CME/CE CERTIFIED. James D. Griffin, MD EDUCATIONAL OBJECTIVES. A Freedom Magazines Publication

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1 James D. Griffin, MD Director, Multi-Specialty Anesthesia Zale Lipshy University Hospital Director, Anesthesiology Medical Student Education Associate Professor Department of Anesthesiology and Pain Management Southwestern Medical School University of Texas Southwestern Medical Center Dallas, Texas CME/CE CERTIFIED EDUCATIONAL OBJECTIVES Upon completion of this activity, participants should be able to: Describe the epidemiology of postherpetic neuralgia (PHN). Identify the pathophysiologic mechanisms underlying the development of PHN. Assess the comorbidities associated with PHN. Evaluate the efficacy, tolerability, and safety results of various agents evaluated in clinical trials of PHN. Discuss the mechanisms of action for various drugs used for the symptomatic management of PHN. An accredited program sponsored by Medical Education Resources, Inc., a nonprofit medical education company. Supplement to Annals of Long-Term Care and Clinical Geriatrics A Freedom Magazines Publication

2 Sponsorship and Accreditation Information Postherpetic Neuralgia in the Elderly Target Audience This activity is intended for physicians, pharmacists, and nurses who treat elderly patients with postherpetic neuralgia. Educational Objectives Upon completion of this activity, participants should be able to: Describe the epidemiology of postherpetic neuralgia (PHN). Identify the pathophysiologic mechanisms underlying the development of PHN. Assess the comorbidities associated with PHN. Evaluate the efficacy, tolerability, and safety results of various agents evaluated in clinical trials of PHN. Discuss the mechanisms of action for various drugs used for the symptomatic management of PHN. Program Completion Time Based upon trials, the estimated time to complete this activity is 1 hour. Educational Grant This activity is made possible by an unrestricted educational grant from Pfizer, Inc. Sponsorship This activity is sponsored by Medical Education Resources, Inc., a nonprofit medical education company. Physician Accreditation Medical Education Resources (MER) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. Credit Designation MER designates this educational activity for a maximum of 1 category 1 credit toward the AMA Physician s Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity. This CME activity was planned and produced in accordance with the ACCME Essentials. Nursing Accreditation This program qualifies for 1.25 contact hours. MER is approved as a provider of continuing education in nursing (CNE) by the Colorado Nurses Association, which is accredited as an approver of CNE by the American Nurses Credentialing Center s Commission on Accreditation. Provider approved by the California Board of Registered Nursing, Provider CEP #12299 for 1.25 contact hours. Each participant should claim only those credits that he/she actually spent in the educational activity. Pharmacy Accreditation MER is approved by the Accreditation Council for Pharmacy Education as a provider of continuing pharmaceutical education. MER designates this continuing education activity for 1.0 contact hour (0.1 CEUs) in states that recognize ACPE. Universal Program Number: L04. Faculty Disclosure Policy It is the policy of MER to ensure balance, independence, objectivity, and scientific rigor in all their educational acitivites. All faculty participating in this activity are expected to disclose any relationships they may have with commercial companies whose products or services may be mentioned so that participants may evaluate the objectivity of the presentations. Dr. Griffin indicated that he serves on the speaker s bureau for Pfizer, Inc., and that he may discuss off-label use of products. Obtaining Continuing Education Credit To receive credit, participants must complete the CME/CE Examination and Evaluation that appear at the end of this program and fax or mail to: Medical Education Resources 1500 West Canal Court Littleton, CO Fax: A minimum score of 70% on the CME/CE Examination is required for credit. A certificate of completion will be mailed within 3 weeks of receipt of the completed answer sheet. Disclaimer The content and views presented in this educational activity are those of the author and do not necessarily reflect those of Medical Education Resources, Pfizer, Inc., or MultiMedia Health- Care/Freedom, LLC. The author has disclosed if any unlabeled use of products is mentioned in the material. Before prescribing any medicine, primary references and full prescribing information should be consulted. Program Release Date: April 2004 Program Expiration Date: April Postherpetic Neuralgia in the Elderly APRIL 2004

3 Introduction Postherpetic neuralgia is a chronic neuropathic pain disorder that develops in some individuals after an acute episode of herpes zoster infection, commonly known as shingles. It is associated with chronic infection of the dorsal root ganglia and nerves caused by reactivation of varicella zoster virus. Nearly 500,000 people in the United States experience shingles each year. 1 Advanced age (> 65 years) is the most well-established risk factor. 2 Over 100 years ago, Head and Campbell 3 reported the largest series of postmortem examination of patients who had herpes zoster infection. Their findings provided the basis for some of the earliest descriptions of the neurosegmental anatomy and description of the dermatomal map. The neuropathological changes and sensory evolution, including initial hemorrhagic inflammation in the sensory ganglia and nerves followed by fibrotic changes in the dorsal root ganglia and degenerative changes in the sensory roots and tracts, were described in their series of 20 patients. 3 Prevalence The incidence of herpes zoster is relatively high compared to various other neurological disorders. The estimated annual incidence of herpes zoster varies with age, ranging from /100,000 among people under 20 years of age, to ,000/100,000 among those age 80 years or older. 4 Recent studies indicate that more than 1 million new cases of herpes zoster occur annually in the United States. Approximately 10-15% of these individuals will develop postherpetic neuralgia (PHN). 5 However, the incidence of herpes zoster and the risk of developing PHN increase dramatically with age. 6 Elderly patients who develop zoster are 12 times more likely to be hospitalized than children. 