184. 34. Palecek J, Dougherty PM, Kim SH, et al. Responses of spinothalamic tract neurons to mechanical and thermal stimuli in an experimental model of peripheral neuropathy in primates. J Neurophysiol 1992;68:1951–1966.

408

Argoff et al.

35. Shortland P, Woolf CJ. Chronic peripheral nerve section results in a rearrangement of the central axonal arborizations of axotomized alpha-beta primary afferent neurons in the rat spinal cord. J Comp Neurol 1993;330(1):65–82. 36. Woolf CJ, Shortland P, Coggeshall RE. Peripheral nerve injury triggers central sprouting of myelinated afferents. Nature 1992;355:75–78. 37. Laird JM, Bennett GJ. An electrophysiological study of dorsal horn neurons in the spinal cord of rats with an experimental peripheral neuropathy. J Neurophysiol 1993;69:2072–2085. 38. Gilden KH, Dueland AN, Devlin ME, et al. Varicella-zoster virus infection without rash. J Infect Dis 1992;166:S30–S34. 39. Backonja MM et al. Pain assessment and evaluation of patients who have neuropathic pain. Neurol Clin 1998;16:775–790. 40. Galer BS, Jansen MP. Development and preliminary validation of a pain measure specific to neuropathic pain: the Neurpathic Pain Scale. Neurology 1997;48:332–338. 41. Krause SJ, Backonja MM. Development of a neuropathic pain questionnaire. J Pain 2003;19(5): 306–314. 42. Watson CP, Evans RJ, Reed K, et al. Amitriptyline versus placebo in postherpetic neuralgia. Neurology 1982;32:671–673. 43. Kishore-Kumar R, Max MB, Schafer SC. Desipramine relieves postherpetic neuralgia. Clin Pharmacol Ther 1990;47:306–312. 44. Max MB, Schafer SC, Culnane M, Smoller B, Dubner R, Gracely RH. Amitriptyline, but not lorazepam, relieves postherpetic neuralgia. Neurology 1988;38:1427–1432. 45. Watson CP, Chipman M, Reed K, et al. Amitriptyline versus maprotiline in postherpetic neuralgia: a randomized, double-blind crossover trial. Pain 1992;48:29–36. 46. Basbaum AI, Fields HL. Endogenous pain control mechanisms: review and hypothesis. Ann Neurol 1978;4:451–462. 47. Pancrazio JJ, Kamatchi GL, Roscoe AK, et al. Inhibition of neuronal Na⫹ channels by antidepressant drugs. J Pharmacol Exp Ther 1998;284(1):208–214. 48. Nau C, Seaver M, Wang SY, et al. Block of human heart H-1 sodium channels by amitriptyline. J Pharmacol Exp Ther 2000;292(3):1016–1023. 49. Eisenach JC, Gebhart GF. Intrathecal amitriptyline acts as an N-methyl-d-aspartate receptor antagonist in the presence of inflammatory hyperalgesia in rats. Anesthesiology 1995;83:1046–1054. 50. Kanazi GE, Johnson RW, Dworkin RH. Treatment of postherpetic neuralgia: an update. Drugs 2000;59:1113–1126. 51. Watson CP, Evans RJ. A comparative trial of amitriptyline and zimelidine in post-herpetic neuralgia. Pain 1985;23:387–394.

Vol. 28 No. 4 October 2004

52. Watson CP, Vernich L, Chipman M, et al. Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial. Neurology 1998;51:1166–1171. 53. Attal N. Chronic neuropathic pain: mechanisms and treatment. Clin J Pain 2000;16:S118–S130. 54. Sindrup SH, Gram LF, Brosen K, et al. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain 1990;42:135–144. 55. Sindrup SH, Bjerre U, Dejgaard A, et al. The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy. Clin Pharmacol Ther 1992;52:547–552. 56. Semenchuk MR, Sherman S, Davis B. Doubleblind, randomized trial of bupropion SR for the treatment of neuropathic pain. Neurology 2001;57:1583– 1588. 57. Taylor K, Rowbotham MC. Venlafaxine hydrochloride and chronic pain. West J Med 1996;165: 147–148. 58. Tremont-Lukats IW, Megeff C, Backonja MM. Anticonvulsants for neuropathic pain syndromes: mechanisms of action and place in therapy. Drugs 2000;60:1029–1082. 59. Peiris JB, Perera GLS, Dvendra SV, et al. Sodium valproate in trigeminal neuralgia. Med J Aust 1980; 2:278–279. 60. Savitskaya O. Comparative effectiveness of antiepileptic preparations in treatment of patients with neuralgia of the trigeminal nerve. Zh Psikhiatr Im S S Korsakova 1980;80:530–535. 61. Backonja M-M. Anticonvulsants (antineuropathics) for neuropathic pain syndromes. Clin J Pain 2000;16:S67–S72. 62. Simpson DM, Olney R, McArthur J, et al. Lamotrigine in the treatment of HIV-associated painful sensory polyneuropathy: a placebo-controlled study. Neurology 1999;52(Suppl 2):A190(abstract). 63. Eisenberg E, Lurie Y, Braker C, et al. Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology 2001;57:505–509. 64. Zakrewska JM, Chaudhry Z, Nurmikko TJ, et al. Lamotrigine (Lamictal) in refractory trigeminal neuralgia: results from a double-blind placebo controlled crossover trial. Pain 1997;73:223–230. 65. D’Andrea G, Granella F, Ghiotto N, et al. Lamotrigine in the treatment of SUNCT syndrome. Neurology 2001;57:1723–1725. 66. Edwards JM, Glantz MJ, Button J, et al. Efficacy and safety of topiramate in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study (Abstract S15: 001) Neurology 2000; 54(S3):A81. 67. Zakrzewska JM, Patsalos PN. Long-term cohort study comparing medical (oxcarbazepine) and surgical management of intractable trigeminal neuralgia. Pain 2002;95:259–266.

