Evidence-Based Treatment of Herpes Zoster and Postherpetic Neuralgia

Transcription

1 2004 Volume 1, Issue 1 FROM GRAND ROUNDS AND OTHER CLINICAL CONFERENCES OF THE MGH PAIN CENTER, MASSACHUSETTS GENERAL HOSPITAL Evidence-Based Treatment of Herpes Zoster and Postherpetic Neuralgia By ANNE LOUISE OAKLANDER, M.D., PH.D. MGH 1811 MASSACHUSETTS GENERAL HOSPITAL Shingles (herpes zoster) and its chronically painful sequel, postherpetic neuralgia (PHN), occupy an important position among neuropathic pain syndromes. This is because shingles is the most common potentially neuropathic disease, affecting an estimated 20% of the American population, most of whom are otherwise healthy people. Because shingles and PHN are easily diagnosed and free of legal implications, they are the major target for research into mechanisms and treatment of neuropathic pain. Virtually all new medications for neuropathic pain undergo a clinical trial by PHN patients and most insights gained from studying PHN are applicable to other types of neuropathic pain syndromes. ACUTE SHINGLES (HERPES ZOSTER) Herpes zoster represents the focal recrudescence of the varicella-zoster virus (VZV) that has been dormant in sensory ganglia since an episode of chickenpox (varicella) acquired decades before during childhood. 1 Shingles has the highest incidence of all the neurological diseases, with approximately 500,000 new cases yearly in the United States. 2 One-quarter of all Americans will contract shingles at some point. 3 PHN has been estimated to affect 1 million Americans. 4 Shingles most commonly appears as a unilateral painful rash primarily within a single dermatome. The most common location is thoracic, followed by the first trigeminal division on the upper face. 5 However, shingles and subsequent PHN can affect any area of the body and even the less common presentations of this prevalent disease are not rare. The major risk factor for herpes zoster has been shown to be simply living, ie, the older the person, the greater the risk of developing herpes zoster, especially after age 40 when immunocompetence declines. 6 However, cases in young adults and children do arise. Other risk factors include immunosuppression, either from disease or medication (eg, corticosteroids such as prednisone). 7 The majority of shingles patients are otherwise healthy older individuals. Treatment The most important treatment for acute zoster is the administration of antiviral medications as early as possible. These medications interact with viral, but not eukaryotic DNA, and have virtually no side effects when taken orally. 8 However, they have proven efficacy in reducing shingles lesions, pain, and the risk of subsequent PHN. 9 Several analyses have documented a 50% reduction in PHN after treatment with any of the 3 antiviral medications that are currently commercially available in the United States: acyclovir, valacyclovir, or famciclovir. 10 Antiviral treatment should be initiated and continued for as long as new lesions are forming. Because of the outstandingly high benefit-to-harm ratio of antivirals, their administration should be considered even in cases where a diagnosis of zoster is uncertain or when the disease is in its earliest stages and pain and paresthesias appear prior to rash onset (preherpetic neuralgia). There is preliminary evidence for a second disease-modifying treatment that may reduce the risk of PHN after shingles. Bowsher s group has shown that administration of tricyclic antidepressants (TCAs), even in low doses during the first few months after acute shingles, may independently halve the risk of later PHN. 11,12 Occasionally, patients with acute zoster will need other treatments for managing secondary infections and scarring, particularly after shingles affecting the eye. 13 All patients with zoster in, or near, MGH PAIN CENTER Jane C. Ballantyne, M.D. Director, MGH Pain Center Editor, Pain Management Rounds Martin Acquadro, M.D., D.M.D. Director of Cancer Pain Service Shihab Ahmed, M.D., M.P.H. Medical Director, MGH Pain Clinic Steve Barna, M.D. Gary Brenner, M.D., Ph.D. Director, Pain Medicine Fellowship Lucy Chen, M.D. Katharine Fleischmann, M.D. Director, Acute Pain Service Jatinder Gill, M.D. Asi Hacobian, M.D. Karla Hayes, M.D. Eugenia-Daniela Hord, M.D. Nathaniel P. Katz, M.D. Director, Opioid Research Center Ronald Kulich, Ph.D. Jianren Mao, M.D., Ph.D. Anne Louise Oaklander, M.D., Ph.D. Director, Nerve Injury Unit Director, Center for Shingles and Postherpetic Neuralgia Gary Polykoff, M.D. Jan Slezak, M.D. Milan Stojanovic, M.D. Director, Interventional Pain Management MGH PAIN CENTER 15 Parkman Street, Suite 324 Boston, MA Fax : The editorial content of Pain Management Rounds is determined solely by the MGH Pain Center, Massachusetts General Hospital. Pain Management Rounds is approved by the Harvard Medical School Department of Continuing Education to offer continuing education credit