7 After an episode of herpes zoster, 43% of patients aged 50 years or older will develop PHN compared with only 6% of patients under 50 years of age. The elderly are at extreme risk, as up to 75% of patients aged 70 years or older may develop PHN as a complication of herpes zoster infection. 8 Once established, PHN may continue for many years, and nearly half of patients aged 60 years or older will have enduring neuropathic pain. 5 Natural History Primary infection with the varicella zoster virus usually results in the mild, childhood disease chickenpox (varicella). Acute herpes zoster involves the reactivation of latent varicella zoster virus in a sensory ganglion and transport of the virus along neural tissue. The virus lies dormant for a variable period of time (up to several decades). It lies latent for decades because of varicella zoster virus specific, cell-mediated immunity acquired during the primary infection, as well as endogenous and exogenous boosting of the immune system periodically throughout life. 9 Reactivation of the virus is thought to follow a decline in cell-mediated immunity. 7 Cellular immunity may be compromised as a result of chemotherapy in cancer patients, 10 HIV infection, 11 or advanced age. 12 Upon reactivation, the virus spreads proximally and distally from the dorsal root ganglion causing pain and a vesicular rash. In most patients with shingles, the disease is self-limiting and the rash and pain disappear completely. In others, however, there is irreversible skin and sensory damage 13 when the dorsal root ganglion and its processes are attacked by the varicella zoster virus. Damage by the virus may occur anywhere along neural tissue from the spinal cord to the epidermis. 14 Subclinical presentations of herpes zoster have been reported, whereby the varicella zoster virus herpes zoster had migrated to the central nervous system (CNS) of immunocompetent patients without symptoms of CNS infection. 15 Preherpetic neuralgia is experienced by some patients. Forty percent of patients experience pain more than 4 days prior to the skin eruption, and 35% experience pain less than 48 hours prior to the development of the rash. 16 Pruritis, paresthesias, fever, malaise, and myalgia may accompany the pain of preherpetic neuralgia. 17 Acute herpes zoster is characterized by a unilateral vesicular eruption. Early in the course of the disease, erythematous, macropapular lesions appear that rapidly evolve into a vesicular rash. Vesicles may coalesce to form bullous lesions. Lesions continue to form over 3-5 days. The rash usually affects one dermatome. Dermatomal distribution reflects the skin innervated by infected sensory ganglions. 18 Thoracic and lumbar dermatomes are most commonly involved. 2 The first (ophthalmic) division of the trigeminal nerve is also a common site of herpes zoster infection. 19 Pain that occurs during acute herpes zoster results from inflammation of the ganglion and transport of virus along a peripheral nerve. The rash and pain from acute zoster lasts between 2-4 weeks for most patients, but can persist for months to years after healing of the rash. 2 Some patients experience unilateral pain characteristic of zoster but never develop a pathognomonic rash. 2 Furthermore, pain due to reactivation of varicella zoster virus without the characteristic rash is known as zoster sine herpete. 15 Neurological complications of acute zoster are uncommon: peripheral motor weakness, 20 meningitis, 21 encephalitis, myelitis, 22 cerebral angitis, 23 and Ramsay-Hunt syndrome 24 have been described. APRIL 2004 Postherpetic Neuralgia in the Elderly 2

4 Diagnosis of acute herpes zoster is typically made by history and physical examination. The unilateral localization and distribution of a vesicular rash makes the diagnosis of herpes zoster highly likely. Viral cultures may be useful in certain clinical presentations to confirm the diagnosis. If pain persists for more than 3 months, it may be classified as PHN. 25 Acute Herpes Zoster Treatment The most important treatment objective during the acute phase of herpes zoster is to keep the patient comfortable and attempt to prevent the development of PHN. The mainstay of acute herpes zoster treatment is antiviral therapy. In the United States, three oral antiviral agents are commercially available for treatment: acyclovir, 26 famciclovir, 27 and valacyclovir 28 (Table I). Famciclovir and valacyclovir are prodrugs, producing acyclovir and pencyclovir, respectively. The goals of antiviral therapy are to hasten healing of cutaneous lesions, Medication reduce the severity of acute neuritis, and reduce the intensity and Famciclovir Acyclovir duration of chronic pain, 18 which Valacyclovir these agents will accomplish if initiated within 72 hours of the rash onset. All of these agents have been shown to promote resolution of skin lesions and reduce the duration of viral shedding and pain. 15,27 Studies have indicated that antiviral treatment started within hours of the development of the herpes zoster rash may also decrease the risk of PHN. 29,30 However, even with antiviral therapy, some patients will develop PHN. Antiviral therapy should be provided for patients at extreme risk for developing PHN, including the elderly and individuals with decreased cell-mediated immunity due to malignancy, chronic HIV infection, or chemotherapy. The pharmacokinetic profiles of valacyclovir and famciclovir are more favorable in a clinical setting. Major drawbacks of orally administered acyclovir include its lower bioavailability compared with other agents and its dosing frequency (5 times daily). Valacyclovir is also more bioavailable than acyclovir, and oral administration produces blood drug levels comparable to the intravenous administration of acyclovir. The advantages of famciclovir are its dosing schedule (3 times daily), its longer intracellular half-life compared with acyclovir, and its better bioavailability compared with acyclovir and valacyclovir. Patients who present with significant pain at onset and who have a significant number TABLE I of active lesions are likely to benefit more from antiviral therapy. Famciclovir was found to reduce the median duration of postherpetic neuralgia in subjects over 50 years of age, from 163 days to 63 days, when compared to placebo. 