NEUROPATHIC PAIN (E EISENBERG, SECTION EDITOR)

Vaccination Against and Treatment of Acute Herpes Zosterfor Prevention of Post-Herpetic Neuralgia

Yuko Kanbayashi & Toyoshi Hosokawa

Published online: 1 September 2013# Springer Science+Business Media New York 2013

Abstract Zostavax (zoster vaccine) is a 1-dose, high-potency, live, attenuated varicella zoster virus (VZV) vaccinethat boosts VZV-specific cell-mediated immunity (CMI),and this is its presumed mechanism of action. Other strat-egies focus on preventing the major complication of HZ,post-herpetic neuralgia (PHN). Evidence that the vaccine iseffective in older patients comes from the pivotal ShinglesPrevention Study. That study demonstrated that HZ vac-cine significantly reduced morbidity due to HZ and PHN inolder patients. However, the duration of efficacy beyond5 years after vaccination remains unclear. The Long-TermPersistence Substudy, currently under analysis, may pro-vide additional data on the duration of efficacy for zostervaccine. This review discusses vaccination against HZ, andfurther reviews recent pharmacotherapy for prevention ofPHN.

Keywords Varicella zoster virus . Herpes zoster . Zostavax .

Zoster vaccine . Post-herpetic neuralgia

Introduction

Herpes zoster (HZ), also known as shingles, presents as apainful vesicular rash that is caused by reactivation of thevaricella zoster virus (VZV) within dorsal root or cranial nerveganglia. Increasing age is the primary risk factor for HZ. Otherrisk factors include infection with human immunodeficiencyvirus, neoplastic diseases, organ transplantation, use of immu-nosuppressive drugs, and other conditions that cause declinesin cell-mediated immunity (CMI) [1, 2]. Replication of VZVin the basal ganglia damages the nerves, leading to pain withinthe affected dermatome. Post-herpetic neuralgia (PHN) maytake several forms, including allodynia (nonpainful stimuliperceived as painful), hyperpathia (slightly painful stimuliperceived as very painful), and dysesthesia (abnormal sensa-tions in the absence of stimuli) [1, 3]. PHN is a form ofrefractory chronic neuralgia that, despite the importance ofprevention, currently lacks any effective prophylaxis. Themain risk factor for PHN is increasing age [4–6], and thecondition is uncommon among individuals <50 years old.Among those who have experienced acute HZ, PHN de-velops in 20 % of patients 60–65 years old and in >30 % ofpatients >80 years old [6]. The efficacy of live zoster vaccinein preventing PHN was recently reported. Zostavax (zostervaccine; Merck, Whitehouse Station, NJ) is a 1-dose, high-potency, live, attenuated VZV vaccine that boosts VZV-specific CMI and, thus, is its presumed mechanism of action[7]. Other strategies focus on preventing the major complica-tion of HZ, PHN [8–10, 11•]. Furthermore, various drugs arebeing tested to prevent PHN in patients who develop HZ,including early (pre-emptive) treatment with tricyclic antide-pressants, anticonvulsants, and analgesics. Additional strate-gies, such as the use of antivirals and nerve blocks, areconsidered [12, 13]. This review discusses vaccination againstHZ, and further reviews recent pharmacotherapy for preven-tion of PHN.

This article is part of the Topical Collection on Neuropathic Pain

Y. Kanbayashi (*)Department of Hospital Pharmacy, Kyoto Prefectural University ofMedicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566,Japane-mail: ykokanba@koto.kpu-m.ac.jp

Y. Kanbayashi : T. HosokawaDepartment of Pain Treatment and Palliative Care Unit, UniversityHospital, Kyoto Prefectural University of Medicine, Kyoto, Japan

T. HosokawaDepartment of Anesthesiology, Graduate School of Medical Scienceand Department of Pain Management and Palliative Care Medicine,Kyoto Prefectural University of Medicine, Kyoto, Japan

