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VOVOLL XX I XXIII• NO 1• NO• JU 4N E• MAY2013 2015 Treating Herpes Zoster and Postherpetic Vol.ÊXXI,ÊIssueÊ1Ê JuneÊ2013 Editorialostherpetic Board neuralgia (PHN) but a minority of patients experience months and 15% had at 2 years in is the most frequent chronic pain (PHN) persisting for months, years, a Dutch study.6 In the landmark zoster Editor-in-Chief PsychosocialÊAspectsÊofÊChronicÊPelvicÊPain complication of herpes zoster or even a lifetime. study, which included almost JaneÊC.ÊBallantyne,ÊMD,ÊFRCA ().1 Herpes zoster (HZ) Anesthesiology,ÊPainÊMedicine 40,000 people aged 60 years or older PUSA represents a reactivation of the vari- of HZ and PHN (of whom fewer than 1000 developed cella zoster virus (VZV), a ubiquitous, Pain is unwanted, is unfortunately common, and remains essential for survival (i.e., AdvisoryÊBoard HZ) and where PHN was defined as highly neurotropic, exclusively human Accordingevading toda ang recenter) and systematic facilitating medical diagnoses. This complex amalgamation of MichaelÊJ.ÊCousins,ÊMD,ÊDSC pain intensity of 3/10 or more, 30% of -herpesvirus. Primary causes review,sensati theon, incidence emotions, of a ndHZ t houghis 3–5 ts manifests itself as pain behavior. Pain is a moti- α PainÊMedicine,ÊPalliativeÊMedicine 1patients who developed HZ had PHN - Australia casesvati perng f1000actor person-years.for physician 3c Theonsu ltations and for emergency department visits and is varicella (), after which VZV at 1 month, 12% at 3 months, and 5% age-specific incidence rates of HZ were becomes latent in sensory ganglia along at 6 months in the group.7 Ac- similar across countries, with a steep the entire neuraxis. With the decline in cording to a meta-analysis, incidence rise after 50 years of age. The incidence VZV-specific cell-mediated immunity rates of PHN varied from 3.9 cases per was 6–8 cases/1000 person-years at in elderly and immunocompromised 100,000 person-years to 42.0 cases per individuals, VZV reactivates to cause 60 years of age and 8–12 cases/1000 100,000 person-years across all ages.8 HZ, characterized by a painful maculo- person-years at 80 years of papular or vesicular rash in all or part of age. The incidence of HZ has the skin territory innervated by a single increased in the past several .2 The most common decades across seven coun- 3 site of HZ is thoracic, comprising about tries. A study in the United half of all cases, followed by trigemi- States could not explain the nal (usually the ophthalmic branch), increase by changes in age cervical, and lumbar distributions. HZ or by the prevalence of im- 4 generally resolves within a few weeks, munocompromised people. Two-thirds of HZ cases occur in those 50 years or older, and Maija Haanpää, MD, PhD the lifetime risk is 30%.2 Department of Neurosurgery, Helsinki University Hospital Estimates of the inci- Mutual Insurance Company Etera, dence of PHN vary widely Helsinki, Finland depending on the popula- Email: [email protected] tion and the definition of PHN used. PHN risk increases with age. In Andrew S.C. Rice, MB BS, MD, Definitions include the duration of a study from the United States, the FRCA, FFPMRCA persistent pain (30, 90, or 180 days) and incidence of PHN (defined as pain at 3 Pain Research, Department of Surgery months) in zoster patients was 18% in and Cancer, the severity of pain, either clinically Faculty of Medicine meaningful pain (i.e., pain intensity of persons older than 50 years and 33% Imperial College London at least 3/10) or any pain.3 In a popula- in those older than 80 years. Overall, Chelsea and Westminster Hospital Campus 80% of all PHN occurs among persons London, United Kingdom tion-based study using medical records 2 Email: [email protected] in the United States, 18% of patients aged 50 years and older. Analysis of reported pain for at least 30 days and data from the United Kingdom General Michael C. Rowbotham, MD 10% for at least 90 days.4 Similarly, Practice Research Database showed California Pacific Medical Center Research Institute 20% of patients had pain for at least 30 that the incidence of PHN (as defined Department of , days and 14% for at least 90 days in a by pain at 3 months) rose from 8% at UCSF School of Medicine study from the United Kingdom,5 and 50–54 years of age to 21% at 80–84 San Francisco, Calif., USA Email: [email protected] 20% of zoster patients had pain at 3 years of age.5

