13

with acute herpes zoster, but it may affectas many as 90% of patients withPHN.10,13,17 In addition to having paincharacterized as aching, burning or boring,patients with PHN frequently experienceother sensory abnormalities, such as dyses-thesia, hyperalgesia and hyperesthesia.These uncomfortable sensations can also be spontaneous or evoked, and continuousor paroxysmal.18

Haanpaa et al16 evaluated the prognos-tic value of certain types of paresthesias as-sociated with herpes zoster, concluding thatmechanical allodynia and pinprick hypes-thesia were both strongly associated withthe development of PHN. However, theauthors cautioned that this associationcould not be used as a predictive rule for in-dividual patients.16 The severity and dura-tion of PHN represent the true burden ofherpes zoster, because the pain and pares-thesia of this condition can be so onerousas to make such routine daily tasks asbathing and dressing extremely difficult oreven impossible.

Appropriate treatment of patients with

120 days after the onset of rash.8 A recentstudy of 94 patients showed that 50% ofpatients with shingles reported at least somepain persisting for three months, and 32%of patients continued to report pain at sixmonths.14

Postherpetic neuralgia is difficult—ifnot impossible—to prevent once herpeszoster infection is manifested, because thenerve damage caused by VZV reactivationoccurs before the rash is evident.2 Just as theincidence of herpes zoster infection increas-es with advancing age, the risk for PHNlikewise increases with age.8 As noted byBennett,15 if neuropathic low back pain isincluded, PHN cases would rank third inprevalence behind low back pain andpainful diabetic peripheral neuropathy.

The pain of PHN may be spontaneous(ie, with no apparent cause) or evoked, andit may be continuous or intermittent. Acharacteristic feature of PHN is allodynia,which is pain that is provoked by innocu-ous or normally nonpainful stimuli, suchas a slight breeze.6,16 Allodynia is present in approximately 45% to 55% of patients

By Katherine E. Galluzzi, DO, CMD

The time-honored adage that prevention isbetter than cure, as with all infectious dis-eases, is certainly true for herpes zoster.Commonly known as shingles, herpeszoster is caused by reactivation of the vari-cella-zoster virus (VZV) after a period of la-tency following the primary infection ofvaricella (ie, chickenpox).1 The varicella-zoster virus remains dormant in dorsal rootganglia of the host during this latent peri-od, which may last decades.

In 1965, R. Edgar Hope-Simpson,MD,2 recognized that as the human hostof VZV ages, a gradual waning of cell-me-diated immunity occurs. When the level ofcell-mediated immunity drops below a crit-ical threshold, VZV reemerges to cause aprodrome of tingling, burning, or itchingpain that heralds the appearance of the red,vesicular, dermatomal rash of shingles.3

Herpes zoster infection develops in ap-proximately one million people in theUnited States every year,4-7 with approxi-mately 40% to 50% of these cases occur-ring in the rapidly growing segment of thepopulation older than age 60 years.5 Morethan 90% of adults are susceptible to her-pes zoster, but there is no way to predict inwhom the disease will develop.8,9 Of thoseindividuals who reach age 85 years, approx-imately 50% will have had herpes zoster,6,10

and the lifetime risk of zoster is close to30%.6,11

The acute pain of herpes zoster infec-tion has substantial effects on the lives ofpatients, resulting in reduced physical func-tioning, increased emotional distress, anddecreased social functioning.10,12 Evenmore debilitating than the acute pain of shingles is the persistent pain known as postherpetic neuralgia (PHN),4,8,10,13

which is variously defined as pain that per-sists after the blistering rash of shingles hashealed or as pain and discomfort that eitherpersists or appears more than 90 to

13

Case report:Tackling challenges of postherpetic neuralgia

PHN is fraught with difficulty, requiringtrials of different pharmacologic agents aswell as cautious titration to avoid adverseeffects of the drugs. Medications typicallyused for management of pain—such asacetaminophen, narcotic and non-narcot-ic analgesics, nonsteriodal anti-inflamma-tory drugs (NSAIDs), and topical agents—may have limited efficacy in managingPHN pain.19,20 Because current treatmentstrategies for patients with PHN are onlypartially effective, consultation with a pain-management specialist may be necessary.8

Consider the following case, which il-lustrates diagnostic and treatment difficul-ties often seen with herpes zoster and PHN.In this case, various pharmacologic strate-gies are evaluated, and the importance ofvaccination is highlighted.

