The Use of Corticosteroids in the Management of Herpes Zoster Lori L. MacFarlane, PharmD, BCPS, Department of Famil Medicine!

Melissa M. Simmons, PharmD, Department of Pharmac Practice! Melissa H. H"nter, MD, Department of Famil Medicine, Medical Uni#ersit of So"th Carolina, Charleston. $% &m Board Fam Pract ''()*+,,-.,,/, '00/. 1&0 '00/ &merican Board of Famil Practice2 Stepped Care+ &n 3#idence.Based &pproach to Dr"g Therap 3ditors4 5ote+ This month 6e contin"e the ne6 feat"re .. ST3Pped Care+ &n 3#idence.Based &pproach to Dr"g Therap . These articles are designed to pro#ide concise ans6ers to the dr"g therap 7"estions that famil ph sicians enco"nter in their dail practice. The format of the feat"re 6ill follo6 themnemonic ST3P+ safet (an anal sis of ad#erse effects that patients and pro#iders care a8o"t*, tolera8ilit (pooled drop.o"t rates from large clinical trials*, effecti#eness (ho6 6ell the dr"gs 6or9 and in 6hat patient pop"lation$s2*, and price (costs of dr"g, 8"t also cost. effecti#eness of therap *.$'2 Hence, the name ST3Pped Care. Since the informatics pioneers at McMaster Uni#ersit introd"ced e#idence.8ased medicine,$,2 Sla6son and Sha"ghness $),-2 ha#e 8ro"ght it to mainstream famil practice. &"thors 6ill pro#ide information in a str"ct"red format that allo6s the readers to get to the meat of a therape"tic iss"e in a 6a that can help ph sicians (and patients* ma9e informed decisions. The articles 6ill disco"rage the "se of disease.oriented e#idence to ma9e treatment decisions. 3:amples of disease.oriented e#idence incl"de 8lood press"re lo6ering, decreases in hemoglo8in &'c, and so on. ;e 6ill incl"de st"dies that pro#ide P<3Ms .. patient.oriented e#idence that matters (m ocardial infarctions, pain, stro9es, mortalit , etc* .. 6ith the goal of offering patients the most practical, appropriate, and scientificall s"8stantiated therapies. ;hene#er possi8le, n"m8er needed to treat to o8ser#e 8enefit in a single patient 6ill also 8e incl"ded as a 6a of defining ad#antages in terms that are relati#el eas to "nderstand.$=,>2 medicine ed"cation and practice. This feat"re is designed to f"rther the mission of searching for the tr"th in medical

&t times this effort 6ill 8e fr"strating. 3#en as #ast as the 8iomedical literat"re is, it does not al6a s s"pport 6hat clinicians do. ;e 6ill a#oid ma9ing concl"sions that are not s"pported 8 P<3Ms. 5e#ertheless, P<3Ms sho"ld 8e incorporated into clinical practice. The rest is "p to the reader. Blending P<3Ms 6ith rational tho"ght, clinical e:perience, and importantl , patient references can 8e the essence of the art of medicine. ;e hope o" 6ill find these articles "sef"l and eas to read. ?o"r comments and s"ggestions are 6elcome. ?o" ma contact the editors thro"gh the editorial office of %&BFP or on the @nternet (http+AAclinic.is".ed"Adr"gstepsAintro.html*. ;e hope the articles pro#ide o" 6ith "sef"l information that can 8e applied in e#er da practice, and 6e loo9 for6ard to o"r feed8ac9. Be: ;. Force, PharmD, ST3Pped Care Feat"re 3ditor %ohn Ce man, MD 3ditor %o"rnal of the &merican Board of Famil Practice Beferences

'. Sha"ghness &F, Sla6son DC, Bennett %H. Separating the 6heat from the chaff+ identif ing fallacies in pharmace"tical promotion. % Cen @ntern Med '00-!0+=>)./. ,. 3#idence.8ased medicine+ a ne6 approach to teaching the practice of medicine. 3#idence. Based Medicine ;or9ing Cro"p. %&M& '00,!,>/+,-,D.=. ). Sla6son DC, Sha"ghness &F, Bennett %H. Becoming a medical information master+ feeling good a8o"t not 9no6ing e#er thing. % Fam Pract '00-!)/+=D=.'). -. Sha"ghness &F, Sla6son DC, Bennett %H. Becoming an information master+ a g"ide8oo9 to the medical information E"ngle. % Fam Pract '00-!)0+-/0.00.