PAIN: CLINICAL UPDATES • MAY 2015 1 Advancing age and the severity component.13 Itching and dysesthesias HZ and PHN also cause a substan- of acute HZ pain are the strongest risk may accompany the pain, and in some tial economic burden to society in the factors for PHN. Other predictors of patients these symptoms can be even form of increased health care use and PHN are the severity of the rash, the more annoying than the pain itself. need for medication, lost working days presence of prodromal pain, and the A longitudinal study of zoster in those at working age, and the need occurrence of sensory abnormalities patients using quantitative sensory test- for assistance or even loss of indepen- such as hypoesthesia or .9,10 ing (QST) and skin biopsies showed that dence in frail, elderly, people with mul- Ophthalmic location of rash, psycho- those who developed PHN (defined as tiple comorbidities. In a study from the social distress in the acute phase, and pain at 6 months) had significantly more United Kingdom, the average total cost problems with usual activities before impaired sensory function and more of a PHN case was estimated to be £340 developing HZ (the last reflecting severe allodynia in the acute phase com- in 2006. The cost included outpatient poorer health) are also reported as risk pared to those who experienced pain visits and prescribed medication, but 14 factors.11 resolution. Sensory recovery pro- at that time and ceeded at the same rate in both groups patches were not available there, which during the first 6 months. Epidermal would increase the current cost.20 Course of the Disease nerve fiber density was decreased by HZ viral replication first manifests as about 40% in the affected skin but not Pharmacotherapy of Acute ganglionitis and then spreads along the in contralateral “mirror image” skin, Herpes Zoster corresponding peripheral nerve and with no improvement during the first The treatment of HZ aims to limit the the skin. Hemorrhage and inflam- 6 months.15 In a long-term follow-up of duration and severity of the attack, mation in the affected dorsal root 7 years, epidermal nerve fiber density relieve symptoms, and prevent com- ganglion and associated nerve may remained low in spite of good clinical plications. All patients should receive be seen, and in patients with PHN, recovery, which strongly supports the a medical and psychosocial history fibrosis and cell loss have been docu- concept that recovery of sensory func- evaluation and targeted physical mented post mortem in the dorsal root tion and anatomical reinnervation of examination to confirm the diagnosis, ganglion.12 Pain and unilateral rash the skin are not prerequisites for pain document comorbid illnesses, and are typical symptoms, often accompa- resolution.16 provide a basis for treatment. nied by and itching. Most patients experience pain during HZ. Burden of the Disease Antiviral Agents Pain precedes rash in three-quarters of cases, lasting usually for some days Pain is the most important outcome of Although HZ is a self-limiting and before the eruption of the rash. As HZ. It interferes with general activity, benign disease in most patients, those described above, only a minority of sleep, and mood, and patients with who have a high risk of develop- patients continue to have pain long more severe pain are more likely to re- ing complications should be treated after the healing of the rash. port symptoms of anxiety and depres- actively. Systemic antiviral therapy HZ can also give rise to non-pain sion.17, 18 Health-related quality of life is strongly recommended as first-line complications, which can be ophthal- instruments measure four key health treatment for all immunocompetent mic (e.g., keratitis or uveitis), neuro- domains: physical, psychological, so- patients with HZ who fulfill any of the logical (e.g., cranial and peripheral cial, and functional. Both HZ and PHN following criteria (ideally within 72 nerve palsies), circulatory (vasculitis have effects on patients’ lives across hours of the onset of rash): (1) are at and stroke), dermatological (e.g., bacte- all four health domains. Reduced qual- least 50 years of age; (2) have moder- rial superinfection), or visceral (e.g., ity of life is a particular problem in ate or severe pain; (3) have a moderate pneumonia).13 patients whose pain persists as PHN, or severe rash; or (4) have non-truncal 21 Those who continue to suffer from and there is a correlation between in- involvement. prolonged pain after HZ may describe creasing pain severity and the extent Acyclovir, , and valacy- one or more of three broad types of of PHN’s negative impact on quality of clovir have been approved by the U.S. pain: (1) a constant deep aching or life.13 A study comparing patients with Food and Drug Administration for the burning pain; (2) an intermittent parox- PHN to patients with chronic low back treatment of HZ. All of them inhibit ysmal pain with a lancinating quality; pain showed similar pain intensity, viral replication in the infected cells, and (3) an intermittent pain evoked by physical function, cognitive function, resulting in accelerated healing of rash normally innocuous sensory stimuli and mood in both groups, but pain and decreased severity and duration of (allodynia), typically mechanical but in severity depended on different things acute pain. Oral acyclovir does not re- some patients thermal as well. Allodyn- (PHN typically increased with touch, duce the incidence of PHN significant- ia is present in at least 70% of patients air movement, and stress, whereas ly, but there is insufficient evidence to and is usually considered to be the low back pain increased with activity determine the effect of other antiviral 22 most distressing and debilitating PHN and exercise).19 treatments preventing PHN.