Case presentationMarion Powers is a generally healthy, pleas-ant and fit 67-year-old woman who is thesole guardian of her two young grand-daughters. She was seen by her primarycare physician for pain and tingling on theright side of her face, extending from thelateral margin of her eyebrow to her fore-head and scalp. This unpleasant sensationhad been present for two days before shesaw the physician. She also told the physi-cian that her right eye had been “twitch-ing,” but she denied having visual loss orpain in the eye itself.

The physician thoroughly examinedMarion but was unable to find any obviouscause for her discomfort, though a slighteye tic was noted. Since the patient’s report-ed pain was distributed along the right tem-poral artery, the physician was concernedthat the pain might represent temporal ar-teritis. The physician ordered tests for com-plete blood count and erythrocyte sedi-mentation rate, and she referred Marion toa surgeon for temporal artery biopsy at thenext available appointment, which was inthree days. Marion was also given a pre-scription for high-dose prednisone with ataper, and she was instructed to phone thephysician immediately if she experiencedany changes in vision.

Two days later, a visibly upset Marionreturned to the physician’s office with her

granddaughters in tow. She said she hadawoken that morning with a terriblypainful rash on the right side of her fore-head (which fortunately spared her eye).She had immediately realized that the rashwas shingles and rushed to the office to obtain treatment.

The physician, upon seeing evidence ofherpes zoster infection, was apologetic. Thesurgical consult was cancelled. Marion was told to finish the steroid taper and was given a one-week prescription for the antiviral medication valacyclovir hy-drochloride, along with directions for gen-tle cleansing and drying of the lesions. Shewas also given a prescription for tramadolhydrochloride (50 mg every eight hours)for pain. Medications prescribed for herpeszoster in the current case are:y High-dose prednisone with tapery Valacyclovir hydrochloride

(for one week)y Tramadol hydrochloride

(50 mg every eight hours, refillable).At Marion’s next visit to the office, later

that month, her shingles vesicles were crust-ed and drying, and the erythema and in-flammation were almost gone. Postinflam-matory hyperpigmentation, with minimalscarring, remained on her face.

Marion said that the tramadol had less-ened the burning pain and tingling on herface and scalp, but she complained thatlight touch—even something as soft as abreeze from the window—seemed to causesearing pain. Her physician explained thatthis phenomenon, called allodynia, wascommon with shingles, and she noted thatit should resolve over time. The physicianthen gave her a refillable prescription forthe tramadol.

Three months later, Marion returned tothe physician’s office. She had lost 7.3 kilo-grams (16 pounds) since her previous visitand was visibly distressed. Marion com-plained of excruciating pain across her scalpand forehead that was much worse than thetingling, burning pain that had precededand accompanied the healing of the rash.She described the new pain as the suddenjolting sensation of a “hot poker beingjabbed into my cheekbone,” with result-ing searing, electric shock-like feelings run-

ning up her forehead and scalp. She indi-cated that an area of pain much larger thanhad been occupied by the rash extendedfrom the top of her head to behind her earand into her neck.

Having run out of tramadol, Marionsaid she had been taking over-the-counteribuprofen and acetaminophen with codeine,which a friend had given her. Since she re-membered that the tramadol had made herfeel drowsy and “out of it” she decided notto seek another prescription. She said shewas also applying ice packs to the affectedarea several times daily. She reported thatshe had obtained only minimal relief fromthese measures.

Marion told the physician that it wasnearly impossible to perform her routinedaily tasks, which included getting hergranddaughters ready for school, meetingthe girls after school for the walk home,preparing their meals, doing laundry andcleaning house, shopping, and paying bills.She confessed that she had been in so muchpain that she had been unable to help thegirls with their homework or to enjoy theirnightly ritual of watching a favorite televi-sion program together.

During the office visit, Marion brokedown, crying, “I can’t go on with this pain!I have to be able to provide for my grand-daughters. I’m all they’ve got! It’s hardenough keeping up with them when I amfeeling well, but this is the worst pain I’veever had. Oh, why didn’t you just give methe medicine for shingles when I saw youthe first time? At least then I might nothave gotten that horrible rash and this pain.Now, you’ve got to help me with this pain.Please, please help me!”

