Wim Opstelten

The PINE study of epidural steroids and local anaesthetics to prevent postherpetic neuralgia: a randomised controlled trial

BACKGROUNDnPostherpetic neuralgia is the most frequent complication of herpes zoster. Treatment of this neuropathic pain syndrome is difficult and often disappointing. We assessed the effectiveness of a single epidural injection of steroids and local anaesthetics for prevention of postherpetic neuralgia in older patients with herpes zoster.nnnMETHODSnWe randomly assigned 598 patients older than 50 years, with acute herpes zoster (rash <7 days) below dermatome C6, to receive either standard therapy (oral antivirals and analgesics) or standard therapy with one additional epidural injection of 80 mg methylprednisolone acetate and 10 mg bupivacaine. The primary endpoint was the proportion of patients with zoster-associated pain 1 month after inclusion. Analyses were by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN32866390.nnnFINDINGSnAt 1 month, 137 (48%) patients in the epidural group reported pain compared with 164 (58%) in the control group (relative risk [RR] 0.83, 95% CI 0.71-0.97, p=0.02). After 3 months these values were 58 (21%) and 63 (24%) respectively (0.89, 0.65-1.21, p=0.47) and, at 6 months, 39 (15%) and 44 (17%; 0.85, 0.57-1.13, p=0.43). We detected no subgroups in which the relative risk for pain 1 month after inclusion substantially differed from the overall estimate. No patient had major adverse events related to epidural injection.nnnINTERPRETATIONnA single epidural injection of steroids and local anaesthetics in the acute phase of herpes zoster has a modest effect in reducing zoster-associated pain for 1 month. This treatment is not effective for prevention of long-term postherpetic neuralgia.

Estimating the cost-effectiveness of vaccination against herpes zoster in England and Wales.

A live-attenuated vaccine against herpes zoster (HZ) has been approved for use, on the basis of a large-scale clinical trial that suggests that the vaccine is safe and efficacious. This study uses a Markov cohort model to estimate whether routine vaccination of the elderly (60+) would be cost-effective, when compared with other uses of health care resources. Vaccine efficacy parameters are estimated by fitting a model to clinical trial data. Estimates of QALY losses due to acute HZ and post-herpetic neuralgia were derived by fitting models to data on the duration of pain by severity and the QoL detriment associated with different severity categories, as reported in a number of different studies. Other parameters (such as cost and incidence estimates) were based on the literature, or UK data sources. The results suggest that vaccination of 65 year olds is likely to be cost-effective (base-case ICER=pound20,400 per QALY gained). If the vaccine does offer additional protection against either the severity of disease or the likelihood of developing PHN (as suggested by the clinical trial), then vaccination of all elderly age groups is highly likely to be deemed cost-effective. Vaccination at either 65 or 70 years (depending on assumptions of the vaccine action) is most cost-effective. Including a booster dose at a later age is unlikely to be cost-effective.

Predicting postherpetic neuralgia in elderly primary care patients with herpes zoster: prospective prognostic study.

Abstract Postherpetic neuralgia (PHN) is the most frequent complication of herpes zoster (HZ) and difficult to treat. Timely identification of high‐risk HZ‐patients enables physicians to focus on PHN prevention. To assess which simple to measure factors are independent predictors of PHN, and whether psychosocial and serological/virological parameters have additional predictive value, a prospective cohort study in primary care was conducted. We included 598 elderly (>50 years) consecutive patients with acute HZ (rash <7 days) below sixth cervical dermatome. At baseline demographic, clinical (e.g., duration and severity of pain and rash), psychological (Pain Cognition List [PCL] and Spielberger’s Anxiety Inventory), serological (VZV‐antibodies) and virological (viremia presence) variables were measured. Blood tests were performed in a random subset of 218 patients. Primary outcome was significant pain (VAS >30 on 0–100 scale) after three months. The final prediction model obtained from multivariable logistic regression was (internally) validated using bootstrapping techniques, and adjusted for optimism. Forty‐six (7.7%) patients developed PHN. Independent predictors were age (odds ratio [OR] = 1.08 per year), acute pain severity (OR = 1.02 per unit), presence of severe rash (OR = 2.31), and rash duration before consultation (OR = 0.78 per day): area under receiver‐operating‐characteristic curve [ROC area] = 0.77 (95% CI: 0.71–0.82). Of the five PCL scores, only factor V (‘trust in healthcare’) was an additional predictor (OR = 1.01 per unit), though it increased the ROC area with only 0.01 to 0.78. The Spielberger’s anxiety scores and serological and virological variables were no additional predictors. Thus, four simple variables can help physicians to timely identify elderly HZ‐patients at risk of PHN.