31 Many adjunctive therapies are useful in the treatment of acute herpes zoster. Tricyclic antidepressants, corticosteroids, and individualized oral analgesics are used to achieve the comprehensive treatment objectives in acute herpes zoster. Low-dose amitriptyline (25 mg daily) given within 1 month after the onset of zoster for a 90-day course can reduce the risk of PHN by one-half. 32 Corticosteroids added to antiviral therapy have been shown to accelerate healing of skin lesions, reduce analgesic requirement, improve sleep, and promote faster return to normal activity. However, they do not affect the Antiviral Therapy for Treatment of Acute Herpes Zoster incidence of PHN. 33,34 The pain of acute zoster should not be underestimated. Clinicians should consider narcotic analgesics as needed for acute exacerbations of pain, in all age groups of patients. Patients with mild-tomoderate pain may respond to over-the-counter analgesics. Diagnosis Dosage 800 mg orally 5 times daily for 7-10 days 500 mg orally 3 times daily for 7 days 1000 mg orally 3 times daily for 7 days The medical literature supports several definitions of postherpetic neuralgia. These definitions account for the temporal relationship between the ongoing pain and the rash of herpes zoster A clinically useful definition of postherpetic neuralgia is recurrent or persistent localized pain arising or persisting in areas affected by herpes zoster at least 3 months after healing of the skin lesion. 15 The diagnosis of PHN is primarily based on history, clinical presentation and course, and physical examination. The temporal relationship of pain to acute zoster facilitates the clinical diagnosis of PHN. Some patients clinical courses present challenges in distinguishing prolonged zoster pain from PHN. PHN is one of the most painful syndromes seen in a pain practice. 16 The clinical presentation of PHN is variable, and no two individuals experience identical symp- 3 Postherpetic Neuralgia in the Elderly APRIL 2004

5 toms. Patients may describe their pain as burning, deeply aching, tearing, electric shock like, lancinating, itching, and/or stabbing. 5,8,38 The pain in PHN can be either spontaneous or stimulus-evoked (Table II). TABLE II Spontaneous and Stimulus-Evoked Symptoms of PHN Symptom Spontaneous Symptoms Spontaneous pain Dysesthesias Paresthesias Description Burning, shock-like Abnormal, unpleasant sensations (eg, shooting, lancinating, burning) Abnormal sensations that are not unpleasant (eg, tingling) Stimulus-Evoked Symptoms Allodynia Painful response to a nonpainful stimulus Hyperalgesia Heightened response to a painful stimulus Hyperpathia* Delayed, explosive pain response to a painful stimulus * May occur in addition to allodynia or hyperalgesia. Some patients also report abnormal sensation in affected dermatomes, including allodynia and/or hyperpathia. 5,8,38 Sensory function may remain intact or sensory function may be lost in a dermatomal pattern. Mechanical allodynia to light touch is very common, heat hyperalgesia may be present in some patients, and cold hyperalgesia is rare. Patients may have distinct sensory symptoms and findings, which can coexist in all combinations. 39 This variability results from damage to a variety of neurologic pathways. Treatment in these cases must be tailored to the most likely pathophysiology present. Peripheral and central mechanisms of pain are common in PHN. Aberrant somatosensory processing in the peripheral and central nervous system may be present. 40 Peripheral irritable nociceptors, peripheral and central ectopic discharge, central sensitization, alpha beta reorganization and loss of descending inhibitory control are all proposed mechanisms of pain in PHN. Irritable nociceptors are present in some patients and are caused by abnormal sensitization of unmyelinated peripheral nociceptors. Abnormal sensitization is characterized by ongoing discharge, nerve hypersensitivity, and heightened response to noxious stimuli. These nociceptors could be responsible for spontaneous or stimulus-evoked pain. 41 Damage to peripheral nerves may result in regions of demyelination and neuroma formation. 42 This type of damage is associated with spontaneous ectopic electrical activity. 41 Peripheral nerves and dorsal root ganglions are susceptible to this type of aberrant function. Central sensitization results from phenomena such as central disinhibition and increased peripheral Consequences nociceptor drive. 42 Rewiring of the neural connections of alpha beta fibers at the level of the spinal cord can occur following peripheral nerve damage. 43 This rewiring in the dorsal horn results in non-noxious input from the mechanoreceptive alpha beta fibers, stimulating pain pathways and being perceived as pain. 39 Loss of descending inhibitory control may result from downregulation of gamma-aminobutyric acid (GABA) and GABA receptors 44 in the spinal dorsal horn after nerve injury or changes in descending inhibitory pathways. Feinstein 45 introduced the concept of comorbidity. Comorbidity is the presence of one or more additional clinically important conditions in a patient that is being treated for a specific disease or dysfunction (called the index disease). For example, a patient who is being treated for postherpetic neuralgia may also be experiencing difficulty sleeping. The coexistence of two or more conditions in a single patient has important implications for overall management because it may be difficult to accurately assess the index disease, resulting in treatment not producing the expected outcome. 45 The most common comorbidities associated with chronic pain are sleep disturbances and depression and/or anxiety. However, the relationship among these factors is not straightforward. Despite a scarcity of formal studies directly connecting chronic pain syndromes with sleep interference, depression, and anxiety, 2,46,47 it is apparent that PHN can disrupt sleep and possibly mood. 48 In a study of chronic pain sufferers, 82% of participants reported insomnia. 49 Of these, 6% reported difficulty falling asleep, 37% reporting waking during the night, 2% reported waking too early in the morning, and 37% reported some combination of these sleep disturbances. Additionally, 20% of all subjects complained that they did not feel rested and restored after sleep, and 10% APRIL 2004 Postherpetic Neuralgia in the Elderly 4