2 the eye need urgent ophthalmologic evaluation as specific treatment may be needed to reduce the risk of visual loss. Pain management during zoster conforms to known principles for management of acute pain. The majority of patients can be effectively managed as outpatients. Many will need opioid medications. The role of anti-inflammatories, both for pain management and for potential reduction of immune-mediated neural damage, has not yet been defined. Corticosteroids have not been convincingly shown to reduce PHN, 14 although they are standard treatment for zoster corneal keratitis. 13 Rare patients will need hospitalization for more intensive pain management such as patient-controlled intravenous analgesia or placement of thoracic epidural catheters. Since zoster affects somatic, but not sympathetic neurons, there is no rationale for the use of sympathetic ganglion blocks. It has not yet been established whether use of somatic blocks has protective benefits, 15 but given that the neural injury and inflammation of acute shingles can last up to 3 or 4 weeks, blockade would probably need to be sustained to have a long-term effect. A major change in the epidemiology of VZV diseases has been the widespread use of an attenuated live vaccine to prevent varicella in children. Although in the long-run, shingles should become less common because the attenuated vaccine is less likely to reactivate, a marked increase in the incidence of zoster (and PHN) has been forecast for the next 50 years due to fewer exposures to children with chickenpox, a factor that reboosts immunity and delays onset of zoster in adults. 16 POSTHERPETIC NEURALGIA PHN can be loosely defined as pain in the area of the shingles rash that persists after the resolution of acute lesions. A more precise definition namely, pain still present 3 or more months after the onset of shingles is the definition recommended by a consensus of shingles experts to facilitate study comparisons. Age is also the major risk factor for PHN after shingles, independent of its effects on other risk factors for acquiring shingles. 17 The biological explanation for this has not been elucidated, but may have implications for understanding pain mechanisms in general. Zoster in middle-aged and older patients comprises a neurologic emergency similar to acute stroke and optimal medical treatment is mandatory to minimize the risk of PHN. In rare cases, patients may have serious complications due to vascular involvement affecting the brain or spinal cord. 18 Additional epidemiologic risk factors for PHN after shingles are related to the severity of the shingles attack (ie, more lesions present, greater acute pain severity, etc.). 19 These are likely to be surrogate measures for estimating the severity of neuronal damage. Diagnosis of PHN is obvious in a patient with a history of previous zoster in the same dermatome as their chronic pain. Most, but not all, PHN patients have persisting scars that will provide objective evidence of the diagnosis. However, the diagnosis can be challenging if the rash is subtle or not noticed by either the patient or the physician, or if it is zoster sine herpete (zoster without rash). 20 Occasionally, the PHN is tardive and appears after a pain-free interval. If there is a question about whether a neuralgia represents PHN, a radiological examination should be performed to ensure that other conditions (eg, tumors compressing nerve roots) that require intervention are not missed. PHN patients typically experience the usual symptoms of neuralgia or neuropathic pain, including stimulus-independent or ongoing pain that is independent of activity. Typically, patients notice this more at night when their attention is not diverted by activity. Nocturnal exacerbation is helpful in differentiating neuropathic pain from orthopedic or inflammatory pain, which usually worsens with activity and improves with rest at night. Many