Managing ophthalmic herpes zoster in primary care

During their professional career, most general practitioners will be consulted by various patients with an acute manifestation of ophthalmic herpes zoster. In addition to the diagnostic dilemma that doctors face in the initial phase of the disease, they may be uncertain about the course and treatment (when is referral indicated, who should be prescribed antiviral medication?). We present an evidence based policy.nnHerpes zoster (shingles) is a commonly encountered disorder in general practice. One fifth of the population, mainly elderly people, will present with this neurocutaneous infection during their lifetime. Most immunocompetent patients will experience spontaneous and complete recovery within a few weeks. Some, however, will develop complications such as postherpetic neuralgia and, in cases of ophthalmic herpes zoster, sight threatening eye problems. We outline the main points that general practitioners should keep in mind when faced with a case of ophthalmic herpes zoster.nnIn February 2005, we searched the Cochrane Controlled Trial Register (keyword: “herpes zoster”), Embase, and Medline (MESH terms: “herpes zoster” and “therapy”) for clinical trials, randomised controlled trials, meta-analyses, practice guidelines, and reviews. We selected only articles written in English and disregarded any studies of immunocompromised patients.nnHerpes zoster is a commonly seen disorder; one fifth of the population will present with the disease during their lifetime. The reported incidence varies from 2.2 per 1000 to 3.4/1000 people per year. Herpes zoster develops mainly in elderly people: its incidence in people aged over 80 is about 10 in 1000/year.1 2 It is caused by reactivation of the varicella zoster virus (human herpes virus type 3). In temperate climates, primary infection with this virus usually occurs before the age of 10 and manifests itself clinically as chickenpox (varicella). The virus then becomes latent, nestling in the sensory ganglia. Later it may become active again, spread to …

Interventions to prevent postherpetic neuralgia: cutaneous and percutaneous techniques

Herpes zoster (HZ) or shingles is a common disease, with a reported incidence varying from 2.2 to 3.4 per 1000 persons/year (Donahue et al., 1995). For most patients skin healing and pain resolution occur within 3–4 weeks. Pain can, however, continue after the rash has healed. This condition, referred to as postherpetic neuralgia (PHN), may last for several months to years. Depending on the applied definition, 9–34% of all HZ patients develop PHN (Dworkin and Portenoy, 1996). The most important risk factors for this pain syndrome include age and the severity of acute pain and inflammation during HZ (Whitley et al., 1999). PHN has a high impact on the quality of life: many patients develop severe physical, occupational, and social disabilities as a result of the unceasing pain (Dworkin and Portenoy, 1996). Since PHN commonly occurs in the elderly, its incidence is expected to increase in our aging society. Because treatment of PHN has been disappointing, much attention is currently being given to the evaluation of interventions administered to HZ patients to prevent PHN. Several systematic reviews have addressed pharmacotherapeutic prevention of PHN (Alper and Lewis, 2000; Jackson et al., 1997; Lancaster et al., 1995; Wood et al., 1996). Their conclusions, however, are controversial, because of various methodological issues of the included studies (e.g. differences in designs used, subgroups assessed, and selected endpoints). In general, the reviews support short-term benefit of antiviral drugs, but note limited evidence for a reduction in the incidence of PHN. Famciclovir and valaciclovir, however, were shown to reduce the duration of PHN. Oral steroids reduced the severity of acute HZ pain, but had no effect on the incidence, severity, or duration of PHN. Only one small study showed that early treatment of HZ patients with the antidepressant amitriptyline caused a reduction in PHN occurrence (Bowsher, 1997). Interventions such as infiltration with local anesthetics and sympathetic and epidural blocks have also been proposed and applied to reduce the risk of PHN development. In this paper we briefly outline the current hypotheses of PHN pathophysiology as well as the possible modes of action of these interventions, and critically review the available studies that have evaluated different, cutaneous and percutaneous, techniques aimed at preventing PHN.