Curr Pain Headache Rep (2013) 17:371DOI 10.1007/s11916-013-0371-6

Vaccination Against HZ

The live, attenuatedHZ vaccine (Zostavax) has been approvedfor the prevention of HZ in adults with a healthy immunesystem. In the United States and Canada, the vaccine isrecommended for people ≥60 years old, whereas in Europeand Australia the vaccine is approved for adults ≥50 years old[14]. The adoption of live VZV vaccines around the world isvariable and still evolving [12, 14–16]. To date, Australia,Canada, Germany, Greece, New Zealand, Qatar, Taiwan,South Korea, the United States, and Uruguay have establishedprograms for routine immunization in childhood. Many coun-tries have licensed the use of VZV vaccines, but use themselectively [17]. VZV vaccination has not yet been approvedin Japan for coverage by the national health insurance system.

The recommendation to receive VZV vaccination at50 years of age extends to those individuals who have previ-ously experienced an episode of HZ and those with chronicmedical conditions, such as chronic renal failure, diabetesmellitus, rheumatoid arthritis, or chronic pulmonary disease.It seems likely that the HZ vaccine can be safely administeredto patients without a history of chickenpox, because it hasbeen safely administered to VZV-naïve individuals. The vac-cine is not indicated for the treatment of acute HZ or PHN, orto prevent PHN in patients who develop HZ. The AdvisoryCommittee on Immunization Practices (ACIP) of the Centersfor Disease Control and Prevention in the United States hasmade specific recommendations regarding the use of the HZvaccine in immunocompromised patients [2, 12, 16–18, 19••].Special considerations for HZ vaccination are presented inTable 1 [1, 16]. The HZ vaccine can be co-administered withthe trivalent inactivated influenza vaccine and several otherinactivated vaccines, such as tetanus-diphtheria (Td) andtetanus-diphtheria-pertussis (Tdap), but each vaccine mustbe administered separately, at a different body site [12, 16].As simultaneous administration of the HZ vaccine and thepneumococcal polysaccharide vaccine results in some degreeof depression of the VZVantibody response, it is now recom-mended that administration of these 2 vaccines be separatedby an interval of at least 4 weeks, similar to the ACIP recom-mendation that the HZ vaccine and other live, attenuatedvaccines be separated by a period of 4 weeks [12].

Evidence that the vaccine is effective in older patientscomes from the pivotal Shingles Prevention Study (Depart-ment of Veterans Affairs Cooperative Study 403) [12, 20].That study demonstrated that HZ vaccine significantly re-duced morbidity due to HZ and PHN in older adults. TheShingles Prevention Study was a randomized, double-blind,placebo-controlled trial involving 38,546 adults ≥60 years old.The HZ vaccinated group showed a 51.3 % (95 % confidenceinterval [CI], 44.2 %–57.6 %) lower incidence of HZ, a66.5 % (95%CI, 47.5 %–79.2 %) reduction in PHN (definedas pain rated as ≥3 on a scale ranging from 0 [no pain] to 10

[the worst pain imaginable], persisting or occurring ≥3monthsafter onset of rash), and a 61.1 % (95 % CI, 51.1 %–69.1 %)lower burden of illness (a composite measure of the incidence,severity, and duration of pain and discomfort caused by HZ),indicating that vaccination achieved decreases in both inci-dence of HZ and mean severity of HZ in vaccinees whodeveloped HZ. Moreover, a 73 % reduction was also seen inthe number of cases of HZ with severe and long-lasting pain.