6 indicated that they had problems with nightmares. Of the subjects who reported sleep disturbances, 60% attributed their sleep problems to pain alone, 89% reported that their sleep was disturbed at least 3 nights per week, and 53% indicated that they had never had a problem sleeping before they began experiencing chronic pain. 49 The cause-and-effect relationship between chronic pain and sleep disturbances cannot be assumed. Sleep deprivation studies has suggested that severe sleep disturbances can increase sensitivity to pain. Depression is frequently a comorbid condition of chronic pain. The prevalence of depression in patients with chronic pain is high. Although it may seem obvious that someone suffering with a chronic condition would be depressed, it is interesting to compare the prevalence of depression in a chronic pain population with that seen in other chronic, debilitating conditions. In one study, 44% of chronic pain patients were found to have major depression, 50 whereas only 18% of hospitalized severely ill patients demonstrated symptoms of depression. 51 In another study by Davidson et al, 52 79% of patients with chronic pain had some evidence of depression. Many of these patients had symptoms of atypical depression, including weight gain and increased appetite. 52 As in patients with sleep deprivation, it is unclear whether chronic pain leads to depression or whether depression causes an increased sensitivity to pain. Both a depressed mood and anxiety can lead to an increase in the intensity of pain perceived by the patient. This triad of pain, sleep disturbances, and mood disorders causes functional impairment in many areas of life, including an inability to concentrate, loss of employment or reduction in status at work, and a decrease in the ability to take part in outdoor activities and sports. 53 Thus, it is important to comprehensively assess a patient s illness. Evaluation of pain, sleep disturbances, and mood disorders influence treatment options and increase TABLE III the possibility of a successful outcome. Use of tools like the Patient Global Impression of Change (PGIC) and the Clinician Global Impression of Change (CGIC) may represent the best overall assessment of treatment efficacy by providing a concise and focused view of the impact of therapy, encompassing not only relief of pain, but also functional, social, and emotional wellbeing. 54 Quality of life for PHN patients generally deteriorates in parallel with rash and pain symptoms and rebounds after symptoms resolve. 46 Patients with painful symptoms persisting for more than 6 months report greater disability and psychological distress than those whose pain remits within 6 months. Patients with depression also report physical, occupational, and social disruptions to their lives. 1,2,55 Thus, effective treatment of PHN is of considerable clinical importance. Treatment Options for PHN There are two approved therapies for PHN in the United States. They are gabapentin and the lidocaine patch 5%. Results of randomized, controlled clinical trials confirm the efficacy of additional agents within the drug classes of antidepressants, anticonvulsants, opioids, and topical analgesics in relieving PHN symptoms. However, because of the heterogeneic nature of this disorder, treatment must always be based on the individual needs and pathophysiology of the patient. Understanding of the proposed mechanisms of pain in PHN allows the clinician to direct therapeutic efforts toward important physiologic targets. These targets include modulation of opioid receptors (descending inhibition), modulation of monoaminergic systems (descending inhibition), modulation of peripheral sensitization, modulation of central sensitization (Table III). Pharmacologic Treatment of PHN Tricyclic Antidepressants Antidepressants can be effective adjuncts in reducing the neuropathic pain of postherpetic neuralgia. These agents inhibit the reuptake of norepinephrine and serotonin, important pain-modulating neurotransmitters. 56 These inhibitory transmitters act on descending path- Classes of Drugs Used in the Treatment of Postherpetic Neuralgia Drug Class Opioids Antidepressants Anticonvulsants Topical local anesthetics Proposed Mechanistic Target Descending inhibition, modulation of the opioid receptors Descending inhibition, modulation of the monoaminergic systems Modulation of peripheral sensitization Modulation of peripheral sensitization Modulation of central sensitization Modulation of peripheral sensitization 5 Postherpetic Neuralgia in the Elderly APRIL 2004

7 ways between the brain stem and the dorsal horn of the spinal cord. Amitriptyline is commonly used to treat PHN. The clinical literature supports a high response rate, generally at least 50%. Nortriptyline appears to be as effective as amitriptyline, produces less severe side effects, and may be better tolerated. 57 However, side effects (anticholinergic effects such as sedation or postural hypotension) of the tricyclic antidepressants (TCAs) as a class are troublesome, especially in the elderly, and represent a significant limitation to their use. The selective serotonin reuptake inhibitors (SSRIs) are a potential alternative class, but there are as yet no controlled clinical trials in PHN. Additionally, TCAs appear to have some peripheral effects on sodium flux. This secondary proposed mechanism of action may provide insight into the clinical observation that TCAs have greater efficacy in treating neuropathic pain when compared to SSRIs. Mixed norepinephrine/serotonin reuptake inhibitors (nortriptyline, amitriptyline) have been found to be more effective than SSRIs 58 and tetracyclic antidepressants (maprotiline). 59 Anticonvulsants Anticonvulsants such as phenytoin, carbamazepine, valproate, clonazepam, gabapentin, and pregabalin are other treatment options for neuropathic pain. A recent review of gabapentin shows this agent to be important in the management of chronic neuropathic pain syndromes. 60 Although the mechanism of action of gabapentin in PHN is not well understood, studies suggest that it binds to spinal cord neuronal calcium channels, thereby modulating calcium influx and reducing the multiple firing of action potentials in sensory neurons. 5 Results from two clinical trials in PHN show reduced pain, acceptable adverse-effect profile (dizziness and somnolence were the most common events), and improved quality of life. 5,61 Rapid dose titration to a range of mg/day provided clinical benefits in 1 week or less. 5 The drug is well tolerated and has minimal potential to interact with other drugs. The dosage of gabapentin may also be adjusted for elderly patients with renal insufficiency. A new agent, pregabalin, is an alpha- 2 ligand with analgesic, anxiolytic, and anticonvulsant activity in animal models Pregabalin s mechanism of action in the efficacious treatment of fibromyalgia, 66 painful diabetic neuropathy, 67 and postherpetic neuralgia 68,69 remains to be elucidated. It was synthesized as a lipophilic analog of GABA capable of penetrating the blood-brain barrier. 