PHN patients also report tactile or mechanical allodynia, where light touch even by clothing is painful. Although they are not always able to put it into words, patients who appear with unusual clothing (eg, without a bra or belt or with bandages under their clothes to shield their skin) clearly have tactile allodynia. A substantial minority of patients also complain of lancinating pains, (ie, brief jolts of severe pain). These are near pathognomonic for neuralgias. Motor symptoms are not a major problem primarily because the most commonly affected dermatomes do not have major motor functions. However, patients with shingles involving the arms or legs may develop muscle atrophy, weakness, and loss of deep tendon reflexes. Because zoster exclusively affects the sensory ganglia, such motor damage usually represents nonspecific bystander damage due to severe inflammation within zoster-affected nerve roots or nerves. 21 Autonomic symptoms are rare and not usually of clinical significance. In rare cases, patients have visceral involvement, eg, pleural or bone pain, or a neurogenic bladder or rectum. TREATMENT OF ESTABLISHED PHN Nonpharmacologic treatments are of little benefit in PHN and other neuralgias. The substrate for recovery appears to be regeneration of damaged axons, and this has not been shown to be influenced by psychological therapy, physical therapy or exercise, acupuncture, 22 or other modes of nonmedical treatment. However, nonmedical treatments can help treat the secondary problems associated with PHN and other chronic pain syndromes (eg, inactivity, depression, and disuse) and so, these are often prescribed as well. There are no surgical therapies with established efficacy, although many have been tried. An excellent overview of attempted surgical therapies for PHN (by Dr. John Loeser of the University of Washington in Seattle) is available on the website of the MGH Center for Shingles and PHN ( mgh.harvard.edu). For most patients, medications will be the main treatment. It is important for the clinician to rely on the 4 classes of medications that have documented efficacy and safety in randomized clinical trials (RCT) for PHN patients. A summary of these will follow. Although the vast majority of RCTs involve comparison against placebo, the ability to compare different treatment options is important and the concept of number needed to treat (NNT) allows at least a rudimentary comparison of the

3 TABLE 1: The 4 classes of medications with documented efficacy and safety for postherpetic neuralgia 51 Name Starting Starting Dosing Increase Target dose Possible adverse Relative dose dose interval by one pill (to assess effects contraindications (older pts) (younger pts) efficacy) Tricyclics Nortriptyline 10 mg in pm 25 mg in pm Once daily Dry eyes, mouth, Use of MAO vagina; constipation; inhibitors, recent Once or 75 mg cognitive changes; MI, epilepsy, twice weekly, once daily sedation; orthostatic urinary retention, as tolerated hypotension; narrow-angle tachycardia; glaucoma, heart Desipramine 10 mg in am 25 mg in am Once daily urinary retention; block, hypotension blurred vision Anti- Gabapentin 100 mg 300 mg Every 8 hr Every mg Sedation, ataxia, Lower dose if renal epileptics (or 6 if 1-2 days, q 8 hr peripheral edema function impaired high doses as tolerated needed) Carbamaze- 100 mg 200 mg Every 12 hr Twice weekly, mg Ataxia, sedation, Marrow supprespine twice daily twice daily (extended as tolerated daily nausea, rare cases of sion, use of MAO (extended release) bone marrow, liver, inhibitors, oral release) cutaneous reactions contraceptives, warfarin Opioids Tramadol As little as 1 tab Every 4-6 hr, Twice weekly, 3-4 tabs daily Ataxia, nausea, Epilepsy, use of 1 /4 tab (50 mg only) if needed as tolerated (in elderly) constipation, sedation MAO inhibitors, (50 mg only) cirrhosis Oxycodone 10 mg (lowest 10 mg Every 12 hr mg (extended dose avail); (extended q 12 hr Sedation, nausea, release) use immediate release) Use lowest release for itching (usually History of lower dose effective dose Morphine 15 mg (lowest 15 mg Every 12 hr 15 mg resolves with substance (extended dose avail.); (extended to minimize q 12 hr release) use immediate release); continued use), abuse release for also available tolerance and lower dose in once-every constipation 24-hour adverse effects formulation (indefinite) Methadone As little as 1 /4 5 mg Every 12 or 10 mg (5 mg) tab 