=. La"pacis &, Sac9ett DL, Bo8erts BS. &n assessment of clinicall "sef"l meas"res of the conse7"ences of treatment. 5 3ngl % Med '0//!)'/+'F,/.)). >. ;iffen P%, Moore B&. Demonstrating effecti#eness .. the concept of n"m8ers.needed.to. treat. % Clin Pharm Ther '00>!,'+,).F. @ntrod"ction The diagnosis of ac"te herpes Goster often introd"ces the iss"e of treatment 6ith anti#iral agents, 6ith or 6itho"t corticosteroids. &ltho"gh there is e#idence to s"pport the "se of anti#iral agents (ac clo#ir, famciclo#ir, #alac clo#ir* to red"ce the d"ration of ac"te Goster pain and postherpetic ne"ralgia, the "se of corticosteroids is not as clearl defined.$',,2 ;hile the ac"te phase of herpes Goster is some6hat 8othersome, the occ"rrence of postherpetic ne"ralgia can 8e de8ilitating. Herpes Goster is an ac"te #esic"lar er"ption in#ol#ing one or t6o adEacent dermatomes, 6ith pain often preceding the er"ption 8 da s to 6ee9s.$'2 @t is ca"sed 8 the reacti#ation of latent #ir"s dormant in sensor ner#es from a pre#io"s episode of primar #aricella. 3pidemiologic data indicate the ann"al incidence of cases of herpes Goster ranges from D.-.'.>A'DDD in imm"nocompetent persons o"nger than ,D ears to -.=.''.DA'DDD in those older than /D ears. &c"te Goster pain "s"all resol#es spontaneo"sl , 8"t in some cases the pain persists for months to ears. Postherpetic ne"ralgia is generall pain that persists ' month or longer after the #esic"lar rash has cleared. <#erall, postherpetic ne"ralgia occ"rs in 0 to '- percent of patients 6ith herpes Goster. &s age increases, ho6e#er, the ris9 and d"ration of postherpetic ne"ralgia also rises.$)2 Treatment of postherpetic ne"ralgia is diffic"lt, and the comple:it of the "nderl ing changes acco"nt for the lac9 of efficac of a single therape"tic approach. Ph sicians contin"e to search for an effecti#e means to pre#ent postherpetic ne"ralgia.

Methods

;e searched M3DL@53 from %an"ar '0>> thro"gh 5o#em8er '00F "sing the search terms Hherpes Goster,H Hne"ralgia,H Hgl"cocorticoids,H Hs nthetic,H Hprednisone,H and Hadrenal corte: hormones.H The search 6as limited to h"man clinical trials p"8lished in 3nglish lang"age Eo"rnals. St"dies 6ere selected if the e#al"ated patient.oriented e#idence that matters (P<3Ms*, s"ch as the d"ration of ac"te Goster pain and postherpetic ne"ralgia or 7"alit of life, as primar o"tcomes. The n"m8er needed to treat to pre#ent one negati#e o"tcome, 6hen possi8le, 6as calc"lated. @n this re#ie6 6e e:amine the "se of corticosteroids in the treatment of herpes Goster and the pre#ention of postherpetic ne"ralgia "sing the ST3P approach+ safet (an anal sis of ad#erse effects that patients and pro#iders care a8o"t*, tolera8ilit (pooled dropo"t rates from clinical trials*, effecti#eness (ho6 6ell do corticosteroids 6or9 and in 6hat patient pop"lation$s2*, and price (costs of dr"g, and also cost effecti#eness of therap , if a#aila8le*. Safet The maEor safet iss"e regarding the "se of corticosteroids in herpes Goster is the ris9 of #iral dissemination in the presence of corticosteroid.ind"ced imm"nos"ppression. &ltho"gh this concern is largel theoretical, Merselis and colleag"es$-2 descri8ed a series of case reports in '0>- in 6hich 'F of 'F= patients de#eloped disseminated herpes Goster. Fi#e of the 'F patients 6ere recei#ing corticosteroids or adrenocorticotropin hormone (&CTH*. 3le#en patients also had a serio"s "nderl ing illness, s"ch as Hodg9in disease or le"9emia. Beca"se there 6ere other predisposing factors in addition to corticosteroid "se in this case series, it is impossi8le to esta8lish a ca"sati#e relation. BandomiGed clinical trials ha#e not sho6n an increase in #iral dissemination in an patients treated 6ith corticosteroids 6hen compared 6ith a control gro"p.$=.''2 The onl trial in 6hich dissemination 6as reported incl"ded ,D' patients randomiGed to recei#e com8inations of ac clo#ir, prednisone, and place8o.$''2 <ne patient in the ac clo#ir.place8o gro"p and t6o patients in

the prednisone.place8o gro"p de#eloped c"taneo"s dissemination, all of 6hich resol#ed 6itho"t f"rther complications. Most st"dies, ho6e#er, e:cl"ded patients 6ith "nderl ing imm"nos"ppression or hematologic malignancies.$=.''2 @t appears, therefore, that corticosteroids do not mar9edl enhance the ris9 of #iral dissemination in patients 6ho ha#e herpes Goster and no "nderl ing imm"nos"ppression.