Vol. 28 No. 4 October 2004

Treatment of Postherpetic Neuralgia

68. Caccia MR. Clonazepam in facial neuralgia and cluster headache: clinical and electrophysiological study. Eur Neurol 1975;13:560–563. 69. Swerdlow M. Anticonvulsant drugs and chronic pain. Clin Neuropharmacol 1984;7:51–82. 70. Sang CN, Booher S, Gilron I, et al. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-response trials. Anesthesiol 2002;96:1053–1061. 71. Singh L, Field MJ, Ferris P, et al. The antiepileptic agent gabapentin (Neurontin) possesses anxiolytic-like and antinociceptive actions that are reversed by D-serine. Psychopharmacology (Berl) 1996;127:1–9. 72. Hwang JH, Yaksh TL. Effect of subarachnoid gabapentin on tactile-evoked allodynia in a surgically induced neuropathic pain model in the rat. Reg Anesth 1997;22:249–256. 73. Field MJ, McCleary S, Hughes J, et al. Gabapentin and pregabalin, but not morphine and amitriptyline, block both static and dynamic components of mechanical allodynia induced by streptozocin in the rat. Pain 1999;80:391–399. 74. Taylor CP, Gee NS, Su T-Z, et al. A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Res 1998;29:233–249. 75. Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998;280:1837– 1842. 76. Rice AS, Maton S, for the Postherpetic Neuralgia Study Group. Gabapentin in postherpetic neuralgia: a randomized, double blind, placebo controlled study. Pain 2001;94:215–224. 77. Dworkin RH, Backonja M, Rowbotham MC, et al., for the Fourth International Conference on the Mechanisms and Treatment of Neuropathic Pain. Advances in neuropathic pain: Diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003;60:1524–1534. 78. Argoff CE. Topical analgesics: A review of recent clinical trials and their application to clinical practice. Adv Stud Nursing 2003;3(7A):S642–S647. 79. Ritchie JM, Greene NM. Local anesthetics. In: Gilman AG, Rall TW, Nies A, et al., eds. The pharmacological basis of therapeutics, 8th ed. Singapore: McGraw-Hill, Inc. 1992:311–331. 80. Comer AM, Lamb HM. Lidocaine patch 5%. Drugs 2000;59:245–249. 81. Rowbotham MC, Davies PS, Fields HL. Topical lidocaine gel relieves postherpetic neuralgia. Ann Neurol 1995;37:246–253. 82. Rowbotham MC, Davies PS, Verkempinck C, et al. Lidocaine patch: double-blind study of a new treatment method for post-herpetic neuralgia. Pain 1996;65:39–44.