Marion was experiencing the dreadedconsequence of herpes zoster infection—PHN. Her description of piercing, burn-ing pain is the classic description of neuropathic pain, which is the clinicalmanifestation of destruction of nerve cellbodies by VZV. Because PHN involves thedestruction of both spinal cord and periph-eral nerves,2,3 the pain that is experiencedis much greater than the apparent injury,and the affected area is more widespreadthan that occupied by the rash.21

Marion was correct in identifying the

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scribed the lidocaine patch 5%, to be ap-plied to the temporal area every eighthours. Three days later, however, Marionbrought a half-empty box of the patches tothe office stating, “Please show me how youexpect me to go out in public with this bigpatch covering the side of my face!”

The physician, realizing that the patchtherapy was indeed impractical, prescribedduloxetine hydrochloride (20 mg daily)and recommended that Marion obtainover-the-counter capsaicin cream and apply

it sparingly to the affected area two or threetimes daily as needed. Medications pre-scribed for PHN in the current case are:y Oxycodone hydrochloride (5 mg,

one or two tablets every six hours, as needed)

y Pregabalin (50 mg twice daily, titratedto three times daily)

y Lidocaine patch 5% (applied to temporal area every eight hours)

y Duloxetine hydrochloride (20 mg daily)

y Capsaicin creamAt the following office visit, one month

later, Marion stated that her pain had fur-ther diminished with the two new medica-tions (pregabalin and duloxetine), but thecapsaicin cream caused redness and sting-ing. She reported that she was using theoxycodone less than twice daily, usually atnight to help her sleep. Rating her pain as4 on the NPIS, she thanked the physicianfor helping her get to a point where she was“more like myself again.”

DiscussionMarion’s case illustrates the inherent diffi-culty in diagnosing herpes zoster, which haspresenting complaints that can mimic nu-merous other diseases. In Marion’s case,temporal arteritis was believed to be amajor concern. Incipient shingles has been

More than 90% of adults aresusceptible to herpes zoster,but there is no way to predictin whom the disease will develop.

origin of her pain as shingles, but she wasmistaken about the potential for antiviralmedications to have aborted or reduced thedevelopment of PHN. Although corticos-teroids have been shown to produce mod-est improvements in rash healing and acutepain,22,23 neither antiviral medications norsteroids have been shown to preventPHN.24,25 Marion’s painful conditionmight have been avoided had she receivedherpes zoster immunization, but the clinical goal at the time of her presentationwas to provide support, reassurance and as much pain relief as possible so that Marion could continue to perform her im-portant activities of daily living. Marion’sphysician asked her to rate her pain on the11-point Numeric Pain Intensity Scale(NPIS), which ranges from 0 to 10, with 0representing no pain and 10 representingthe worst pain experienced by the individ-ual.21 Marion rated her pain as 9, reiterat-ing that the pain was so debilitating that shewas unable to function. The physicianwrote her a prescription for oxycodone hy-drochloride (5 mg, one or two tablets everysix hours, as needed for pain) and instruct-ed her to return to the office in one week.

Three days later, Marion phoned the of-fice to report that the medication relievedthe pain, but she experienced nausea andsedation when she increased the dose totwo tablets. She requested a drug for painthat had fewer adverse effects. The physi-cian called in a prescription for pregabalin(50 mg twice daily, titrated to three timesdaily) and instructed Marion to continuetaking oxycodone as needed for break-through pain.

Two weeks later, Marion rated her painas 6 on the NPIS and reported that her dis-comfort had lessened. She said she was also sleeping better, but she complained ofsome sedation from the pregabalin. Mari-on was surprised to see that her weight hadreturned to its preshingles level, though she noted that she did not have much of anappetite.

Marion continued to complain ofepisodes of stabbing pain in her face andscalp that was exacerbated by touch, heat,or water—making it difficult to showerand brush her hair. Thus, the physician pre-

mistakenly diagnosed as acute cholecysitis,herniated nucleus pulposus, and myocar-dial infarction—among other condi-tions—depending on the location. Al-though the diagnosis of herpes zosterbecomes evident once the rash presents it-self, management of the long-term seque-lae of PHN remains a clinical “trial-and-error” scenario.

It is useful to consider the course ofMarion’s treatment, the medications thatwere initially prescribed as treatment forher acute pain of shingles and the medica-tions that were later prescribed as treatmentfor her ongoing PHN pain.