24 hr q 12 hr Topical Lidocaine 1 3 every 24 hr Every 24 hr local 5% patch (can be worn hr) Not Use for Open skin lesions, anesthetic Local Apply as needed under As needed applicable 1 week Local skin irritation allergic reaction anesthetic plastic wrap cream, gel, ointment MI = myocardial infarction; MAO = monoamine oxidase efficacy of separate high-quality RCTs. NNT is defined as the inverse of the difference between the proportion of patients improved by placebo (control group event rate or CER) and the proportion of those improved by treatment (experimental group event rate or EER). Thus NNT = 1/[CER EER]. The lower the NNT, the more efficacious the therapy. An NNT of 1 means that only 1 patient needs to be treated to get 1 patient with pain relief, usually defined as a 50% reduction in visual analogue scale (VAS) pain scores. Some of the NNT values for analgesics studied in placebo-controlled trials of PHN are 2.3 for tricyclics, 3.2 for gabapentin, and 2.5 for oxycodone, meaning 30%-40% of patients will have 50% or more pain relief from any 1 medication. Often patients must try several of the efficacious medications to find the one that offers them the best result. The 4 classes of medications with documented efficacy and safety for PHN are topical local anesthetics, tricyclic antidepressants (TCAs) with noradrenergic activity, medications originally marketed as antiepileptic drugs (AED), and opioids (Table 1). Since there is no single treatment that outstandingly surpasses the others, therapeutic decisions must consider the patient s symptoms, age, circumstances, and other medical history. It is important to get a detailed history of exactly which medications have been tried to date, their efficacy, dosage use, and any side effects, in order to ensure that all of the major treatment options have been considered. Topical local anesthetics Topical treatments deserve first mention because of their excellent safety profile. These are medications that are administered to the skin and remain in the skin, where they exert their

4 effects. They must be distinguished from transdermal systemic medications, such as fentanyl or estrogen patches that use cutaneous routes for systemic administration. Topical capsaicin was one of the earliest available treatments for PHN, and is available over-the-counter in the U.S., but its efficacy is low, (NNT = 5.9), and it has low tolerability because of burning pain upon application. 23 Its primary use today is as a research tool for psychophysical studies. Topical local anesthetics have a much better track record. They are available in several forms, including viscous lidocaine, local anesthetic gels, creams, and sprays, but the 5% lidocaine patch is the most popular (though expensive) route of administration. 24 Viscous lidocaine dripped into the external ear canal helps some patients with aural PHN after Ramsay Hunt syndrome. The beneficial effects of the Lidoderm patch come from both design, which protects allodynic skin from contact, as well as the active ingredient, which is 5% lidocaine. 25 The beneficial effects extend to ongoing and lancinating pain as well as allodynia. 26 The NNT for the Lidoderm patch has been reported to be 4.4 for overall pain, and 8.4 for allodynia. 27 Although efficacy is due to cutaneous neural blockade, the class of neurons that is affected by blockade remains undefined. By definition, such neurons must be low-threshold mechanoreceptors, but the location where they stimulate central nociceptive neurons has not been determined. Tricyclic antidepressants (TCAs) TCAs are a mainstay for treating PHN and are arguably the treatment of choice for young healthy patients or those with limited funds for medications. TCAs have several modes of action, those important for efficacy against neuropathic pain potentiate the noradrenergic descending inhibitory pathway (decreasing dorsal horn hyperactivity), mu opioid activity, and cation channel blockade. 28 TCAs have been well-evaluated in several double-blind placebo-controlled trials in PHN patients, with confirmed efficacy for amitriptyline, nortriptyline, and desipramine The advantages of TCAs include experience due to decades of clinical use and low cost due to generic availability. An additional reason for using them is their potential disease-modifying activity when used during shingles healing. 