A continuation trial from the Shingles Prevention Studyinvolving over 14,000 patients, with approximately 7000 inthe HZ vaccine and placebo groups, confirmed that the effi-cacy of vaccination against HZ is durable through 7 years interms of a significantly reduced incidence of HZ, a reducedincidence of PHN, and a markedly lower burden of illness.Although significant improvements have been made, avail-able therapeutic options are only partially effective, and man-agement is difficult once PHN is established. Introduction ofthe zoster vaccine thus represents a promising strategy toreduce morbidity associated with HZ, a particular concern inolder adults [7, 17, 18, 21–23]. On the other hand, Schmaderet al reported that vaccine efficacy for each study outcomewaslower in the Short-Term Persistence Substudy than in theShingles Prevention Study [24••]. There is evidence of the

Table 1 Special considerations for herpes zoster virus vaccination(Zostavax)

Special consideration Recommendations

Anticipatingimmunosuppression

Recommended; administer 2–4 wk beforeinitiating immunosuppressive therapy

History of herpes zoster Recommended; administer as soon as rashand pain resolve

Age <60 years Recently approved by the U.S. Food andDrug Administration for patients 50–59y old; awaiting recommendation fromthe Advisory Committee onImmunization Practices

History of varicellavaccination

Not labeled for this indication; however,few adults ≥40 y old have received thevaccine

AIDS Contraindicated, including in persons withclinical manifestations of humanimmunodeficiency virus or a CD4 cellcount of 200 mm 3 (0.20×109 per L) orless

Anaphylaxis to gelatin orneomycin

Contraindicated; contact dermatitis fromneomycin is not a contraindication

Blood cancers Contraindicated; may vaccinate patientswith leukemia if in remission and nochemotherapy or radiotherapy has beenadministered for ≥3 mo

High-dose steroid therapy(>20 mg/d for ≥2 wk)

Contraindicated; defer vaccination for 1mo after discontinuation of steroid

Pregnancy Contraindicated

Information from references [1, 16]

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persistence of vaccine efficacy through the fifth year aftervaccination, but vaccine efficacy beyond that point remainsuncertain.

Cost

The mean wholesale cost of Zostavax is $194 per dose, andmany insurance plans do not cover vaccination. Health eco-nomics studies have suggested that vaccination of adults ataround 60 years old would be cost-effective [7, 25, 26]. Theduration of protection following vaccination is the subject ofongoing surveillance, as is the potential benefit of vaccinatingyounger and sicker members of the population.

Storage

The vaccine must be frozen, and in-office administrationrequires a monitored, temperature-controlled freezer. Patientsmay be referred to a pharmacy for immunization or given aprescription for the vaccine, which must be kept cold andadministered within 30 minutes. Physicians can play a keyrole in overcoming these barriers and should encourage vac-cination to prevent HZ and PHN [7].

Dosage and Administration

Zoster vaccine is currently approved in the EuropeanUnion (EU) for the prevention of HZ and HZ-relatedPHN in adults ≥50 years old. In the United States andCanada, the vaccine is approved for the prevention of HZin adults ≥60 years old. The EU approved the use of zostervaccine in an extended age range on the grounds of thesignificant burden of suffering due to HZ among adultsaged 50–59 years and the absence of evidence that the risk/benefit ratio for this age group would be any different fromthat in adults ≥60 years old. In accordance with EU regu-latory approval, zoster vaccine contains not less than19,400 plaque-forming units per dose of the Oka/Merckstrain of VZV. The vaccine is administered as a single0.65 mL subcutaneous injection, preferably in the deltoidregion. Before administration of the vaccine, the lyophi-lized powder must be reconstituted with the provided dil-uent and used within 30 minutes. The vaccine does notcontain mercury or thimerosal as inactive ingredients [7].

Contraindication

The vaccine should not be administered to anyone receivingan antiviral drug that could interfere with VZV replication,such as acyclovir, famciclovir, or valacyclovir. However, itcan be administered if these drugs have been discontinued ≥24hours before receiving the HZ vaccine and are not reinitiatedfor ≥14 days. The vaccine is contraindicated in patients with a