Tolera8ilit Beactions to corticosteroids range from mild gastrointestinal effects to profo"nd s"ppression of the h pothalamic.pit"itar a:is. @n general, short.term corticosteroid therap does not res"lt in persistent meta8olic effects or long.term complications. Short.term dosing is not free of ad#erse effects, ho6e#er. & trend to6ard an increase in 8lood press"re and total 8od 6eight 6as fo"nd in patients 6ho too9 &CTH or prednisone for a period of ) 6ee9s,$F2 altho"gh e:act #al"es 6ere not reported. &c"te cardiac ins"fficienc 6as reported in ' patient recei#ing prednisone therap in a st"d in#ol#ing F/ patients, 8"t 8lood gl"cose and 8lood press"re 6ere not e#al"ated in an attempt to ass"re 8linding.$/2 Patients ta9ing prednisolone com8ined 6ith ac clo#ir for F to ,' da s 6ere fo"nd to ha#e a higher incidence of side effects 6hen compared 6ith those ta9ing ac clo#ir alone, 8"t dropo"t rates 6ere similar among gro"ps ('D.'percent*.$'D2 5ineteen percent reported at least one ad#erse e#ent in the com8ination gro"p compared 6ith ') percent in the ac clo#ir.onl gro"p. D spepsia, edema, and hot fl"shes occ"rred more fre7"entl in patients ta9ing corticosteroids, 8"t the difference 6as not statisticall significant. La8orator a8normalities, incl"ding changes in gran"loc tes,hemoglo8in, ne"trophils, platelets, and "rea nitrogen, occ"rred 6ith greater fre7"enc in the gro"p ta9ing corticosteroids! each a8normalit ret"rned to normal

after tapering the prednisolone. <ne patient ta9ing prednisolone de#eloped hematemesis se#eral 6ee9s after discontin"ation, and the a"thors concl"ded this condition co"ld ha#e 8een related to corticosteroid "se. The Colla8orati#e &nti#iral St"d Cro"p fo"nd no significant difference in the n"m8er of ad#erse e#ents reported or in dropo"t rates (').'0 percent*in patients treated 6ith com8inations of ac clo#ir, prednisone, and place8o.$''2 @n all fo"r gro"ps, the most fre7"entl reported e#ents 6ere gastrointestinal, especiall na"sea and #omiting. H pergl cemia (8lood gl"cose greater than '/D mgAdL* de#eloped in F patients, = of 6hom 6ere recei#ing prednisone. The remaining clinical trials reported no ad#erse effects associated 6ith corticosteroid therap .$=.02 Ps chiatric effects of corticosteroids 6ere not reported in an clinical trial.$=.''2 Most trials e:cl"ded patients 6ith "nderl ing disease states, s"ch as renal ins"fficienc , h pertension, osteoporosis, dia8etes mellit"s, and peptic "lcer disease. &s a res"lt, patients 6ho 6ere more li9el to e:perience ad#erse side effects to corticosteroids did not participate.

3fficac Historicall , ph sicians ha#e prescri8ed corticosteroids to patients 6ith herpes Goster in hopes of pre#enting postherpetic ne"ralgia. This practice 6as 8ased on small, poorl controlled clinical trials.$=,>,',.'=2 More recentl , the "se of anti#iral agents in the treatment of herpes Goster has res"lted in red"ctions of earl Goster pain and resid"al pain at > months.$,2 The "se of corticosteroids has remained contro#ersial, ho6e#er, as small, controlled trials failed to confirm their percei#ed 8enefit.$F.02 Becentl t6o large, randomiGed, do"8le.8lind, place8o.controlled trials e#al"ated the 8enefit of com8ining corticosteroids and ac clo#ir in the management of herpes Goster.$'D,''2 @mm"nocompetent patients 6ere incl"ded