409

83. Galer BS, Rowbotham MC, Perander J, et al. Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: results of an enriched enrollment study. Pain 1999; 80:533–538. 84. Katz NP, Gammaitoni AR, Davis MW, et al. Lidocaine patch 5% reduces pain intensity and interference with quality of life in patients with postherpetic neuralgia: an effectiveness trial. Pain Med 2002;3: 324–332. 85. Devers A, Galer BS. Topical lidocaine patch relieves a variety of neuropathic pain conditions: an open-label study. Clin J Pain 2000;16:205–208. 86. Watson CPN. A new treatment for postherpetic neuralgia. New Engl J Med 2000;343:1563–1565. 87. Gammaitoni AR, Alvarez NA, Galer BS. Pharmacokinetics and safety of continuously applied lidocaine patches 5%. Am J Health-Syst Pharm 2002; 59:2215–2220. 88. Campbell BJ, Rowbotham M, Stitzlein Davies P, et al. Systemic absorption of topical lidocaine in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes zoster. J Pharmaceut Sci 2002;91:1343–1350. 89. Bernstein JE, Korman NJ, Bickers DR, et al. Topical capsaicin treatment of chronic postherpetic neuralgia. J Am Acad Dermatol 1989;21(2 Pt 1): 265–270. 90. Watson CP, Tyler KL, Bickers DR, et al. A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia. Clin Ther 1993;15:510–526. 91. Petersen KL, Fields HL, Brennum J, et al. Capsaicin evoked pain and allodynia in post-herpetic neuralgia. Pain 2000;88:125–133. 92. Nolano M, Simone DA, Wendelshafer-Crabb G, et al. Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation. Pain 1999; 81(1-2):135–145. 93. Watson CP, Evans RJ, Watt VR. Post-herpetic neuralgia and topical capsaicin. Pain 1988;33:333– 340. 94. DeBenedittis G, Besana F, Lorenzetti A. A new topical treatment for acute herpetic neuralgia and postherpetic neuralgia: the aspirin diethyl ether mixture. An open label study plus a double-blind, controlled clinical trial. Pain 1992;48:383–390. 95. King RB. Topical aspirin in chloroform and the relief of pain due to herpes zoster and postherpetic neuralgia. Arch Neurol 1993;50:1046–1053. 96. Tajti J, Szok D, Vecsei L. Topical acetylsalicylic acid versus lidocaine for postherpetic neuralgia: results of a double-blind comparative clinical trial. Neurobiology 1999;7:103–108. 97. Alexander JL. Postherpetic neuralgia. Anaesthesia 1985;40:1133–1134.

410

Argoff et al.

98. Coniam SW, Hunton J. A study of benzydamine cream in postherpetic neuralgia. Res Clin Forums 1988;10:65–67. 99. McQuay HJ, Carroll D, Moxon A, et al. Benzydamine cream for the treatment of post-herpetic neuralgia: minimum duration of treatment periods in a cross-over trial. Pain 1990;40:131–135. 100. Iseki M, Mitsuhata H, Miyazaki T, et al. Relief of subacute herpetic pain and postherpetic neuralgia with repeated application of 10% lidocaine cream. Masui 2000;49:1204–1209. 101. Meno A, Arita H, Hanaoka K. Preliminary report: the efficacy of clonidine hydrochloride ointment for postherpetic neuralgia. Masui 2001;50: 160–163. 102. Attal N, Chen YL, Kayser V, et al. Behavioral evidence that systemic morphine may modulate a phasic pain-related behavior in a rat model of peripheral mononeuropathy. Pain 1991;47(1):65–70. 103. Rowbotham MC, Reisner–Keller LA, Fields HL. Both intravenous lidocaine and morphine reduce the pain of postherpetic neuralgia. Neurology 1991;41:1024–1028. 104. Dellemijn PL, van Duiin H, Vanneste JA. Prolonged treatment with transdermal fentanyl in neuropathic pain. J Pain Symptom Manage 1998;16: 220–229. 105. Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology 1998;50:1837–1841. 106. Raja SN, Haythornthwaite JA, Pappgallo M, et al. Opioids versus antidepressants in postherpetic neuralgia. Neurology 2002;59:1015–1021. 107. Rowbotham M, Twilling L, Davies PS, et al. Oral opioid therapy for chronic peripheral and central neuropathic pain. New Engl J Med 2003;348:1223– 1232. 108. Pappagallo M, Campbell JN. Chronic opioid therapy as alternative treatment for post-herpetic neuralgia. Ann Neurol 1994;35(Suppl):S54–S56. 109. Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology 1998;50(6):1837–1841. 110. McQuay HJ, Carroll D, Jadad AR, et al. Dextromethorphan for the treatment of neuropathic pain: a double-blind, randomized controlled crossover trial with integral n-of-1 design. Pain 1994;59:127–133. 111. Nelson KA, Park KM, Robinovitz E, et al. Highdose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology 1997;48:1212–1218. 112. Eide PK, Jorum E, Stubhaug A, et al. Relief of post-herpetic neuralgia with the N-methyl-d-aspartic acid receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo. Pain 1994;58:347–354.