65 Similar to gabapentin, pregabalin is believed to act on alpha-2 delta ligands of neuronal voltage-activated calcium channels. Neuronal calcium channels are important components of central sensitization. In many models of neuropathic pain, increased alpha-2 delta expression is involved. Dendritic areas of the brain 70 and the dorsal horn of the spinal cord are locations where alpha-2 delta sites are prominent. The dorsal horn location is where mechanoreceptive alpha beta fiber rewiring and central sensitization occur. Pregabalin has two important differences between gabapentin. Pregabalin possesses greater in vivo potency and has a more linear relationship between dose and plasma levels. This pharmacokinetic property has been demonstrated to result in a low daily dose (less than 300 mg/day) to decrease neuropathic pain in patients. 71 Pregabalin additionally improved sleep quality, fatigue, global measures of improvement, and quality of life. 66 Pregabalin has not been approved by the Food and Drug Administration (FDA) for clinical use in the United States. Opioids Patients who are refractory to efficacious treatment of pain with non-narcotic agents may need opioid analgesics for management. Opioids have a presynaptic mechanism of action by closing voltage-gated calcium channels. 72 Opioids also have a postsynaptic mechanism of action, resulting in hyperpolarization or inhibition of the postsynaptic neurons by opening potassium channels. 73 A small but well-designed placebo-controlled crossover trial of sustained-release oxycodone in PHN showed that efficacy was sustained through at least 4 weeks of treatment and was not related to a depressed, affective state. 74 These data do not address long-term safety or efficacy. A recent trial directly comparing opioids and TCAs in PHN showed that opioids are equally effective and possibly better tolerated than TCAs. Opioids were found to cause clinically significant pain reduction with minimal cognitive effects. 75 Although opioids can alleviate pain, the side effects of these agents can be particularly problematic in older patients. The incidence of adverse effects such as sedation and drowsiness, nausea, pruritis, and constipation is relatively high among persons aged 65 years and older and may cause many patients to discontinue therapy. 8 Topical Agents The topical lidocaine patch 5% was the first drug with an FDA-approved indication for postherpetic neuralgia. It provides an effective treatment option with minimal side effects. The lidocaine diminishes ectopic dis- APRIL 2004 Postherpetic Neuralgia in the Elderly 6

8 charges within superficial sensory afferents by blocking sodium channels, while the patch itself serves as a mechanical barrier between skin and clothing in patients with allodynia. 76 Systemic side effects are unlikely because the patch results in clinically insignificant serum lidocaine levels, even with chronic use. 77 The most common adverse event reported with the topical lidocaine patch 5% is transient minor local irritation of the skin. 78 The lidocaine patch was evaluated in a double-blind, placebo-controlled, randomized trial. A majority of patients experienced partial pain relief, suggesting that the patch is a safe and well-tolerated supplemental modality for PHN. 76 Capsaicin preparations (0.025% and 0.075%) have been reported to reduce PHN pain, but often produce intolerable burning upon application, causing many patients to discontinue use. 79 Case Reviews A review of clinical cases illustrates the use and limitations of various treatment modalities of patients with postherpetic neuralgia. Case #1 Mr. T is a 56-year-old man who had developed a herpes zoster rash over his upper left thorax (T4 dermatome), which eventually healed. He subsequently developed significant pain in the area where his rash had healed, making shifting uncomfortable. Upon his initial visit to his primary care physician, the man was prescribed the tricyclic antidepressant, nortriptyline, and the lidocaine patch 5% to manage his pain. Nortriptyline was titrated to an ultimate dose of 100 mg over an 8-week period. However, both medications failed to alleviate this condition. The pain persisted for more than 14 weeks. The man was referred to a pain specialist, who assessed his pain based on an 11-point Likert scale. The severity of the patient s pain was graded as 7. The pain specialist prescribed a standard regimen of gabapentin for the patient (300 mg qd on day 1, 300 mg bid on day 2, 300 mg tid on day 3). Nortriptyline was reduced to 25 mg qd. Oxycodone controlled-release 10 mg bid was added for 3 weeks. After 2 weeks the dosage of gabapentin was titrated up to 1800 mg/day to alleviate the patient s pain. The lidocaine patch 5% was continued. The patient was able to report a reduction in pain after receiving the effective dosage of gabapentin. Upon a follow-up visit to his pain specialist, the patient s Likert score had improved to a 4. This case illustrates that patients with significant allodynia may benefit from the combination of topical lidocaine in combination with systemic agents. Choice of systems agents are based on the specific symptoms of the patient. The use of nortriptyline as the sole systemic medication was inadequate. The addition of gabapentin to the tricyclic antidepressant allowed for a significant reduction in the dose of nortriptyline, thus reducing the likelihood of anticholinergic side effects. Opiates are often used to control the acute exacerbations of pain. However, scheduled doses of narcotic analgesic are preferred to as needed prescriptions. The lidocaine patch 5% was reported to provide adequate relief from the allodynia symptoms and was continued. As noted earlier, PHN affects a disproportionate number of elderly patients. As a result, the presence of comorbid medical illness and concomitant medical treatment are important considerations when selecting therapy for elderly patients with PHN. Drugs with favorable sideeffect profiles and minimal interaction potentials are extremely important in this population. Case #2 Mrs. RL is a 78-year-old woman with PHN presenting 2 years after resolution of acute zoster. She complains of continuous burning pain over her left buttock and posterior thigh and into the plantar surface of her foot. She states that the pain (pins and needles) increases on the bottom of her foot with weight-bearing