Marion’s physician appropriately usedthe NPIS to rate her pain and to measureher response to ongoing treatment. Becausecareful titration of pain medications is vitalfor patients with PHN—especially for eld-erly individuals, who are at greatest risk foradverse drug reactions—an accurate assess-ment of pain using a validated pain scale isstrongly recommended.5,26-29 Numerouspain scales are available in addition to theNPIS, including the Wong-Baker FACESPain Rating Scale30 and the Visual AnalogScale.29 Well-validated pain-rating scalesshould be used for all patients who havechronic pain in order to assist in the titra-tion of medications to achieve the desiredresponse, which is analgesia.

Like other types of neuropathic pain,PHN cannot be reliably relieved with medications commonly used to treat mostpain.3 Instead, the armamentarium againstPHN includes ligands (eg, gabapentin, pregabalin); anticonvulsants (eg, carbama-zepine); opioid analgesics (eg, oxycodone,tramadol); serotonin-norepinephrine reup-take inhibitors (SNRIs) (eg, duloxetinel);tricyclic antidepressants (eg, amitriptylinehydrochloride); and topical agents, includ-ing anaesthetic and nonsteroidal anti-inflammatory creams, gels, or patches(eg, capsaicin, diclofenac sodium, lido-caine).31-33

Marion’s prescribed use of the antiviralmedication valacyclovir and the taperingdose of the oral steroid prednisone mayhave contributed to a swift resolution of theshingles rash and acute pain. However, aspreviously noted, neither of these treat-

ments has been shown to reduce the inci-dence of PHN.22,23 It must also be empha-sized that no indication exists for the use ofsteroids in treatment of patients with acuteherpes zoster infection in the absence of ap-propriate antiviral therapy.6,22,23

Tramadol—the exact mechanism ofwhich is unknown—is a central opioid ag-onist that binds to m-receptors and weak-ly inhibits serotonin-norepinephrine reup-take. Tramadol was helpful in managingpain in the acute phase of Marion’s shin-gles. This medication has also been shownto provide relief of PHN in some patients,and it recently became available in an im-mediate-release/delayed-release combina-tion form.34 However, Marion did not re-fill her tramadol prescription when PHNdeveloped two months later. Instead, shetook over-the-counter ibuprofen and acet-aminophen/codeine supplied by a friend.She also implemented a home remedy inthe form of ice packs applied to the affect-ed area, which garnered some relief of her pain.

Although oral NSAIDs are typicallyused for pain management, these medica-tions have limited use in cases of PHN. Theuse of NSAIDs in elderly patients is riskynot only because of their potential for caus-ing gastrointestinal bleeding, but also be-cause of their adverse effects on renal func-tion.12 Recently, NSAID patches and gelshave become available, but there is onlylimited data on their usefulness for patientswith PHN.

Opioids, the backbone of the armamen-tarium against moderate-to-severe pain, arelikewise often inadequate for managingPHN. It is not surprising that ibuprofenand acetaminophen/codeine were inade-quate to manage Marion’s PHN pain. Oxy-codone, which—like tramadol—has beenshown to provide relief for moderate-to-severe pain, was poorly tolerated by Mari-on, who complained of drowsiness, seda-tion, and nausea at higher doses. Opioidanalgesics are less well-tolerated in elderlypatients than in younger patients as a resultof adverse effects. Opioid analgesics mayalso cause constipation, delirium, my-oclonus and pruritus.19,35,36

Tricyclic antidepressants, such as

amitriptyline and nortriptyline hydrochlo-ride, have been used for decades to managecertain types of neuropathic pain, and theymay be efficacious in management ofPHN. Their usefulness in elderly patients,however, is limited because of their anti-cholinergic adverse effects—such as blurredvision, dry mouth, constipation and uri-nary retention—which may become worseduring the titration phase. An alternativeto tricyclic antidepressants is provided bythe SNRI class of antidepressants, of whichduloxetine is approved by the US Food and Drug Administration (FDA) for treat-ing patients with neuropathic pain.37,38

Anticonvulsant medications have longhad a role in treatment for neuropathicpain (eg, carbamazepine for trigeminalneuralgia).39-41 Recently, however, their usehas been eclipsed by the a2d ligands (ie, the“gabapentenoids”) gabapentin and prega-balin, which have a different mechanism ofaction. Approved by the FDA for PHN,these medications bind to the a2d subunitof calcium channels, where they reduceneurotransmitter release, resulting in bothantinociceptive and antiseizure effects.