2 PAIN: CLINICAL UPDATES • MAY 2015 Treatment of Acute Zoster- zoster-associated pain at 1 month but no Associated Pain significant reduction in the likelihood Active treatment of acute HZ pain is of PHN.6 A randomized nonblinded recommended. In the absence of an study reported effective pain relief and Editorial Board extensive dataset of direct evidence prevention of PHN (defined as presence from high-quality randomized con- of any pain) at 1, 6, and 12 months with Editor-in-Chief trolled trials, it is reasonable to adhere repeated paravertebral blockades of a lo- Jane C. Ballantyne, MD, FRCA Anesthesiology, Pain Medicine 27 to generic principles of acute pain cal and steroid. All patients USA management; patients with mild to (aged 50 years or over) were treated Advisory Board moderate pain should take acetamino- with oral acyclovir, and the paraver- Michael J. Cousins, MD, DSC phen () or NSAIDs, alone tebral blockade group received four Pain Medicine, Palliative Medicine or in combination with codeine or repeated treatments within one week, Australia . Those with severe pain may whereas the standard group received Maria Adele Giamberardino, MD need a strong . In a randomized simple analgesics for their pain. Accord- Internal Medicine, Physiology Italy controlled study, the number-needed- ing to this study, repeated paravertebral to-treat for clinically meaningful pain blockades are effective for acute pain Robert N. Jamison, PhD relief (>30% pain reduction) was 2.9 Psychology, Pain Assessment and prevention of PHN. However, this USA for controlled-release and procedure is obviously not suitable for 9.6 for during the 4-week patients suffering from cranial zoster. Patricia A. McGrath, PhD Psychology, Pediatric Pain 23 study. In another study, a single dose Canada (900 mg) of gabapentin decreased pain Treatment of Postherpetic Neuralgia M.R. Rajagopal, MD severity and both severity and area of Pain Medicine, Palliative Medicine allodynia in patients with acute zoster.24 The efficacy of current treatments is India For , individual titration, routine still far from satisfactory. PHN is a clas- Maree T. Smith, PhD laxative use, and close follow-up are sical model to test the efficacy of poten- Pharmacology Australia needed to ensure the best compromise tial new drugs for . A between efficacy and side effects. global database of all registered PHN Claudia Sommer, MD Low-dose amitriptyline (25 mg trials and results (if any are available) Germany once daily for 3 months) has been has been reported28 and was updated in recommended because it significantly mid-2014.29,30 The database is available Harriët M. Wittink, PhD, PT Physical Therapy reduced the prevalence of PHN at 6 as part the Repository of Registered The Netherlands months in a placebo-controlled trial.25 Analgesic Clinical Trials (RReACT) Publishing However, this small study requires through the ACTTION website (http:// Daniel J. Levin, Publications Director repetition on a larger scale. www.acttion.org/). Of 112 unique reg- Elizabeth Endres, Consulting Editor Corticosteroids in combination with istered trials, 66 were reported as com- Timely topics in pain research and treatment acyclovir reduced pain and improved pleted. Only 20 completed trials had have been selected for publication, but the short-term quality of life compared results available in the peer-reviewed information provided and opinions expressed have not involved any verification of the find- with placebo in patients with HZ, but literature, and another 17 had results ings, conclusions, and opinions by IASP. Thus, opinions expressed in Pain: Clinical Updates do they had no appreciable effect on the available via the “gray” literature or not necessarily reflect those of IASP or of the incidence or duration of PHN.26 Corti- posted on a trials registry. In addition to Officers or Councilors. No responsibility is as- sumed by IASP for any injury and/or damage costeroids are associated with a consid- the lack of results from a large propor- to persons or property as a