34 Tricyclics may also help with the depression that can accompany PHN and other chronic pain syndromes. However, the use of tricyclics is limited by their adverse events. These are far greater for amitriptyline, a tertiary amine with serotonergic as well as adrenergic potentiation, than for the secondary adrenergic-specific amines nortriptyline 32 or desipramine; 31 thus, amitriptyline is not a first-line treatment option. It is contraindicated for use in patients >65 years by the American Geriatrics Society 35 and the U.S. General Accounting Office. 36 The most common adverse events of TCAs are generally cholinergic, including, cognitive changes (eg, sedation, constipation, blurred vision, dry mouth and eyes), orthostatic hypotension, sexual dysfunction, urinary retention, and prolongation of the cardiac Q-T interval. Desipramine has alerting and arousing cognitive effects in some patients that make it an option for combating medication-induced sedation. Serotonin-specific reuptake inhibitors, modafinil, 37 and methylphenidate may be considered for that purpose as well. Narrow-angle glaucoma and cardiac dysrhythmia are relative contraindications to the use of tricyclics; therefore, physicians treating these conditions should be consulted prior to initiating treatment for PHN. Antiepileptic drugs (AED) AEDs decrease neuronal hyperexcitability, often making them efficacious against neuropathic pain caused by hyperactive pain-processing neurons. Gabapentin was the AED that popularized these crossover benefits, but 2 older anticonvulsants can be considered as second-line treatment for PHN. These are carbamazepine, 38 which is FDA approved for the treatment of trigeminal neuralgia, and phenytoin. 39 Gabapentin has been well-evaluated for PHN in at least 3 multicenter randomized clinical trials Gabapentin binds to a subunit of the calcium channel, decreasing calcium-mediated synthesis and release of excitatory neurotransmitters. 43 Gabapentin will be expensive for patients until the upcoming expiration of patent protection. A chemical analogue, pregabalin, with similar efficacy against PHN 44 but a longer half-life permitting twice daily dosing, is expected to come on the market in the U.S. in Gabapentin has no drug-drug interaction and serious adverse effects are rare. The most common side effects are sedation and other cognitive side effects, and ataxia. Rare patients develop peripheral edema. Gabapentin has a short half-life and so must be administered every 6 to 8 hours. A typical dosage for PHN is approximately 3,600 mg daily, although lower and higher dosages may be optimal for selected individuals. Gabapentin is renally excreted, making it useful in patients with hepatic dysfunction. The dosage must be reduced in patients with significantly elevated creatinine clearance, but levels do not need to be monitored in most circumstances. Oxcarbazepine is a recently marketed chemical analogue of carbamazepine that lacks carbamazepine s rare, but potentially serious, side effects (hepatotoxicity, bone marrow suppression). There is preliminary evidence for efficacy against neuropathic pain and trials are under way. 45,46 Other new anticonvulsants are also being tested for efficacy against PHN; results of 3 unpublished trials of topiramate are reportedly negative. Opioids Several opioid medications have been evaluated in well-designed trials and their safety and efficacy are well-

5 established in PHN. Although opioids are not usually a first-line treatment option, they come to the fore in geriatric patients who comprise the majority of PHN sufferers. This is because geriatric patients have a lower tolerance for tricyclics and there is a low risk of de-novo abuse in older patients with no previous history. Although cognitive side effects may be more common in elderly patients, a recent randomized, double-blind, crossover trial comparing opioids and tricyclics for PHN reported slightly greater efficacy, no cognitive side-effects, and better patient preference with opioids (54%) than with TCAs (30%). 33 Most PHN patients will need a long-acting opioid (eg, controlled-release oxycodone); 47 however, patients with cognitive side-effects may do better with a short-acting opioid that can be used only as needed. Tramadol is a mild opioid agonist useful for inititiating opioid therapy. 