Introducing a pneumococcal vaccine to an existing influenza immunization program : vaccination rates and predictors of noncompliance

PURPOSEnInfluenza vaccination has been recommended for all elderly people in The Netherlands since 1996, with greater than 80% compliance. It is unknown, however, if the addition of another vaccine to this immunization program will affect compliance.nnnSUBJECTS AND METHODSnGeneral practitioners offered a pneumococcal vaccine together with the yearly influenza vaccination to 3365 patients aged 65 years and older. A questionnaire was then mailed to a stratified sample (n = 972) of these patients. Factors associated with noncompliance with vaccination were assessed using polytomous logistic regression.nnnRESULTSnA total of 2529 patients (75%) received the pneumococcal vaccine and 2812 (84%) received the influenza vaccine. Predictors of noncompliance with the pneumococcal vaccine were perceived lack of recommendation by the general practitioner (odds ratio [OR] = 4.6; 95% confidence interval [CI], 2.6 to 8.3) and fear of local side effects (OR = 2.8; 95% CI, 1.6 to 4.6). Predictors of noncompliance with both vaccinations also included unwillingness to comply with the doctors advice (OR = 6.1; 95% CI, 2.4 to 15.4), the belief that vaccinations weaken ones natural defenses (OR = 2.7; 95% CI, 1.4 to 5.3) or that influenza is not dangerous (OR = 2.9; 95% CI, 1.5 to 5.4), and the fear of becoming sick from pneumococcal vaccination (OR = 2.9; 95% CI, 1.1 to 7.9). People who felt healthy, found it difficult to visit the doctors office, had private medical insurance, or were younger than 75 years of age also had a greater risk of not being vaccinated.nnnCONCLUSIONnIntroducing a pneumococcal vaccine to an existing influenza immunization program resulted in high pneumococcal and influenza vaccination rates. A wider diversity of patient characteristics and attitudes was present when neither vaccination was received.

High vaccination rates for seasonal and pandemic (A/H1N1) influenza among healthcare workers in Dutch general practice

In previous years, the influenza vaccination rate among Dutch general practitioners (GPs) was low (36% during the 2007/2008 season). Since 2008, yearly influenza vaccination has been actively recommended for GPs in The Netherlands. Moreover, in 2009 the Dutch government urged healthcare workers to receive additional vaccination against the pandemic influenza (A/H1N1). The effects of these recommendations are unknown. In February 2010, a questionnaire was mailed to random samples of GPs (n=810) and GP-trainees (n=300). Vaccination rates were determined and motives and barriers for vaccination were assessed. The response rates for GPs and GP-trainees were 83% and 90%, respectively. In total, 63% of the GPs were vaccinated against seasonal influenza and 85% against pandemic (A/H1N1) influenza. For GP-trainees, these percentages were 47% and 77%, respectively. With regard to the medical staff working in the respondents practices, 60% received the seasonal and 76% the pandemic (A/H1N1) influenza vaccine. Reducing the risk of transmitting the virus to vulnerable patients and the individuals personal protection were the most frequently reported motives for vaccination. Having no medical indication for influenza vaccination and the conviction of being protected against influenza because of frequent professional exposure to the virus were the most frequently mentioned reasons for not being vaccinated. In conclusion, the seasonal influenza vaccination rate among Dutch GPs has risen considerably since the previous survey and the vaccination rate against pandemic (A/H1N1) influenza was very high. Moreover, Dutch GPs were convinced that influenza vaccination will reduce the risk of transmitting the virus to their patients.