matter of product erable number of adverse effects and tion of completed trials, some important liability, negligence, or from any use of any methods, products, instruction, or ideas con- hence should be used only in patients clinical issues have not been tested in a tained in the material herein. Because of the rapid advances in the with severe symptoms at presentation . For example, none of the medical sciences, the publisher recommends or in whom no major contraindications available serotonin and norepinephrine independent verification of diagnoses and drug dosages. to corticosteroids exist, and only in com- reuptake inhibitors (SNRIs) have been © Copyright 2014 International Association bination with antiviral treatment. studied for PHN. for the Study of Pain. All rights reserved. Although epidural local anesthetic Numerous meta-analyses and For permission to reprint or translate injection, with or without a steroid, treatment guidelines have been pub- this article, contact: has been common practice for many lished. A PHN-specific meta-analysis International Association for the Study of Pain decades in patients with severe acute or was published in 2005,31 but recommen- 1510 H Street NW, Suite 600, Washington, D.C. 20005-1020, USA subacute zoster pain, there are few pro- dations provided here are largely based Tel: +1-202-524-5300 spective controlled trials. A large study on analyses from 2014 and 2015.1,32 Fax: +1-202-524-5301 Email: [email protected] that examined the effect of a single Tricyclic antidepressants (TCAs), www.iasp-pain.org epidural injection of local anesthetic , opioids, and topi- and a steroid demonstrated reduced cal have strong evidence

PAIN: CLINICAL UPDATES • MAY 2015 3 Table I Studies on evidence of TCAs, gabapentinoids, opioids, and topical capsaicin for postherpetic neuralgia showing positive (P) or negative (N) outcomes Number Study Drug, Maximal Daily Dose Outcome Randomized Duration TCAs Watson et al. 1982 Amitriptyline, average 73 mg P 24 3 weeks Max et al. 1988 Amitriptyline, average 65 mg P 62 6 weeks Graff-Radford et al. 2000 Amitriptyline, 200 mg NA 24/49 8 weeks Kishore-Kumar et al. 1990 , 250 mg P 26 6 weeks Raja et al. 2002 or desipramine, 160 mg P 76 8 weeks PREGABALIN Dworkin et al. 2003 Pregabalin, 600 mg P 173 8 weeks Sabatowski et al. 2004 Pregabalin, (150), 300 mg P 157/238 8 weeks van Seventer et al. 2006 Pregabalin, (150), 300, 600 mg P 281/370 13 weeks Stacey et al. 2008 Pregabalin, 300, 600 mg P 270 4 weeks GABAPENTIN Rowbotham et al. 1998 Gabapentin, 3600 mg P 229 8 weeks Rice and Maton 2001 Gabapentin, 1800, 2400 mg P 334 7 weeks GABAPENTIN ER or ENACARBIL Wallace et al. 2010 Gabapentin ER, 1800 mg N 407 10 weeks Sang et al. 2012 Gabapentin ER, 1800 mg P 452 10 weeks Irving et al. 2009 Gabapentine ER, 1800 mg P twice daily; 158 4 weeks N once daily NCT00619476 , 1200, 2400, P 376 13 weeks ClinTrials.gov 3600 mg TRAMADOL Boureau et al. 2003 Tramadol, 400 mg P 127 6 weeks OPIOIDS Watson and Babul 1998 Oxycodone, 60 mg P 50 4 weeks Raja et al. 2002 , 240 mg, or P 76 8 weeks CAPSAICIN 8% Backonja et al. 2008 Capsaicin, 8%, single application P 402 12 weeks Backonja et al. 2010 Capsaicin, 8%, single application P 38 4 weeks Irving et al. 2011 Capsaicin, 8%, single application P 418 12 weeks Webster et al. 2010 Capsaicin, 8%, single application P 299 12 weeks Webster et al. 2010 Capsaicin, 8%, single application N 155 12 weeks CAPSAICIN CREAM Bernstein et al. 1989 Capsaicin, 0.075% P 32 6 weeks Watson et al. 1993 Capsaicin, 0.075% P 143 6 weeks

Source: Data from supplementary material of Finnerup et al.32 Abbreviations: ER, extended release; NA, not applicable; TCAs, tricyclic antidepressants. for efficacy in PHN (Table 1). Topical double-blind, four-session study.34 In First-Line Agents According lidocaine gel (5% in a nonstandard an open-label, non-inferiority study, 5% to the NeuPSIG Guidelines formulation) for PHN showed efficacy lidocaine patch showed better efficacy The lack of evidence for different in a double-blind, three-session study,33 compared with pregabalin in patients efficacies for most drugs in distinct neu- as did topical lidocaine patch (5%) in a with PHN.35 ropathic pain disorders caused NeuPSIG