history of anaphylactic reactions to neomycin, gelatin, or anyvaccine component and in immunosuppressed patients, in-cluding those with human immunodeficiency virus infectionwho have CD4+ T-lymphocyte counts <200/mm3 or <15 % oftotal lymphocytes . The vaccine should not be administered topregnant women or women of childbearing age. Transmissionof the zoster vaccine virus has not been reported in clinicaltrials, but may occur in rare circumstances between vaccineesand susceptible contacts. The risk of transmission should beweighed against the risk of transmitting VZV as result ofnaturally acquired HZ. Local prescribing information shouldbe consulted for detailed information, including contraindica-tions, precautions, drug interactions, interactions with othervaccines, and use in special populations. However, data on theeffectiveness of VZV vaccination in severely immunosup-pressive states are lacking. Specialist advice is therefore rec-ommended for decisions on the appropriateness and timing ofvaccination [7].

Safety

In the Shingles Prevention Study, patients were followed forup to 42 days to record any adverse events that might havebeen associated with the vaccine. Serious adverse events,including death, occurred at similar rates between the placeboand vaccine groups. In a substudy of adverse effects,injection-site reactions, including erythema (35.8 % vs7.0 %), pain or tenderness (34.5 % vs 8.5 %), and swelling(26.2 % vs 4.5 %), occurred more frequently with the vaccinevs placebo [7, 20, 21].

Adverse events as a result of the vaccine are for the mostpart transient local phenomena. Widespread transient rashmay occur within 1 month of administration; again, this hasno known significant sequelae. The incidence of adverseeffects with the Oka vaccine has been reported as 3.4 per10,000 vaccine doses. Neurological side-effects includingaseptic meningitis and cerebellar ataxia were reported in 30of the 16,683 total reported cases of adverse events. In no caseof documented neurological sequelae in the study was OkaVZV vaccine identified using polymerase chain reaction oncerebrospinal fluid, but this has occurred in case reports.

Clinical varicella in a patient who has received the vaccinemust be confirmed by analysis of restriction fragment lengthpolymorphisms to determine whether the condition representswild-type infection or disease caused by the vaccine itself.Vaccine failure is defined as chickenpox caused by a non-vaccine strain occurring >42 days after vaccination.

The possibility of latent vaccine reactivation to cause shin-gles is real, but has been shown to occur at a lower frequencythan that seen with wild-type VZV. Meningoencephalitiscaused by vaccine strain has been documented, but is rare.

A review by Willison et al concluded that live attenu-ated zoster vaccine is well tolerated and recommended for

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patients ≥60 years old. Side-effects are predominantlytransient local reactions [17]. Specific issues related tothe use of HZ vaccine among immunosuppressed individ-uals are addressed in Table 2 [8].

Recent Pharmacotherapy and Other Strategiesfor Prevention of PHN

Antiviral Therapy

Acyclovir, famciclovir, and valacyclovir are nucleoside ana-logues that inhibit replication of human herpes viruses, in-cluding VZV. When taken orally, these agents reduce theduration of viral shedding, hasten rash healing, reduce theseverity and duration of acute pain, and reduce the risk ofprogression to PHN. These antivirals are safe and well-

tolerated, and should be considered for all patients withHZ. Antiviral treatment is specifically recommended for pa-tients >50 years old, those with moderate or severe pain orrash, and those with involvement of non-truncal dermatomes(eg, the face). Antiviral medicines should be started as soon aspossible after the onset of clinical signs. A review regardingthe efficacy of this treatment showed that antiviral treatment,provided it starts within 72 hours after the development ofvesicles, accelerates the healing of vesicles by approximately1–2 days. However, antiviral treatment seems unlikely toprevent PHN. Four systematic reviews have been published,each reaching different conclusions. Antiviral medicines re-duce, at most to a slight degree, the incidence and duration ofPHN [6, 8].