activity (static allodynia) and that burning pain awakens her 2-3 times per night. She says that her pain ranges from 3-8 on a Visual Analog Scale (VAS) based on activity and stress. In addition to a history of acute zoster, the patient has severe osteoarthritis, hypertension, renal insufficiency (creatinine clearance = 29 ml/min), and depression. Her medication regimen included bisoprolol fumarate/hydrochlorothiazide 5 mg/6.25 mg qd, propoxyphene napsylate/acetaminophen 100 mg/650 mg qid, sertraline 100 mg qd, and celecoxib 200 mg qd. Physical examination reveals well-healed lesions on the left buttock and posterior thigh and hypoesthesia to cold and brush/touch perception over the lesions. No allodynia or hyperalgesia is present except for static allodynia on the plantar surface of her foot. As her initial therapy, the patient had been given acyclovir 800 mg 5 times each day for 7 days and hydrocodone/acetaminophen 5 mg/500 mg tid along with amitriptyline 25 mg at bedtime. The patient did well on this regimen for several months; however, it is discontinued when she began to complain of constipation and nausea. The patient now reports that her pain is always an 8/10 on a VAS. She describes the pain as so severe that she has been unable to sleep or engage in normal daily activ- 7 Postherpetic Neuralgia in the Elderly APRIL 2004

9 ities. The patient is placed on gabapentin 300 mg/day titrated over 3 days to accommodate her renal insufficiency and minimize the drug s sedative effects. Low-dose nortriptyline is substituted for amitriptyline at bedtime, and oxycodone 5 mg prn is given for acute exacerbations of pain. At her 4-week follow-up visit, the patient reports a significant improvement in her pain (VAS 4/10 with activity and 2/10 at rest). Static allodynia and burning pain are both improved, as is her ability to sleep through the night. The patient also notes that her mood has improved and that she has begun to resume some of her daily activities. Treatment of complex patients with chronic pain and comorbid depression, like the patient described in this case study, represent important clinical challenges. Chronic pain can cause depression and adversely impact mood and quality of life, while existing depression may affect pain perception and adversely impact response to treatment. The addition of gabapentin to this patient s treatment regimen provided several benefits in addition to well-tolerated and satisfactory pain relief. As has been shown in recent studies, gabapentin also has a positive effect on quality of life and mood. 5 Although the switch to nortriptyline provided immediate improvement in sleep with fewer anticholinergic side effects than amitriptyline, gabapentin has also been shown to improve sleep and help maintain normal sleep architecture. 5,61 Gabapentin also allowed this patient to limit the use of opioids in favor of a long-acting narcotic agent for acute pain flares. Finally, this case demonstrates that gabapentin is safe and well-tolerated, even in patients with renal insufficiency, when titrated and dosed appropriately. Conclusion Successful treatment of PHN requires thorough assessment and evaluation of the patient to optimize pain management strategies. Along with pain assessment, using tools such as the Visual Analog Scale, mood scales, sleep diaries, and global evaluations can provide a comprehensive profile of the patient s pain experience. In some cases, polypharmacy will be required. Although pain is usually of immediate concern, treatments that address comorbidities as well as pain should be selected. Restoring the patient s quality of life and functional capacity is the ultimate goal of treatment. The ability to carry out daily activities and function with limited restrictions is also essential. Comorbid disorders can confound treatment of the primary disease and worsen the prognosis. Therefore, it is essential in the initial assessment of the neuropathic pain patient to consider these circumstances, as these conditions tend to exacerbate pain, and in turn, pain exacerbates them. It is because of this vicious circle that the treatment of these comorbid conditions should be considered part of an overall approach to managing the patient. The clinician must be aware of this relationship between chronic neuropathic pain, daily function, and the comorbidities of sleep disturbance and mood disorders. The patient must be evaluated carefully through a symptom-based approach, and a comprehensive treatment plan must be derived to address all facets of the patient s suffering. The current treatment paradigm for chronic pain uses an interdisciplinary approach to treat the whole patient with a goal of improving patient quality of life and functionality. The non-pain specialist may be called upon to take a leadership role in the management of patients with chronic pain. References 1. Dworkin RH, Schmader KE. The epidemiology and natural history of herpes zoster and postherpetic neuralgia. In: Watson CPN, Gershon AA, eds. Herpes Zoster and Postherpetic Neuralgia. 2nd ed. New York, NY: Elsevier; 2002: Gershon AA. Epidemiology and management of postherpetic neuralgia. Semin Dermatol 1996;15: Head H, Campbell AW. The pathology of herpes zoster and its bearing on sensory localization. Brain 1900; 23: Kost RG, Straus SE. Postherpetic neuralgia: Pathogenesis, treatment, and prevention. N Engl J Med 1996;335: Rowbotham M, Hayden N, Stacey B, et al. Gabapentin for the treatment of postherpetic neuralgia: A randomized controlled trial. JAMA 1998;280: Beydoun A. Postherpetic neuralgia: Role of gabapentin and other treatment modalities. Epilepsia 1990;40(suppl 6):S51-S Edmunds WJ, Brisson M, Rose JD. The epidemiology of herpes zoster and potential cost-effectiveness of vaccination in England and Wales. Vaccine 2001;19: Berger A, Dukes E, McCarberg B, et al. Change in opioid use after the initiation of gabapentin therapy in patients with postherpetic neuralgia. Clin Ther 2003; 25: Oxman MN. Immunization to reduce the frequency and severity of herpes zoster and its complications. Neurology 1995;45:S41-S Devine SM, Wingard JR. Viral infections in severely immunocompromised cancer patients. Support Care Cancer 1994;2: Veenstra J, Krol A, van Praag RM, et al. Herpes zoster, immunological deterioration and disease progression in HIV-1 infection. AIDS 1995;9: Miller AE. Selective decline in cellular immune response to varicella-zoster in the elderly. Neurology 1980;30: Rowbotham MC, Fields HL. Post-herpetic neuralgia: The relation of pain complaint, sensory disturbance, and the skin temperature. Pain 1989;39: Rowbotham MC, Fields HL. The relationship of pain, allodynia and thermal sensation in post-herpetic neuralgia. Brain 1996;119: Haanpää M. Neurologic complications of herpes zoster. In: Watson CPN, Gershon AA, eds. Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition: Pain Research and Clinical Management, Vol 11. Amsterdam, The Netherlands: Elsevier Science BV; 2001: Wood MW, Ogan PH, McKendrick MW, et al. Efficacy of oral acyclovir treatment of acute herpes zoster. Am J Med 1989;85(suppl 2a): Lycka BAS. Dermatologic aspects of herpes zoster. In: Watson CPN, ed. Herpes Zoster and Postherpetic Neuralgia (Pain Research and Clinical Management, vol 8). New York, NY: Elsevier; Whitley RJ. Herpes zoster: Natural history, diagnosis and therapy. In: Watson CPN, Gershon AA, eds. Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition: Pain Research and Clinical Management, Vol 11. Amsterdam, The Netherlands: Elsevier Science BV; 2001: Fromm GH. Facial pain with herpes zoster and postherpetic neuralgia and a comparison with trigeminal neuralgia. In: Watson CPN, Gershon AA, eds. Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition: Pain Research and Clinical Management, Vol 11. Amsterdam, The Netherlands: Elsevier Science BV; 2001: APRIL 2004 Postherpetic Neuralgia in the Elderly 8

10 20. Thomas JE, Howard FM. Segmental zoster paresis: A disease profile. Neurology 1972;22: Echevarria JM, Casao I, Martinez-Martin P. Infection of the nervous system caused by varicella zoster virus: A review. Intervirology 1997;40: Devinsky O, Cho ES, Petito CK, et al. Herpes zoster myelitis. Brain 1991;114: Sarazin l, Duong H, Bourgouin PM, et al. Herpes zoster vasculitis: Demonstration by MR angiography. J Comput Assist Tomogr 1995;19: Robillard RB, Hilsinge AL Jr, Adour KK. Ramsay Hunt facial paralysis: Clinical analysis of 185 patients. Otolaryngol Head Neck Surg 1986;95: Cunningham AL, Dworkin RH. The management of post-herpetic neuralgia. BMJ 2000;321: Wood MJ, Kay R, Dworkin RH, et al. Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: A meta-analysis of placebo-controlled trial. Clin Infect Dis 1996;22: Dworkin RH, Boon R, Griffin DRG, Phung D. Postherpetic neuralgia: Impact of famciclovir, age, rash severity and acute pain in herpes zoster patients. J Infect Dis 1998;178:S76-S Decroix J, Partsch H, Gonzales R, et al. Factors influencing pain outcome in herpes zoster: An observational study with valacyclovir. Valacyclovir International Zoster Assessment Group (VIZA). J Eur Acad Dermatol Venereol 2000;14: Johnson R. Herpes zoster: Predicting and minimizing the impact of post-herpetic neuralgia. J Antimicrob Chemother 2001;47(suppl T1): Stankus SJ, Dlugopolski M, Packer D. Management of herpes zoster (shingles) and postherpetic neuralgia. Am Fam Physician 2000;61: Tyring S, Barbarash RA, Nablik 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: Bowsher D. The effect of preemptive treatment of postherpetic neuralgia with amitriptyline: A randomized double-blind placebo-controlled trial. J Pain Symptom Manage 1997;13: Wood MJ, Johnson RW, McKendrick MW, et al. 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 1994;330: Whitley RH, Weiss H, Gnann JW, et al. A randomized, placebo-controlled trial of acyclovir with or without steroids for the treatment of herpes zoster. Ann Intern Med 1996;125: Rogers RS III, Tindall JP. Geriatric herpes zoster. J Am Geriatr Soc 1971;19: Max MB, Schafer SC, Culnane M, et al. Amitriptyline but not lorazepam relieves postherpetic neuralgia. Neurology 1988;38: Harding SP, Lipton JR, Wells JCD. Natural history of herpes zoster ophthalmicus: Predictors of postherpetic neuralgia and ocular involvement. Br J Ophthalmol 1987;71: Wu CL, Marsh A, Dworkin RH. The role of sympathetic nerve blocks in herpes zoster and postherpetic neuralgia. Pain 2000;87: Baron R. Peripheral neuropathic pain: from mechanisms to symptoms. Clin J Pain 2000;16:S12-S Bonezzi C, Demartini L. Treatment options in postherpetic neuralgia. Acta Neurol Scand 1999;173(suppl): Attal N, Bouhassira D. Mechanisms of pain in peripheral neuropathy. Acta Neurol Scand 1999:173(suppl): Woolf CJ, Mannion RJ. Neuropathic pain: Etiology, symptoms, mechanisms, and management. Lancet 1999;353: Attal N. Chronic neuropathic pain: Mechanisms and treatment. Clin J Pain 2000;16:S118-S Fukouka T, Tokunaga A, Kondo E, et al. Changes in mrnas for neuropeptides and the GABA (A) receptor in dorsal root ganglion neurons in a rat experimental neuropathic pain model. Pain 1998;78: Feinstein AR. The pre-therapeutic classification of co-morbidity in chronic disease. J Chronic Dis 1970;23: Haythornthwaite JA, Benrud-Larson LM. Psychological aspects of neuropathic pain. Clin J Pain 2000;16:S101-S Schmader KE. Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clin J Pain 2002;18: Morin CM, Gibson D, Wade J. Self-reported sleep and mood disturbance in chronic pain patients. Clin J Pain 1998;14: Smith MT, Perlis ML, Smith MS, et al. Sleep quality and presleep arousal in chronic pain. J Behav Med 2000;23: Atkinson JH Jr, Ingram RE, Kremer EF, Saccuzzo DP. MMPI subgroups and affective disorder in chronic pain patients. J Nerv Ment Dis 1986;174: Stewart MA, Drake F, Winokur G. Depression among medically ill patients. Dis Nerv Syst 1965;26: Davidson J, Krishnan R, France R, Pelton S. Neurovegetative symptoms in chronic pain and depression. J Affect Disord 1985;9: Galer BS, Gianas A, Jensen MP. Painful diabetic polyneuropathy: Epidemiology, pain description, and quality of life. Diabetes Res Clin Pract 2000;47: McQuay H, Moore RA. Pain measurement, study design and validity. In: An Evidence-Based Resource for Pain Relief. London, England: Oxford University Press; 1998: Davies L, Cossins L, Bowsher D, Drummond M. The cost of treatment for post-herpetic neuralgia in the UK. Pharmacoeconomics 1994;6: Ardid D, Guilbaud G. Antinociceptive effects of acute and chronic injections of tricyclic antidepressant drugs in a new model of mononeuropathy in rats. Pain 1992;49: Kanazi GE, Johnson RW, Dworkin RH. Treatment of postherpetic neuralgia: An update. Drugs 2000;59: Watson CPN, Evans RJ. A comparative trial of amitriptyline and zimelidine in post herpetic neuralgia. Pain 1985;23: Watson CPN, Chipman M, Reed K, et al. Amitriptyline versus maprotiline in post herpetic neuralgia: A randomized, double-blind, crossover trial. Pain 1992;48: Rose MA, Kam PC. Gabapentin: Pharmacology and its use in pain management. Anaesthesia 2002;57: Rice