4 PAIN: CLINICAL UPDATES • MAY 2015 to prepare recommendations for neu- and ), and ortho- for PHN (Table 1). Their advantage is ropathic pain in general instead of for static hypotension. In a head-to-head lack of pharmacokinetic interactions, various etiologies.32 First-line agents for comparison, amitriptyline and nortrip- as they are not bound to plasma pro- neuropathic pain are TCAs, SNRIs, and tyline were equally effective, but nor- teins and are secreted to urine without gabapentinoids on the basis of evidence triptyline was better tolerated.37 These hepatic metabolism. Gabapentin has a of their efficacy and safety. However, drugs are contraindicated in patients saturable transport mechanism in the there are no published reports of ran- with cardiac conduction problems or gut, whereas absorption of pregabalin domized controlled clinical trials of any recent myocardial infarction. Patients is more linear. The typical side effects of the SNRIs in PHN patients. Table 2 may complain of excessive sedation of gabapentinoids are somnolence, presents the mechanisms of action and or confusion as the most troublesome dizziness, and peripheral edema. Doses dosing for these drugs. side effect, and pre-existing cognitive must be adjusted downward if renal TCAs are inexpensive drugs. The impairment may become significantly function is impaired. Gabapentin is presence of depression is not required worse, which may require a caution- dosed differently depending on the for their analgesic effect, and pain ary approach to driving. Accidental or preparation. Neurontin and generic relief occurs with lower doses than intentional overdose with a TCA may gabapentin differ from the gabapentin are required for an effect on mood.36 be lethal, and is more dangerous com- extended-release (Gralise) preparation The most common side effects of pared to SSRI antidepressants. and the gabapentin enacarbil prodrug TCAs include sedation, anticholinergic Gabapentinoids (gabapentin and (Horizant) (see each manufacturer’s effects (e.g., dry mouth, , pregabalin) have been studied extensively recommendations).

Table 2 Mechanisms of action and dosing of systemic drugs for neuropathic pain Maximum Recommended Medication Mechanism of Action Starting Dose Titration Dose TCAs Nortriptyline, desipramine, Serotonin and norepineph- 10–25 mg at Increase by 10–25 Usual effective doses in (amitriptyline, imipramine)1 rine reuptake inhibition, bedtime mg every 3–7 75–100 mg/day range. sodium channel block, days as tolerated Upward titration from 75 NMDA-receptor antago- mg/day guided by blood nism concentration of the drug and its active metabolite. Pretreatment cardiac con- duction screening in older patients and re-screening as the dose rises may be indicated. Do not exceed 150 mg daily. Gabapentinoids

Gabapentin Calcium-channel a2δ bind- 100–300 mg at Increase by 3600 mg daily (divided into ing, which reduces release bedtime 100–300 mg 3 doses) of presynaptic transmitters three times daily every 1–7 days

Pregabalin Calcium-channel a2δ bind- 75 mg twice Increase to 300 600 mg daily (divided into ing, which reduces release daily mg daily after 3–7 2–3 doses) of presynaptic transmitters days, then by 150 mg/d every 3–7 days Opioid Agonists Tramadol µ-opioid receptor bind- 50 mg once or Increase by 400 mg daily; in patients ing and serotonin and twice daily 50–100 mg daily older than 75, 300 mg daily norepinephrine reuptake in divided doses inhibition every 3–7 days as tolerated Oxycodone CR µ-opioid receptor binding 10 mg twice Increase by 20 120 mg daily (divided into 2 daily mg daily or more doses)2 slowly as tolerated Abbreviations: CR, controlled release; TCAs, tricyclic antidepressants. 1 Secondary amine TCAs (nortriptyline, desipramine) are preferred owing to better tolerability. 2 Highest dose used in randomized controlled studies for neuropathic pain.