48 Methadone 33 stands out among long-lasting opioids, both for theoretical reasons and because of its unusually low cost, which can be less than $1 per day. It is particularly useful in geriatric patients because it is produced in a very low-strength pill, 5 mg, which can be halved or quartered, to permit very low doses. Miscellaneous Local anesthetic blockage has no role in the treatment of established PHN. Although it can transiently relieve PHN pain, these procedures have complications and there is no evidence of long-term or disease-modifying effects to justify these risks. A single group found intrathecal steroid administration beneficial for established PHN. 49 Unfortunately, the methods used in this study are not easily duplicated since there is no commercially available form of methylprednisolone for intrathecal administration in the U.S. Intrathecal administration of local anesthetics, also performed in this study, may cause hypotension. Therefore, these results should be viewed as preliminary until otherwise confirmed. A single uncontrolled study supports the use of spinal cord stimulation for PHN. There are theoretical reasons to expect efficacy and further trials are indicated. A single study of dextromethorphan, an NMDA-antagonist, was not efficacious in PHN. 50 In summary, most patients with PHN will be able to find a medical treatment option that improves their pain and quality of life. Research on shingles and PHN has been pivotal in establishing treatment options useful for other forms of neuropathic pain. 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Abstract of Interest Result of an open-label, prospective trial of oxcarbazepine monotherapy in post-herpetic neuralgia C RISCUOLO, S, SIENA, ITALY Oxcarbazepine is a new anticonvulsant drug whose clinical efficacy in several neuropathic pain conditions (trigeminal neuralgia, painful diabetic neuropathy, etc.) is being investigated. Preliminary data do suggest that oxcarbazepine is efficacious and well tolerated for the treatment of neuropathic pain. To our best knowledge, no data have been published so far in the literature regarding the efficacy and tolerability of oxcarbazepine for the treatment of postherpetic neuralgia. The aim of this open label study has been to assess the efficacy and tolerability of oxcarbazepine monotherapy in postherpetic neuralgia. 24 subjects (12 males,12 females; mean age 71±11.72 years) affected by postherpetic neuralgia participated in the study. All subjects failed previous treatment with carbamazepine and gabapentin. Subjects had a history of severe pain and allodynia for at least 8 weeks. Treatment was started at 150 mg/day and gradually increased every 2 days by 150 mg till the maintenance dosage of 900 mg/day. Treatment duration was 8 weeks. Pain was evaluated by Visual Analog Pain Scale (VAS) at baseline, weekly for the first two weeks of treatment and then every 2 weeks. A complete neurological examination of subjects with determination of the allodynic area was performed at the same time as the VAS. Adverse events were collected. 19/24 (79%) subjects completed the study. 5 (21%) subjects discontinued treatment due to lack of efficacy during the titration period (3 subjects) or due to adverse events like dizziness, nausea and sedation (2 subiects), which promptly remitted after drug discontinuation. VAS mean score significantly decreased from baseline (±5.33, paired t-test: p<0.0001, see Fig.1). Furthermore, oxcarbazepine treatment was effective from the first week of treatment. Allodynia almost completely disappeared in all subjects and this effect significantly improved their functionality and quality of life. Subject treatment satisfaction was rated as very good by 50% of subjects, good by 29% of subjects and not applicable for 21% of subjects who discontinued treatment. No adverse effects have been reported by the 19 subjects who completed the study. A poster presentation at the American Pain Society 22nd Annual Scientific Meeting; Chicago C14-Postherpetic Neuralgia, Poster #711 Upcoming Scientific Meetings July 2004 Comprehensive Interventional Pain Management Cadaver Course The Society for Pain Practice Management Cambridge, MA CONTACT: Tel Website: September 2004 The American Academy of Pain Management 15 th Annual Clinical Meeting San Antonio, TX CONTACT: Joy McCurry Tel Website: This publication is made possible by an educational grant from Pfizer, Inc The MGH Pain Center, Massachusetts General Hospital, which is solely responsible for the contents. 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