Vol. 28 No. 4 October 2004

113. Balfour HH Jr, Bean B, Laskin OL, et al. Acyclovir halts progression of herpes zoster in immunocompromised patients. N Engl J Med 1983;308: 1448–1453. 114. Acosta EP, Balfour HH Jr. Acyclovir for treatment of postherpetic neuralgia: efficacy and pharmacokinetics. Antimicrob Agents Chemother 2001; 45:2771–2774. 115. Milligan NS, Nash TP. Treatment of post-herpetic neuralgia: a review of 77 consecutive cases. Pain 1985;23:173–183. 116. Winnie AP, Hartwell PAW. Relationship between time of treatment of acute herpes zoster with sympathetic blockade and prevention of postherpetic neuralgia: clinical support for a new theory of the mechanism by which sympathetic blockade provides therapeutic benefit. Reg Anesth 1993;18: 277–282. 117. Kikuchi A, Kotani N, Sato T, et al. Comparative therapeutic evaluation of intrathecal versus epidural methylprednisolone for long-term analgesia in patients with intractable postherpetic neuralgia. Reg Anesth Pain Med 1999;24:287–293. 118. Kotani N, Kushikata T, Hashimoto H, et al. Intrathecal methylpredinisolone for intractable postherpetic neuralgia. NEJM 2000;343:1514–1519. 119. Terrence CF, Fromm GH, Tenicla R. Baclofen as an analgesic in chronic peripheral nerve disease. Eur Neurol 1985;24:380–385. 120. Harke H, Gretenkort P, Ladleif HU, et al. Spinal cord stimulation in postherpetic neuralgia and in acute herpes zoster pain. Anesth Analg 2002;94: 694–700. 121. Meglio M, Cioni B, Prezioso A, et al. Spinal cord stimulation (SCS) in the treatment of postherpetic pain. Acta Neurochir 1989;46(Suppl):65–66. 122. Kumar K, Toth C, Nath RK. Spinal cord stimulation for chronic pain in peripheral neuropathy. Surg Neurol 1996;46:363–369. 123. Kang FC, Chang PJ, Chen HP, et al. Patientcontrolled epidural analgesia for postherpetic neuralgia in an HIV-infected patient as a therapeutic ambulatory modality. Acta Anaesthesiol Sin 1998; 36:235–238. 124. Petersen KL, Rice FL, Suess F, et al. Relief of post-herpetic neuralgia by surgical removal of painful skin. Pain 2002;98:119–126. 125. Kotani N, Kushikata T, Suzuki A, et al. Insertion of intradermal needles into painful points provides analgesia for intractable abdominal scar pain. Reg Anesth Pain Med 2001;26:532–538. 126. Abram SE. Intrathecal steroid injection for postherpetic neuralgia: what are the risks? Reg Anesth Pain Med 1999;24:283–285. 127. Kanazi GE, Johnson RW, Dworkin RH. Treatment of postherpetic neuralgia: an update. Drugs 2000;59:1113–1126.

Vol. 28 No. 4 October 2004

Treatment of Postherpetic Neuralgia

128. Huff JC, Drucker JL, Clemmer A, et al. Effect of oral acyclovir on pain resolution in herpes zoster: a reanalysis. J Med Virol 1993;(Suppl 1):93–96. 129. Wood MJ, Kay R, Dworkin RH, et al. Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebocontrolled trials. Clin Infect Dis 1996;22:341–347. 130. Tyring S, Barbarash RA, Nahlik JE, et al. Famciclovir for the treatment of acute herpes zoster: Effects on acute disease and postherpetic neuralgia: a randomized double-blind placebo-controlled trial. Ann Intern Med 1995;123:89–96. 131. Kost RG, Straus SE. Postherpetic neuralgia: pathogenesis, treatment, and prevention. N Engl J Med 1996;335:32–42. 132. Beutner KR, Friedman DJ, Forszpaniak C, et al. Valacyclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 1995;39:1546– 1553. 133. Jackson JL, Gibbons R, Meyer G, et al. The effect of treating herpes zoster with oral acyclovir in

411

preventing postherpetic neuralgia: a meta-analysis. Arch Intern Med 1997;157:909–912. 134. Crooks RJ, Jones DA, Fididan AP. Zoster-associated chronic pain: an overview of clinical trials with acyclovir. Scand J Infect Dis 1991;80(Suppl.):62–68. 135. Dworkin RH, Perkins RM, Nagasake EM. Prospects for the prevention of postherpetic neuralgia in herpes zoster patients. Clin J Pain 2000;16:S90–S100. 136. Wallace MS, Oxman MN. Acute herpes zoster and postherpetic neuralgia. Anesthesiol Clin North America 1997;51:371–405. 137. Bowsher D. The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: a randomized, double-blind, placebo-controlled trial. J Pain Symptom Manage 1997;13:327–331. 138. Tenicela R, Lovasik D, Eaglestein W. Treatment of herpes zoster with sympathetic blocks. Clin J Pain 1985;1:63–67. 139. Drug facts and comparisons. St. Louis: Wolters Kluwer Co., 2002.