PAIN: CLINICAL UPDATES • MAY 2015 5 Second-Line Agents According response to tramadol compared to “ex- Combining a locally acting preparation to the NeuPSIG Guidelines tensive metabolizers” and “ultra-rapid (lidocaine or capsaicin) with a systemic Lidocaine patches (5%), capsaicin metabolizers.” The typical side effects drug is reasonable and should be tried, patches (8%), and tramadol are recom- of tramadol are nausea, dizziness, seda- especially for those with comorbidities mended as a second line of treatment. tion, and . Tramadol should and multiple medications, to reduce the The reason for their being second-line be used with caution with concomitant risk of interactions of systemic drugs. is a low quality of evidence (lidocaine), antidepressant medication owing to its a relatively small effect size (topi- interaction potential.38 Drugs Not Recommended by NeuPSIG cal capsaicin), or lower tolerability or The recommendations for tapentadol, safety (tramadol). Third-Line Agents According other antiepileptics, capsaicin cream, to the NeuPSIG Guidelines Topical lidocaine blocks voltage- topical clonidine, selective serotonin dependent sodium channels in the Strong opioids (particularly oxycodone reuptake inhibitor antidepressants, and area of application. Lidocaine patches and morphine) and botulinum toxin A NMDA antagonists are inconclusive, (a maximum of three patches) are ap- are recommended as third line mainly be- mainly because of discrepant findings. plied to the region of pain once a day cause of safety concerns (opioids) or weak Cannabinoids and valproate have weak 32 for up to 12 hours. For old and frail quality of evidence (botulinum toxin A). recommendations against their use in patients and for those with concerns Strong opioids (oxycodone, mor- neuropathic pain, and levetiracetam about the side effects or safety of phine and methadone) have shown and mexiletine have strong recom- first-line treatments, lidocaine patches efficacy in PHN. Typical side effects mendations against their use because might be a first-line option. If lidocaine are constipation, nausea, itching, and of generally negative trials or safety patch is not available, lidocaine gel or sweating. Opioids are recommended as concerns, or both.32 cream (5%) can be tried instead (dosing a third-line option owing to their abuse three times daily), although alternate potential and side effects, including Role of Invasive Treatments for preparations have not been tested for endocrine effects. Long-term opioid Postherpetic Neuralgia efficacy in a clinical trial. treatment should be considered for A recent comprehensive review on Topical capsaicin is an agonist nonmalignant pain only when other interventional management of neuro- of the TRPV1 ion channel and binds relevant treatment options have been pathic pain concluded that owing to the its receptors, which are expressed by tried. Psychosocial evaluation should low quality of the available evidence nociceptive primary sensory , precede commencement of opioid and the potential for adverse events, causing excitation of neurons and a pe- treatment. After a treatment trial, the the role of spinal cord stimulation, riod of enhanced sensitivity perceived achieved beneficial effects (pain relief deep brain stimulation, and intrathe- as itching, pricking, or burning, with and improved function) are weighed cal medication delivery is inconclusive cutaneous vasodilatation. This phase is against adverse drug reactions. Slow- in PHN.39 The authors recommended followed by persistent desensitization. release formulations are preferred. against sympathetic blocks for PHN be- A high-concentration capsaicin plaster Botulinum toxin has been studied cause nonrandomized studies have not (8%) has shown efficacy in clinical trials for PHN in two randomized controlled shown benefit and there are no well- as a single treatment applied to the trials with positive results. Currently controlled prospective clinical trials. painful area for 60 minutes by a medi- this treatment is recommended only A randomized controlled study cal professional. The treatment can be for specialist use in refractory cases.32 appeared to demonstrate efficacy over repeated in every 3 months, if needed. 1–2 years for four intrathecal injec- Tramadol has good evidence of ef- Combination Therapy tions of methylprednisolone performed ficacy and a lower potential for misuse, Few studies of drug combinations have over 1 month compared with lidocaine abuse, and dependency compared to been published, even though combi- alone and with a no-treatment control strong opioids, but it is recommended nation therapy reflects actual clinical group.40 Another group attempted to as a second-line drug owing to poten- practice. Randomized trials suggest replicate the findings, but the trial was tial safety concerns. It exerts its analge- that the combination of pregabalin or terminated early after all six patients sic action by increasing noradrenergic gabapentin and duloxetine or tricy- randomized to intrathecal methylpred- and serotonergic neurotransmission in clic antidepressants is an alternative nisolone experienced an increase in the central nervous system. The parent option to increasing doses of one class pain at 8 weeks (compared to one of compound is demethylated to an active of drugs for patients unresponsive to four participants in the control group).41 metabolite, trans-O-desmethyltram- moderate doses of monotherapy.32 As Given the failure to replicate the strik- adol, by the CYP2D6 enzyme. This multiple pain mechanisms coexist in ing result of the first study and the biotransformation is a prerequisite for PHN, combining drugs with different potential risks of intrathecal methyl- the clinical opioid effect of tramadol. mechanisms of action is rational and prednisolone injections, the role of this “Poor metabolizers” lack this bioactiva- should be studied further to better treatment remains inconclusive,39 and tion, and they have a weaker analgesic understand its value in the clinic. we strongly recommend against its use.