Acyclovir, famciclovir, and valacyclovir have been ap-proved by the Food and Drug Administration (FDA) in theUnited States for the treatment of acute HZ. These agents areconsidered safe and are well tolerated with minimal adverseeffects (eg, headache, nausea). These antiviral agents decreasethe severity and duration of acute HZ. In 1 randomized con-trolled trial, valacyclovir led to complete resolution of painsooner than acyclovir (44 vs 51 days) and required less-frequent dosing. Famciclovir has shown similar effectivenessto valacyclovir. Topical antiviral agents are not effective [1].Although antiviral medications slow the production of thevirus and decrease the viral load in dorsal root ganglia, evi-dence that these medications alter the incidence and course ofPHN is inconsistent. Some studies have suggested that noantiviral agent prevents PHN, whereas others have reported areduced duration of symptoms. Famciclovir and valacyclovirare associated with better outcomes than placebo or acyclovir[1]. Antivirals alone are usually insufficient to relieve the oftendebilitating pain of acute HZ [1]. Valacyclovir and famciclovirare generally more convenient for outpatient treatment, be-cause they are more bioavailable and hence require less-frequent dosing than acyclovir. Immunocompromised patientsare at greater risk of complications and may require intrave-nous antiviral therapy [8].

Pain Control (Mild to Moderate)

Mild to moderate pain may be controlled using acetamino-phen or non-steroidal anti-inflammatory drugs (NSAIDs),either alone or in combination with a weak opioid or tramadol.No studies have evaluated the effects of NSAIDs and/oracetaminophen. Clinical experience has shown that these an-algesics reduce acute pain. Opioids are effective in reducingacute HZ pain [1, 2].

Tramadol

A synthetic codeine analogue, tramadol has central analgesicproperties with effects similar to opioids, such as morphine

Table 2 Herpes zoster vaccine use in immunocompromised individuals

Condition/Therapy Recommendations

Impaired humoral immunity (eg,hypogammaglobulinemia)

Vaccine can be administered

Leukemia, lymphoma, or otherhematological malignancyinvolving bone marrow orlymphatic system

Vaccine contraindicated duringactive disease or treatment

Vaccine can be administered ifdisease is in remission, providedthat the patient has not receivedchemotherapy or radiation in theprevious 3 mos

Impaired cell-mediated immunity,including humanimmunodeficiency virusinfection with CD4 count ≤200cells/mm3 or ≤15 % of totallymphocytes

Vaccine contraindicated

Hematopoietic stem cell transplantrecipients

Consider vaccine on case-by-casebasis

Wait 324 mo after transplant

Corticosteroid therapy Vaccine can be administered ifpatient has been taking systemiccorticosteroids for <14 d or at adosage equivalent to <20 mg/dof prednisone

Inhaled/topical/intra-articularcorticosteroids are not acontraindication to vaccine

Recombinant immune modulators(eg, infliximab, adalimumab,etanercept)

Other immunosuppressivemedication

Defer vaccine for 31 mo after end oftherapy

Vaccine can be given with low-dosetreatment

Methotrexate ≤0.4 mg/kg/wkAzathioprine ≤3 mg/kg/d6-Mercaptopurine ≤1.5 mg/kg/d

Information from references [8]

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and codeine, acting on specific opioid receptors. Used as anarcotic analgesic for severe pain, this agent can be addictive.Tramadol is used to treat moderate-to-severe pain in adults,and binds to opioid receptors in the central nervous system(CNS) [27]. Tramadol also weakly inhibits noradrenaline andserotonin (5-hydroxytryptamine: 5-HT) reuptake and cantherefore interact with serotonergic drugs (both selective nor-adrenaline reuptake inhibitors and selective serotonin reup-take inhibitors), causing serotonin syndrome, although thisrisk seems to be low in clinical practice [28, 29].

Pain Control (Moderate to Severe)

Moderate to severe pain requires scheduled opioids (eg, oxy-codone, morphine). The intensity of pain during the acuteattack is an important predictor for the development of PHN,and medications given during this phase may influence theoutcomes of later interventions for PHN. If pain does notrapidly respond to opioid analgesics or if opioids are nottolerated, prompt addition of an adjunctive therapy shouldbe considered. Amitriptyline, nortriptyline, gabapentin, andpregabalin have all been recommended, but have not beenextensively studied for pain relief in patients with acute HZ. Asmall placebo-controlled study showed that amitriptyline(25 mg/day taken for 90 days in the evening) during the acutephase of HZ reduced the risk of PHN by 50 %.Another studyshowed that gabapentin reduced acute HZ pain.