AS, Maton S. Gabapentin in postherpetic neuralgia: A randomized, double blind, placebo controlled study. Pain 2001;94: Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: A summary of the fourth Eilat conference (EILAT IV). Epilepsy Res 1999;34(1): Bryans JS, Wustrow DJ. 3-substituted GABA analogs with central nervous system activity: A review. Med Res Rev 1999;19(2): Kinsora JJ Jr, Serpa KA, Snyder BJ, et al. Anxiolytic-like effects of pregabalin. Soc Neurosci Abst 1999;25: Field MJ, Oles RJ, Singh L. Pregabalin may represent a novel class of anxiolytic agents with a broad spectrum of activity. Br J Pharmacol 2001;132: Crofford L, Russell IJ, Mease P, et al. Pregabalin improves pain associated with fibromyalgia syndrome in a multicenter, randomized, placebo-controlled monotherapy trial. Arthritis Rheum 2002;46(9 suppl):s613, abstract Stacey B, Sharma U, Glessner C, et al. Pregabalin is efficacious for relief of painful diabetic neuropathy. Anesthesiology 2003;99:A Dworkin RH, Corbin AE, Young JP Jr, et al. Pregabalin for the treatment of postherpetic neuralgia: A randomized, placebo-controlled trial. Neurology 2003;60: Sabatowski R, Galvez R, Cherry D, et al. Pregabalin reduces pain and improves sleep and mood disturbances in patients with postherpetic neuralgia: Results of a randomized, placebo-controlled clinical trial. Anesthesiology 2003;99:A Hill DR, Sauman-Chauhan N, Woodruff GN, et al. Localization of [3H] gabapentin to a novel site in rat brain: Autoradiographic studies. Eur J Pharmacol 1993;224: Bockbrader HN, Burger P, Miller R, et al. Exposure response relationship of pregabalin: A novel therapy for the treatment of neuropathic pain. Anesthesiology 2003;99:A Kaneko S, Fukuda K, Yada N, et al. Calcium channel inhibition by kappa opioid receptors expressed in Xenopus oocytes. Neuroreport 1994;5: Grudt TJ, Williams JT. Kappa-opioid receptors also increase potassium conductance. Proc Natl Acad Sci USA 1993;90: Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: A randomized trial in postherpetic neuralgia. Neurology 1998;50: Raja SN, Haythornthwaite JA, Pappagallo M, et al. Opioids versus antidepressants in postherpetic neuralgia: A randomized, placebo-controlled trial. Neurology 2002;59: Rowbotham MC, Davies PS, Verkempinck C, et al. Lidocaine patch: Double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain 1996;65: Argoff CE. New analgesics for neuropathic pain: The lidocaine patch. Clin J Pain 2000;16(2 suppl):s62-s A Clinical Guide to Neuropathic Pain. Galer BS, Dworkin RH, eds. Minneapolis, MN: McGraw-Hill Healthcare Information; 2000: 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: Postherpetic Neuralgia in the Elderly APRIL 2004

11 CME/CE Examination & Evaluation Postherpetic Neuralgia in the Elderly To receive credit, participants must complete the following CME/CE Examination and Evaluation and fax or mail to: Medical Education Resources 1500 West Canal Court Littleton, CO Fax: A minimum score of 70% on the CME/CE Examination is required for credit. A certificate of completion will be mailed within 3 weeks of receipt of the completed answer sheet. Program expiration is April CME/CE EXAMINATION Please circle the correct answer. 1. Patients of advanced age are more likely to develop herpes. Their risk of being hospitalized compared to children has been quoted to be as high as: a. 2 times more likely b. 5 times more likely c. 12 times more likely d. 25 times more likely 2. Neurological complications of acute herpes do not include which of the following: a. Peripheral motor weakness b. Vertigo c. Meningitis d. Cerebral angitis 3. Goals of antiviral therapy started within 72 hours of an acute herpes zoster rash include: a. Accelerate healing of cutaneous lesions b. Reduce severity of acute neuritis c. Reduce duration of chronic pain d. All of the above 4. The neuropathic pain of PHN is likely to be caused by the following mechanisms: a. Peripheral sensitization b. Central sensitization c. Alpha beta reorganization d. All of the above e. None of the above 5. The pain associated with PHN is described as: a. Radiating, burning, shooting, stabbing, or tingling b. Worse at night c. Always accompanied by allodynia or hyperalgesia d. All of the above 6. Comorbid medical conditions commonly associated with chronic pain conditions include all of the following except: a. Sleep disturbance b. Substance abuse c. Depression d. Anxiety 7. Gabapentin is the only oral agent currently approved for the treatment of PHN. a. True b. False 8. Which of following therapies is FDA-approved for the treatment of PHN? a. Nerve blocks b. Topical capsaicin c. Topical lidocaine 5% d. IM hydrocortisone 9. Which statement(s) is/are false? a. Gabapentin is contraindicated in patients with renal insufficiency. b. Only gabapentin and the lidocaine patch 5% are approved by the FDA for the treatment of PHN. c. Tricyclic antidepressants are considered first-line therapy for PHN. d. Both a and c 10. In patients with neuropathic pain, TCAs a. Have the potential for adverse events in the elderly and should be used carefully b. Inhibit the reuptake of norepinephrine and serotonin c. May work as sodium channel blockers d. All of the above CME/CE EVALUATION Using a scale from 1 to 5, with 5 = excellent, 4 = very good, 3 = adequate, 2 = fair, 1 = poor, please circle the number corresponding to your rating of the following: Excellent Poor 1. Overall quality of the material Clinical applicability or relevance of the material to participants practice Extent to which the material met stated objectives Extent to which participant will modify his/her practice as a result of participation in the program Fair balance and objectivity of the material Completion time Additional Comments: Please provide the following information (please print) in order to receive your CME/CE certificate: Name: Degree: Institution/Affiliation: Address: City: State: Zip code: Telephone: Fax: Signature: I certify that I have completed this activity as designed.

12 This special report was sponsored by Medical Education Resources and produced by MultiMedia HealthCare/Freedom, LLC, under an unrestricted educational grant from Pfizer, Inc. The views expressed in this publication are not necessarily those of Medical Education Resources, Pfizer, Inc., or the publishers. This publication may not be reproduced in whole or in part without the express written permission of MultiMedia HealthCare/Freedom, LLC. Copyright 2004 MultiMedia HealthCare/Freedom, LLC. All rights reserved. Printed in USA. PFI-03605