Gabapentin and pregabalin both re-quire uptitration to a therapeutic dose, withpregabalin having greater bioavailabilityand, thus, being more easily titrated to effect. Both gabapentin and pregabalin canproduce the adverse effects of sedation andweight gain, but tolerance to these effectsusually develops by the maintenancephase.19,42

Lidocaine patch 5% and lidocainegel 5% are useful in treatment of patientswith PHN, especially when the area of painor paresthesia is amenable to patch place-ment. The obvious advantage to this modeof treatment is that the anaesthetic agent isplaced at the site of pain, where it takes ef-fect. Few adverse effects have been report-ed with lidocaine in either the patch or gelform.43 Another topical agent, capsaicin, isthought to work by causing depletion of“substance P” (a neurotransmitter associat-ed with inflammatory processes and painsyndromes) at the localized area of pain.Capsaicin was the first agent to be ap-proved by the FDA for treatment of pa-tients with PHN.44 Available as an over-the-counter cream, capsaicin, which isderived from hot chili pepper, must be applied in small amounts directly to thepainful area several times daily. Care mustbe taken to thoroughly cleanse the handsafter application and to avoid contact withthe eyes, mucous membranes, or brokenskin, because capsaicin can cause burningor redness, as experienced by Marion.

The European Commission has ap-proved a high-concentration capsaicin dermal patch, called NGX-4010, for use in PHN management. The FDA has notyet approved NGX-4010 for use in theUnited States, but the patch has been ac-cepted for filing by the FDA.45

No single treatment has been shown tobe completely effective for treatment of patients with PHN. In clinical practice,

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combinations of medications are common-ly used to control the pain and discomfort associated with PHN.

In a meta-analysis published in 2005 ofavailable medications for PHN, Hempen-stall et al19 searched databases for studies ofPHN and found 65 studies for potentialinclusion. Of that number, 31 studies wererandomized, placebo-controlled clinical tri-als, and 25 of these trials included dichoto-mous data extraction appropriate for meta-analysis. After careful review and analysis of these 25 trials, the investigators foundthat sufficient evidence existed to supportthe use of gabapentin, pregabalin, tra-madol, tricyclic antidepressants and certainopioid analgesics (morphine, oxycodone)as effective oral agents for PHN. Hempen-stall et al19 further noted that topical ther-apies showing evidence for efficacy werecapsaicin and lidocaine patch 5%.

Hempenstall et al19 found that medica-tions not associated with efficacy for PHNincluded acyclovir, codeine, ibuprofen, lo-razepam, N-methyl-D-aspartate receptorantagonists and certain 5HT1 receptor agonists.

Final notesMarion’s physician quickly recognized herpainful syndrome as PHN, validating thesymptoms that she was experiencing. Thephysician also demonstrated a willingnessto try different approaches to managingMarion’s PHN pain, and she was respon-sive to Marion’s concerns and problemswith adverse effects.

This case provides an example of theimportance of the patient-physician rela-tionship in achieving optimum pain con-trol, which also requires accurate assess-ment of pain, trials of different treatmentapproaches, and possible use of combina-tions of medications. Clearly, the tangiblebenefits of an effective patient-physician relationship are achieved through commu-nication, trust, reassurance and a willing-ness to “be there” for the patient.

Stated at the beginning of the currentarticle was the adage that, as always, pre-vention is superior to cure. With this adagein mind, vaccination is the most effectivemethod of managing herpes zoster and its

debilitating complication of PHN. Thus,it is important that all individuals aged60 years or older receive the herpes zostervaccine. It is also important that all clini-cians—especially primary care physi-cians—collaborate to overcome any and all logistical barriers to immunization of patients. yww

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18

Katherine E. Galluzzi, DO, has been practicinggeriatric medicine in Philadelphia, Pa, for over 15years. She currently serves as the 2008-2010 pres-ident of the Pennsylvania Osteopathic FamilyPhysicians Society. Dr Galluzzi is board certifiedin family practice, osteopathic manipulative med-icine and geriatrics, and certified in hospice andpalliative medicine. Dr Galluzzi is professor andchair of the Department of Geriatrics at thePhiladelphia College of Osteopathic Medicine andserves as vice chair of the American OsteopathicAssociation’s Council on Palliative Care Issues. Shecan be reached at KatherineG@pcom.edu.