The addition of corticosteroids to acyclovir decreases thepain of acute HZ and speeds lesion healing and return to dailyactivities. Combination therapy with corticosteroids and anti-virals should be considered in older patients with no contra-indications. Although corticosteroids have anti-inflammatoryeffects that could be expected to decrease nerve damage andthe risk of PHN, a Cochrane review found no significantdifference between corticosteroids and placebo in preventingPHN within 6 months after onset of the rash. Corticosteroidsmay cause dissemination of HZ infection. There is limitedevidence that gabapentin and oxycodonemay reduce the acutepain of HZ [1, 2].

Morphine

The sulfate salt of morphine is an opiate alkaloid that wasisolated from the plant Papaver somniferum and is now pro-duced synthetically. Morphine binds to and activates specificopiate receptors (δ, μ, and κ), each of which are involved incontrolling different brain functions. In the CNS and gastro-intestinal system, this agent exerts widespread effects includ-ing analgesia, anxiolysis, euphoria, sedation, respiratory de-pression, and smooth muscle contraction in the gastrointesti-nal system. A sustained-release tablet formulation contains thesulfate salt of the opiate alkaloid morphine to provide analge-sic activity. Morphine binds to and activates μ-opioid

receptors in the CNS, thereby mimicking the effects of endog-enous opioids. The binding of morphine to opioid receptorsstimulates the exchange of guanosine 5'-triphosphate for gua-nosine 5'-diphosphate, inhibits adenylate cyclase, and de-creases intracellular cyclic adenosine monophosphate. Thisinhibits the release of various nociceptive neurotransmitters,such as substance P, γ-amino butyric acid (GABA), dopa-mine, acetylcholine, noradrenaline, vasopressin, and somato-statin. In addition, morphine closes N-type voltage-gated cal-cium channels and opens calcium-dependent inwardly recti-fying potassium channels, causing hyperpolarization of neu-ronal membranes and reductions in neuronal excitability, withsubsequent analgesia and sedation [29, 30].

Oxycodone Hydrochloride

The hydrochloride salt of oxycodone is a methylether ofoxymorphone and a semisynthetic opioid agonist with anal-gesic and antitussive properties. Oxycodone binds to μ-receptors in the CNS, thereby mimicking the effects of endog-enous opiates as well as morphine. In addition to analgesiaand a depressive effect on the cough center in the medulla, thisagent may cause euphoria, anxiolysis, miosis, sedation, phys-ical dependence, constipation, and respiratory depression,depending on dosage and variations in individual metabolism[29, 30].

Amitriptyline Hydrochloride

Amitriptyline hydrochloride is the hydrochloride salt of thetricyclic dibenzocycloheptadiene amitriptyline, and shows an-tidepressant and anti-nociceptive activities. Amitriptyline in-hibits the re-uptake of noradrenaline and serotonin by thepresynaptic neuronal membrane in the CNS, thereby increas-ing synaptic concentrations of noradrenaline and serotonin.Due to constant stimulation of these receptors, amitriptylinemay produce a down-regulation of adrenergic and serotoninreceptors, which may contribute to the antidepressant activity.In the CNS, the anti-nociceptive activity of this agent mayinvolve high-affinity binding to and inhibition of N-methyl-D-aspartate receptors and/or enhancement of the action of sero-tonin at the spinal terminals of the opioid-mediated intrinsicanalgesia system [29, 30].