if the had a clinical diagnosis of herpes Goster and a rash for F, ho"rs or less. @n general, e:cl"sion criteria 6ere pregnanc , 6omen of child8earing potential not protected 8 contraception, renal ins"fficienc , h pertension, ins"lin.dependent dia8etes, peptic "lcer disease, osteoporosis, se#ere psoriasis, h persensiti#it to ac clo#ir, and patients ta9ing 8ar8it"rates, anticon#"lsant dr"gs, s stemic corticosteroids, rifampin, or other anti#iral dr"gs. ;ood and colleag"es$'D2 st"died )-0 patients, mean age =0 ears, 6ith an a#erage d"ration of rash 8et6een -0 and == ho"rs (Ta8le '*. Patients 6ere randoml assigned to one of fo"r treatment gro"ps+ F da s of oral ac clo#ir therap (/DD mg fi#e times a da * and place8o, F da s of ac clo#ir therap and ,' da s of oral prednisolone (-D mgAd da s D.>, )D mgAd da s F.'D, ,D mgAd da s ''.'-, 'D mgAd da s '=.'/, = mgAd da s '0.,'*, ,' da s of ac clo#ir therap and place8o, or ,' da s of ac clo#ir therap and ,' da s of prednisolone. Patients 6ere fre7"entl e:amined to assess the progression of the rash and intensit of pain d"ring the ac"te phase (,' da s*, then monthl for > months. Patients 9ept a pain and sleep diar , 6hich 6as re#ie6ed 8 an in#estigator to pro#ide a 6ee9l assessment of pain. 5o significant differences in ac"te rash progression or percentage of rash healed at da s F, '-, or ,' 6ere detected. ;ith respect to ac"te Goster pain (to da ,'*, the changes from 8aseline in pain intensit scores 6ere compara8le in all gro"ps! ho6e#er, patients treated 6ith corticosteroids had a greater red"ction in pain on da s F and '-. There 6ere no significant differences detected 8et6een an of the fo"r treatment gro"ps in the incidence or se#erit of postherpetic ne"ralgia at > months. The n"m8er needed to treat co"ld not 8e calc"lated from the data pro#ided. The a"thors concl"ded that corticosteroids conferred onl limited initial 8enefit 8"t had no apprecia8le infl"ence on the incidence or se#erit of postherpetic ne"ralgia.

The Colla8orati#e &nti#iral St"d Cro"p st"died ,D' patients, median age >' ears, F> percent of 6hom had a d"ration of rash of less than , da s (Ta8le ,*.$''2 Patients 6ere randoml assigned to one of fo"r treatment gro"ps+ ac clo#ir (/DD mg = times a da * and prednisone (>D mgAd da s '.F, )D mgAd da s /.'-, and '= mgAd da s '=.,'*, ac clo#ir and prednisone place8o, prednisone and ac clo#ir place8o, or t6o place8os. Participants 6ere e:amined dail "ntil their s9in had completel healed, and then monthl for a total of > months. @n patients ta9ing ac clo#ir, c"taneo"s healing 6as significantl 8etter &t ' month and res"lted in a more rapid ret"rn to the patients4 "s"al dail acti#ities. Corticosteroids offered no significant 8enefit 6ith respect to c"taneo"s healing, 8"t the 7"alit .of.life e#al"ation fo"nd that corticosteroids offered a significant 8enefit at ' month. @mpro#ements in 7"alit of life in com8ination (ac clo#ir and prednisone* and place8o gro"ps, respecti#el , incl"ded time to cessation of ac"te ne"ritis (specific data not pro#ided*, time to "ninterr"pted sleep (= #ers"s ,> da s*, time to ret"rn to normal acti#it () #ers"s ,' da s*, and time to no "se of analgesic agents ('- #ers"s ,/ da s*.$'>2 5either ac clo#ir nor prednisone led to earlier resol"tion of postherpetic ne"ralgia. The n"m8er needed to treat co"ld not 8e calc"lated from the data pro#ided. The a"thors concl"ded that com8ination therap impro#ed 7"alit of life in patients older than =D ears of age 6ith ac"te herpes Goster, altho"gh this st"d again confirmed that the addition of corticosteroids had no effect on the co"rse of postherpetic ne"ralgia.

Price The cost of ,' da s of corticosteroids is minor 6hen compared 6ith the cost of anti#iral agents. Begardless of the tapering sched"le, prednisone costs