6 PAIN: CLINICAL UPDATES • MAY 2015 Prevention of Postherpetic that vaccinating individuals aged 60 fees, travel costs, accommodation) has Neuralgia years seems to represent the most cost- been financially supported by Astellas The only well-documented means of pre- effective strategy.44 Future and Pfizer. Lecture fees related with venting PHN is the prevention of HZ. A cost-effectiveness analyses should also lectures at seminars or symposia are live attenuated VZV vaccine is approved incorporate the employment-related pro- paid by Astellas, Eli Lilly, Janssen Cilag, for immunocompetent persons of age 50 ductivity loss in addition to health care MSD, Mundipharma, Orion, Pfizer, and years or older. The Shingles Prevention costs and lost quality of life.18,45 Sanofi-Pasteur MSD. Study, which included people 60 years or Andrew Rice is a member of older, showed that the vaccine reduced Conclusion varicella zoster the Joint Committee the incidence of HZ by 51% and the inci- on Vaccination and Immunisation HZ and PHN present challenges to dence of PHN by 66%.7 A much smaller (JCVI), which advises U.K. health health care systems, as they are preva- study involving persons 50 to 59 years of departments on . He is lent, cause suffering and impaired age showed that vaccination reduced the a member of the scientific advisory function, and are difficult to treat sat- incidence of HZ by 70%.42 A long-term board of Spinifex Pharmaceuticals and isfactorily, especially in societies with persistence substudy showed that vac- holds share options in the company. aging populations. The optimal use of cine efficacy decreased from 51% to 21% Through Imperial College Consul- the current therapies by tailoring the for incidence of HZ and from 66% to 35% tants, he has in the past 24 months treatment individually, monitoring the for incidence of PHN from 7 through provide consultancy services from patients to assess efficacy, tolerability, 11 years post-vaccination. Statistically Spinifex, Relamda, Neusentis, Astellas, and functional status, and provid- significant vaccine efficacy for incidence Abide, Aquilas, Mitsubishi, Medivir, ing support in psychosocial aspects of HZ persisted only through year 8.43 and Asahi Kasei Pharma. His labora- when needed may improve the results. Cost-effectiveness analyses of the zoster tory has within the last 24 months is available to prevent vaccine have estimated the cost of a qual- received research funding from Pfizer zoster, and new compounds to treat ity-adjusted life year from US$10,000 to and Astellas. PHN are awaited. more than US$100,000 depending on as- Michael Rowbotham has served sumptions regarding duration of vaccine as a consultant to Xenoport, Lilly, Conflicts of Interest protection and the magnitude of the loss Chromocell, Signature Therapeutics, in quality of life associated with HZ and Maija Haanpää has been a member of ViroBay, and Nektar. He holds stock PHN.3 In the United Kingdom, research- the advisory boards of Abbvie, Aller- or stock options in Xenoport, Afferent, ers estimated that vaccination at either gan, Astellas, Eli Lilly, Janssen Cilag, Signature Therapeutics, VistaGen, and 65 or 70 years is the most cost-effective,20 Pfizer, and Sanofi-Aventis. Interna- Centrexion. whereas a German study concluded tional congress attendance (registration

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