Nortriptyline

A tricyclic antidepressant used for short-term treatment ofvarious forms of depression, nortriptyline blocks the nor-adrenaline presynaptic receptors, thereby blocking reuptakeof this neurotransmitter and raising concentrations in thesynaptic clefts of the CNS. Nortriptyline also binds to α-adrenergic, histaminergic, and cholinergic receptors. Long-term treatment with nortriptyline produces down-regulation

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of adrenergic receptors due to increased stimulation of thesereceptors [27, 29].

Pregabalin

Pregabalin is a 3-isobutyl derivative of GABA with anti-convulsant, anti-epileptic, anxiolytic, and analgesic activities.Although the exact mechanisms of action remain unclear,pregabalin selectively binds to α2-δ subunits of presynapticvoltage-dependent calcium channels located in the CNS. Thisbinding prevents calcium influxes and the subsequentcalcium-dependent release of various neurotransmitters, in-cluding glutamate, noradrenaline, 5-HT, dopamine, and sub-stance P, from the presynaptic nerve terminals of hyperexcitedneurons. As a result, synaptic transmission is inhibited andneuronal excitability is diminished. Pregabalin does not binddirectly to GABA-A or GABA-B receptors and does not alterGABA uptake or degradation [30].

Pregabalin has also been associated with dose-related risksof somnolence (5 %–14 %), dizziness (7 %–28 %), andperipheral edema (6 %–16 %) [31–33]. At higher doses(600 mg/day), pregabalin has been associated with weightgain (9 %), asthenia (9 %), dry mouth (6 %), and vertigo(5 %) [31, 34, 35]. Discontinuations due to these adverseevents were seen in ≤1 % of patients treated with pregabalinat 150 mg/day and 4 %–15% among patients receiving a 600-mg/day dose. Serious adverse events were reported in 2 %–5 % of patients treated with pregabalin at 150, 300, and600 mg/day, compared with 3 % in those assigned to receiveplacebo [31, 35]. Symptoms including insomnia, nausea,headache, and diarrhea were reported by some patients fol-lowing abrupt withdrawal of pregabalin. Pregabalin shouldtherefore be tapered gradually over a minimum of 1 weekrather than discontinued abruptly. Weight gain noted in clin-ical trials of pregabalin was not limited to patients with pe-ripheral edema. Weight gain was related to the dose andduration of exposure to pregabalin, but did not appear to beassociated with sex, age, or baseline body mass index. Higherincidences of weight gain and peripheral edema were noted inpatients taking both pregabalin and a thiazolidinedione, com-pared with patients taking either agent alone. As a result, careshould be taken when co-administering pregabalin and one ofthese agents [29, 36].

Gabapentin

Gabapentin is a synthetic analogue of the neurotransmitterGABA and shows anticonvulsant activity. Although the exactmechanisms of action are unknown, gabapentin appears toinhibit excitatory neuron activity. This agent also exhibitsanalgesic properties [30]. In clinical trials, the most frequentadverse events observed with gabapentin were somnolence(16 %), dizziness (21 %), and peripheral edema (8 %) [37].

Twelve percent of patients discontinued gabapentin becauseof the adverse events, compared with 8 % who discontinuedplacebo. Serious adverse events with gabapentin and placebooccurred in 4 % and 3 % of patients, respectively [29, 31].

Conclusions

The incidences of HZ and PHN increase with increasingpatient age. Early diagnosis of HZ and treatment with antiviralmedications decreases the risk of PHN. PHN is very difficultto treat. Even with the use of a variety of medications andreferral to a pain specialist, pain relief may be incomplete.Zoster vaccine continued to reduce the burden of HZ illness,the incidence of PHN, and the incidence of HZ in the Short-Term Persistence Substudy population. The duration of effi-cacy for zoster vaccine beyond 5 years after vaccinationremains unclear. The Long-Term Persistence Substudy, cur-rently being analyzed, may provide additional data on theduration of efficacy for zoster vaccine.

Compliance with Ethics Guidelines

Conflict of Interest Yuko Kanbayashi declares no conflicts of interest.Toyoshi Hosokawa declares no conflicts of interest.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

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