less than I'D. 5o cost.effecti#eness anal ses ha#e e#al"ated corticosteroids in the treatment of herpes Goster and the pre#ention of postherpetic ne"ralgia. S"mmar &ltho"gh corticosteroids ha#e 8een e#al"ated in the management of herpes Goster since the '0=Ds, their role has not 8een 6ell esta8lished "ntil the p"8lication of recent clinical trials. Corticosteroids in com8ination 6ith ac clo#ir can red"ce ac"te Goster pain and impro#e short.term (' month* 7"alit of life in patients older than =D ears. 5"mero"s patients 6ere e:cl"ded from clinical trials, ho6e#er, 8eca"se of concomitant chronic conditions, incl"ding renal ins"fficienc , h pertension, ins"lin.dependent dia8etes, peptic "lcer disease, and osteoporosis. Beca"se this patient mi: is commonl enco"ntered in primar care, is this information "sef"l to famil ph siciansJ Practicall spea9ing, short co"rses of corticosteroids are commonl prescri8ed for other ac"te conditions, 6ith appropriate monitoring for corticosteroid.related ad#erse effects. Similarl , corticosteroid "se is reasona8le for patients 6ith herpes Goster and 6ell.controlled chronic conditions, if appropriate monitoring is "nderta9en. @f corticosteroids are to 8e added to an anti#iral agent, 8oth sho"ld 8e initiated 6ithin F, ho"rs of the onset of the herpes Goster rash. Corticosteroids, ho6e#er, ha#e no apprecia8le effect on the incidence or d"ration of postherpetic ne"ralgia (Ta8le )*. S"8mitted, re#ised, 'D March '00/. &ddress reprint re7"ests to Lori L. MacFarlane, Pharm D, Department of Famil Medicine, Medical Uni#ersit of So"th Carolina, 'F' &shle &#e, Charleston, SC ,0-,=.

Beferences '. Kost BC, Stra"s S3. Postherpetic ne"ralgia .. pathogenesis, treatment, and pre#ention. 5 3ngl % Med '00>!))=+),.-,. ,. %ac9son %L, Ci88ons B, Me er C, @no" e L. The effect of treating herpes Goster 6ith oral ac clo#ir in pre#enting postherpetic ne"ralgia. & meta.anal sis. &rch @ntern Med '00F!'=F+0D0.',. ). ;atson P5, 3#ans B%. Postherpetic ne"ralgia. & re#ie6. &rch 5e"rol '0/>!-)+/)>.-D. -. Merselis %C, Ka e D, Hoo9 3;. Disseminated herpes Goster+ a report of 'F cases. &rch @ntern Med '0>-!'')+>F0./>. =. 3aglstein ;H, KatG B, Bro6n %&. The effects of earl corticosteroid therap on the s9in er"ption and pain of herpes Goster. %&M& '0FD!,''+'>/'.). >. KecG9es K, Basheer &M. Do corticosteroids pre#ent post.herpetic ne"ralgiaJ Br % Dermatol '0/D!'D,+=='.=. F. Clemmensen <%, &ndersen K3. &CTH #ers"s prednisone and place8o in herpes Goster treatment. Clin 3:p Dermatol '0/-!0+==F.>). /. 3smann L, Ceil %P, Kroon S, Fogh H, Petersl"nd 5&, Petersen CS, et al. Prednisolone does not pre#ent post.herpetic ne"ralgia. Lancet '0/F!,+',>.0 0. Benoldi D, MiriGGi S, Z"cchi &, &llegra F. Pre#ention of post.herpetic ne"ralgia. 3#al"ation of treatment 6ith oral prednisone, oral ac clo#ir, and radiotherap . @nt % Dermatol '00'!)D+,//.0D. 'D. ;ood M%, %ohnson B;, McKendric9 M;, Ta lor %, Mandal BK, Croo9s %. & randomiGed trial of ac clo#ir for F da s or ,' da s 6ith and 6itho"t prednisolone for treatment of ac"te herpes Goster. 5 3ngl % Med '00-!))D+/0>.0DD. ''. ;hitel B%, ;eiss H, Cnann %; %r, Tr ing S, MertG C%, Pappas PC,et al. &c clo#ir 6ith and 6itho"t prednisone for the treatment of herpes Goster+ a randomiGed, place8o.controlled trial. The 5ational @nstit"te of &llerg @nfectio"s Diseases Colla8orati#e &nti#iral St"d Cro"p. &nn @ntern Med '00>!',=+)F>./). ',. Cefland M. Treatment of herpes Goster 6ith cortisone. %&M& '0=-!'=-+0''.,. '). &ppleman DH. Treatment of herpes Goster 6ith &CTH. 5 3ngl % Med '0==!,=)+>0).=.

'-. Sa"er CC. Herpes Goster+ treatment of post.herpetic ne"ralgia 6ith cortisone, corticotropic, and place8os. &rch Dermatol '0==!F''+-//.0'. '=. 3lliot F&. Treatment of herpes Goster 6ith high doses of prednisone. Lancet '0>-!,+>'D.'. '>. ;hitle B, Cnann %;, ;eiss H. &c clo#ir pl"s steroids for herpes Goster. &nn @ntern Med '00F!',>+/),.