Assessing the potential effects and cost-effectiveness of programmatic herpes zoster vaccination of elderly in the Netherlands

BackgroundHerpes zoster (HZ) is a painful disease affecting a considerable part of the elderly. Programmatic HZ vaccination of elderly people may considerably reduce HZ morbidity and its related costs, but the extent of these effects is unknown. In this article, the potential effects and cost-effectiveness of programmatic HZ vaccination of elderly in the Netherlands have been assessed according to a framework that was developed to support evidence-based decision making regarding inclusion of new vaccines in the Dutch National Immunization Program.MethodsAn analytical framework was used combining a checklist, which structured relevant data on the vaccine, pathogen and disease, and a cost-effectiveness analysis. The cost-effectiveness analysis was performed from a societal perspective, using a Markov-cohort-model. Simultaneous vaccination with influenza was assumed.ResultsDue to the combination of waning immunity after vaccination and a reduced efficacy of vaccination at high ages, the most optimal cost-effectiveness ratio (€21716 per QALY) for HZ vaccination in the Netherlands was found for 70-year olds. This estimated ratio is just above the socially accepted threshold in the Netherlands of €20000 per QALY. If additional reduction of postherpetic neuralgia was included, the cost-effectiveness ratio improved (~€10000 per QALY) but uncertainty for this scenario is high.ConclusionsVaccination against HZ at the age of 70 years seems marginally cost-effective in the Netherlands. Due to limited vaccine efficacy a considerable part of the disease burden caused by HZ will remain, even with optimal acceptance of programmatic vaccination.

Clinical Diagnosis of Herpes Zoster in Family Practice

PURPOSE Family physicians usually diagnose herpes zoster on clinical grounds only, possibly resulting in false-positive diagnoses and unnecessary treatment. We wanted to determine the positive predictive value of the physicians’ judgment in diagnosing herpes zoster and to assess the applicability of dried blood spot analysis for diagnosis of herpes zoster in family practice. METHODS Our study population consisted of 272 patients older than 50 years with herpes zoster (rash for less than 7 days). Dried blood spot samples were collected from all patients and sent by mail to the laboratory. Baseline measurements included clinical signs (localization, severity, and duration of rash) and symptoms (duration and severity of pain). Varicella-zoster virus antibodies were determined at baseline and 5 to 10 days later. Multivariate logistic regression was used to assess independent associations between clinical variables and serological confirmation of herpes zoster. RESULTS Dried blood spot analysis was possible in 260 patients (96%). In 236 the diagnosis of herpes zoster was confirmed serologically (positive predictive value of clinical judgment 90.8%; 95% confidence interval, 87.3%–94.3%). Independent clinical variables for serologically confirmed herpes zoster were severity and duration of rash at first examination. CONCLUSION Family physicians have good clinical judgment when diagnosing herpes zoster in older patients. Dried blood spot analysis is a logistically convenient method for serological investigation of patients in family practice, but it is rarely needed for diagnosing herpes zoster.

The impact of varicella zoster virus: chronic pain.

Herpes zoster (HZ) is a common condition that affects all age groups and both immunocompetent and immunocompromised individuals. However, it mainly impacts elderly and immunocompromised people and is associated with important and sometimes permanent detriment to quality of life and activities of daily living. Age-related decline in cell-mediated immunity (CMI) permits reactivation of varicella zoster virus (VZV) from latency. The risk of developing post-herpetic neuralgia (PHN) can be predicted using epidemiologically identified risk factors, thus indicating which patients may benefit most from protection by appropriate means, including vaccination. Despite increasing knowledge of the pathology causing PHN, the management modalities for acute HZ pain and PHN remain inadequate. Public, and probably physician, understanding of HZ and its complications is poor, potentially leading to low utilisation of HZ vaccination and delayed presentation for treatment.